All posts by teachingneurologist

Subacute Encephalopathies (Rapidly Progressive Dementias)

Diseases,

This is a group of conditions that are collected under the term subacute encephalopathy, which is also called rapidly progressive dementias. These conditions manifest with cognitive dysfunction over weeks or months. Therefore the onset and progression is slower than encephalopathy due to systemic disease and faster than usual causes of dementia which progress over years. The subacute encephalopthies encompass an uncommon group of conditions such as autoimmune or paraneoplastic limbic encephalitis, chronic meningitis, Creutzfeldt Jakob disease, Hashimoto’s encephalitis and central nervous system vasculitis. They require extensive investigations and significant clinical expertise to manage. It is important to think of these conditions in patients with encephalopathy who are not responding after treatment of systemic illness, and also in patients who present with this subacute time course.

Rapidly progressive dementia, investigations to consider:

MRI:

  • Features of CJD, CNS vasculitis, paraneoplastic encephalopathy/encephalomyelitis

CT thorax, abdomen & pelvis:

  • Occult neoplasm

Blood tests:

  • Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50: SLE, Sjogren’s syndrome and others.
  • HIV, syphilis, Lyme serology
  • Mercury, lead, arsenic
  • Thiamine, vitamin B12 levels
  • Paraneoplastic antibodies/autoimmune antibodies: Anti-Hu (ANNA-1), CV2 (CRMP5), Ma2/Ta, amphiphysin, Yo, Ri, Zic4, voltage gated potassium channel (VGKC), anti-NMDA antibodies
  • Thyroid function tests TFTs & anti-thyroglobulin or anti-thyroperoxidase antibodies: Hashimoto’s encephalopathy

EEG: features of CJD, Hashimoto’s encephalopathy
CSF:

  • Protein 14-3-3 & S100 protein: CJD
  • CMV PCR: CMV encephalitis in AIDS patients

Catheter angiogram: for CNS vasculitis
Tests for: CJD, Diffuse Lewy body disease, corticobasalganglionic degeneration,
 

Causes of subacute encephalopathy (rapidly progressive dementia):

Encephalitis:

Central nervous system vasculitis:

Chronic meningitis:

Prion disease:

Related articles:

Non-vasculitic Autoimmune Inflammatory Meningoencephalitis (NAIM)

Diseases, ,

Clinical features:

Progressive encephalopathy, cognitive impairment. Ataxia, seizures, tremors and visual hallucinations can occur.

Findings on investigations:

ESR may be raised
SS-A or SS-B: may be positive
CSF analysis:

  • Often raised WCC and protein
  • Immunoglobulin (Ig)G index and synthesis rate

EEG: mild-moderate diffuse slowing
MRI: normal
Cerebral angiography: normal

Pathology, brain biopsy:

Leptomeningeal perivascular lymphocytic inflammation, mild without evidence of vasculitis.

  • Vessel walls are intact
  • Immunohistochemistry: CD3+ T-cell and B-cell infiltration
Salivary gland biopsy:

Lymphocytic infiltration, Immunohistochemistry: CD3+ T-cell and B-cell infiltration

Treatment:

Steroid therapy with methylprednisone or prednisone

Associated conditions:

  • Sjogren’s syndrome
  • Hypereosinophilic syndrome
  • Hashimoto’s disease
  • Systemic lupus erythematosus

Related articles:

References:

  1. Caselli RJ, Boeve BF, Scheithauer BW, O’Duffy JD, Hunder GG. Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy. Neurology. 1999 Oct 22;53(7):1579-81.
  2. Josephs KA, Rubino FA, Dickson DW. Nonvasculitic autoimmune inflammatory meningoencephalitis. Neuropathology. 2004 Jun;24(2):149-52.

 

Glucose Transporter Type I Deficiency Syndrome GLUT1 DS

Diseases, , ,

Clinical features:

Seizures, developmental delay, spasticity, acquired microcephaly, and ataxia
Dystonia

Genetics:

Autosomal dominant, de novo mutation
SLC2A1 gene,

Findings on investigations:

CSF: low glucose, low glucose:serum ratio, low CSF lactate
Erythrocyte glucose transporter activity: reduced uptake into erythrocytes

Related articles:

Niemann-Pick Disease

Diseases, , , ,

Diagnosis:

A type of lysosomal storage disease
Biochemical diagnosis:

  • Fibroblast culture to test for impaired LDL-cholesterol trafficking.
  • Filipin staining: accumulated free cholesterol.
  • Impaired LDL-induced cholesterol ester formation.
  • A variant biochemical form exists

Genetics:

Autosomal recessive
Niemann-Pick disease type C: gene= NPC1 at 18q11 or NPC2 14q

Clinical features:

Type A: Infantile, severe, cherry red macula, lungs are also involved
Type B: Massive hepatomegaly, splenomegaly. No neurological involvement.
Type C and D: Adult form (adolescent to adult). See below.
Neurologically:

  • Cortical (Cognitive, psychiatric and seizures)
  • Deep brain (cerebellar ataxia, dysarthria, vertical supranuclear ophthalmoplegia, deafness, dysphagia, cataplexy, pyramidal syndrome, movement disorder/dystonia/myoclonic jerks)

Visceral (hepatomegaly, splenomegaly) involvement.

Findings on investigations:

MRI in Type C:

  • Normal initially
  • Atrophy corresponding to the clinical syndrome i.e. Frontal lobes, corpus callosum, brainstem, cerebellum,

EEG: Generalised slowing

Pathology:

Foam cells (marcophages with abundant vacuolated cytoplasm) in bone marrow, spleen, lymph nodes
Brain (types A,C): atrophy, severe gliosis, neurons are enlarged with abundant cytoplasm and small vacuoles.

Treatment:

Consider:
Miglustat intravenously

Related articles:

Porphyria

Diseases,

Clinical features (neurological porphyrias):

General features:

  • Acute ascending paralysis with areflexia, affecting VII nerve as well
  • Sensory loss may occur “swimming trunk distribution”
  • Autonomic neuropathy: tachycardia and orthostatic hypotension
  • Confusion, anxiety
  • Urine becomes dark on exposure to sunlight.

Subtypes:

  • Acute forms: Cause neurological disease and raised ALA
  • Acute intermittent porphyria AIP: no cutaneous rash
  • Variegate porphyria
  • Hereditary coproporphyria: extremely rare
  • Non-Acute forms: no neurological disease
  • Porphyria cutanea tarda PCT
  • Cutaneous hepatic porphyria
  • Congenital porphyria
  • Erythropoietic protoporphyria EPP

 

Acute intermittent porphyria AIP:

Screen: 24 hr urinary collection for porphyrin levels
Aminolevulinic acid ALA: high
Porphobilinogen PBG: high

Diagnosis:

RBC enzymes:
Porphobilinogen PBG deaminase: reduced
Delta ALA synthetase: high
Causes neurological symptoms. Note differential diagnosis: Lead poisoning

Treatment:

For crisis: hematin I.V.
Prevention of attacks

Variegate porphyria (South African):

Causes neurological symptoms

Porphyria cutanea tarda PCT:

Urine uroporphyrin I (URO I): high
Stool isocoproporphyrin (ISOCOPRO): high
Does not causes neurological symptoms

Erythropoietic protoporphyria EPP:

Screen: erythrocyte porphyrins
Protoporphyrinogen IX (PROTO IX)
Does not causes neurological symptoms

Related articles:

Cerebrotendinous Xanthomatosis

Diseases, , ,

Clinical features:

Neonates: cataracts, diarrhea, pyramidal and cerebellar signs, learning disability later on
Adults:

  • Seizures, dementia, myelopathy (spinal form),
  • Enlarged tongue, tendon xanthomas, premature vascular disease, cataracts

Genetics:

Autosomal recessive, CYP27A1 gene on chromosome 2q, sterol 27-hydroxylase deficiency,

Findings on investigations:

Lipid profile: increased cholesterol
CT: white matter hypdensities in cerebrum, cerebellar dentate nucleus hypdensities,
MRI: FLAIR increased signal in white matter in cerebrum, cerebellum
Muscle biopsy:

  • Reduced respiratory chain enzymes activity

Raised lactate

Treatment:

Chenodeoxycholic acid

Related articles:

Refsum Disease

Diseases

A type of leukodystrophy. A type of peroxisome disorder.

Synonyms:

a.k.a. hereditary ataxic neuropathy a.k.a. phytanic acid storage disease a.k.a. hereditary motor sensory neuropathy type IV a.k.a. heredopathia atactica polyneuritiformis

Clinical features:

Deafness, ataxia, anosmia
Retinitis pigmentosa (night blindness)
Progressive peripheral neuropathy
Ichthyosis: dry scaly skin
Cardiac arrhythmias
Short metacarpals and metatarsals

Findings on investigations:

Phytanic acid level:

  • Highly raised phytanic acid level (> 200 µmol/L; normal < 30 µmol/L)

CSF: increased protein

Related articles:

Zellweger Syndrome

Diseases, ,

Synonyms:

a.k.a. cerebro-hepato-renal syndrome

Diagnosis:

A type of Leukodystrophy and peroxisome biogenesis disorders (PBD)
Confirmed by Serum very long chain fatty acids: elevated

Genetics:

PEX3 gene mutations

Clinical features:

  • Severe weakness, hypotonia, seizures and developmental delay
  • high forehead, underdeveloped eyebrow ridges, deformed earlobes
  • Hepatomegaly
  • Facial features: high forehead, hypoplastic supraorbital ridges, and midface hypoplasia.
  • A type of leukodystrophy

Findings on investigations:

Biochemistry: confirmed by elevated levels of saturated and unsaturated very long chain fatty acids in body fluids
MRI:

  • Impaired myelination (white matter disease), periventricular pseudocysts, polymicorgyria, polygyria,

Other labs:

  • high iron, high copper, renal failure,

Related articles:

Vanishing White Matter disease VWM

Diseases,

Synonyms:

a.k.a. leukoencephalopathy with vanishing white matter a.k.a. childhood ataxia and cerebral hypomyelination CACH

Diagnosis:

A type of leukodystrophy. A type of dysmyelination

Genetics:

Autosomal recessive
Mutations in one of five genes for translation factor (eukaryotic initiation factor 2B, elF2B) on chromosome 3: ELF2B1, ELF2B2, ELF2B3, ELF2B4, ELF2B5

Clinical features:

<6 year olds at presentation, febrile illness trigger major neurological deterioration

Findings on investigations:

+Imaging:

  • Hemispheric white matter except U fibres. Cystic change periventricularly and in lobes (frontal and occipital). Cerebellar atrophy.
  • MRI: white matter signal intensity= CSF on all sequences T1, T2.
  • T2 MRI: pons hyperintensity

Pathology:

Cystic degeneration of white matter, foamy oligodendrocytes. Normal grey matter.

Related articles:

Pelizaeus-Merzbacher-Like Disease

Diseases, ,

A type of leukodystrophy

Genetics:

heterogeneous
Autosomal recessive,
Protein= gap junction protein 12 a.k.a. connexin 46.6 (Cx 46.6), a.k.a. connexin 47 (Cx 47),
Gene= GJA12 gene mutation

Clinical features:

First months of life: impaired motor development and nystagmus
Later on: ataxia, dystonia, dysarthria, and progressive spasticity
Spastic paraplegia: childhood onset, progressive and may occur without other features

Findings on investigations:

MRI: hypomyelination pattern,

  • T2 or FLAIR diffuse hyperintensity in cerebral hemispheric white matter.
  • T1+gadolinium: poor or no enhancement

Related articles:

Pelizaeus Merzbacher Disease PMD

Diseases, ,
Diagnosis:

A type of leukodystrophy

Genetics:

X-linked recessive disease, Gene: PLP1 gene, rearrangements or mutations. Protein= proteolipid protein 1

Clinical features:

First months of life: impaired motor development and nystagmus
Later on: ataxia, dystonia, dysarthria, and progressive spasticity
Spastic paraplegia: childhood onset, progressive and may occur without other features

Findings on investigations:

MRI: hypomyelination pattern,

  • T2 or FLAIR diffuse hyperintensity in cerebral hemispheric white matter.
  • T1+gadolinium: poor or no enhancement

Related articles:

Sudanophilic Leukodystrophy

Diseases

Diagnosis:

A type of leukodystorphy. A type of dysmyelination

Findings on investigations:

Imaging:

  • White matter (hemispheres, cerebellum and brainstem) and grey matter
  • CT: hypodense
  • T2 MRI: hyperintense white matter. Hypointense lentiform nucleus, thalamus, substantia nigra, dentate nucleus

Pathology:

Sudanophilic material in macrophages.
Reduced oligodendrocytes.
Tigroid appearance: abnormal white matter background, normal neurons.

Subtype:

  • Pelizaeus-Merzbacher disease

Related articles:

Canavan Disease

Diseases,

A type of leukodystrophy. A type of dysmyelination.

Synonyms:

a.k.a. spongiform degeneration a.k.a. N-acetylaspartatoacylase deficiency

Genetics:

Autosomal recessive. Gene encoding acetylaspartoacylase.

Findings on investigations:

Imaging:

  • Deep grey matter, subcortical white matter, U fibres, cerebellar, brain stem. Ventriculomegaly/megalencephaly.
  • CT: low density
  • T2 MRI: hyperintense
  • MRS magnetic resonance spectroscopy: Raised NAA

Pathology:

Vacuolation of white matter. Gliosis. Absent myelin. Preserved axons.

Related articles:

Alexander Disease

Diseases,

Diagnosis:

A type of leukodystrophy a.k.a. dysmyelination. A type of intermediate filament disease.

Genetics:

Sporadic. GFAP gene mutation. Encoding Glial fibrillary acidic protein.

Findings on investigations:

Imaging:

  • Cerebral white matter lesions frontal >occipital. Brain stem atrophy
  • CT: hypodense white matter diffusely. Hyperdense caudate.
  • T1: hypodense white matter.
  • T2: hyperintense white matter
  • Enhancement early in disease with cranial nerve enhancement.

Pathology:

Subependymal, subpial and perivascular diffuse Rosenthal fibres
GFAP positive

Related articles:

Adrenoleukodystrophy and Adrenomyeloneuropathy

Diseases, ,

Diagnosis:

Very long chain fatty acids VLCFAs: raised C26:0 level, raised C26:0/C22:0 ratio, raised C24:0/C20:0 ratio. This is diagnostic. Genetic tests usually follow.
A type of peroxysomal disease. A type of leukodystrophy a.k.a. dysmyelination

Genetics:

X-linked or Autosomal recessive (neonatal)
ALD gene a.k.a. X-linked adrenoleukodystrophy gene chr. Xq28, encoding perioxysomal ATP binding cassette half-transporter protein ABCD1.
Very long chain fatty acids VLCFAs: raised C26:0 level, raised C26:0/C22:0 ratio, raised C24:0/C20:0 ratio. This is diagnostic. Genetic tests usually follow.
Acyl-CoA synthetase deficiency

Findings on investigations:

MRI:

  • Affects white matter in brain and spinal cord. Advances from posterior to anterior or anterior to posterior. Frontal, parietal, occipital, temporal lobes, corpus callosum. Spares U (arcuate) fibres.
  • Trigonal or frontal calcification may occur
  • T2: hyperintense
  • Enhancement of advancing edge or major white matter tracts  indicates disease activity.

Endocrine:

  • Adrenal insufficiency: low cortisol, high ACTH
  • Primary Hypogonadism

Electrophysiology/NCS:

  • Peripheral neuropathy, demyelinating

CSF: raised protein

Pathology:

Symmetric pathology in white matter
Demyelination i.e. myelin loss (Luxol fast blue LFB stain), lipid laden macrophages (PAS positive). Secondary changes in the spinal cord.
In chronic lesions: central cavitation, central astrocytic gliosis. Peripheral macrophages. Perivascular lymphocytes mainly T cells CD8. Cytoplasmic inclusions in macrophages (lamellar on EM)
Adrenals: cytoplasmic inclusions in cells in zona fasciculata-reticularis
Testes: cytoplasmic inclusions in interstitial cells

Treatment:

If early in the disease consider allogeneic hematopoietic stem-cell transplantation.
Promising therapies: Lenti-D gene therapy (autologous CD34+ cells transfected with a lentiviral vector that contains ABCD1 complementary DNA).

Related articles:

References:

  1. Aubourg P, Blanche S, Jambaqué I, et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 1990;322:1860-1866.
  2. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 2017;377:1630-1638
  3. Loes DJ, Hite S, Moser H, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 1994;15:1761-1766.

Krabbe Disease (Globoid Cell Leukodystrophy)

Diseases,

Synonyms:

a.k.a. galactocerebroside b-galactosidase deficiency

Diagnosis:

Assay of beta galatosylcerebrosidase activity is diagnostic.
A type of leukodystrophy. A type of dysmyelination.

Pathogenesis:

Oligodendrocyte apoptosis and gliosis

Clinical features:

Clinical:

  • Progressive cognitive decline, seizures, and cortical blindness.
  • Peripheral weakness.

Peripheral neuropathy demyelinating pattern, up to 60% of patients, may be asymmetric,

Genetics:

Autosomal recessive

Findings on investigations:

Biochemical:

  • Assay of beta galatosylcerebrosidase activity is diagnostic.

Electrophysiology/NCS:

  • Peripheral neuropathy

Imaging:

  • White matter and grey matter
  • CT: hyperdense in basal ganglia, thalami, corona radiate, cerebellar cortex
  • MRI:
    • T2 : hyperintense in cortex (especially parietal lobes), splenium of corpus callosum, cortical spinal tract, posterior limb internal capsule, cerebellar white mater, optic nerves
    • May be normal even with neurological symptoms.

Pathology:

Globoid cells (multinucleated, large), oligodendroglial apoptosis, gliosis

Related articles:

Metachromatic Leukodystrophy MLD

Diseases,

Synonyms:

a.k.a. arylsulfatase A deficiency

Diagnosis:

A type of leukodystrophy a.k.a. dysmyelination
Enzyme activity:

  • Reduced arylsufatase A deficiency
  • Test leukocytes

Urine: sulfatide accumulation

Clinical features:

Peripheral neuropathy

Findings on investigations:

Electrophysiology:

  • Demyelinating sensorimotor Peripheral neuropathy

Imaging:

  • Symmetrical demyelination, corpus callosum, centrum semiovale, cerebellum, spares the cortical U fibres. Multifocal frontal lobe lesions can occur.
  • Atrophy, corpus callosum thinning, ventricular dilatation.
  • T2: hyperintense
  • No enhancement

Pathology:

Neurons containing Metachromatic staining lipid granules (sulfatides)
Toluidine blue: pink metachromasia
Cresyl violet: brown metachromasia
CNS and peripheral nerve diffuse myelin loss
Symmetrical demyelination

Genetics:

Autosomal recessive

Related articles:

Leukodystrophy

Diseases, , ,

Synonyms:

Leucodystrophy, leukodystrophies

Introduction:

This is a group of various disorders of abnormal white matter myelination. They are often referred to as dysmyelinating disorders.

Types:

Approach by MRI pattern:

Parieto-occipital pattern:
Frontal pattern:
Periventricular pattern:
Subcortical Pattern
  • L-2-hydroxyglutaric aciduria
Brainstem involvement:
  • Alexander disease
  • Leukoencephalopathy with Brainstem and Spinal Cord Involvement, aspartyl-tRNA synthetase 2 (DARS2) mutation.
  • Adult-onset Autosomal Dominant Leukodystrophy (Lamin B1, LMNB1 gene mutation).
Cerebellar involvement:
Spinal cord involvement:
  • Adult-onset Autosomal Dominant Leukodystrophy (Lamin B1, LMNB1 gene mutation).
  • Alexander disease
  • Leukoencephalopathy with Brainstem and Spinal Cord Involvement, aspartyl-tRNA synthetase 2 (DARS2) mutation.

Abnormal peak on MR Spectroscopy:

Related articles:

Necrotizing Autoimmune Myopathy NAM

Diseases,

Diagnosis:

Clinical features plus positive antibodies and usually with necrotizing myopathy on biopsy

Clinical features:

Age range 30-60, progressive myopathy with profound proximal muscle weakness. May also occur in patients recieving statins, but most patients are statin naive

Antibodies:

Positive antibodies Anti-HMGCR Abs (3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase)

Muscle biopsy:

H&E: Necrotic fibers with a few regenerating fibres. Some macrophage infiltration can occur but typically no lymphocytic infiltration.
Immunohistochemistry:

  • major histocompatibility complex class I demonstrates macrophages as part of myophagocytosis but no upregulation in un-invovled muscles fibres
  • Complement: no deposition in microvasculature
  • CD3: no T cells

Treatment:

Corticosteroids
Consider other immunotherapy

Related articles:

References:

  1. Ramanathan S, Langguth D, Hardy TA, et al. Clinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy. Neurology® Neuroimmunology & Neuroinflammation. 2015;2(3):e96. doi:10.1212/NXI.0000000000000096.
  2. Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, Maisonobe T, Dubourg O, Behin A, Laforet P, Stojkovic T, Eymard B, Costedoat-Chalumeau N, Campana-Salort E, Tournadre A, Musset L, Bader-Meunier B, Kone-Paut I, Sibilia J, Servais L, Fain O, Larroche C, Diot E, Terrier B, De Paz R, Dossier A, Menard D, Morati C, Roux M, Ferrer X, Martinet J, Besnard S, Bellance R, Cacoub P, Arnaud L, Grosbois B, Herson S, Boyer O, Benveniste O; French Myositis Network. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore). 2014 May;93(3):150-7. doi: 10.1097/MD.0000000000000028.
  3. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013 Oct;48(4):477-83. doi: 10.1002/mus.23854. Epub 2013 Aug 30.

Leigh’s disease (Subacute necrotizing encephalomyelopathy)

Diseases,

Synonyms:

Leigh’s disease a.k.a. Subacute necrotizing encephalomyelopathy

Clinical features:

3 months- 2 years of age, poor suck, loss of head control, seizures, cardiac problems

Genetics:

Mutations in the mitochondrial DNA or deficiencies of pyruvate dehydrogenase

Findings on investigations:

MRI: symmetric hyperintensity in periaqueductal area, midbrain tectum, caudate, putamen, globus pallidus, substantia nigra. Spares mammillary bodies and red nucleus,
Labs: lactic acidosis

Pathology:

Involves brain-stem primarily but may involve any CNS area
Necrosis without glial or small cell reaction,

Treatment:

Vitamin B1
If deficient in pyruvate dehydrogenase: High fat, low carbohydrate diet,

Related articles:

Mitochondrial Neurogastrointestinal Encephalomyopathy MNGIE

Diseases, ,

Synonyms:

a.k.a. MINGE, rare

Diagnosis:

Genetic analysis

Genetics:

POLG gene or Thymidine phosphorylase (TP) mutation
TP mutation: Autosomal recessive
Mitochondrial DNA (mtDNA) analysis: depletion, deletions, and point mutation

Clinical features:

External ophthalmoplegia, gastrointestinal dysmotility (dysphagia and intestinal pseudoobstruction) and pain, cachexia, peripheral neuropathy, encephalopathy

Findings on investigations:

MRI: leukoencephalopathy
Muscle biopsy: ragged red fibres

Treatment:

Peritoneal dialysis

Related articles:

Alper Syndrome

Diseases

Synonyms:

a.k.a. Alper-Huttenlocher syndrome a.k.a. progressive infantile poliodystrophy

Diagnosis:

POLG gene (polymerase gamma), nuclear DNA mutation analysis

Genetics:

POLG gene (polymerase gamma), nuclear DNA mutation
Secondary findings, Mitochondrial DNA (mtDNA) analysis: depletion, deletions, and point mutations

Clinical features:

Status epilepticus, abnormal liver enzymes, axonal neuropathy,

Findings on investigations:

CSF lactate: increased
CSF: may show an inflammatory pattern
EEG: seizures may occur

Related articles:

Kearns-Sayre Syndrome KSS

Diseases, ,

Clinical features:

Onset before 20 years of age. Progressive external opthalmoplegia (restricted eye movements, usually movements are not dysconjugated) and pigmentory retinopathy. Also myopathy, heart block, CNS deficits, short stature.

Pathology:

Muscle biopsy:

Gomori trichrome: Ragged red fibres
Variation in muscle size
COX negative fibres

Brainstem and cerebellum:

neuronal loss. Spongy to vacuolar myelinopathy. May extend to cerebral white matter.
Basal ganglia and thalamus: may mineralize

Genetics:

mitochondrial DNA (mtDNA) deletions

Related articles:

Mitochondrial Disorders

Diseases, ,

There are many diseases that are included in mitochondrial disorders. They often share common features.

Synonyms:

a.k.a. mitochondrial cytopathies, mitochondrial neurological disorders

Subtypes of mitochondrial disorders:

Diagnosis:

Based on Genetics +muscle biopsy +clinical +other tests

Muscle biopsy:

False negatives can occur
HE: angulated atrophic fibres, subsarcolemmal granular appearance. GMT: ragged red fibres. COX: COX deficient fibres
EM: pleomorphic mitochondria, subsarcolemmal mitochondria
NCS/EMG: Axonal peripheral neuropathy

Findings on investigations:

OGTT: diabetes mellitus
Fundoscopy: retinitis pigmentosa
Lactic acid: increased
Abdominal X-ray: intestinal pseudoobstruction

Related articles:

Lipid Storage diseases

Diseases,

Lipide storage myopathies:

  • Carnitine deficiency
  • Carnitine palmityl transferase II deficiency

 

Carnitine deficiency:

Diagnosis:

There are various forms:

  • Muscle carnitine deficiency
  • Systemic carnitine deficiency
  • Secondary carnitine deficiency

Muscle carnitine deficiency:

  • Low muscle carnitine levels. Normal systemic carnitine levels
Muscle biopsy:
  • Vacuolar myopathy. Lipid droplets in type 1 fibres.

Systemic carnitine deficiency:

Systemic carnitine levels: low
Secondary carnitine deficiency:
Secondary to liver disease, hemodialysis, mitochondrial myopathy, Valproate VPA therapy
 

Carnitine palmityl transferase II a.k.a. carnitine palmitoyltreansferase II deficiency:

Clinical features:

Commonest form: Myoglobinuria after prolonged effort. Hyperlipidemia might occur
Childhood: fasting induced hypoglycemia, hepatic failure, cardiomyopathy, peripheral neuropathy

Muscle biopsy:

Normal between episodes of rhabdomyolysis
During myoglobinuric episodes: vacuoles, necrotic fibres
Oil red O: Lipid storage in some patients.
Toluidine blue: pale green vacuoles
Testing for enzyme deficiency in: muscle, leukocytes, cultured fibroblasts

Genetics:

Autosomal recessive, chr. 1p32
 

Related articles:

Sporadic Late Onset Nemaline Myopathy SLONM

Diseases,

Synonyms:

a.k.a. Adult from of nemalin myopathy a.k.a. acquired nemaline myopathy, rare:

Clinical features:

Adults a.k.a. late onset nemaline myopathy: usually >40 year olds, head drop, proximal >distal weakness, dysphagia, respiratory weakness, proximal and axial atrophy
Associated conditions:

  • SPEP: monoclonal gammopathy.
  • HIV associated nemaline myopathy.

Muscle biopsy:

HE fibre atrophy without grouping, subsarcolemmal increased eosinophilic staining. GMT subsarcolemmal purple/red nemaline rods in type 1 fibres. Often type 1 fibre hypertrophy, type 1 fibre predominance.
EM: nemaline rods= osmiophilic rods
Immunohistochemistry: Alpha actinin type 2 positive rods in a lot of cases, myotilin positive rods
Note: nemaline rods can occur in inflammatory muscle disease and in central core disease and nemaline myopathy (a form of congenital myopathy).

Findings on investigations:

NCS/EMG: Myopathic, fibrillation
CK: normal
Also see nemaline myopathy (a form of congenital myopathy)

Treatment:

Consider:

  • Stem cell transplantation. [case reports]

Related articles:

Condrodystrophic Myotonia

Diseases,

This is a very rare condition

Synonyms:

a.k.a. Schwartz-Jampil Syndrome SJS

Clinical features:

Myotonia +distichiasis (double row of eyelashes)

Findings on investigations:

EMG: Myotonia

Genetics:

Autosomal recessive
Genetics: Perlecan gene mutation, HSPG2 gene chr. 1p35-p36.1

Related articles:

Non-Dystrophic Myotonias

Diseases,

Diagnosis:

Clinical features: childhood onset of myotonia +muscle hypertrophy
There are multiple forms:

  • Becker myotonia: Autosomal recessive
  • Thomsen disease: (see appropriate section)

Genetics:

  • Autosomal dominant
  • Genetic analysis: chloride channel CLCN1 gene mutations on chromosome 7. Different mutations for each.

Muscle biopsy:

  • Variation in fibre size. Rare centronucleation. Type 2A fibre hypertrophy. Type 2B fibres may be absent.

Related articles:

Myotonia Congenita

Diseases,

A form of nondystrophic myotonia

Synonyms:

a.k.a. Thomsen’s disease

Clinical features:

1st and 2nd decade
When infant: inability to open eyes after face is washed, peculiar cry
Muscular hypertrophy (generalized), myotonia (worse in cold),
No weakness
Warm up phenomenon: improved strength and movement after warm up

Genetics:

  • Autosomal dominant
  • Genetic analysis: chloride channel CLCN1 gene mutations on chromosome 7. Different mutations for each.

Muscle biopsy:

  • Variation in fibre size. Rare centronucleation. Type 2A fibre hypertrophy. Type 2B fibres may be absent.

Findings on investigations:

EMG:

  • Myotonia

Related articles:

Myotonic Dystrophy DM1

Diseases,

Synonyms:

a.k.a. Dystrophia myotonica a.k.a. DM a.k.a. DM1 a.k.a. Steinert disease

Diagnosis:

Clinical +EMG +consistent labs

Clinical features:

Early frontal baldness,
Wasting of temporalis (hatchet face), massester and sternocleidomastoid (swan neck),
Ptosis, facial weakness. Weakness and atrophy of distal arms and finger flexors, and quadriceps and tibialis anterior (foot drop)
Decreased reflexes
Myotonia: difficulty releasing hand grip, percussion myotonia,
+cataracts

Findings on investigations:

CK: normal or slightly high
EMG:

  • Evidence of myotonia

ECG:

  • Conduction abnormalities

Muscle Biopsy:

Non-grouped Atrophy, nuclear bags. Centronucleation. NADH: Striated annulets ‘ringbinden’. Ring fibres. Usually no or mild necrosis or excess connective tissue. Atrophy of type 1 fibres
Electron microscopy: myofibrils at the periphery perpendicular to the central portion

Genetics:

CTG repeat expansion in DM protein kinase DMPK on chromosome 19

Treatment:

Treat cardiac conduction abnormalities
Symptomatic for myotonia with:

  • 1st line: Phenytoin PHT
  • 2nd line: may worsen conduction abnormalities quinine sulphate tid, procainamide qid

Orthoses
Genetic counselling

Related articles:

Congenital Muscular Dystrophies CMD

Diseases,

These are a type of muscular dystrophy. Don’t confuse these diseases with non-dystrophic congenital myopathies.

Merosin (Laminin 2) negative CMD:

Clinical features:

Cause hypotonia in the infant

Pathology, Muscle or skin biopsy:

H and E: dystrophic picture
Immunohistochemistry: absent Mersonin (Laminin 2) in basement membrane.

Findings on investigations:

MRI: white matter changes
 

Merosin positive CMD:

This is a group of diseases.
CMD with CNS malformations: a group of diseases. Merosin is positive.

Findings on investigations:

MRI: various CNS malformations
 

Related articles:

Oculopharyngeal Dystrophy OPMD

Diseases,

Synonyms:

a.k.a. oculopharyngeal muscular dystrophy OPMD

Muscle biopsy:

Rare rimmed vacuoles. Intranuclear inclusions. Occasionally type 1 fibre predominance and occasionally ragged red fibres

Genetics:

Autosomal dominant
PABP2 gene, Chr. 14q11.2-q13, expanded trinucleotide repeat (polyalanine) GCG in PABP2 poly A binding nuclear protein 2.

Clinical features:

Ptosis, dysphagia
Later on proximal limb weakness and gait abnormalities can occur

Related articles:

Fascioscapulohumeral Myopathy FSH

Diseases,

Synonyms:

a.k.a. Landuzy-Dejerine disease

Muscle biopsy:

3 patterns

  • Pseudoneurogenic: atrophied angulated fibres in nests
  • Dystrophic: whorled fibres, moth eaten fibres, lobulated fibres. Endomysial fibrosis.
  • Pseudomyositic: inflammatory cellular mononuclear infiltrates

Diagnosis:

Genetic analysis (blood test): deletion at 4q35. i.e. deletion of the telomeric region

Genetics:

Genetic analysis (blood test): deletion at 4q35. i.e. deletion of the telomeric region

Clinical features:

Onset 10-40 years old
Facial weakness (Bell’s phenomenon)
+/- Shoulder girdle weakness:

  • Serratus anterior (Winging of scapula), pectoralis and trapezius
  • With relative sparing of deltoids and forearms (Popeye arms).
  • Preserved lower limbs
  • Congenital absence of pectoralis, biceps or brachialis may occur, forearm pseudohypertrophy may occur

Related articles:

 

Emery-Dreifuss Muscular Dystrophy

Diseases,

Synonyms:

a.k.a. Humeroperoneal dystrophy

Genetics:

X linked recessive

Clinical features:

Weakness in biceps, triceps, distal leg muscles
Early contractures
Rigid spine
Findings on investigations:
Cardiac conduction block

Muscle biopsy:

Dystrophic changes similar to Duchenne muscular dystrophy
Immunohistochemistry: absent Emerin is diagnostic.

Investigations to consider:

Monitor cardiac function: conduction abnormalities

Treatment:

Consider insertion of pacemaker
Physical therapy to maintain mobility

Related articles:

Becker Muscular Dystrophy, BMD

Diseases,

Diagnosis:

Must confirm with Western Blotting and genetic testing
Quantitative dystrophin analysis by Western blotting: decreased dystrophin

Muscle biopsy:

Similar findings to Duchenne muscular dystrophy, but less severe.
Immunohistochemistry: variation in staining for dystrophin between and within fibres. Use antibodies against different regions of dystrophin to avoid false negatives.
Must confirm with Western Blotting and genetic testing
Quantitative dystrophin analysis by Western blotting: decreased dystrophin

Genetics:

X linked recessive

Related articles:

Glycogenoses (glycogen storage diseases)

Diseases,

Pompe disease:

Synonyms:

a.k.a. type 2 glycogenosis a.k.a. glycogen storage disease type II GSD II a.k.a. acid maltase deficiency, rare:

Diagnosis:

A type of lysosomal storage disease and a glycogen storage disease.

Genetics:

GAA gene chr. 17. Protein= alpha glucosidase
Autosomal recessive

Biochemical assay:

Confirms the diagnosis.
Enzyme activity: reduced
Skin fibroblasts are best
Muscle biopsy: Decreased activity of acid maltase, but normal neutral maltase

Clinical features:

Wide spectrum. Usually fixed weakness. Proximal muscle weakness. Axial muscle weakness. Respiratory muscle weakness.
Pompe disease= infant with massive cardiomyopathy +hypotonia

Muscle biopsy:

HandE: Vacuoles. GMT: vacuolations, mitochondrial change. PAS: positive vacuoles. Acid phosphatase: stained vacuoles
Electron microscopy: lysosomal glycogen lakes

Findings on investigations:

EMG:

  • Myopathic picture in limbs: increased insertional activity, irritation, fibrillation potentials.
  • Myotonic discharges in paraspinal muscles

CK: modestly raised, normal

Treatment:

Enzyme replacement therapy ERT:

  • Acid a-glucosidase 20 mg/kg I.V. every 2 weeks
  • For all infants
  • Consider in adults

 

Forbes disease a.k.a. type 3 glycogenosis

Muscle biopsy:

Electron microscopy: cytoplasmic storage
Amylo-1,6 glucosidase deficiency
 

McArdle disease:

Synonyms:

a.k.a. type 5 glycogenosis a.k.a. myophosphorylase deficiency MPH deficiency:

Diagnosis:

Biochemical assay confirms the diagnosis

Clinical features:

Exercise intolerance, exercise induced cramps and exercise induced Myoglobinuria
Fixed weakness (proximal) may occur
Second wind phenomenon occurs
Renal failure may occur

Muscle biopsy:

Subtle findings
HandE: sometimes shows subsarcolemmal vacuoles. Necrosis may occur in myoglobinuric phase. PAS: positive vacuoles. Acid phosphatase: negative vacuoles
Electron microscopy: cytoplasmic storage of glycogen i.e. nonlysosomal. But this is nonspecific
Myophosphorylase stain: Negative phosphorylase reaction confirms the diagnosis, positive staining in blood vessels (internal control)

Findings on investigations:

EMG:

  • Electrical silence during a cramp
Genetics:

Autosomal recessive. PYGM gene chr. 11q13
 

Tarui disease:

Synonyms:

a.k.a. type 7 glycogenosis a.k.a. phosphofructokinase deficiency PFKM deficiency

Clinical features:

Broad: exercise intolerance, cramps. Fixed weakness
Moderate hemolytic anemia, gout

Muscle biopsy:

Electron microscopy: cytoplasmic storage
Normal phosphorylase reaction
PFK Muscle isoform: absent staining
PFKM gene mutation chr. 12q13.3, PFK Muscle isoform

Findings on investigations:

CK, bilirubin, uric acid, reticulocytes: increased
 

Type 8 glycogenosis

Synonyms:

a.k.a. phosphorylase kinase deficiency PHK deficiency

Clinical features:

Broad: exercise intolerance, cramps
PHKA gene mutation chr. Xp22.2,
 

Related articles:

Congenital Myopathies

Diseases,

These are the non-dystrophic congenital myopathies

Nemaline myopathy a.k.a. nemaline rod myopathy:

Clinical features:

Floppy infant with facial weakness and respiratory insufficiency.
Also see adult from a.k.a. sporadic late onset nemaline myopathy

Genetics:

Heterogeneous,
Autosomal dominant, autosomal recessive
Mutations in the following Proteins:

  • Alpha-skeletal actin
  • Nebulin
  • Troponin.
Muscle biopsy:

HE fibre atrophy without grouping, subsarcolemmal increased eosinophilic staining. GMT subsarcolemmal purple/red nemaline rods in type 1 fibres. Often type 1 fibre hypertrophy, type 1 fibre predominance.
EM: nemaline rods= osmiophilic rods
Immunohistochemistry: Alpha actinin type 2 positive rods in a lot of cases,
Note: nemaline rods can occur in inflammatory muscle disease and in central core disease.
Also see adult from a.k.a. sporadic late onset nemaline myopathy.

Centronuclear myopathy a.k.a. myotubular myopathy:

A group of genetic disorders: infantile (X linked), childhood (autosomal dominant, autosomal recessive), adult (autosomal dominant)

Muscle biopsy:

Type 1 fibres: Central nuclei and small. Normal type 2 fibres usually.
Type 1 fibre predominance.
 

Central core disease:

Clinical features:

Floppy infant: hypotonia
Childhood and adults. Proximal weakness, neck flexors and facial muscles. Associated with skeletal abnormalities scoliosis, developmental dysplasia of the hip

Genetics:

A group of disorders:

  • Autosomal dominant,
  • Rarely recessive (multiminicore disease)
  • RYR1 gene ryanodine receptor mutation (Ca++ channel).
Muscle biopsy:

Type 1 fibres: central area devoid of staining with NADH, also devoid of staining with SDH and COX
Strong Type 1 fibre predominance.
Myopathic features may occur
EM: central areas devoid of mitochondria extending the full length of the muscle fibre
 

Related articles:

Limb Girdle Muscular Dystrophies LGMDs

Diseases,

Synonyms:

formerly pelvifemoral type, Laden-Mobius variant and scapulohumeral type

Diagnosis:

Autosomal: most are recessive. Must confirm with genetic testing especially for sarcoglycan and dysferlin.

Muscle biopsy:

Similar to Duchenne muscular dystrophy
Cytoplasmic changes may occur: split fibres, whorls, moth eaten fibres, lobulated fibres
Hints to subtypes:

  • GMT, Rimmed vacuoles= Telethoninopathy LGMD2G
  • GMT, Rod-like structures= myotilinopathy
  • NADH, lobulated fibres= Calpainopathy

Genetics:

Autosomal dominant types:

LGMD 1A, Myotilin, TTID gene chr. 5q31
LGMD 1B, Lamin A/C
LGMD 1C, Caveolin-3
LGMD 1D, chr. 7q
LGMD 1E
LGMD 1F, chr. 7q32

Autosomal recessive types:

LGMD 2A, Calpain-3
LGMD 2B, dysferlin. If distal it’s called Miyoshi myopathy a.k.a. distal myopathy
LGMD 2C, gamma-Sarcoglycan
LGMD 2D, alfa-Sarcoglycan
LGMD 2E, beta-Sarcoglycan
LGMD 2F, delta-Sarcoglycan
LGMD 2G, Telethonin, TCAP gene chr. 17q12
LGMD 2H, TRIM32
LGMD 2I, Fukutin-related protein
LGMD 2J, Titin
LGMD 2K, protein o-mannosyltransferase-1 POMT1 gene chr. 9q34.1

Clinical features:

Onset 10-30 years
Pelvic or shoulder girdle weakness and wasting, gradually progressive.
Preserved facial muscles and ocular muscles
Preserved ankle jerks, depressed other jerks
Calve pseudohypertrophy may occur as well as quadriceps pseudohypertrophy

Related articles:

Duchenne Muscular Dystrophy, DMD

Diseases,

Diagnosis:

Genetic testing confirms the diagnosis, as does muscle biopsy

Muscle biopsy:

Early: variation in fibre size, atrophic fibres, round hypertrophied fibres, centronucleation, regenerating fibres, split fibres. Endomysial connective tissue begins to appear.
Later: infiltration by adipose tissue. Poor differentiation of fibre type on ATPase reactions.
Inflammatory infiltrates may occur.
Immunohistochemistry: total absence of dystrophin (antibodies to C terminal are more specific). Normal expression of spectrin. Confirms the diagnosis.
Quantitative dystrophin analysis by Western blot: markedly decreased or absent dystrophin. Confirms the diagnosis.

Genetic:

X linked recessive

Clinical features:

Onset 3-10 years, Progressive
Proximal lower limb weakness, neck flexor weakness.
Preserved neck extensors, face and ocular muscles
Preservation of ankle reflexes, other reflexes are depressed
Pseuohypertrophy of calf muscles (and sometimes deltoids), Gower’s manoeuvre on standing.

Treatment:

Prednisolone P.O. or deflazacort P.O.
Creatine monohydrate
Preserve ambulation

Related articles:

Malignant Hyperthermia Syndrome

Diseases,

Genetics:

Autosomal dominant
Ca++ ryanodine receptor 1 RYR1.
Ca++ CACN1A3 muscle DPH sensitive Ca++ channel

Clinical features:

Hyperthermia
Rigidity, tachycardia, hypertension, fever, rising CO2, lactic acidosis, rhabdomyolysis
Triggered by anesthetic administration e.g. halothane. Also suxamethonium
Findings on investigations:
Rhabdomyolysis

Muscle biopsy:

Normal or Non-specific changes
Or pre-existing underlying myopathy: central core disease. Some forms of myotonic syndromes.

Investigations to consider:

ABG
Creatine kinase
Urine Myoglobin
Basic metabolic panel

Treatment:

Stop anaesthesia
Give Dantrolene
If acidotic; give bicarbonate
Following surgeries:
Pre-treat with dantrolene four times daily on the preceding day
Atropine is contraindicated
Consider the following anaesthetics:

  • Nitrous oxide, opiates, barbiturates, droperidol

Related articles:

Hyperkalemic Periodic Paralysis

Diseases,

Synonyms:

formerly Gamstorps disease, adynamia episodica hereditaria

Genetics:

SCN4A 17q23, M1592V. Cold induced weakness I693T
Autosomal dominant
Mutations in sodium channel alfa subunit SCN4A

Clinical features:

Recurrent attacks of weakness.
All limbs, spares, respiratory and ocular
Weakness after exercise. Myotonia may occur e.g. cold induced
Precipitated by K+. Alleviated by Ca++.
Improves with age

Findings on investigations:

Electrophysiology NCS/EMG:

  • CMAP: decrement in amplitude after exercise

Long exercise test a.k.a. McManis Protocol:

  • Good specificity, better for hyperkalemic periodic paralysis than hypokalemic periodic paralysis
  • CMAPs on abductor digiti minimi ADM, Intermittent strong voluntary contraction: during first 2-5 minutes increase in CMAP. During following 20 minutes decrease in CMAP to below pre-exercise level

Pathology, Muscle biopsy:

H and E stain: Usually normal. Vacuolation in some. GMT: red subsarcolemmal aggregates.
Ultrastructure/Electron microscopy: vacuoles/aggregates are expansion of T tubules and sarcoplasmic reticulum.

Treatment:

Lifestyle management (reduce K+)
Reduce K+ (thiazide diuretics, beta agonists)
Acute and prophylactic: Acetazolamide P.O.

Related articles:

 

Hypokalemic Periodic Paralysis

Diseases,

Genetics:

Autosomal dominant, reduced penetrance in females
Ca++ CACN1A3 muscle DPH sensitive Ca++ channel. CACNL1A3 (CACNA1S) gene chr. 1q32 protein= calcium channel L type 1S subunit,
Na+ SCNA4A 17q23-q25.3. Or sodium channel alfa subunit SCN4A gene chr. 17q25
Or potassium channel KCNE3 gene chr. 11q13

Clinical features:

Commonest form.
Recurrent attacks of flaccid weakness. Attacks are longer 12-24 hrs
Weakness:

  • Precipitated by rest or high carbohydrates or low serum K+.

Findings on investigations:

Electrophysiology NCS/EMG:

  • CMAP: decrement in amplitude after exercise

Long exercise test a.k.a. McManis Protocol:

  • Good specificity, better for hyperkalemic periodic paralysis than hypokalemic periodic paralysis
  • CMAPs on abductor digiti minimi ADM, Intermittent strong voluntary contraction: during first 2-5 minutes increase in CMAP. During following 20 minutes decrease in CMAP to below pre-exercise level

Pathology, Muscle biopsy:

H and E stain: Usually normal. Vacuolation in some. GMT: red subsarcolemmal aggregates.
Ultrastructure/Electron microscopy: vacuoles/aggregates are expansion of T tubules and sarcoplasmic reticulum.

Treatment:

Lifestyle management
Acute: Potassium P.O.
Prophylactic: Acetazolamide P.O.

Related articles:

Statin Myopathy

Diseases,

Diagnosis:

Clinical features consistent with statin myopathy, exclusion of other causes and improvement of myopathy on discontinuation of statin. Antibody tests can be useful in distinguishig between statin induced necrotizing myopathy and necrotizing autoimmune myopathy.

Clinical features:

Proximal symmetric muscle weakness, usually spares the face, bulbar muscles and sphincters
CK: usually elevated, may be normal

+Muscle biopsy:

Fibre size variation, atrophic rounded fibres
Necrotic fibres, regenerating fibres,
No inflammation
In some mitochondrial features: ragged red fibres, COX deficient fibres, lipid excess

Genetics:

Associated with polymorphism in SLCO1B1 gene, organic-anion transporting polypeptide OATP1B1, C allele of the rs4149056 polymorphism.

Antibodies:

Anti-HMGCR Abs (3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase): associated with necrotizing autoimmune myopathy

Related articles:

References:

  1. SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008 Aug 21;359(8):789-99. doi: 10.1056/NEJMoa0801936. Epub 2008 Jul 23.
  2. Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, Maisonobe T, Dubourg O, Behin A, Laforet P, Stojkovic T, Eymard B, Costedoat-Chalumeau N, Campana-Salort E, Tournadre A, Musset L, Bader-Meunier B, Kone-Paut I, Sibilia J, Servais L, Fain O, Larroche C, Diot E, Terrier B, De Paz R, Dossier A, Menard D, Morati C, Roux M, Ferrer X, Martinet J, Besnard S, Bellance R, Cacoub P, Arnaud L, Grosbois B, Herson S, Boyer O, Benveniste O; French Myositis Network. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore). 2014 May;93(3):150-7. doi: 10.1097/MD.0000000000000028.
  3. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013 Oct;48(4):477-83. doi: 10.1002/mus.23854. Epub 2013 Aug 30.

Drug Induced Myopathies

Diseases,

Corticosteroid myopathy:

Statin myopathy:

Ziduvodine Mitochondrial myopathy:

+Muscle biopsy:
  • Ragged red fibres. COX negative fibres, Pleomorphic mitochondria
  • Distinguishes it from HIV associated inflammatory myopathy

Choroquine neuromyopathy

+Muscle biopsy:

Vacuolar myopathy, especially in type 1 fibres. PAS positive.
Electron microscopy: muscle and nerve. Membranous whorlings, myelin figures, curvilinear inclusions.

Hypokalemic drugs:

Related articles:

Critical Care Myopathy

Diseases,

Synonyms:

a.k.a. acute quadriplegic myopathy

Diagnosis:

This is a clinical diagnosis supported by exclusion of other causes. Usually it does not require biopsy but often it is used in cases of uncertainty

Clinical features:

All limbs, diaphragmatic and intercostal weakness,
Occurs in severe illness +/-sepsis, +/-steroids, +/-neuromuscular blocking agents

Findings on investigations:

+CK normal or moderately raised
+EMG myopathic pattern +reduced excitability to direct muscle stimulation
+NCS normal, or slightly reduced CMAP, to exclude Critical care neuropathy
+RNST to exclude Myasthenia Gravis

+Muscle Biopsy:

HE: Nonspecific changes, fibre atrophy especially type 2, necrosis may occur
+EM loss of myosin (absent A bands= thick bands), preserved Z-bands and thin filaments
Immunohistochemistry: myosin heavy chain: reduced

Related articles:

Corticosteroid Myopathy

Diseases,

Synonyms:

Steroid induce myopathy

Diagnosis:

This is a clinical diagnosis supported by exclusion of other causes. Usually it does not require biopsy but often it is used in cases of uncertainty

Clinical features:

Proximal weakness, usually gradual onset

Findings on investigations:

+/-CK normal or reduced
+/-Muscle biopsy: Type 2 fibre atrophy, especially type 2B. Lipid and/or glycogen accumulation can occur. Vacuolar myopathy can occur.

Related articles:

Eosinophilic Myositis and Eosinophilic Fasciitis

Diseases,

Eosinophilic myositis

Occurs in hypereosinophilic syndrome, parasitic infections, Churg Strauss syndrome,

Muscle biopsy:

  • Inflammatory cells including eosinophils

 

Eosinophilic fasciitis a.k.a. Shulman syndrome:

Clinical features:

Subcutaneous induration sparing the face and fingers
Stiff joints
FBC: raised eosinophils

Biopsy:

Scleroinflammatory lesions in the fascia, may extend into the dermis or muscle.
Well circumscribed or absent eosinophilia
Perivascular lymphocytes and plasma cells

Related articles:

Inclusion Body Myositis

Diseases,

Synonyms:

a.k.a. inclusion body myopathy IBM

Diagnosis:

Clinical +Muscle biopsy +neurophysiology

Clinical features:

Usually >50 year old patients Progressive weakness of quadriceps, ankle dorsiflexors, finger flexors and facial muscles. Dysphagia is common.

Pathology, Muscle biopsy

Inflammation
HE: Rimmed vacuoles: Basophilic granules around vacuoles. Endomysial and perivascular lymphocytes. Increased connective tissue
GMT: rimmed vacuoles (red rim), ragged-red fibres, COX: COX negative fibres.
Congo red: amyloid in the rims
Immunohistochemistry: lymphocytes: CD8 positive. Amyloid deposits: beta amyloid, tau and ubiquitin positive
EM: tubulofilaments in cytoplasm and nucleus i.e. inclusions.

Findings on investigations:

CK: elevated or normal
EMG:

  • Myopathic
  • But mixed potentials (polyphasic units of short and long duration) occur

cN1a antibodies in inclusion body myositis
Hereditary forms:

  • VCP gene chr. 9p13-p12. Protein= Valosin-containing protein: IBM +Paget disease +Frontotemporal dementia IBMPFD
  • GNE gene mutation, protein= UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase,

Investigations to consider:

CK
EMG
Muscle biopsy

Monitor:

Weakness not CK

Treatment:

General measures:

  • Assistive devices and general support for complications

Some clinicians try:

  • IVIG, Prednisolone, methotrexate

Related articles:

Bacterial Myositis

Diseases,

Pyomyositis and Tropical pyomyositis:

Features:

  • Very debilitated patients in ICU or tropical form
  • Acute, spontaneous i.e. non-traumatic suppurative infection, abscess formation
Gas gangrene, Clostridium perfringens

Diagnosis:

  • Traumatic or surgical. Also spontaneous gas gangrene Clostridium septicum in colon cancer patients.
  • Gram stain of bullae fluid: gram positive rods
  • Tissue biopsy may be necesary to confirm the diagnosis

Investigations to consider:

Blood tests:

  • ABG: metabolic acidosis
  • FBC: anemia, hemolysis, thrombocytopenia
  • Basic metabolic panel: hyperkalemia.
  • LFTs: hyperbilirubinemia. Raised enzymes
  • Coagulation: abnormal.
  • Blood cultures

Myoglobinuria

Related articles:

Viral Myositis

Diseases,

Acute viral myositis:

Viral causes:

Influenza virus: Acute benign myositis or rhabdomyolysis.
Coxsackie B virus: Bornholm disease or epidemic myalgia

AIDS myopathy:

HIV associated myopathy: Similar to seronegative polymyositis
Muscle biopsy:

  • HIV antigens in the endomysial and perivascular macrophages are usually present
  • Muscle fibres express MHC-1 molecules
  • Primary muscle lymphoma can occur in AIDS patients

Related articles:

  • Myopathy,
  • polymyositis, zidovudine myopathy, pyomyositis, toxoplasmic polymyositis, nemaline myopathy (acquired)

Rhabdomyolysis

Diseases,

Diagnosis:

This is a clinical diagnosis supported by laboratory tests

Findings on investigations:

+CK markedly raised
+/-EMG Florid myopathic motor unit pattern. Spontaneous potentials in many muscles
Muscle biopsy, if done:

  • Necrosis of a large number of fibres

Other tests:

  • Urinalysis: hematuria on dipstick which is actually myoglobinuria
  • BASIC METABOLIC PANEL: hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia

Related articles:

Denervation Atrophy

Diseases,

Diagnosis:

Muscle biopsy:

  • Fibre size variation with angulated fibres (rounded fibres in spinal muscular atrophy)
  • Grouped atrophy, bags of nuclei
  • Target fibres
  • Pseudomyopathic pattern
  • Fibre distribution (ATPases): fibre type grouping, grouped atrophy of type 2 and type 1 fibres
  • NADH: target fibres, central clearing

Related articles:

Idiopathic Cramps

Diseases

Diagnosis:

Cramps occurring without physical examination findings of neurological disease and with normal electrolytes and calcium

Clinical features:

Cramps occurring without physical examination findings of neurological disease

Treatment:

Day time cramps:

  • Carbamazepine CBZ P.O.
  • Phenytoin PHT P.O.

Nocturnal cramps:

  • Carbamazepine CBZ, Phenytoin PHT, diazepam

Note: Quinine P.O. nocte works however risks out-way benefits

Paroxysmal Extreme Pain Disorder PEPD

Diseases

Synonyms:

formerly familial rectal pain syndrome

Diagnosis:

A type of channelopathy

Genetics:

Autosomal dominant
SCN9A gene. Protein= Nav1.7 voltage gated sodium channel alpha subunit

Clinical features:

Begins in infancy
Autonomic: syncope, bradycardia, skin colour changes (flushing, or harlequin),
Tonic nonepileptic seizures
Paroxysmal pain: rectal, periorbital or jaw

Treatment:

Carbamazepine CBZ P.O.

Related articles:

Morvan's fibrillary chorea, Morvan's syndrome, neuromyotonia NMT, and Isaac syndrome

Diseases

Synonyms:

Morvan’s ‘fibrillary chorea’ a.k.a. Morvan’s syndrome, neuromyotonia NMT a.k.a. Isaac syndrome:

  • Both conditions have been described with anti-voltage-gated potassium channel antibodies anti-VGKC (Kv1)
  • VGKC is positive in patients with limbic encephalitis, Morovan’s syndrome. These have different targets.
  • Caspr2: contactin-associated protein-antibody-2, a subtype of VGKC found in Morovan’s syndrome
  • Lgi1: leucine-rich, glioma inactivated 1 protein, a subtype of VGKC found in limbic encephalitis.

Morvan syndrome:

Diagnosis:

Clinical features: neuromyotonia (myokymia with cramping), hyperhidrosis and disordered sleep. Other features pain, weight loss, severe insomnia and hallucinations.
Fibrillations and myokymia may also occur.

Neuromyotonia NMT a.k.a. Isaac syndrome a.k.a Isaac’s-Merten’s syndrome a.ka. acquired neuromyotonia a.k.a. continuous muscle fiber activity syndrome a.k.a. quantal squander syndrome:

Diagnosis:

This is determined by clinical features, plus EMG findings and antibody testing

Clinical features:

neuromyotonia (myokymia with cramping, that isn’t elicited by muscle percussion), without CNS manifestations
Fibrillations and myokymia may also occur.

EMG:

Neuromyotonia i.e. abnormal spontaneous activity of a single motor unit potential at 150-250 Hz (very high) with a decrementing response. “pinging” sound on EMG. MUAP morphology.

Treatment:

Phenytoin PHT P.O.
Or Carbamazepine CBZ P.O.

Related articles:

Pure autonomic failure (PAF)

Diseases

Synonyms:

a.k.a. Bradbury-Eggleston syndrome a.k.a. idiopathic orthostatic hypotension

Diagnosis:

A type of alpha-synucleinopathy

Clinical features:

Middle-late life,
Gradual onset and progression of orthostatic hypotension +other features of autonomic failure e.g. Nocturia and erectile dysfunction
Coat hanger pain occurs: shoulder and neck ache on standing
Without other neurologic signs

Findings on investigations:

Noradrenaline:

  • After supine for 30 minutes and then after standing for 5 minutes: 50-100% increase is normal. In PAF, levels are low supine and barely increase on standing.

Post ganglionic
Cardiac denervation by:

  • Cardiac SPECT 123I –labelled MIBG: impaired uptake
  • PET scan

Pathology:

Alpha-synuclein in pre- and post-ganglionic neurons in the sympathetic and parasympathetic nervous system. Lewy bodies and Lewy neurites (nerve fibres with eosinophilic material).
Epicardial space nerve fibres: Tyrosine hydroxylase staining is decreased (cardiac denervation, sympathetic)

Related articles:

Autoimmune Autonomic Ganglionopathy AAG

Diseases,

Synonyms:

a.k.a. Pandysautonomia a.k.a. idiopathic autonomic neuropathy a.k.a. acute panautonomic neuropathy a.k.a. autoimmune autonomic neuropathy, rare:

Diagnosis:

Clinical features +Anti-ganglionic nAChR antibodies +supported by electrodiagnostic tests

Clinical features:

Failure of sympathetic (orthostatic hypotension, anhidrosis) and parasympathetic (dry eyes, dry mouth, gastroparesis, constipation, urinary retention) nervous system with relative sparing of somatic nerves
Preceded by viral illness

Findings on investigations:

Anti-ganglionic nAChR antibodies
CSF: mildly raised protein sometimes
CT: thymoma, small cell lung cancer
NCS/EMG: normal or near normal somatic nerves
Intact Cardiac innervation by:

  • Cardiac SPECT 123I –labelled MIBG, reduced uptake
  • PET scan

Pathology:

Epineurium: small mononuclear cell infiltrate and perivascular

Related articles:

Idiopathic Sensory Ganglionopathy

Diseases,

Synonyms:

a.k.a. chronic ataxic neuropathy

Diagnosis:

Clinical features +NCS/EMG findings +Exclusion of other causes: Sjogren syndrome, paraneoplastic syndrome, paraproteinemia, Refsum disease etc.

Clinical features:

Global sensory loss (especially proprioception), sensory ataxia (pseudoathetosis), normal power
Exclusion of other causes: Sjogren syndrome, paraneoplastic syndrome, paraproteinemia, Refsum disease etc.

Findings on investigations:

+NCS +EMG:

  • Axonal Sensory neuropathy (may be normal initially)
  • Normal motor,
Pathology, nerve biopsy:

Dorsal root ganglia: lymphocytic infiltration, destruction of nerve cells,
Sural nerve biopsy:

  • Loss of myelinated axons

Related articles:

Hereditary sensory neuropathy HSN (Hereditary sensory autonomic polyneuropathy HSAN)

Diseases, ,

Synonyms:

Hereditary sensory neuropathy HSN or Hereditary sensory autonomic polyneuropathy HSAN

Diagnosis:

Clinical +genetic testing

Clinical features:

All have sensory neuropathy without motor features

HSN1 a.k.a. Denny-Brown neuropathy:

Clinical features:
  • Loss of pain and temperature sensation, ulceration of feet and hands, Charcot joints. No autonomic features
Findings on investigations:

NCS/EMG: axonal

HSN2 a.k.a. congenital sensory neuropathy, formerly Morvan’s disease:

Clinical features:

Onset in infancy

HSN3, a.k.a. Familial dysautonomia a.k.a. Riley-Day syndrome:

Autosomal recessive, IKBKAP gene chromosome 9

Clinical features:
  • Absent fungiform papillae of the tongue (smooth tongue)
  • Absent reflexes
  • Alacrima, Hypersensitivity of pupils to parasympathomimetics, dry mouth, absent skin response to scratch and histamine injection, orthostatic hypotension
Sural nerve biopsy:

Markedly diminished number of unmyelinated and small-diameter myelinated axons

HSN4 a.k.a. congenital sensory neuropathy with loss of sweating:

Autosomal recessive

Clinical features:

Infants. Fever, loss of pain sensation

Related articles:

Fabry Disease: alpha-galactosidase A deficiency

Diseases, ,

Synonyms:

a.k.a. alpha-galactosidase A deficiency a.k.a. Angiokeratoma corporis diffusum

Clinical features:

Rash: Telangiectasia on lower trunk and upper legs
Peripheral neuropathy: painful
Stroke
Cardiac and renal dysfunction

Genetics:

X-linked recessive

Findings on investigations:

Leukocyte alpha-galactosidase A: low
CT: pulvinar hyperdensity (mineralization)
MRI brain:

  • Pulvinar sign T1 hyperintensity

Other tests:
Basic metabolic panel: creatinine: renal failure

Related articles:

Tangier disease: Familial alpha-lipoprotein deficiency

Diseases, ,

Synonyms:

High density lipoprotein HDL deficiency,

Clinical features:

Enlarged orange tonsils
Impaired pain and temperature sensation

Findings on investigations:

Lipid profile: low to absent HDL

Related articles:

Sjogren Syndrome Neuropathy

Diseases, ,

Diagnosis:

Clinical features of neuropathy plus diagnosis of Sjogren syndrome (by serology or biopsy) plus exclusion of other causes. Vasculitis may occur.

Clinical features:

Features of neuropathy: small fibre neuropathy, or sensory axonal polyneuropathy, facial palsy CN VII may occur,

Findings on Investigations:

NCS/EMG:

  • Features of the underlying pattern: small fibre sensory neuropathy, or sensory axonal polyneuropathy,

Related articles:

Coeliac Disease Neuropathy

Diseases, ,

Synonyms:

a.k.a. gluten neuropathy

Diagnosis:

Diagnosis of Coeliac disease or serology positive for coeliac disease, plus clinical or electrodiagnostic neuropathy and exclusion of other causes

Clinical features:

Different patterns: sensorimotor neuropathy >mononeuropathy multiplex >motor neuropathy >small fibre neuropathy.

Findings on investigations:

+NCS/EMG:

  • Axonal neuropathy pattern, different patterns (sensorimotor neuropathy >mononeuropathy multiplex >motor neuropathy >small fibre neuropathy)

Other tests:

  • Associated with HLA-DQ2, HLA-DQ8

Pathology:

Epineurium: lymphocytic infiltrate. Endoneurium: lymphocytic infiltrate. Wallerian degeneration.

Related articles:

Idiopathic Sensory Perineuritis

Diseases, ,

Diagnosis:

Clinical features of polyneuropathy, mononeuropathy multiplex, biopsy findings of perineuritis and exclusion of secondary causes

Clinical features:

sensory patchy neuropathy, sensorimotor forms exist.

Pathology, nerve biopsy:

Perineurium: inflammatory lymphocytic infiltrate, thickening of perineurium
Exclusion of other causes

Treatment:

Consider corticosteroids

Related articles:

Migrant sensory neuritis (Wartenberg Syndrome)

Diseases,

Synonyms:

a.k.a. Wartenberg Syndrome:

Clinical features:

decreased sensation in individual cutaneous nerves. i.e. sensory mononeuropathy multiplex. Precipitated by stretching the limb and preceded by pain. Normal motor

Findings on investigations:

+NCS: axonal pattern in involved nerves

Pathology, nerve biopsy:

Endoneurium: increased connective tissue, fascicular Wallerian degeneration or inflammatory infiltrate

Related articles:

Nonhereditary Amyloid Neuropathy

Diseases,

Diagnosis:

Appropriate clinical features plus evidence of amyloid on biopsy

Clinical features:

Small fibre neuropathy +/-autonomic failure (see under small fibre neuropathy)

Findings on investigations:

NCS/EMG:

  • Normal
  • Or features of carpel tunnel syndrome

Pathology, sural nerve biopsy:

Eosinophilic deposits in the endoneurium and vessel walls
Congo red: apple green birefringence
Sirius red: stains amyloid red
Axonal loss
Loss of small fibres and preservation of large fibres may be seen
Can occur in systemic AL amyloidosis

Related articles:

Mycobacterium leprae Neuropathy

Diseases,

Synonyms:

a.k.a. Leprosy a.k.a. Hansen’s disease a.k.a. leprous polyneuritis

Diagnosis:

Clinical features of neuropathy plus evidence of Mycobacterium leprae infection

Clinical features:

Skin changes (hyperpigmentation, papule)
+loss of touch and pain (anesthesia)
Spared reflexes
Or multiple compression neuropathies (may mimic mononeuritis multiplex) in tuberculoid leprosy
Thickened nerves

Pathology, nerve biopsy:

Acid fast bacilli in perineurium
RPR: false positive

Treatment:

Dapsone, rifampin, clofazimine, thalidomide

Related articles:

HIV Neuropathy

Diseases, ,

Synonyms:

a.k.a. HIV associated polyneuropathy:

Diagnosis:

HIV infection with clinical features of neuropathy (many forms) with exclusion of other causese
Many forms:

  • CIDP, GBS, mononeuritis multiplex, sensory ataxic neuropathy, lumbosacral plexopathy, polyneuropathy

Clinical features:

Depends on the underlying subtype (see above)

Findings on investigations:

NCS/EMG, same as respective idiopathic forms
Note: Guillain-Barre Syndrome occurs at seroconversion, CIDP can also occur due to HIV

Pathology, nerve biopsy:

Nonspecific
Loss of axons

Related articles:

Heavy Metal Neuropathy and Solvent Neuropathy

Diseases, , ,

Diagnosis:

Neuropathy
+documented high heavy metal level
+improvement of symptoms/signs/NCS/EMG after withdrawal of agent

Clinical features:

Clinical features of neuropathy: may be motor neuropathy, sensori-motor polyneuropathy

Findings on investigations:

NCS/EMG:

  • Axonal pattern

Specific causes:

  • Lead neuropathy (see lead poisoning), Mercury (see mercury poisoning),
  • Others, arsenic, thallium, gold, N-Hexane inhalation

Related articles:

Alcohol Neuropathy

Diseases, , ,

It is unclear if alcoholism without associated nutritional deficiency can cause neuropathy

Clinical features:

Painful sensory polyneuropathy. Pain on light touch a.k.a. allodynia. Loss of ankle jerks
Improvement with withdrawal of alcohol and B1 supplementation

Related articles:

Chronic Renal Failure Neuropathy

Diseases, , ,

Synonyms:

a.k.a. uremic neuropathy

Diagnosis:

Clinical or electrodiagnostic features of neuropathy plus chronic renal failure and exclusion of other cause

Clinical features:

Distal sensorimotor neuropathy
+chronic renal failure
+resolves with dialysis or treatment of chronic renal failure

Findings on investigations:

EMG/NCS:

  • Distal Sensorimotor neuropathy
  • In some cases carpel tunnel syndrome

Pathology/Nerve biopsy:

Axonal loss

Related articles:

Hypophosphatemia Neuropathy

Diseases, , ,

Diagnosis:

Clinical features of neuropathy plus phosphate deficiency and exclusion of other causes

Clinical features:

Acute, Sensorimotor, areflexia, dysarthria
Phostphate levels: <2.4 mg/dl

Findings on investigations:

NCS/EMG:

  • Demyelinating pattern (Prolonged distal latencies, reduced conduction velocities) [case report]
  • In some cases axonal pattern [case reports]
  • F-waves absent
  • Decreased recruitment (neurogenic recruitment)

Pathology/Nerve biopsy:

Sub-perineural edema, mild axonal atrophy
Response to phosphate supplementation

Treatment:

Phosphate supplementation

Related articles:

Nutritional Deficiency Neuropathy

Diseases, , ,

Synonyms:

a.k.a. nutritional neuropathy

Diagnosis:

The diagnosis is based on clinical features of neuropathy supported by electrodiagosis and confirmation of nutritional deficiency with exclusion of other causes
+improvement of symptoms/signs/NCS/EMG after supplementation

Clinical features:

Usually features of polyneuropathy. Most commonly sensori-motor neuropathy
+documented deficiency

Findings on investigations:

NCS/EMG:

  • Usually Axonal pattern

Pathology, nerve biopsy:

Perineuritis can occur
Axonal loss can occur

Specific causes of nutritional neuropathy:

Hypophosphatemia neuropathy, B12 deficiency,
B1 beriberi
Axonal forms:

  • Folate deficiency
  • Niacin deficiency Pallegra
  • Pantothenic acid
  • Vitamin E (causes ataxia, ophthalmopelgia)

Related articles:

Charcot-Marie-Tooth disease CMT

Diseases, , ,
Synonyms:
  • Hereditary Motor and Sensory Neuropathy HMSN
  • Now the whole group is called Charcot-Marie-Tooth disease CMT

Diagnosis:

Clinical +electrodiagnostics (EMG/NCS) +Genetic testing:

Clinical features:

Abnormal LMN features: weakness
Atrophy: champagne-glass legs, stork legs
Deformity: claw toe, Friedreich’s foot, kyphoscoliosis
Sensory features: loss of vibration and later on loss of proprioception
Palpable nerves

Genetics:

CMT1 a.k.a. HMSN1 a.k.a. Charcot-Marie-Tooth CMT disease a.k.a. peroneal muscular artrophy, demyelinating:
CMT1 Autosomal dominant forms:

  • CMT1A: PMP22 gene chr. 17p11.2, peripheral myelin protein-22 PMP22
  • CMT1B: MPZ gene chr. 1q22, protein= myelin protein zero MPZ
  • CMT1C: LITAF gene chr. 16p13.3-p12
  • CMT1D: early growth response EGR2 gene chr. 10q21.1-q22.1,
  • CMT1E:
  • CMT1F: NEFL gene chr. 8p21, protein= Neurofilament light chain,

Dejerine-Sottas disease DSD a.k.a. HMSN3:

  • DSD A AD (AR) 17p11.2-12, protein PMP-22
  • DSD B AD (AR) 1q22-q23
  • DSD C AD 10q21-q22, Gene= EGR2

CMT1 AR: autosomal recessive forms (formerly CMT4):

  • CMT1 ARA (CMT4A) chr. 8q13 – 21.1. Gene= GDAP1
  • CMT1 ARB1 (CMT4B1) chr. 11q22. Gene=  MTMR2
  • CMT1 ARB2 (CMT4B2) chr. 11p15. Gene=  MTMR13
  • CMT1 ARC (CMT 4C) chr. 5q23-q33. Gene= KIAA1985
  • CMT1 ARD (CMT4D) chr. 8q24. Gene=  NDRG1
  • CMT1 ARE (CCFDN) chr. 18q
  • CMT1 ARF (CMT4F) chr. 19q13.1-13.3. Gene=  Periaxin
  • CMT1 ARG (HMSNR) chr. 10q22-q

CMT 1X i.e. CMT type 1 X-linked, demyelinating, X-linked. Xq13.1
CMT2 a.k.a. HMSN2, axonal:

  • CMT2 AD, Autosomal dominant forms:
    • CMT 2A AD, chr. 1p35. Gene=KIF1B. Protein= GTPase mitofusin 2
    • CMT 2B AD, chr.  3q13 – q22. Gene= RAB7
    • CMT 2C AD, chr.  12q23 – q24
    • CMT 2D AD, chr.  7p14. Gene= GARS
    • CMT2E AD: NEFL gene chr. 8p21, protein= Neurofilament light chain,
    • CMT 2F AD, chr.  7q11-q21. Gene= HSP 27
    • CMT 2G AD, chr.  12q12-q13.3
    • CMT 2L AD, chr.  12q24. Gene= HSP 22
    • CMT 2 AD, chr. 1q22-q23
  • CMT2 AR, autosomal recessive forms:
    • CMT2 AR, chr. 1q21.2 – 21.3. Gene= LMNA
    • CMT2 AR, chr. 19q13.1
    • CMT2 AR, chr. 8q21. Gene= GDAP1 3.
  • CMT 2X i.e. CMT type 2 X-linked, axonal, X-linked. Xq24-26

Pathology, nerve biopsy:

CMT1, CMTX:

  • Loss of myelinated fibres, affects all fascicles to the same extent
  • Onion bulb formation: demyelination and remyelination, except in young children
  • Increased size of fascicles

CMT2:

  • Nonspecific. Loss of axons

Investigations to consider:

EMG, NCS: axonal vs. demyelinating
Appropriate genetic testing

Related articles:

Acromegaly Neuropathy

Diseases, , ,

Diagnosis:

Clinical features of neuropathy plus diagnosis of acromegaly and exclusion of other causes

Clinical features:

Carpal tunnel syndrome, tarsal tunnel syndrome
Polyneuropathy

Findings on investigations:

NCS/EMG:

  • Carpal tunnel syndrome, tarsal tunnel syndrome
  • Polyneuropathy

Pathology, Nerve biopsy:

  • Initially: demyelination
  • Onion bulb formation in end stage

Related articles:

Cranial Neuropathies

Diseases, , ,

Here are some lists to help with the cranial neuropathies. Please see the underlying sections. Also see the section on vertigo for cranial nerve VIII diseases.

Synonyms:

Cranial neuropathy

Causes of Oculomotor nerve palsy (CN III): think of anatomy

Nuclear & fasciular:

  • Tumours: Glioma
  • Part of a brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar aneurysms
  • Posterior communicating artery PCOM aneurysm
  • Temporal lobe herniation (uncal herniation)

Cavernous sinus area:

  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma
  • Internal Carotid artery aneurysms
  • Cavernous sinus thrombosis
  • Mucormycosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vascular:
    • Vasculopathy: diabetes mellitus, hypertension & atherosclerosis, giant cell arteritis
  • Wegner’s granulomatosus
  • Hodgkin’s disease, VZV, encephalitis, collagen vascular disease, Paget’s disease
  • Trauma

Causes of trochlear nerve palsy (CN IV):

Nuclear & fasciular:

  • Tumours: glioma, medulloblastoma
  • Part of a Brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Trauma

Causes of abducens nerve palsy (CN VI):

Nuclear & fasciular:

  • Tumours: glioma
  • Part of a Brainstem stroke syndrome
  • Multiple sclerosis

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Petrous tip area:

  • Raised intracranial pressure ‘false localising sign’
  • Hydrocephalus
  • Mastoiditis
  • Nasophareygeal tumours, paranasal sinus tumours
  • Lateral sinus thrombosis

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis
  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Wegner’s granulomatosus

Causes of isolated facial nerve palsy (CN VII):

Upper motor neuron lesion:

  • Stroke, most common
  • Vasculitis
  • Syphilis
  • HIV

Lower motor neuron lesion:

  • Bell’s palsy a.k.a. Idiopathic (but HSV-1 is implicated), most common
  • VZV a.k.a. Herpes zoster, Ramsay Hunt Syndrome
  • Otitis media
  • Cholesteatoma
  • Tumours:
    • Cerebellopontine angle, acoustic or facial neuroma
    • Glomus tumour
    • Parotid tumour
  • Temporal bone fracture
  • Diabetes mellitus
  • Lyme disease
  • Sarcoidosis
  • Amyloidosis
  • AIDS
  • Sjogren’s syndrome
  • Lesions of the facial nucleus (usually affects other nerves as well)

Recurrent or bilateral lower motor neuron facial palsy:

  • Base of the skull tumour e.g. Lymphoma
  • Lyme disease
  • Sarcoidosis
  • Gullian-Barre syndrome
  • If immunocompromised, VZV

DDx. of bilateral facial palsy (compare with causes of bilateral facial palsy above):

  • Myasthenia gravis

Causes of cavernous sinus syndrome:

  • Sepsis
  • Tumour
  • Carotid artery aneurysms
  • Wegener’s granulomatosis

Causes of skull base syndromes including jugular foramen syndrome:

Intracranial:

  • Neoplastic:
    • Extension of cerebellopontine angle tumour
    • Meningioma
    • Cholesteotoma
    • Neurofibroma
  • Guillain-Barre syndrome & variants
  • Chronic tuburculosis
  • Syphilis
  • Diabetes mellitus

Skull:

  • Fractured base of the skull
  • Paget’s disease

Extracranial:

  • Neoplastic:
    • Lymphoma
    • Carotid body tumour
    • Glomus jugulare turmour
    • Nasopharyngeal carcinoma
    • Metastatic Squamous cell carcionoma, others
  • Jugular vein thrombosis
  • Carotid dissection

 

Diabetic Neuropathy

Diseases, , , ,

There are various types of diabetic neuropathy

Diabetic polyneuropathy (sensory type and sensorimotor type):

Diagnosis:

Features of polyneuropathy and meeting criteria for diabetes mellitus

Clinical features:

Symmetric sensory polyneuropathy, loss of vibration, pain, touch and temperature sensation and in some cases proprioception loss and Charcot joints
Areflexia
Painful
May become sensorimotor

Pathology, nerve biopsy:

Nonspecific
Loss of axons, hyalinization of perineurium and of vessels in the endoneurium

Treatment:

Improve glycemic control
Foot care
 

Autonomic diabetic neuropathy:

Diagnosis:

Features of autonomic neuropathy and meeting criteria for diabetes mellitus

Clinical features:

Usual features of autonomic neuropathy
 

Compression neuropathies:

Diagnosis:

Features of the compression mononeuropathy and meeting criteria for diabetes mellitus and exclusion of other causes

Clinical features:

Same as those caused by other local disease
 

Extraocular nerve palsies (III, IV and VI palsies):

Diagnosis:

Underlying features of the neuropathies

Clinical features:

Same as those caused by other local disease
 

Multifocal diabetic neuropathy a.k.a. Diabetic amyotrophy a.k.a. diabetic amyotrophy of Garland:

Diagnosis:

Features of lumbosacral plexopathy and meeting criteria for diabetes with exclusion of other causes

Clinical features:

Weight loss
Severe pain in femoral nerve and L4 distribution
Followed by weakness and wasting in the distribution of the femoral nerve and loss of Knee jerk
Also weakness in L2, L3 distribution occurs i.e. plexopathy

Pathology, nerve biopsy:

Multifocal loss of axons
Inflammation, lymphocytic of endoneurial and epineurial vessels
Immunohistochemsitry: CLA for lymphocytes
CSF: protein high
NCS: Asymmetrical, Axonal, multifocal,

Treatment:

Pain management
Control of glucose
 

Related articles:

 

Paraneoplastic Sensory Neuropathy

Diseases, ,

Diagnosis:

The diagnosis is made based on clinical features of neuropathy supported by electrodiagnostic testing and isolation of the underlying neoplasm

Clinical features:

Painful from: spontaneous pain and mechanical hyperalgesia i.e. painful sensation provoked or exacerbated by pinprick sensation a.k.a. pinprick hyperalgesia or gentle tactile stimulation a.k.a. allodynia
Ataxic form: Romberg positive, impaired vibration and proprioception
Usually asymmetric and only mild motor symptoms if present

Findings on investigations:

+NCS+EMG:

  • Sensory involvement>motor
  • Reduced or absent SNAPs. Prolonged sensory nerve conduction velocity SCV, motor conduction velocity MCV and distal latency

+CSF analysis: increased protein usually
+/-onconeuronal antibodies: anti-Hu antibodies positive in most. Anti CV2 positive in some
+evidence of an underlying cancer

Pathology:

Dorsal root ganglion damage: loss of large diameter sensory nerve cell bodies. Secondary degeneration of axons in the dorsal columns and peripheral nerves.
Sural biopsy: reduced large myelinated fibres and in some reduced small myelinated fibres.

Investigations to consider:

CT chest, abdomen, pelvis: lung cancer, ovarian cancer
Breast exam, mammography: breast cancer

Related articles:

Paraneoplastic Vasculitic Neuropathy PVN

Diseases, , ,

Synonyms:

or paraneoplastic neuromyopathy

Diagnosis:

A subtype of nonsystemic vasculitic neuropathy, requires features of neuropathy on clinical exam or electrodiagnostic studies plus evidence of vasculitis and underlying neoplastic disorder

Clinical features:

Weakness +/-sensory abnornalities, often with features of mononeuropathy multiplex

Findings on investigations:

+Nerve conduction studies +EMG:

  • Polyneuropathy or mononeuritis multiplex, axonal neuropathy
  • +/-evidence of myopathy

+CSF analysis: increased protein
+ESR: increased

Pathology, nerve biopsy:

Sural nerve or superficial peroneal nerve biopsy

  • Arterioles of the epineurium:
  • Inflammation: Infiltrate of lymphocytes
  • Necrosis of intima and media
  • Endothelial cell changes
  • Fibrinoid necrosis: a definite sign
  • Axons: loss of axons in the periphery of the fascicle i.e. subfascicular ischemic change
  • Clusters of demyelination/remyelination is consistent
  • Immunohistochemistry: CD3 for T cells

+/-muscle biopsy (peroneus brevis): perivascular infiltrate +/-perifasicular infiltrates
+evidence of an underlying cancer

Treatment:

Treat the underlying cancer
Immunosuppresion:

  • Prednisolone P.O. +cyclophosphamide I.V.

Related articles:

Nonsystemic vasculitic neuropathy NSVN

Diseases, , ,

Diagnosis:

This is based on clinical features +nerve/muscle biopsy findings of vasculitis +exclusion of systemic causes

Clinical features:

Clinical features: usually subacute, painful, distal, asymmetric,

Findings on investigations:

+Nerve conduction studies +EMG:

  • Axonal neuropathy

+CSF analysis: increased protein
+ESR: might be increased
+ANCA negative

Pathology, nerve biopsy:

Sural nerve or superficial peroneal nerve biopsy +/-muscle biopsy (peroneus brevis)

  • Arterioles of the epineurium:
    • Inflammation: Infiltrate of lymphocytes
  • Necrosis of intima and media
  • Endothelial cell changes
  • Fibrinoid necrosis: a definite sign
  • Axons: loss of axons in the periphery of the fascicle i.e. subfascicular ischemic change
  • Clusters of demyelination/remyelination is consistent
  • Immunohistochemistry: CD3 for T cells

Treatment:

Immunosuppression:

  • Prednisolone P.O. +cyclophosphamide I.V.

Related articles:

Systemic Vasculitic Neuropathy

Diseases, , ,

Diagnosis:

The diagnosis is made based on clinical features +Peripheral neuropathy, +evidence of vasculitis, +evidence of other organ involvement

Clinical features:

acute, mononuritis multiplex or less commonly mononeuritis simplex or symetric polyneuropathy, sensorimotor
+Peripheral neuropathy
+evidence of vasculitis
+evidence of other organ involvement

Findings on investigations:

+NCS/EMG:
NCS:

  • Axonal neuropathy
  • Conduction block: often transient
  • CMAP: reduced
  • Motor conduction velocity: normal or slightly reduced
  • SNAP: reduced

EMG: fibrillation potentials occasionally,

Pathology, nerve biopsy:

Sural nerve or superficial peroneal nerve biopsy

  • Arterioles of the epineurium:
    • Inflammation: Infiltrate of lymphocytes
  • Necrosis of intima and media
  • Endothelial cell changes
  • Fibrinoid necrosis: a definite sign
  • Axons: loss of axons in the periphery of the fascicle i.e. subfascicular ischemic change

Immunohistochemistry: CD3 for T cells

Related articles:

Anti-sulfatide Neuropathy

Diseases, , ,

Synonyms:

a.k.a. anti-chondroitin sulfate neuropathy:

Diagnosis:

The diagnosis is made based on clinical features supported by electrodiagnostic tests and antibodies

Clinical features:

Polyneuropathy (sensory, or sensorimotor, sensory>motor), ataxia may occur,

Findings on investigations:

Anti-sulfatide antibody (a.k.a. anti-chondroitin sulfate): positive, > 1:1000 titre
SPEP +IFE: usually have monoclonal IgM
NCS/EMG:

  • Mainly demyelinating pattern with secondary axonal loss

Related articles:

Anti-GALOP syndrome: Gait ataxia, autoantibody, late onset polyneuropathy

Diseases, , ,

Synonyms:

a.k.a. gait ataxia and polyneuropathy GAPN

Diagnosis:

Clinical features:

Late onset 70 year olds, gait ataxia (wide based with falls) and polyneuropathy (sensorimotor, sensory>motor, impaired proprioception)
Anti-GALOP (IgM against central myelin antigen a.k.a. galopin): positive,
SPEP +IFE: monoclonal IgM

Treatment:

Intravenous immunoglobulin IVIG
cyclophosphamide

Related articles:

Lymphoma Associated Neuropathy

Diseases, , ,

Diagnosis:

Clinical and electrodiagnostic features supported by isolation of lymphoma

Clinical features:

Sensorimotor neuropathy, polyradiculopathy in carcinomatous meningitis

Findings on investigations:

CSF analysis: cytology and flow cytometery in carcinomatous meningitis
NCS/EMG:

  • Sensorimotor neuropathy
  • Or polyradiculopathy in carcinomatous meningitis

Pathology revealing lymphoma:

  • Cytology, flow cytometery
  • Bone marrow biopsy
  • Lymphnode excitional biopsy

Pathology, Nerve biopsy:

Axonal neuropathy in carcinomatous meningitis

Related articles:

Anti-MAG syndrome

Diseases, ,

Diagnosis:

This is diagnosed by a combination of clinical features, NCS/EMG and antibodies

Clinical features:

Distal symmetric, sensorimotor (sensory> motor),

Findings on investigations:

Anti-MAG: positive, IgM against myelin associated glycoprotein MAG
SPEP +IFE: IgM paraprotein, monoclonal
NCS/EMG:

  • Distal slowing

Pathology/nerve biopsy:

Demyelination, axonal degeneration
IgM deposits at sites of MAG localisation
Immunohistochemsitry:

  • Immunofluorescence with Anti-immunoglobulin

Treatment:

Intravenous immunoglobulin IVIG, plasmapharesis
Cyclophosphamide

Related articles:

POEMS syndrome: Polyneuropathy Organomegally Endocrinopathy M protein and Skin changes

Diseases, ,

Diagnosis:

A paraneoplastic syndrome to osteoclastic plasmacytoma

Pathology:

Muscle actin stain; increased vessels in nerves
VEGF: elevated serum levels

Criteria/Features:

Polyneuropathy: Demyelinating sensorimotor polyneuropathy (motor>sensory), usually painless, length dependent
Monoclonal gammopathy: Serum protein electrophoresis with immunofixation IFE: M protein, Lambda light chain, immunofixation is necessary to avoid false negatives
Osteoclastic plasmacytoma i.e. note lytic
Skin changes
Endocrinopathy

Other features:

Peripheral edema

Treatment:

Corticosteroids or cyclophosphamide
Consider:

  • Irradiation of solitary osteosclerotic lesions
  • Stem cell transplantation

Related articles:

Polyeuropathy Associated with Paraproteinemia

Diseases, , ,

Diagnosis:

  • This is a category of different neuropathies.
  • Neuropathy due to a gammopathy includes anti-MAG syndrome, POEMS, cryoglobulinemia, IgM MGUS polyneuropathy, Anti-GALOP (IgM against central myelin antigen): Gait Disorder, Autoantibody Late-age Onset Polyneuropathy
  • Evidence of paraproteinemia e.g. SPEP: paraproteinemia

Pathology, nerve biopsy:

Light microscopy:

  • Nonspecific, loss of myelin and/or axons
  • No inflammation except in cryoglobulinemia
  • For cryoglobulinemia: features of vasculitic neuropathy

Immunohistochemsitry:

  • Immunofluorescence with Anti-immunoglobulin for anti-MAG syndrome

Electron microscopy EM:

  • Widened myelin lamellae IgM
  • Uncompacted myelin lamellae (POEMS)
  • Capillary deposits (cryoglobulinemia)

Treatment:

Options:

  • Plasma exchange
  • Prednisone
  • Intravenous immunoglobulin IVIG
  • Azathioprine
  • Cyclophosphamide

For IgM MGUS polyneuropathy:

  • Cyclophosphamide 500 mg P.O. once DAILY X4 days +prednisone 60 mg P.O. once DAILY X5 days, every 28 days for 6 treatments.

Related articles:

Multifocal Acquired Demyelinating Sensory And Motor neuropathy MADSAM

Diseases, ,

Synonyms:

Lewis Sumner syndrome LSS

Diagnosis:

Clinical features supported by +NCS/EMG

Clinical features:

Chronic, asymmetric, distal, sensorimotor, arms >legs, can affect cranial nerves

Findings on investigations:

NCS/EMG:

  • Multifocal conduction block in affected nerves,
  • Widespread sensory abnormalities: helps distinguish from MMN,
  • Asymmetric, helps distinguish it from CIDP
  • Serum anti-GM1 antibody: negative, helps distinguish from MMN

CSF: raised protein occasionally

Treatment:

Intravenous immunoglobulin IVIg 2 g/kg over 3–5 days once a month for 2 months,
Prednisolone 1 mg/kg/day for 4 weeks then taper for 6 weeks

Related articles:

Subacute Inflammatory Demyelinating Polyneuropathy

Diseases, ,

Synonyms:

a.k.a. subacute IDP

Diagnosis:

Clinical +NCS/EMG
Similar to Guillain Barre Syndrome GBS and Chronic inflammatory demyelinating polyradiculopathy CIDP but lasting 4-8 weeks.

Related articles:

Critical Care Neuropathy CIP

Diseases,

Synonyms:

a.k.a. critical illness polyneuropathy CIP

Diagnosis:

This is a clinical diagnosis supported by electrodiagnostic features

Clinical features:

Severely ill patient >1 week in ICU, acute weakness (distal initially), areflexia, flaccid tetraparesis, atrophy, difficulty weaning from ventilator,

Findings on investigations:

+NCS/EMG:

  • EMG/NCS: reduced CMAP amplitude, reduced SNAP amplitude, normal velocities, no conduction block, fibrillations.

NCS:

  • Axonal
  • CMAP: decreased amplitude, normal conduction velocity
  • SNAP: decreased or normal amplitude. Normal Sensory conduction velocity

EMG:

  • fibrillation potentials, positive waves

Other tests:

  • CSF: normal

Pathology:

Axonal loss
No inflammation in nerves

Treatment:

Prevention: Better glycemic control reduces risk of critical care neuropathy.

Related articles:

Idiopathic Lumbosacral Plexitis

Diseases, , ,

Synonyms:

Idiopathic Lumbosacral plexitis a.k.a. lumbosacral plexitis a.k.a. idiopathic neuralgic amyotrophy a.k.a. Lumbosacral plexopathy

Diagnosis:

The diagnosis is based on clinical features, electrophysiological findings and exclusion of competing causes.

Clinical features:

Lumbosacral distribution of pain followed by weakness
See lumbosacral plexopathy

Findings on investigations:

+EMG

  • Localises the lesion to the lumbar/sacral plexus
  • Localises the lesion (short head of biceps femoris, above or below the fibula)
  • Paraspinal muscles (no denervation, distinguishes this from radiculopathy)

Other tests:

  • CSF: protein high
  • ESR: may be high

Pathology, nerve biopsy:

Multifocal loss of axons
Inflammation, lymphocytic of endoneurial and epineurial vessels
Immunohistochemistry: CLA for lymphocytes

Investigations to consider: also see lumbosacral plexopathy

X-ray: fibula fracture
EMG/NCS
HIV testing
ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
CT abdomen and pelvis: rule out retroperitoneal hematoma or tumor

Treatment:

Consider:

  • Intravenous immunoglobulin IVIg
  • Plasmapheresis
  • Corticosteroids

Related articles:

Radiation Induced Plexopathies (Radiation Plexopathy)

Diseases, ,

Diagnosis:

The diagnosis is made based on findings of plexopathy clinically and on imaging supported by exclusion of other causes.

Clinical features:

Exposure to radiation, exclusion of other causes
Weakness, usually painless
Clinical fasciculations and myokymia may occur

Findings on investigations:

NCS/EMG:

  • Fasciculations and myokymia may occur
  • SNAP and CMAP: slowed conduction velocity is common

MRI and other imaging: to rule out recurrence of tumor

Forms:

Transient brachial plexopathy: acute onset within weeks to months, numbness and weakness
Late-delayed brachial plexopathy: onset months to years, numbness and weakness, usually painless,
Lumbosacral plexopathy: slowly progressive unilateral <bilateral leg weakness and sensory symptoms with no or very little pain,

Pathology:

Fibrous encasement of brachial plexus
Axonal loss

Related articles:

Heredofamilial Brachial Plexopathy

Diseases, , ,

Synonyms:

a.k.a. hereditary brachial plexus neuropathy a.k.a. hereditary neuralgic amyotrophy HNA, rare:

Clinical features:

Usually Painless
Attacks of weakness with recovery over weeks +some cranial involvement

Genetics:

Mapped to chr. 17q24-25
Autosomal dominant

Findings on investigations:

NCS/EMG: may be normal between attacks

Pathology, nerve biopsy:

Semithin plastic sections: Tomacula (sausage like excess myelin)
Teased fibres: Tomacula (sausage like excess myelin)

Related articles:

Carcinomatous Plexopathy

Diseases, ,

Diagnosis:

The diagnosis is confirmed by isolation of the causative neoplasm and electrophysiological and clinical findings

Clinical features:

Painful,
Features of brachial plexopathy or those of lumbosacral plexopathy:

  • Weakness in lower plexus C8, T1 distribution +atrophy
  • Associated with Horner’s syndrome
  • Asymmetric leg weakness, reduced reflexes

Findings on investigations:

NCS/EMG:

  • Denervation (fibrillations and positive sharp waves PSW) in affected muscles (usually lower plexus)
  • Decreased recruitment (Neurogenic recruitment)
  • SNAP Abnormal conduction velocities in ulnar and median or radial nerves is common
  • CMAP Abnormal conduction velocities in ulnar and median or radial nerves is common

MRI brachial plexus, infiltration by cancer or lumboscaral plexus infiltration by cancer
CT: lung cancer, retroperitoneal tumor
Mammography and breast exam: breast cancer

Related articles:

Acute Brachial Plexus Neuritis

Diseases, ,

Synonyms:

a.k.a. Parsonage-Turner syndrome formerly brachial neuralgic amyotrophy

Diagnosis:

This is a clinical diagnosis supported by electrophysiological findings and consistent imaging

Clinical features:

Brachial distribution of pain followed in 3-10 days by weakness and atrophy with areflexia
In some cases sensory loss may occur
May be bilateral

Findings on investigations:

+EMG:

  • Localised to brachial plexus, usually upper part,
  • After onset of paresis: fibrillation potentials, positive waves in affected muscles. Spares paraspinal muscles (distinguishes this from radiculopathies)
  • After recovery: giant polyphasic potentials

+NCS: Normal
MRI: T2 high signal in affected muscles

Investigations to consider:

LP with CSF analysis:

  • Cytology

VZV PCR and serology
HIV testing
NCS/EMG
MRI brachial plexus: to help exclude malignancy

Treatment:

Analgesia
Physiotherapy +/-sling
Consider steroids

Related articles:

Neurogenic Thoracic Outlet Syndrome

Diseases, ,

This is a type of cervical rib syndrome. There is a related vascular thoracic outlet syndrome.

Diagnosis:

The diagnosis is made by clinical and electrophysiological (NCS/EMG) and then imaging to identify the underlying case.

Clinical features:

  • Pain: C8 andT1
  • Sensory loss C8 and T1
  • Weakness: abductor pollicis brevis
  • Puling on the arm (down) reproduces sensory symptoms
  • Normal reflexes

Findings on investigations:

NCS:

  • Medial antebrachial cutaneous nerve: SNAP reduced or absent
  • Ulnar: SNAP reduced amplitude
  • Median nerve: SNAPs Spared

EMG:

  • More abnormalities on MEDIAN innervated muscles than ulnar innervated muscles: denervation (fibrillation potentials) reduced MUAP recruitment

X-ray: false negatives if due to cervical band
CT thorax: shows abnormal additional rib
MRI brachial plexus: assess for other lesions

Investigations to consider:

NCS/EMG
MRI brachial plexus
CT thorax

Treatment:

Surgery: excision of rib or band

Relate condition:

Vascular thoracic outlet syndrome:

Clinical features:

  • Raynauds phenomenon, ulcers and gangrene of digits, thrombosis of subclavian vein after exercise, edema and discolouration of hand
  • Adson’s test: decrease in pulse amplitude +symptoms on turning the head to the affected side with neck hyperextension and deep inhalation

Findings on investigations:

  • X-ray: false negatives if due to cervical band
  • CT: shows rib
  • MRI brachial plexus: assess for other lesions
  • CTA: aneurysm in rare cases

Related articles:

Autonomic Neuropathy

Diseases, ,

Synonyms:

Autonomic neuropathy/autonomic failure/autonomic dysfunction

Diagnosis:

Autonomic dysfunction may be central (CNS) or peripheral (PNS)

Clinical features:

Helps define distribution and extent of disease:

  • Sympathetic, parasympathetic
  • Adrenergic, cholinergic

Helps define presents of associated CNS disease
Helps define associated systemic disease

Autonomic function testing:

Baroreceptor function testing a.k.a. Cardiovagal testing by HR variability:
  • Beat to beat heart rate HR variation (the main test):
    • 60 second ECG monitoring, with 5 respiratory cycles (5s inspiration, 5s inspiration)
    • Expiration:inspiration ratio, E:I: 16-20 y.o. >1.23, 76-80 y.o. >1.05
    • Abnormal in parasympathetic dysfunction
  • HR response to the Valsalva manoeuvre a.k.a. Valsalva ratio, VR (another good test):
    • Recumbent patient maintains 30-50mmHg of pressure on exhalation into a bugle with air leak
    • VR= maximum HR with valsalva/minimum HR within 30 seconds of maximum
    • Abnormal in vagal disorders (Parasympathetic cardiovagal dysfunction)

Beat to beat BP respone to Valsalva manoeuvre: (tests the baroreceptor reflex)
HR and blood pressure BP response to standing
BP response to Hand Grip
HR response to IV phenyephrine

Neurochemical:

Plasma norepinephrine (noradrenaline) and epinephrine (adrenaline) supine and standing
Plasma norepinephrine (noradrenaline):

  • Undetectable in Dopamine beta-hydroxylase deficiency
  • Low in pure autonomic failure

Plasma dihydroxyphenylglycol DHPG

  • Undetectable in Dopamine beta-hydroxylase deficiency
  • Low in pure autonomic failure

Plasma epinephrine (adrenaline) and metanephrine

Sudomotor tests= Sympathetic cholinergic function testing:

Thermoregulatory sweat testing TST
Sympathetic skin response
Quantitative sudomotor-axon-reflex testing QSART

Imaging:

For cardiac innervation:

  • Cardiac SPECT MIBG, 123I- labelled Metaiodobenzylguanidine, 123I-MIBG:
  • Reduced uptake i.e. cardiac denervation. Normal i.e. intact cardiac innervation
  • PET scan

Cardiac denervation:

  • Pure autonomic failure PAF
  • Parkinson’s disease
  • Familial amyloidotic polyneuropathy FAP
  • Familial amyloidotic polyneuropathy FAP
  • Diabetes mellitus

Intact Cardiac innervation:

  • Multiple system atrophy
  • Autoimmune autonomic ganglionopathy

MRI: for features of associated CNS disease

Investigations to consider:

  • FBC
  • Fasting blood glucose/glucose tolerance test: diabetes mellitus
  • HIV testing
  • SPEP
  • Fat/rectal/gingival biopsy: Amyloidosis

Paraneoplastic antibodies:

  • Antineuronal (anti-Hu), anti neuronal nicotinic ACh receptors,  ANNA-1, Purkinje cell cytoplasmic antibodies PCA-2, collapsing response-mediator protein CRMP-5
  • Anti-P/Q type calcium channel

Screen for neoplasms:

  • CT thorax +abdomen: small cell lung cancer, pancreatic adenocarcinoma

Autoimmune conditions:

  • Schirmer test, Anti-Ro/SS-A, anti-La/SS-B,
  • Anti-rheumatoid factor,

Electrophysiology:

  • Nerve conduction studies NCS: Lambert Eaton syndrome

Autonomic function testing and Quantitative sensory testing
Genetic testing for autonomic neuropathies
Leukocyte alpha-galactosidase: Fabry disease

Causes of autonomic neuropathy:

Central:

Peripheral:

Related articles:

Radiculopathy

Diseases, ,

Diagnosis:

This is a clinical diagnosis supported by electrophysiological findings on NCS/EMG

Clinical features of radiculopathy in general:

  • Motor or sensory involvement restricted to the distribution of an isolated nerve root level e.g. C5 nerve rooth or L5 nerve root.
  • The motor involvement may include weakness, atrophy or rarely faciculations in a myotome distribution.
  • The sensory involvement is numbness, loss of pin-prick or temperature sensation in a dermatomal distribution.
  • Pain distribution is of less localizing value due to referred pain and non-dermatomal pain distribution patterns
  • The reflexes are reduced or absent in the affected dermatome

Findings on investigations:

Neurophysiology NCS/EMG:

  • Reduced CMAP amplitude may occur
  • SNAP is typically normal as the process is proximal to the distal root ganglion
  • Denervation and reinervation of paraspinal muscles of affected nerve root
  • Denervation and reinervation features in myotome of affected nerve root

NCS:

  • SNAP: normal amplitude, conduction velocity & latency i.e. disease proximal to the dorsal root ganglion
  • CMAP: usually normal, in some cases reduced amplitude may be seen. Normal conduction velocity & latency.
  • H-reflex (gastrocnemius-sleus): distinguishes S1 (abnormal H-reflex, side to side difference >1.5ms) & L5 (normal H-relfex) radiculopathies. H-reflex may be falsely negative & may be falsely positive in >60year olds.
  • F-waves: increased latency or absent. May be falsely normal.

EMG:

  • Can be falsely negative in pure sensory radiculopathy.
  • Fibrillations & positive sharp waves PSW in affected myotomes (starts in paraspinals, then in proximal & then distal muscles). In definitive diagnosis: paraspinal muscles & 2 muscles supplied by different nerves but the same myotome show the changes.
  • MUAP (if reinnervation occurs): long duration, polyphasic.
  • Recruitment: may have reduced recruitment.

MRI features of neuro-foraminal stenosis:

  • Perineural intraforaminal fat reduction
  • Compression of foraminal zone
  • Hypertrophic facet joint (degenerative)
  • Foraminal nerve root impingement/compression
  • Size and shape of foramen is reduced

Investigations to consider:

NCS/EMG
MRI:

  • May show the culprit lesion in cases of compression
    Is over-sensitive and may show lesions that are not clinically responsible for the symptoms
  • C-spine: degenerative disc disease, disc herniation, trauma
  • L-spine: degenerative disc disease, disc herniation (rare above L5), meningioma, neurofibroma, lipoma, metastasis

LP for CSF: Subarachnoid seeding, intrathecal metastasis/carcinomatous meningitis
CT-myelography: Subarachnoid seeding, intrathecal metastasis/carcinomatous meningitis, disc herniation, osteophytes
CT: causative lesions, false negatives with disc disease
X-rays: may be falsely negative

Individual radiculopathies:

C4 radiculopathy:

Motor: none
Sensory: shoulder, upper arm,
Pain: neck
Reflex: none

C5 radiculopathy:

Motor: Shoulder abduction, elbow flexion
Sensory: lateral arm
Pain: Neck, shoulder, scapula, anterior arm
Reflex: loss of biceps & brachioradialis

C6 radiculopathy:

Motor: elbow flexion (with hand midprone & supine), shoulder abduction
Sensory: thumb, index finger, radial forarm
Pain: neck, shoulder, anterior upper arm, antecubital fossa
Reflex: loss of biceps & brachioradialis

C7 radiculopathy:

Motor: elbow extension, wrist extension, wrist flexion, shoulder adduction
Sensory: middle finger +/-dorsal & lateral forearm
Pain: neck, shoulder, dorsum of the forearm
Reflex: loss of triceps reflex

C8 radiculopathy:

Motor: finger flexion,
Sensory: medial hand (ring little finger & hypothenar eminence)
Pain: neck, shoulder, ulnar forearm
Reflex: none

T1 radiculopathy:

Motor: small hand muscles
Sensory: ulnar forearm
Pain: neck, shoulder, ulnar arm
Reflex: none

L1 radiculopathy:

Motor: none
Sensory: inguinal
Pain: inguinal pain
Reflex: none

L2 radiculopathy:

Motor: hip flexion
Sensory: anterior upper, middle & lateral thigh
Pain: anterior thigh & leg
Reflex: none

L3 radiculopathy:

Motor: hip flexion, hip adduction, knee extension
Sensory: medial thigh, knee
Pain: anterior thigh, groin, leg
Reflex: loss of adductor reflex

L4 radiculopathy:

Motor: Mild knee extension, hip adduction, ankle dorsiflexion
Sensory: medial calf & medial foot
Pain: anterior thigh, anterior & medial leg
Reflex: loss of knee reflex

L5 radiculopathy:

Motor: large toe extension, hip abduction, ankle inversion
Sensory: dorsum of the foot, large toe & lateral calf
Pain: posterior & lateral thigh & calf, large toe, dorsum of the foot
Reflex: internal hamstring reflex

S1 radiculopathy:

Motor: ankle plantar flexion, toe curling
Sensory: sole of the foot, lateral foot, posterior calf
Pain: posterior & lateral thigh & calf, lateral toes, heel
Reflex: loss of ankle reflex & biceps femoris reflex (lateral hamstring reflex)

S2-4 radiculopathy:

Motor: none
Sensory: posterior thigh S2, behind the knee S2, medial buttocks S3, perineum S3-4, perianal S4
Pain: medial buttocks
Reflex: bulbocavernosus, anal wink

Cauda equina syndrome:

A combination of nerve roots L1-S4
Lateral cauda equina syndrome: L4, L3, L2
Medial cauda equina syndrome from inside a.k.a. conus lesion: S5, S4 ,S3
Medial cauda equina syndrome from outside: bilateral S2,S3, L2, L3
 

Related articles:

References:

  1. Mamisch N, Brumann M, Hodler J, Held U, Brunner F, Steurer J; Lumbar Spinal Stenosis Outcome Study Working Group Zurich. Radiologic criteria for the diagnosis of spinal stenosis: results of a Delphi survey. Radiology 2012; 264:174–179
  2. Gustav Andreisek G, Imhof M, Wertli M, Winklhofer S, Pfirrmann C, Hodler J, Steurer J; Lumbar Spinal Stenosis Outcome
  3. Study Working Group Zurich.  A Systematic Review of Semiquantitative and Qualitative Radiologic Criteria for the Diagnosis of Lumbar Spinal Stenosis. AJR 2013; 201:W735–W746

Polyradiculopathy

Diseases, ,

Synonyms:

Polyradiculoneuropathy

Diagnosis:

The diagnosis is clinical supported by electrophysiological studies (NCS/EMG)

Clinical features:

A syndrome with involvement of multiple nerve roots and peripheral nerves. Usually equal proximal and distal weakness with reduced reflexes

Findings on investigations:

+NCS:

  • Symmetrical i.e. <50% difference between sides
  • Decreased SNAP
  • Decreased CMAP
  • Motor conduction velocities: mild decrease (remaining >75% of lower limit of normal),
  • Distal latencies: normal or <25% increase
  • F-waves: normal or <25% increase

+EMG:

  • Denervation in paraspinal muscles and distally,

Investigations to consider:

  • NCS/EMG
  • MRI L-spine: lumbar spinal stenosis, compression in cauda equina syndrome
  • CSF analysis including cytology: Guillain-Barre syndrome, CIDP, carcinomatous meningitis
  • HIV testing
  • Lyme serology
  • CMV serology
  • Anti-ganglioside antibodies

 

Causes of polyradiculopathy:

Immune:

Neoplastic:

Infectious:

  • CMV polyradiculitis
  • Lyme disease polyradiculitis

Compressive:

Others:

Related articles:

Brachial Plexopathy

Diseases, ,

Diagnosis:

The diagnosis is made based on clinical features supported by neurophysiology (NCS/EMG)

Findings on investigations:

Neurophysiology (NCS/EMG)

SNAP:

  • More sensitive than CMAP
  • Normal conduction velocity and distal latency
  • Decreased amplitude in affected nerve (may be normal initially).

CMAP:

  • Indicates severe injury
  • Decreased amplitude
  • Conduction block distal to Erb’s point (i.e. amplitude is reduced at Erb’s point and increased distally) may occur
  • Slowing of conduction velocity at Erb’s point indicates demyelinating lesion

F-wave: nonspecific
EMG:

  • Fibrillations and Positive Sharp Waves PSW in denervated muscles
  • If reinnervation has occurred: MUAP shows decreased recruitment, long duration, increased amplitude, polyphasia
  • Paraspinal muscles are normal (dorsal rami supply these)
Upper trunk:

SNAP: affected amplitudes

  • Lateral antebrachial nerve
  • Median nerve to 1st digit
  • Radial

CMAP:

  • Musculocutaneous nerve to Biceps
  • Suprascapular nerve to supraspinatus
  • Axillary nerve to deltoid

EMG:

  • Involvement of: supraspinatus, biceps, pronator teres, deltoid, brachial
Middle trunk:

SNAP: affected amplitudes

  • Median nerve to 3rd digit and 4th digit

CMAP:

  • Radial nerve to extensor digitorum communis

EMG:

  • Involvement of: Latissimus dorsi, teres major, extensor digitorum communis, pronator teres, flexor carpi radialis
Lower trunk:

SNAP:

  • Ulnar nerve to 5th digit
  • Medial antebrachial

CMAP:

  • Ulnar nerve to adductor digiti minimi
  • Median nerve to abductor pollicis brevis

EMG:

  • Involvement of: abductor digiti minimi, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum
Lateral Cord:

SNAP: affected amplitudes

  • Lateral antebrachial nerve
  • Median nerve to 1st digit

CMAP:

  • Musculocutaneous nerve to biceps

EMG:

  • Involvement of: Biceps, pronator teres, flexor carpi radialis, Pectoralis
  • Sparing of: Suprapinatus, infraspinatus, levator scapulae
Posterior Cord:

SNAP: reduced amplitudes in

  • Radial

CMAP:

  • Axillary nerve to deltoid
  • Radial nerve to extensor carpi ulnaris

EMG:

  • Involvement of: Latissimus dorsi, teres major, deltoid, radial muscles
Medial Cord:

SNAP:

  • Ulnar nerve to 5th digit
  • Medial antebrachial nerve

CMAP:

  • Ulnar nerve to abductor digiti minimi
  • Median nerve to abductor pollicis brevis

EMG:

  • Involvement of: Ulnar muscles, flexor digitorum superficialis, flexor pollicis longus, abductor pollicis brevis,

Investigations to consider:

  • CT neck and thorax: cervical rib
  • MRI brachial plexus,
  • NCS/EMG: rule out radiculopathy

 

Causes of brachial plexopathy:

Compressive/traumatic/radiation:

Immune:

Infectious:

  • Herpes Zoster plexitis, neuritis and ganglionitis

Neoplastic:

Hereditary:

Related articles:

Congenital Myasthenic Syndromes

Diseases,

Classification:

Presynaptic:

  • Choline Acetyltransferase

Synaptic:

  • Endplate acetylcholinesterase AChE deficiency

Postsynaptic:

  • AChR deficiencies
  • AChR kinetic abnormalities (slow & fast channel syndromes)
  • Rapsyn mutation

Diagnosis:

In general:

  • AChR antibodies: negative
  • Genetic testing confirms the diagnosis
Clinical features:

At birth or <2 y.o.:

  • Respiratory and feeding difficulties
  • Ocular symptoms (ptosis impaired movements)

NCS/EMG:

  • RNST: decrement in amplitude CMAP
  • Single fibre EMG: increased jitter +transmssion blocking
  • Single supramaximal stimulus: repetitive motor evoked responses
Genetics:

Autosomal dominant, autosomal recessive

AChR Slow channel syndrome:

Clinical features:

  • Limb weakness, spares ocular and oropharynx

Genetics:

  • AChR mutations: 56 mutations, alpha, beta, epsilon subunits

Electrophysiology, NCS/EMG:

  • Repetition CMAP: second peak (after potential)
AChR fast channel syndrome:

Response to ACh is reduced (lower affinity)
Activation episodes are short in duration

Rapsyn mutation:

RAPSN gene, chr. 11p11.2-p11.1. Rapsyn protein.

Dok-7 mutations:

Autosomal recessive
DOK7 gene Chr. 4, Dok-7 protein

Related articles:

Neonatal Myasthenia

Diseases, ,

Diagnosis:

Myasthenia in a new born to a mother with myasthenia gravis
AChR antibodies: positive

Clinical features:

Weakness, hypotonia, dysphagia, weak cry and suck,
Edraphonium/Tensilon test positive
Mother with myasthenia gravis

Treatment:

Neostigmine
Rarely plasma exchange

Related articles:

Clostridium tetani (tetanus)

Diseases,

Diagnosis:

This is a clinical diagnosis supported by electrophysiological features

Clinical features:

Tetany: lockjaw (trismus), wrinkled forehead (frontalis), closed eyes (orbicularis oculi), retracted lips (resus sardonicus), contracted bulbar muscles, neck, limbs, rigidity, board-like abdomen
Spasms: opsotonos, paroxysms of contraction, pharyngeal/laryngeal spasms,
Diaphoresis, BP swings
Localised tetany: rigidity and spasms localised to one part of the body, near a wound. If localised to the head it’s called cephalic tetanus

Findings on investigations:

NCS/EMG:

  • Spasm: Continuous discharges of normal motor units
  • Loss of physiologic silent period after contraction (50-100ms). Best found in masseter.

CK: normal or slightly raised

Treatment:

Antitoxin (tetanus immune human globulin)
Penicillin 10days, Metronidazole or tetracycline
Treatment of the wound
Support:

  • Airway management
  • Neuromuscular blocking agent
  • Benzodiazepines

Related articles:

Clostridium botulinum neurotoxin (Botulism)

Diseases,

Diagnosis:

The diagnosis is by clinical features supported by neurophysiology and confirmed by toxin testing

Clinical features:

Types: Wound botulism, infant botulism, food botulism,
Descending weakness (ocular opthalmoplegia then pharyngeal then limbs)
Loss of pupil accommodation, constipation, ileus
Reflexes reduced or absent
Normal sensation

Findings on investigations:

NCS/EMG:

  • RNST at 20 and 50 Hz: incremental response.
  • CMAP: low amplitude
  • Sensory conduction: Normal
  • EMG, motor unit action potentials MUAP: short duration, low amplitude
  • SFEMG single fibre EMG: increased jitter and blocking

Toxin testing for confirmation:

  • Serum botulinum toxin
  • Food botulinum toxin assay
  • Stool: toxin, in infants consider organism culture

Treatment:

Consider respiratory support
Trivalent antitoxin ABE. Note: current antitoxin is made in horses and associated serum sickness. Usually not needed in infants
Guanidine hydrochloride
Inform health authorities
Wound botulism:

  • Penicillin
  • Surgical debridement

Related articles:

Lambert Eaton Myasthenic Syndrome LEMS

Diseases,

Synonyms:

LEMS a.k.a. Myasthenic syndrome

Diagnosis:

The diagnosis is made by a combination of clinical features, autoantibodies and electrophysiology

Clinical features:

  • Proximal weakness (shoulder and pelvic) and neck muscle weakness
  • Improve with exercise, sometimes this is not clinically detectable
  • Reduced or absent reflexes
  • Cholinergic autonomic failure (dry mouth, constipation, impotence, decreased sweating, blurred vision)

Findings on investigations:

RNST Repetitive nerve stimulation test:

  • at 3 Hz: decremental response
  • at 20-50 Hz: potentiation of response i.e. facilitation
  • Post exercise: potentiation of response i.e. facilitation
  • Anti P/Q VGCC antibodies (Voltage gated Ca++ channel antibodies)

Investigations to consider:

Extensive to rule out cancer

Treatment:

Treat or remove tumor
Consider:

  • Immunosuppresion:
    • Prednisolone
    • Azathioprine
    • Ciclosporin
  • Immunomodulation:
    • IVIg or Plasmaphoresis
  • Cholinergic drugs:
    • 3,4-diamiopyridine
    • 4-aminopyridine
    • Guanidine hydrochloride side effects: renal failure, bone marrow suppression
    • Antiacetylcholinesterase

Avoid:

  • Drugs that block the neuromuscular junction
  • Ca++ channel blockers

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Mononeuropathy Multiplex

Diseases,

Synonyms:

Mononeuropathy multiplex a.k.a. mononeuritis multiplex

Diagnosis:

This is a clinical plus electrophysiological diagnosis

Clinical features:

a syndrome with involvement of at least two separate nerves. Usually sensorimotor.

Findings on investigations:

+NCS:

  • Axonal, asymmetrical i.e. >50% difference between sides, distribution of multiple separate nerves
  • Decreased SNAP
  • Decreased CMAP
  • Motor conduction velocities: mild decrease (remaining >75% of lower limit of normal),
  • Distal latencies: normal or <25% increase
  • F-waves: normal or <25% increase

+EMG:

  • Denervation, axonal, multifocal

Investigations to consider:

  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Anti-GM1: multifocal motor neuropathy
  • ACE levels and Ca++: raised in sarcoidosis
  • Lyme serology, HIV serology

Nerve biopsy:

  • Vasculitis, leprosy

Causes of Mononeuropathy multiplex a.k.a. mononeuritis multiplex:

Vasculitis: (axonal), common

  • Rheumatoid arthritis (axonal)
  • SLE, systemic sclerosis
  • Polyarteritis nodosa
  • Wegener’s granulomatosis
  • Cryoglobulinemia (rare)

Infections:

  • HIV(axonal)
  • Lyme disease
  • Mycobacterium leprae (Leprosy)

Demyelination:

  • Mutifocal form of CIDP (demyelinating)
  • Multifocal motor neuropathy MMN (demyelinating)

Others:

  • Diabetes mellitus, common
  • Sarcoidosis, rarely
  • Amyloidosis
  • Hypereosinophilia syndrome
  • Sickle cell disease
  • Subacute asymmetric idiopathic polyneuropathy
  • Migrant sensory neuritis a.k.a. Wartenberg’s disease (pure sensory, axonal)

Causes of mononeuritis multiplex with lymphocytic meningitis:

  • Lyme Neuroborreliosis
  • Neurosarcoidosis
  • Zoster sine herpete
  • Uveo-meningeal syndromes

Related articles:

Neuromuscular Junction Disorders NMJ

Diseases

Please start with the section on neuromuscular disease patterns for an introduction. Also see the section on the approach to weakness. Here are some notes on neuromuscular junction diseases that may be of interest prior to reading about the individual diseases.
 

Clinical features of neuromuscular junction disorders:

  • No atrophy
  • Normal or reduced tone
  • Weakness: patchy i.e. doesn’t conform to an anatomic structure, fluctuation with time & exercise i.e. fatigability
  • Normal or depressed reflexes
  • No sensory changes
  • Fatigability of weakness or facilitation of power. Weakness that gets worse or better with muscle exertion.

 

Causes of weakness due to interruption of the neuromuscular junction:

Autoimmune Myasthenic syndromes :

Congenital myasthenic syndromes, rare :

  • Presynaptic:
    • Choline Acetyltransferase
  • Synaptic:
    • Endplate acetylcholinesterase AChE deficiency
  • Postsynaptic:
    • AChR deficiencies
    • AChR kinetic abnormalities (slow & fast channel syndromes)
    • Rapsyn mutation

Infective NMJ disorders:

Toxic NMJ disorders:

  • Aminoglycosides

Small Fibre Sensory Neuropathy SFSN

Diseases,

Synonyms:

Small fibre sensory neuropathy SFSN a.k.a. small fibre neuropathy SFN

Clinical features:

  • Small fibre involvement:
    • Neuropathic pain; allodynia, hyperalgesia
  • Reduced sensation to pin prick and temperature.
  • Absence of large fibre involvement: light touch, vibratory, proprioceptive sensory loss or absent deep tendon reflexes
  • Normal motor exam

Findings on Investigations:

+Electrodiagnosis NCS (sensory +motor +F waves) +/-EMG:

  • Normal

+Quantitative sensory testing QST:

  • Abnormal
  • This is used to determine the patients threshold for sensory stimuli (pain, cold, warm and vibration sensation) and comparing them to normative data.

+Skin biopsy:

  • Immunohistochemistry: polyclonal anti-protein-gene-product 9.5 antibodies (this stains nerve fibres in the skin) to assess Intra-Epidermal nerve fibre density IENF: reduced.

Na channel mutations in small fiber neuropathy

Investigations to consider:

  • Fasting blood glucose, HBA1c, TFTs, Lipid profile, ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Infection tests: influenza, HIV
  • Paraneoplastic tests: anti-Hu Antibodies
  • Test for amyloidosis e.g. sural nerve biopsy.
  • Consider:
    • Autonomic neuropathy testing
    • Genetic testing for hereditary amyloid neuropathies

 Related articles:

References:

  • Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, Kincaid JC, Ochoa JL, Parry GJ, Weimer LH; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003 Mar 25;60(6):898-904.

Polyneuropathy

Diseases, ,

Synonyms:

Distal symmetric polyneuropathy

Diagnosis:

This is a clinical diagnosis supported by electrophysiologic (nerve conduction studies and electromyography) testing. The underlying cause may be determined based on blood tests and other testing.

Clinical features:

  • Subtypes: sensory, senosrimotor, autonomic or combination. It may be axonal or demyelinating. Axonal forms are more common.
  • Typical features: Distal symmtric polyneuropathy is usually sensorimotor (affects both sensory and motor nerves), usually affects the distal parts of the extremities first. This may co-exist with small fibre neuropathy and with autonomic neuropathy.
  • The sensory component is usually more prominant than the motor component, but motor predominant types exist.
  • Sensory dysfunction in polyneuropathy:
    • All sensory modalities may be affected in a stocking and glove distribution
    • Prioprioception loss is usually the last modality to be affected
    • Patients may report neuropathic pain, cuts or paresthesias.
    • In hereditary causes the patients rarely report paresthesias
  • Motor dysfunction in polyneuropathy:
    • Tends to affect the distal muscles first
    • Tends to be milder than sensory findings, although motor predominant forms exist
  • Reflexes:
    • These are typically reduced or absent. They are more likely to be absent in demyelinating forms.

Findings on investigations for polyneuropathy in general:

Nerve conduction studies and electromyography NCS/EMG:

  • Protocol should include NCS (sensory +motor +F waves) +/-EMG:
  • Abnormality (>99th or <1st percentile) in two nerves
  • Must include the sural nerve
  • If the patient has normal sural (sensory) and peroneal nerve (sensory/motor) conductions then there is no evidence for polyneuropathy: helps exclude the diagnosis but can not exclude small fibre neuropathy

+Skin biopsy:

  • Immunohistochemistry: polyclonal anti-protein-gene-product 9.5 antibodies (this stains nerve fibres in the skin) to assess Intra-Epidermal nerve fibre density IENF: reduced.
  • If reduced neuropathy is present. If not reduced neuropathy is still possible
  • Helps diagnose co-existent small fibre sensory neuropathy SFSN

Investigations to consider for polyneuropathy in general:

1st line tests:

Nerve conduction studies and electromyography NCS/EMG
If axonal:

  • See patterns below

If demyelinating:

  • See patterns below

1st line blood tests:

  • Fasting blood glucose FBG +/-GTT, B12 level, methylmalonic acid level, Serum protein electrophoresis SPEP and immunoelectrophoresis (immunofixation IFE)
  • FBC, Basic metabolic panel, Creatinine, LFTs, TFTs, ESR
  • LFTs, Phosphate: hypophosphatemia neuropathy

Other tests:

  • Urinalysis: glucose, protein
  • CXR: sarcoidosis
2nd line tests:
  • HIV testing
  • Serum ACE
  • Coeliac disease (gluten neuropathy) antibodies: Antigliadin Ab, antimyelin Ab
  • Syphilis serology, Rheumatoid factor
  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Lyme disease serology, West nile virus serology Hepatitis serology: hepatitis B, hepatitis C
  • Antibodies:
    • Anti-GM1 Ab (multifocal motor neuropathy), anti-MAG Ab (myelin-associated glycoprotein),
    • Anti-GALOP (IgM against central myelin antigen): Gait Disorder, Autoantibody Late-age Onset Polyneuropathy
    • Anti-sulfatide a.k.a. anti-Chondroitin sulfate
    • Anti neuronal antibodies (a.k.a. ANNA-1, anti Hu), anti Yo
  • Cryoglobulins
  • Testing for acromegaly

CSF analysis: IgG index, oligoclonal bands

  • Urine:
    • Bence Jones proteins
    • 24hr urine collection for heavy metal analysis
    • Fresh urine for porphyria

Pathology, biopsies:

  • Lip biopsy: Sjogren syndrome
  • Hair and fingernail clippings for arsenic

Nerve biopsy:

  • Mononeuritis multiplex: vasculitis
  • Sarcoidosis
  • Amyloid neuropathy
  • Leprosy
  • Atypical cases of CIDP
  • Lymphomatous neuropathy (neurolymphomatosis)

Muscle biopsy: see denervation atrophy
Imaging:

  • CT thorax, abdomen, pelvis: small cell carcinoma, ovarian cancer
  • MRI neurography: if NCS/EMG show a localised problem

Genetic testing in polyneuropathy:

  • Demyelinating:
    • AD: PMP22 duplication, PMP22 mutation, (PMP22 is the commonest genetic cause of demyelinating peripheral neuropathy), MPZ mutation
    • X-linked: GJB1 mutation
  • Axonal:
    • AD: MPZ mutation, MFN2 mutation
    • X-linked: GJB1 mutation

 

Classification of distal symmetric polyneuropathy based on clinical and electrodiagnostic pattern:

  • Mixed axonal and demyelinating sensorimotor neuropathy
  • Axonal sensorimotor neuropathy and axonal motor neuropathy
  • Uniform demyelinating neuropathy
  • Acquired Demyelinating neuropathy (sensorimotor) ADN a.k.a. segmental demyelinating neuropathy (sensorimotor)
  • Pure sensory neuropathy (includes sensory ganglioneuronopathy)
  • Small fibre sensory neuropathy SFSN a.k.a. small fibre neuropathy SFN

 

Mixed axonal and demyelinating sensorimotor neuropathy:

NCS:

  • SNAP: reduced amplitude, decreased sensory conducting velocity
  • CMAP: decreased amplitude, decreased motor latency, decreased motor conduction velocity. Mild temporal dispersion may occur.

EMG:

  • Fibrillation and Positive sharp waves PSW in distal muscles.

Investigations to consider:

  • Fasting blood glucose +/-Glucose tolerance test GTT, HbA1c, basic metabolic panel,
  • TFTs, B12, SPEP

 

Axonal sensorimotor neuropathy and axonal motor neuropathy:

NCS:

  • SNAP: reduced amplitude, normal sensory conduction velocity
  • CMAP: reduced amplitude, normal motor latency, normal motor conduction velocity, no temporal dispersion

EMG:

  • Fibrillation and Positive sharp waves PSW in distal muscles.

Investigations to consider:

  • Fasting blood glucose, B1, B12, SPEP, TFT, B6, LFTs (liver disease)
  • Alcohol levels
  • Coeliac disease (gluten neuropathy) antibodies
  • ANA, ANCA, ENA (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere),
  • Lyme serology
  • CXR and ACE level: elevated in sarcoidosis
  • Heavy metal screen: thalium, mercury, gold, lead
  • Paraneoplastic screen
  • CT chest, abdomen, pelvis: underlying neoplasm
  • Nerve biopsy: sarcoidosis,
  • Porphyria testing
  • CSF: increased protein in Axonal Guillain-Barre syndrome
  • CMT Axonal forms

 

Uniform demyelinating neuropathy:

NCS:

  • SNAP: normal amplitude, latency may be increased, conduction velocity may be reduced
  • CMAP: normal amplitude, increased distal latency, reduced conduction velocity
  • No conduction block, no temporal dispersion

EMG:

  • Normal

Investigations to consider:

  • CMT demyelinating subtypes
  • Metachromatic leukodystrophy
  • Krabbe’s disease
  • Adrenomyeloneuropathy
  • Tangier’s disease
  • Cerebrotendinous xanthomatosis

 

Acquired Demyelinating neuropathy (sensorimotor) ADN a.k.a. segmental demyelinating neuropathy (sensorimotor):

*This is an important pattern since many of the causes are treatable
NCS:

  • SNAP: normal or slightly decreased amplitude, decreased sensory conduction velocity
  • CMAP:
    • Conduction block, decreased amplitude may be seen with this
    • Temporal dispersion
    • Increased motor latency, decreased conduction velocity

EMG:

  • Normal

Investigations to consider:

  • CSF: raised protein in CIDP, AIDP
  • SPEP with IFE: osteosclerotic myeloma
  • Tests for CIDP, AIDP
  • Nerve biopsy: Leprosy, CIDP features
  • Arsenic levels: arsenic neuropathy
  • Consider anti-GM1 IgM: multifocal motor neuropathy

 

Pure sensory neuropathy (includes sensory ganglioneuronopathy):

Clinical features:

  • Large fibre involvement:
    • Light touch, vibratory, proprioceptive sensory loss or absent deep tendon reflexes
  • Small fibre:
    • Neuropathic pain; allodynia, hyperalgesia
    • Reduced sensation to pin prick and temperature.
  • Normal motor exam

NCS:

  • SNAP: absent/reduced amplitude, normal sensory conduction velocity
  • CMAP: normal amplitude, normal motor latency, normal motor conduction velocity, no temporal dispersion

EMG:

  • Normal

Investigations to consider:

  • B12
  • B6 levels: high/toxicity
  • Paraneoplastic screen
  • CT chest, abdomen, pelvis: underlying tumor
  • CMT some subtypes
  • Friedrich’s ataxia
  • Spinocerebellar ataxia
  • Abetalipoproteinemia
  • SS-A, SS-B: Sjogren’s syndrome
  • Miller-Fisher variant of Guillain-Barre syndrome
  • SPEP +IFE: paraproteinemia
  • Nerve biopsy: amyloidosis, lymphomatous neuropathy

 

Small fibre sensory neuropathy SFSN a.k.a. small fibre neuropathy SFN:

Clinical features:

  • Small fibre involvement:
  • Neuropathic pain; allodynia, hyperalgesia
  • Reduced sensation to pin prick and temperature.
  • Absence of large fibre involvement: light touch, vibratory, proprioceptive sensory loss or absent deep tendon reflexes
  • Normal motor exam

+Electrodiagnosis NCS (sensory +motor +F waves) +/-EMG:

  • Normal

+Quantitative sensory testing QST:

  • Abnormal

+Skin biopsy:

  • Immunohistochemistry: polyclonal anti-protein-gene-product 9.5 antibodies (this stains nerve fibres in the skin) to assess Intra-Epidermal nerve fibre density IENF: reduced.

Na channel mutations in small fiber neuropathy
Investigations to consider:

  • Fasting blood glucose, HBA1c, TFTs, Lipid profile, ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Infection tests: influenza, HIV
  • Paraneoplastic tests: anti-Hu Antibodies
  • Test for amyloidosis e.g. sural nerve biopsy.
  • Consider:
    • Autonomic neuropathy testing
  • Also see; Tangier disease (high density lipoprotein HDL deficiency), amyloid neuropathy
  • Sensorimotor neuropathy SMN:
    • See under generalised above and under axonal sensorimotor neuropathy and demyelinating sensorimotor neuroapthy

Treatment:

  • Treat the underlying cause
  • Supportive measures and treat complications
  • General measures:
    • Skin care to prevent ulcers
    • Prevention of contractures
    • Protection from minor trauma and burns
  • Monitor respiration function:
    • Forced vital capacity FVC, negative inspiratory force NIF in AIDP
  • Treat orthostatic hypotension if present
  • Treat neuropathic pain if present

 

Causes of polyneuropathy (brief list):

Axonal:

  •  Acute:
    • Porphyria
    • Toxins
    • Axonal form of Guillain Barre syndrome
  •  Subacute:
    • Metabolic and Toxic
  •  Chronic:
    • Metabolic and Toxic
    • Hereditary
    • Diabetic
    • Dysproteinamia

Demyelinating:

Causes of peripheral neuropathy and polyneuropathy (long list):

Immune:

Paraneoplastic:

Endocrine, nutritional and metabolic related:

Toxic:

Infectious:

Hereditary or genetic:

Other causes:

 Related articles:

 

Electrical injury to anterior horn cells

Diseases,

Diagnosis:

This is usually a clinical diagnosis based on exposure to electrical injury and clinical features of lower motor neuron disease

Clinical features

  • LMN disease (weakness, with reduced or absent reflexes), minimally progressive
  • Previous electrical injury

Related articles:

Mononeuropathy

Diseases, ,

Synonyms:

Mononeuropathy, including Compressive neuropathy a.k.a. nerve compression

Diagnosis:

This is a clinical diagnosis supported by electrophysiology (NCS/EMG)

Clinical features:

  • Dysfunction limited to one isolated peripheral nerve for example the median nerve, the ulnar nerve, the radial nerve, the femoral nerve, the peroneal nerve etc.
  • Only one nerve involved. This distinguishes the syndrome from mononeuropathy multiplex
  • Each nerve may have multiple clinical syndromes depending on how proximal or distal the lesion is
  • No involvement outside the isolated nerve. This distinguishes the syndrome from radiculopathy or polyneuropathy
  • Some conditions like diabetes mellitus predispose to compression mononeuropathies

Findings on Investigations:

+NCS/EMG:
  • Confirms the pattern of isolated peripheral nerve involvement and helps distinguish between mononeuropathy and radiculopathy, polyneuropathy or mononeuropathy multiplex
  • Conduction slowing occurs
  • Temporal dispersion occurs
  • EMG findings of denervation and renervation in affected muscles e.g. fibrillations and positive sharp waves PSW)

Investigations to consider:

Blood tests:

  • Diabetes mellitus screening: Fasting blood glucose, HbA1c
  • Thyroid function tests

Imaging:

  • X-ray: fractures or bone abnormalities e.g. humeral fractures in radial neuropathy
  • MRI: for structural lesions
  • CT: for structural lesions e.g. retroperitoneal hematoma in femoral neuropathy

Types of mononeuropathy (see details below):

  • Median nerve compression a.k.a. median neuropathy:
    • Carpal tunnel syndrome (median neuropathy at the wrist)
    • Entrapment at ligament of Struthers, very rare
    • Pronator syndromeAnterior interossesous nerve AIN syndrome (a.k.a. Kiloh-Nevin syndrome)
  • Ulnar nerve and ulnar neuropathy:
    • Ulnar nerve compression at the wrist
    • Ulnar nerve compression at the Elbow
  • Radial nerve and radial neuropathy:
    • Radial nerve compression at the axilla
    • Radial nerve compression at the spiral groove
    • Posterior interosseous nerve neuropathy (PIN)
    • Superficial radial nerve neuropathy
  • Long thoracic nerve a.k.a. Thoracic nerve of Bell
  • Obturator nerve palsy a.k.a. obturator neuropathyFemoral nerve palsy a.k.a. femoral neuropathy
  • Sciatic nerve a.k.a. sciatic neuropathy
  • Peroneal nerve a.k.a. peroneal neuropathy
  • Tibial nerve neuropathy, rare
  • Tarsal tunnel syndrome (posterior tibial nerve compression in tarsal tunnel)
  • Miscellaneous syndromes:
    • Suprascapular nerve: Spinoglenoid notch
    • Lateral fermoral cutaneous nerve (Meralgia paresthetica; at the Inguinal ligament)
    • Obturator nerve at the Obturator canal
    • Plantar branches of the posterior tibial nerve (Morton metatarsalgia, plantar fasica and heads of 3rd and 4th metatarsals)

 

Median nerve compression a.k.a. median neuropathy:

Carpal tunnel syndrome (median neuropathy at the wrist):

Clinical features:

  • Pain up to the shoulder, worse at night
  • Weakness of thenar muscles: LOAF muscles especially adductor pollicis brevis APB
  • Tinels sign and Phalen’s sign
  • Sensory: palm (radial), palmer aspect of 3.5 fingers and over the tips, NO supply to forearm.

NCS and EMG, carpal tunnel syndrome:

  • SNAP, if motor is negative: median nerve latency 0.4 ms > ulnar latency, Median nerve conduction velocity <50 ms. SNAP amplitude is reduced.
  • CMAP: prolonged median nerve latency > 4.4 ms, or median nerve latency more than 1.4 ms greater than ulnar latency. CMAP reduced amplitude
  • EMG: fibrillation potentials and positive sharp waves PSW in Abductor pollicis brevis and not in median innervated muscles proximal to the wrist
  • Motor involvement indicates more severe CTS

Investigations to consider in carpal tunnel syndrome:

  • Fasting blood glucose, Thyroid function tests
  • Testing for acromegaly

Treatment of carpal tunnel syndrome:

  • Avoidance of movements that can exacerbate the condition
  • Splints at night
  • Local steroid injection
  • Consider Surgery:
    • Section of the carpal ligament

Entrapment at ligament of Struthers, very rare:

Clinical features:

  • Forearm pain
  • Paresthesia in median innervated fingers
  • Worsened by hand/forearm supination and extension of elbow
  • Weakness may occur, including pronator teres

NCS/EMG:

  • Stimulate at the axilla as well
  • CMAP: conduction block, temporal dispersion between axilla and antecubital fossa.
  • Prolonged motor latency may occur

X-ray humerus and elbow: boney spur (supracondylar process)

Pronator syndrome:

Clinical features:

  • Weakness: mild median innervated muscles
  • Pain: Nonspecific, worsening by supination and pronation
  • Paresthesia: worsened by forearm pronation with elbow in extension and by elbow flexion with forearm supinated.

Anterior interossesous nerve AIN syndrome (a.k.a. Kiloh-Nevin syndrome):

Clinical features:

  • Weak pincer grip, can’t make the “OK” sign/make a circle with index finger and thumb (Dip extension occurs). Test pronation with arm flexed (pronator quadratus weakness). Weak FDP in 1 and 2.
  • No sensory deficit
  • Pain can occur

NCS/EMG:

  • flexor digitorum profundus FDP 1 and 2, Flexor pollicis longus FPL, pronator quadratus PQ (difficult to study)

Ulnar nerve and ulnar neuropathy:

Clinical features:

  • Weakness of the intrinsic muscles of the hand (esp. Digiti minimi muscles and 1st interossei)
  • Sensation of medial 1 and a half fingers +palm

Points of compression:

  • Bicipital groove
  • Cubital tunnel syndrome: at the elbow
  • Guyon canal (at the wrist)

Guyon canal (at the wrist):

  • The triangular canal at the base medial part of the palm
  • Borders: laterally= hook of the hamate and transverse carpal ligament, medially= the pisiform.
  • Spares sensation
  • Palmar fascia-pisiform bone

Findings on Investigations:

Ulnar nerve compression at the wrist:

NCS/EMG:

  • SNAP:
    • Reduced SNAP amplitude in the 5th digit (may be normal in purely motor lesions)
    • SNAP in dorsal ulnar cutaneous nerve is normal.
  • CMAP:
    • Slowing of distal motor nerve conduction velocity with normal conduction velocity in the rest of the nerve.
    • Normal conduction studies across the elbow
  • EMG:
    • Fibrillation potentials and positive sharp waves PSW in ulnar innervated muscles in the hand. Normal flexor carpi ulnaris and flexor digitorum profundus.

Ulnar nerve compression at the Elbow:

NCS (test with elbow flexed 70-90%):

  • SNAP: decreased amplitude in dorsal ulnar cutaneous nerve. Note that SNAP should be normal in C8 radiculopathy.
  • CMAP:
    • Slower motor nerve conduction velocity across the elbow (>10m/s slowing is significant)
    • Conduction block across the elbow may be present (false positive in Martin-Gruber anastomosis, in this case check median nerve CMAP it may show positive initial deflection, increased conduction velocity and increased CMAP amplitude at the elbow compared to the wrist)
    • Inching may reveal the site where amplitude drops.
  • EMG:
    • Fibrillation potentials and positive sharp waves PSW in ulnar innervated muscles in the hand. Flexor carpi ulnaris and flexor digitorum profundus may also show these signs, however normal EMG in these muscles doesn’t exclude a lesion at the elbow.

Radial nerve and radial neuropathy:

Clinical features:

  • Motor:
    • Triceps (Elbow extension), brachiradialis (elbow flexion in mid pronation), supinator
    • Extensor carpi radialis longus (abduct and extend wrist), extensor carpi ulnaris (adduct and extend wrist), Extensor digitorum,
    • Extensor pollicis (brevis and longus), abductor pollicis longus
    • Wrist drop
  • Sensory: posterior cutaneous nerve of arm, posterior cutaneous nerve of forearm, dorsum of first web-space
  • Posterior interosseus nerve PIN lesions:
    • Cause weakness of wrist extensors and index and thumb extensors. Spares triceps

Findings on investigations:

Radial nerve compression at the axilla:

NCS/EMG:

  • SNAP: decreased amplitude, normal if done early
  • CMAP: decreased amplitude
  • EMG:
    • Abnormal (fibrillations and positive sharp waves PSW) triceps, anconeus, brachioradialis, extensor carpi radialis as well as distal muscles
Radial nerve compression at the spiral groove:
  • SNAP: decreased amplitude, normal if done early
  • CMAP: temporal dispersion and conduction block may occur.
  • EMG:
    • Normal triceps,
    • Abnormal (fibrillations and positive sharp waves PSW) anconeus, brachioradialis, extensor carpi radialis and distal muscles
Posterior interosseous nerve neuropathy (PIN):

NCS/EMG:

  • SNAP: normal
  • CMAP: decreased amplitude
  • EMG:
    • Normal triceps, anconeus, brachioradialis, extensor carpi radialis
    • Abnormal (fibrillations and positive sharp waves PSW) distal muscles
Superficial radial nerve neuropathy:

NCS/EMG:

  • SNAP: abnormal,
  • CMAP: normal amplitude, latency and conduction velocity
  • EMG: normal

Long thoracic nerve a.k.a. Thoracic nerve of Bell:

Clinical Features:

  • Winging of the scapula
  • Pain around the shoulder
  • Exclude other causes such as myopathies (such as Facioscapulohumeral Muscular Dystrophy and others)
  • Typical causes are trauma (blunt or sports), surgery (thoracic, radical mastectomy and 1st rib resection) and occasionally systemic causes such as SLE

Obturator nerve palsy a.k.a. obturator neuropathy:

Clinical features:

  • Weakness of hip adduction
  • Medial thigh pain during exercise
  • Loss of obturator reflex L3
  • Sensory loss and pain around medial side of thigh
  • Unusual to occur in isolation

Causes:

  • Surgery, hemorrhage, tumor, sports injuries

Findings on investigations:

EMG/NCS:

  • Allows localization of the dysfunction to the obturator nerve muscles
  • Adductor muscles: Fibrillation potentials or high-amplitude, long-duration complex motor unit potentials
  • Sparing of quadraceps, sparing of iliospoas, sparing of L-2, L-3 and L-4 paraspinal muscles

CT abdomen, pelvis:

  • Pelvic tumours

Femoral nerve palsy a.k.a. femoral neuropathy:

Clinical features:

  • Weakness of knee extension
  • Loss of knee reflex
  • Sensory loss and pain around knee and medial side of leg

Findings on investigations:

EMG/NCS:

  • Helps distinguish between femoral neuropathy and other conditions

Fasting blood glucose, HbA1c: diabetes mellitus
CT abdomen, pelvis: retroperitoneal hematoma, psoas hematoma, psoas abscess, pelvic tumours
MRA: femoral artery aneurysm

Sciatic nerve a.k.a. sciatic neuropathy:

Clinical features:

  • Peroneal part is more likely to be damaged than tibial part
  • Biceps femoris reflex (Lateral hamstring reflex) is absent in high sciatic/peroneal lesions (above the knee) and spared in peroneal nerve lesions below the knee
  • Absent ankle reflexes
  • Weakness in tibial and peroneal nerve distribution
  • Rarely sensory loss on lateral aspect of foot, sole and foot dorsum

Findings on investigations:

NCS/EMG:

  • Localizes the lesion (above or below the fibula)

CT abdomen, pelvis: pelvic tumours,

Peroneal nerve a.k.a. peroneal neuropathy:

Clinical features:

  • Foot drop, weakness of ankle dorsiflexion and eversion
  • Tinel’s sign at the fibular head
  • Sensation loss and paraesthesia in anterior and lateral shin, dorsum of the foot (superficial peroneal) and 1st web space (deep peroneal nerve a.k.a. anterior tibial nerve).
  • Biceps femoris reflex (Lateral hamstring reflex) is absent in high sciatic/peroneal lesions (above the knee) and spared in peroneal nerve lesions below the knee
  • Present knee and ankle reflexes

Findings on investigations:

NCS:

  • SNAP:
    • Of superficial peroneal nerve normal in purely demyelinating lesions. Reduced amplitude in axonal or mixed axonal/demyelinating lesions.
    • Normal sural nerve sensory.
  • CMAP:
    • If Extensor digitorum brevis is atrophied, place pick-up on tibialis anterior
    • Lesions at the fibular head: slowing across the fibular head may occur
    • Conduction block at the fibular head
    • Reduced amplitudes if axonal
    • Accessory deep peroneal nerve (branch of superficial peroneal nerve): CMAP amplitude at extensor digitorum brevis is larger with stimulation at fibular head than at the ankle.
  • F-waves: may be reduced in lesions at the fibular head. Nonspecific.
  • H-reflex: normal

EMG:

  • Normal in demyelinating neuropathies. Abnormal in axonal neuropathies.
  • Fibrillation and positive sharp waves PSW in affected muscles.
  • Short belly of biceps femoris is affected in lesions proximal to the fibula and helps distinguish them from distal lesions.
  • Superficial peroneal nerve muscles (peroneus longus, peroneus brevis).
  • Deep peroneal nerve muscles (Extensor digitorum brevis-see anomaly below, tibialis anterior)
  • Extensor digitorum brevis may be preserved in deep peroneal nerve muscles when it is supplied by accessory deep peroneal nerve (branch of superficial peroneal nerve).
  • Tibialis anterior is abnormal in fibular lesions
  • Test tibial nerve muscles below the knee (rule out tibial neuropathy/sciatic neuropathy)
  • Test paraspinal muscles (rule out radiculopathy)
  • MUAP: decreased recruitment (in axonal and demyelinating lesions), long duration, increased amplitude and polyphasia in axonal lesions.

Tibial nerve neuropathy, rare:

Clinical features:

  • Weakness of plantar flexion
  • Absent ankle reflex
  • Rarely sensory loss on lateral aspect of foot and sole

Findings on investigations:

NCS/EMG

  • To exclude S1 and sciatic nerve lesions

MRA: popliteal aneurysm

Tarsal tunnel syndrome (posterior tibial nerve compression in tarsal tunnel):

Clinical features:

  • Medial ankle pain. paresthesia and sensory loss in Plantar aspect of the foot, usually unilateral, no weakness. Tinel’s sign positive at tarsal tunnel flexor retinaculum.

Findings on investigations:

  • SNAP: reduced or absent amplitude. False positives occur
  • CMAP of medial and lateral plantar nerves:
    • Demyelinating: reduced distal latency,
    • Axonal: reduced amplitude
  • H-reflex: normal
  • F-waves: abnormal, nonspecific
  • EMG: Painful in this location
    • Fibrillations and positive sharp waves PSWs in involved muscles distal to the tunnel e.g. (lateral plantar nerve) abductor digiti minimi, dorsal and plantar interossei, and (medial plantar nerve) abductor hallucis and flexor digitorum brevis
    • Spared muscles proximal to the tunnel e.g. Gastrocnemius, soleus, popliteaus,

 

Miscellaneous syndromes:

Clinical syndromes:

Suprascapular nerve: Spinoglenoid notch
Lateral fermoral cutaneous nerve:
  • Meralgia paresthetica; at the Inguinal ligament
Obturator nerve at the Obturator canal
Plantar branches of the posterior tibial nerve (Morton metatarsalgia, plantar fasica and heads of 3rd and 4th metatarsals)

 

Related articles:

Tremor

Diseases,

Tremor is a neurological symptom and a neurological sign. It can be due to primary disorders of the nervous system or secondary nervous system dysfunction due to systemic disease. Tremors can also be physiologic and certain substances such a caffeine or circumstances such as anxiety can exaggerate physiological tremors.
 

Clinical features:

  • Involuntary, rhythmic, alternating, oscillatory movements
  • There are many causes of tremor. See the list below for more details. These range from physiologic tremor, drug induced tremor, Parkinson’s disease, Essential tremor, tremor due to metabolic abnormality (CO2 retention for example), hyperthyroidism, anxiety, alcohol withdrawal, cerebellar lesions and other conditions.
  • Enhanced physiological tremor can occur with hyperthyroidism or drugs
  • Describe whether the tremor occurs at rest, or with action (on maintaining posture) or action (intension tremor when approaching a target)

Investigatiosn to consider:

  • FBC, complete metabolic panel including LFTs
  • Thyroid function tests
  • ABG: if CO2 retention is suspected
  • MRI brain: if Wilson disease is suspected
  • If < 40 y.o. serum ceruloplasmin: <20 mg per decilitre +/-slit lamp examination
  • DAT SPECT (123I-FP-CIT SPECT) “DaTSCAN”: if atypical or to distinguish between esstential tremor and Parkinson disease
  • Fragile X PCR: fragile X tremor ataxia syndrome

Causes of Tremor:

Causes of Oculopalatal tremor OPT formerly oculopalatal myoclonus a.k.a. palatal tremour formerly palatal myoclonus:

Causes of Parkinsonism:

 

Related articles:

Spinal and bulbar muscular atrophy, Kennedy disease

Diseases, , ,

Synonyms:

Spinal and bulbar muscular atrophy (SBMA), Kennedy disease

Diagnosis:

This is a clinical diagnosis supported by NCS/EMG

Clinical features:

  • Lower motor neuron (LMN) disease
  • Muscle atrophy, weakness, contraction fasciculations, and bulbar involvement
  • Gynecomastia, testicular failure

Genetics:

Androgen receptor (AR) gene, expansion of CAG trinucleotide repeat

Related articles:

Primary Lateral Sclerosis

Diseases, , ,

Diagnosis:

Clinical features plus unrevealing investigations (NCS/EMG, MRI, lab tests) for other causes. This  is a diagnosis of exclusion.
 

Diagnostic categories of PLS (Gordon et al.)

Autopsy-proven PLS

  • Clinically diagnosed PLS with degeneration in motor cortex and corticospinal tracts, no loss of motor neurons, no gliosis in anterior horn cells, and no Bunina bodies or ubiquinated inclusions.

Clinically pure PLS

  • Evident upper motor neuron signs, no focal muscle atrophy or visible fasciculations, and no evidence of denervation on EMG at 4 years from symptom onset. Age at onset after 40. Secondary and mimicking conditions excluded by laboratory and neuroimaging.

UMN-dominant ALS

  • Symptoms 4 years, or disability due predominately to UMN signs but with minor EMG denervation or LMN signs on examination that are not sufficient to meet diagnostic criteria for ALS.

PLS plus

  • Predominant UMN signs plus clinical, laboratory, or pathologic evidence of dementia, parkinsonism, or sensory tract abnormalities. (If cerebellar signs, urinary incontinence, or orthostatic hypotension are evident, multiple-system atrophy should be considered.)

Symptomatic lateral sclerosis

  • Clinically diagnosed PLS with evident possible cause (e.g., HIV infection, paraneoplastic syndrome).

Clinical features:

Erb’s triad: spasticity, hyperreflexia and mild weaknes. But also pseudobulbar affect, urinary dysfunction, asymptomatic eye movement abnormalities (saccadic breakdown
of smooth pursuit or supranuclear paralysis) and cognitive dysfunction.
This disease begins with spasticity followed by weakenss of the limbs and bulbar muscles.
Begins with leg symptoms that progresses bilaterally. Later on upper limb symptoms occurs followed by bulbar symptoms.
Symptoms are gradually progressive with spread from one leg to the next over 1-4 years, and to the hands in 1-6 years. Bulbar involvement occurs after an additional 0.5-5 years.
UMN features: spasticity, increased reflexes and up-going plantars
No sensory symptoms but mild abnomalities in SSEPs may occur

Findings on Investigations:

MRI brain and MRI spinal cord: atrophy of precentral gyrus, parietal cortex, and primary sensorimotor may occur.
NCS/EMG: electrophysiological evidence of mild denervation does not rule out the diagnosis
MEP, motor evoked potentials: abnormal, worse in the legs, absent MEP, or prolonged central conduction time 2-3 times upper limit of normal,
SSEP, somatosensory evoked potentials: may be prolonged
MRS: reduced N-acetylaspartate/creatine ratio, reduced N-acetylaspartate/creatine, reduced N-acetylaspartate/choline ratio,
DTI: decreased signal intensity in posterior limb of the internal capsule,
FDG-PET: decreased uptake and decreased regional CBF in precentral gyrus region,
Muscle biopsy: denervation or reinervation, minimal angular fibers,

Investigations to consider:

MRI brain and MRI spinal cord
NCS/EMG
Blood tests:

  • HTLV-1 testing
  • B12, RPR, HIV testing
  • Genetic testing for hereditary spastic paraparesis: SPG3A, SPG4, SPG6
  • Serum long-chain fatty acids: adrenomyeloneuropathy
  • CK: elevation can occur in 17-40% of patients

Testing for causes of myelopathy,
MEP, and SSEPs

Treatment:

Supportive care
Treatment of spasticity: baclofen or tizanidine
Treatment of pseudobulbar affect
Treatment of drooling:

  • Anticholinergics: benztropine mesylate, hycoscyamine, glycopyrrolate, or
    scopolamine patches
  • Botulinum toxin injection into salivary glands

Address pulmonary function
Multi-disceplinary supportive care:

  • Physical therapy, occupational therapy speech therapy, nutrition assessment
  • Social work, counselling

Related articles:

References:

  1. . Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, Mitsumoto H, et al. The natural history of primary lateral sclerosis. Neurology 2006;66:647– 653.
  2. Brooks BR. El Escorial World Federaton of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994;124(suppl):96 –107.

Poliomyelitis

Diseases, ,

Diagnosis:

A combination of clinical features and CSF analysis

Clinical features:

Prodrome: upper respiratory tract infection
Followed by:

  • Mild meningismus +headache
  • Myalgial, paraesthesia, paralysis and respiratory weakness
  • After recovery LMN features and flaccid weakness. Autonomic features (swollen, clammy, cold, purple) in Lower limbs.

Findings in Investigations:

CSF:

  • Pleocytosis

Serology
NCS/EMG:

  • Asymmetrical involvement. Motor evoked potential MEP: reduced on affected side.
  • Spontaneous Activity: Fibrillation potentials, Positive waves
  • Motor distal conduction latency: normal
  • F-waves: normal
  • Sensory conduction: normal

Pathology:

Anterior horn cells: Cowdry B inclusions (small, no halo),
 

Post-Polio syndrome:

Clinical features:

  • History of Poliomyelitis
  • New LMN weakness ~30-40 years afterwards

Related articles:

Spinal Muscular Atrophy

Diseases, ,

Synonyms:

  • see eponyms under subtypes

Diagnosis:

A form of motor neuron disease

Genetics:

SMN1 gene chr. 5 (survival motor neuron gene), autosomal recessive with modifier genes,
Modifier genes: SMN2 gene number of copies,

Subtypes:

SMA1 a.k.a. Werdnig-Hoffman disease: onset at birth or prenatally, hypotonia frog-like leg posturing, respiratory muscle paralysis
SMA2 a.k.a. intermediate: onset at 3 months, tongue fasciculation, tongue wasting, leg weakness
SMA3 a.k.a. juvenile SMA a.k.a. Kugelberg-Welander disease a.k.a. Wohlfart-Kugelberg-Welander disease: later onset, gradual progression, proximal weakness, fasciculations, wasting

Pathology:

Spinal cord: loss of anterior horn cells and astrocytosis, chromatolysis, neuronophagia, ballooned cells.
Muscle:

  • SMA1 and SMA2: rounded fibres, grouped atrophy type 1 or type 2, fascicular atrophy, grouped hypertrophy of type 1 fibres,
  • SMA 3: adult pattern of denervation atrophy

Treatment:

Nusinersen (trade name Spinraza) [small RCT]

Related articles:

References:

  1. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF1, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.
  2. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-1722. doi: 10.1056/NEJMoa1706198.

Cryoglobulinemia, Neurological Manifestations

Diseases, ,

Diagnosis:

Clinical features plus isolation of cryoglobulins

Clinical features:

  • Hepatitis
  • Purpura (legs), arthralgia, glomerulonephritis
  • Raynaud’s phenomenon
  • Peripheral neuropathy, precipitated by cold

+serum Cryoglobulins: positive

Type I cryoglobulin: Monoclonal protein without rheumatoid factor activity

  • Associated with plasma cell dyscrasia

Type II mixed cryoglobulin MC (formerly essential mixed cryoglobulinemia): Monoclonal protein with rheumatoid factor activity +polyclonal component

  • Associated with hepatitis C virus

Type III mixed cryoglobulin MC: Polyclonal protein with rheumatoid factor activity

  • Associated with hepatitis C virus

Findings on Investgations:

Serum  cryoglobulins: positive
C4: low
NCS/EMG: peripheral neuropathy pattern, mainly sensory

Pathology/nerve biopsy:

Axonal loss

Treatment:

Options:

  • Prednisone, chlorambucil, cyclophosphamide, plasma exchange

Related articles:

Behcet's Syndrome

Diseases,

Diagnosis:

Recurrent oral ulceration plus two of the following:

  • Recurrent genital ulceration
  • Eye lesions
  • Skin lesions

Pathergy test: skin reaction to intradermal saline injection

Findings on Investigations:

MRI brain:

  • Infarcts: brainstem and thalamic
  • Cerebral Angiogram/angiography:
  • Narrowing, aneurysm (arterial and venous)

Investigations to consider:

  • ESR and CRP: Raised
  • FBC: leukocytosis

Treatment:

Mucous membrane involvement:

  • Glucocorticoid mouthwash or paste
  • Lidomide if severe

Thrombophlebitis: aspirin 325 mg/d
Arthritis: colchicine or interferon a
Uveitis or CNS involvement:

  • Prednisolone +azathioprine
  • or cyclosporin

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Giant Cell Arteritis

Diseases, ,

Synonyms:

a.k.a. cranial arteritis a.k.a. temporal arteritis:

Diagnosis:

Biopsy of the temporal artery within 7 days of starting steroids:

  • With serial sectioning

Or clinical features plus raised ESR or CRP plus response to steroids

Pathology:

Panarteritis:

  • Intimal thickening and proliferation,
  • Lymphocytic infiltration of media and adventitia, giant cells,
  • Disruption of elastic lamina

Chronic phase: intimal thickening, fibrosis, fragmentation of elastic lamina

Clinical features:

Fever, anemia, elderly
Orbital pain, vision loss
Altitudinal visual field defect (superior or inferior), diplopia
Optic disc: Pale, swollen. Central retinal artery occlusion
III, IV, VI palsy
Tender temporal artery

Findings on Investgations:

+ESR >80 or CRP >1 or 10
Catheter angiography:

  • May show abnormalities in extracranial vessels

Treatment:

Do not wait for biopsy to start treatment
Glucocorticoid therapy Prednisone I.V. high dose 60 mg then oral
Monitor with ESR and symptoms. Titrate the steroid dose
Continue therapy for at least 1-2 years

Related articles:

Takayasu’s Disease

Diseases,

Synonyms:

a.k.a. aortic arch syndrome a.k.a. Takayasu’s arteritis:

Diagnosis:

Arteriography:

  • Irregular vessel walls, stenosis, poststenotic dilation, aneurysms, occlusion, collaterals
  • Usually smooth stenosis of the common carotid and the subclavian arteries

Other imaging:

  • Ultrasound: thickened intima layer
  • CT: thickened enhancing walls
  • MRA

Treatment:

Control the symptoms and inflammation before surgery:

  • Prednisolone,

Correct the anatomical defects:

  • Angioplasty +/-Stenting as appropriate
  • Surgery as appropriate

Familial amyloid polyneuropathy FAP

Diseases,

Synonyms:

a.k.a. Familial amyloidotic polyneuropathy FAP, a.k.a. Hereditary amyloid neuropathy

Diagnosis:

Biopsy plus genetic testing

Types of familial amyloid polyneuropathy:

  • Transthyretin amyloidosis
  • Apolipoprotein A-I
  • Gelsolin

 

Transthyretin amyloidosis a.k.a. amyloidogenic mutated transtyretin ATTR: TTR gene mutation, protein= transthyretin, autosomal dominant

Clinical features:

Polyneuropathy:

  • Autonomic, symmetric mainly sensory polyneuropathy (pain and temperature dysfunction >proprioception/vibration)

Genetics:

Transtyretin ATTR: TTR gene mutation, protein= transthyretin, Autosomal dominant, chr. 18,

Findings on investigations:

Cardiac denervation by:

  • Cardiac SPECT 123I –labeled MIBG, reduced uptake
  • PET scan

Treatment:

  • Transthyretin amyloidosis, consider liver transplant

Related articles:

 

Neurosarcoidosis, Sarcoid disease Neurological Manifestations

Diseases, ,

Neurosarcoidosis manifestations:

  • Myelopathy
  • Cranial neuropathies
  • Pituitary disease
  • Dural based lesion
  • Encephalopathy
  • CNS sarcoid angiitis
  • Peripheral sensory neuropathy
  • Myopathy

Diagnosis:

Histology: +typical findings +excluding other diseases confirms the diagnosis
Histology: noncaseating granuloma

Findings on Investigations:

CXR:

  • Stage 0: normal
  • Stage I: bilateral hilar lymphadenopathy or paratracheal lymphadenopathy
  • Stage II: hilar lymphadenopathy +pulmonary infiltrates
  • Stage III: pulmonary infiltrates without hilar lymphadenopathy
  • Stage IV: ‘honey comb lung appearance’

MRI:

  • T2: high signal. Around pituitary stalk, periventricularly, myelopathy
  • +gadolinium: meningeal enhancement (perform this before LP)

CSF:

  • High immunoglobulins
  • Cell cound: 10-200, mainly lymphocytes
  • Glucose: normal or mildly reduced

NCS and EMG: neuropathies or myopathies

  • In neuropathy:
    • LMN VII palsy/recurrent/bilateral,
    • Rarely sensorimotor neuropathy
    • NCS: axonal, multifocal, sensorimotor

Muscle biopsy in myopathy:

  • Interstitial epithelioid and giant cell granulomas.

Tests for hypopituitarism if pituitary/hypothalamic disease is found
Blood tests:

  • FBC: lymphopenia
  • ESR: raised
  • ACE levels: high, not sensitive or specific
  • Immunoglobulins i.e. gammaglobulins: high
  • Ca++: hypercalcemia
  • Hypercalciuria

BAL: increased lymphocytes
PFTs: normal or restrictive
Note, Kveim tests are obsolete
X-rays: punched out lesions in terminal phalanges

Pathology, nerve biopsy, rare:

Epineurium: Noncaseating granuloma (multinucleated giant cells), vasculitis can occur. Perineurium: inflammatory infiltrate i.e. perineuritis. Endoneurium: inflammatory infiltrate, granuloma, asymmetrical axonal loss.

Treatment:

Consider depending on complications:

  • Prednisolone 40 mg daily for 2 weeks, then taper over 2 weeks, then maintenance for at least 6 months

In neurosarcoid:

  • Prednisolone as above
  • 2nd line: cyclosporin, also steroid sparing

Treat eye disease

Related articles:

Febrile Seizures

Diseases, ,

Diagnosis:

Seizures associated with fever in children from 6 months to 6 years old

Complicated febrile seizure:

>15 minutes, recur within 24 hours, localising signs i.e. complex febrile seizures, multiple seizures
These need more evaluation and observation

Investigations to consider:

FBC, U&E, glucose
Blood cultures
Urinalysis +/-urine culture
CSF analysis
Consider EEG and MRI

Treatment:

Antipyretics:
Paracetamol orally or ibuprofen orally but these don’t decrease the incidence [RCT]
Treat underlying cause

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Tuberous Sclerosis

Diseases, , , ,

Synonyms:

a.k.a. Bournvile disease

Genetics:

Genetic tests: chr. 9q34 TSC1 encoding hamartin , chr. 16p13 TSC2 encoding tuberin

Diagnosis:

Clinical features plus findings on investigations

Clinical  features:

Seizures
Retinal hamartomas
Skin:

  • Hypopigmented macules a.k.a. ‘Ash leaf shaped’, easier to see with Wood lamp (UV light)= poliosis (white hair) on the scalp
  • Ungal fibromas, shagreen patches
  • Facial angiofibroma (formerly Adenoma sebaceum= facial skin hamartomas)
  • Café au lait spots may occur

Findings on Investigations:

CT without and with contrast:

  • Subependymal nodular calcifications
  • Widened gyri, tubers may occur
  • Tumor near the interventricular foramen i.e. Subependymal giant cell astrocytoma SEGA: see under brain tumors

MRI:

  • Hypomyelinated lesions
  • Cortical tubers: FLAIR hyperintense, in cortical grey matter
  • Tumor near the interventricular foramen i.e. Subependymal giant cell astrocytoma SEGA: see under brain tumors

EEG:

  • Seizures, epileptiform discharges

Bone X-rays:

  • Thickening in: Skull, spine and pelvis
  • Cystic lesions in hands and feet

CXR and CT lungs:

  • Honey Combing +/-pneumothorax: pulmonary lymphangiomatosis (lymphangioleimyomatosis)

Echocardiography:

  • Rhabdomyoma

Renal ultrasound:

  • Angiomyolipoma +/-obstruction
  • Renal cysts
  • Polycystic kidney disease, if PKD2 gene is also involved

Urinalysis:

  • Hematuria may occur

Pathology:

cortical tubers: loss of cortical layer pattern, dysmorphic neurons, large astroctyes, giant cells,

Monitor:

Renal ultrasound: angiomyolipoma size
MRI brain

Treatment:

Treat complications
Renal angiomyolipomas:

  • Consider embolisation if >3 cm in diameter
  • Treat hypertension

Epilepsy:

  • Treat infantile spasms a.k.a. West syndrome
  • Treat other seizure types

SEGA tumors, treat them
Rhabdomyoma of the heart:

  • Treat arrhythmias

Related articles:

Encephalofacial Angiomatosis, Sturge-Weber disease

Diseases, ,

Diagnosis:

A combination of clinical findings and imaging

Clinical features:

Skin:

  • Facial nevus ‘port wine stain’ ‘nevus flammeus’, may be absent. In the distribution of trigeminal nerve

Eye:

  • Congenital glaucoma, bupthalmus, cloudy enlarged cornea

Findings on Investigations:

CT:

  • Calcification of the cortex
  • Cortical atrophy

MRI:

  • Venous hemangioma of the meninges in the occiptal region. Underlying cortex gliosis & atrophy.
  • Choroidal angioma

EEG:

  • Early: depression of voltage of the involved area
  • Late: epileptiform abnormalities

Familial Hyperekplexia

Diseases, , ,

Synonyms:

a.k.a. Familial startle disease

Diagnosis:

This is a clinical diagnosis

Genetics:

  • Autosomal dominant, autosomal recessive (frame shift)
  • Glycine Receptor alpha subunit GLRA1 5q32

Clinical features:

Infants: stiff (except when sleeping), excessive startle response
Older patients: Sudden myoclonus or falling
Spastic paraparesis in one family
Precipitated by sudden stimuli

Treatment:

Responds to benzodiazepines

Related articles:

Benign Paroxysmal Torticollis

Diseases, ,

Diagnosis:

This is a clinical diagnosis

Clinical features:

Attacks of torticollis
The attacks usually last <1 week
Recur every few days to every few months
Improve by age 2 years, and resolve by age 3
Family history of migraine
Often develop migraine later on in life

Related articles:

Skull Base Syndromes

Diseases, ,

Subtypes:

  • Jugular foramen syndrome= Vernet’s syndrome
  • Collet-Sicard syndrome= Posterior lacerocondylar area syndrome= intercondylar space syndrome
  • Retropharyngeal space syndrome= Villaret’s syndrome
  • Hypoglossal canal syndrome,
  • Foramen magnum syndrome,
  • Carotid canal syndrome

Clinical features:

Features depend on involved nerves:

  • Symptions: Choking, dysphagia, speech changes, auditor canal pain, headache
  • Features by nerve:
    • IX: loss of gag reflex, sensation of the palate, auditor canal pain, glossopharyngeal neuralgia
    • X: hoarse voice, weak cough, difficulty swallowing, nasal regurgitation, loss of gag reflex, auditor canal pain, headache
    • XI: weak/wasted sternocleidomastoid, trapezius
    • XII: tongue atrophy, tongue deviation, difficulty swallowing, laryngeal deviation
    • Sympathetics: Horner’s syndrome
Jugular foramen syndrome (Vernet’s syndrome):

IX, X, XI
If +sympathetics or XII, the lesions is outside of the skull, see other syndromes

Retropharyngeal space syndrome (Villaret’s syndrome):

IX, X, XI, XII, Sympathetics

Collet-Sicard syndrome (Posterior lacerocondylar area syndrome= intercondylar space syndrome):

IX, X, XI, XII

Hypoglossal canal syndrome:

XII

Carotid canal syndrome:

Ipsilateral cerebral infarction, Horner’s syndrome, lower cranial nerve palsies (interrupted pharyngeal branch blood supply)

Foramen magnum syndrome:

Medulla (long tract signs), lower cranial nerves, hydrocephalus
Crossed arm & leg weakness= hemiplegia cruciata
Downbeat nystagmus

Investigations to consider:

HbA1c
CT
MRI T1+gadolinium, T2, MRA
Nasopharyngeal & laryngeal direct visualisation if above is negative
MRV, CTV: juglar vein thrombosis
CTA
Catheter angiography
Testing for Guillain Barre Syndrome
Further search for primary neoplasm or other causes depending on results

Causes of skull base syndromes including jugular foramen syndrome:

Intracranial:

  • Neoplastic:
    • Extension of cerebellopontine angle tumour
    • Meningioma
    • Cholesteotoma
    • Neurofibroma
  • Guillain-Barre syndrome & variants
  • Chronic tuburculosis
  • Syphilis
  • Diabetes mellitus

Skull:

  • Fractured base of the skull
  • Paget’s disease

Extracranial:

  • Neoplastic:
    • Lymphoma
    • Carotid body tumour
    • Glomus jugulare turmour
    • Nasopharyngeal carcinoma
    • Metastatic Squamous cell carcionoma, others
  • Jugular vein thrombosis
  • Carotid dissection

Isolated Facial palsy, CN VII

Diseases, , , , , ,

Upper motor neuron lesion:

Diagnosis:

This is a clinical diagnosis. The underlying cause is determined by investigations and clinical correlation.

Clinical features:

  • Sparing of the forehead muscles
  • Asymmetry of face at rest or on movement: smile, puffing the cheeks and on wincing
  • The palpebral fissure may be widened on the affected side

Investigations to consider:

MRI brain
RPR, HbA1c

Treatment:

Treat the underlying cause
Protect the eye

Lower motor neuron lesion:

Diagnosis:

This is a clinical diagnosis. The underlying cause is determined by investigations and clinical correlation.

Clinical features:

  • Involvemen of the forehead muscles
  • Asymmetry of face at rest or on movement: smile, puffing the cheeks and on wincing
  • Usually palpebral fissure is widened on the affected side
  • Assess VII, VIII, Weber test, otoscopy, parotid
  • Ramsey Hunt syndrome ‘VZV’ a.k.a. herpes zoster oticus:
  • Ear pain, vesicular rash, LMN VII palsy, VIII may also be involved
  • Impaired lacrimation implies lesion involving or proximal to the geniculate ganglion

Investigations to consider:

VZV serology and VZV PCR
ACE levels
ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
HIV testing
CSF analysis
Guillain Barre Syndrome antibodies
MRI brain with and without contrast: if atypical for Bell’s palsy

Treatment:

Treat the underlying cause
Protect the eye
If VZV a.k.a. Ramsay Hunt syndrome:

  • Acyclovir immediately

If traumatic or due to acute/chronic otitis media:

  • Urgent ENT referral

Cerebellopontine angle syndrome CPA syndrome:

  • MRI T2, & T1 +contrast:
  • T2: Filling defects in CSF spaces in CPA
  • T1 +gadolinium:
    • Enhancing: vestibular schwannoma, meningioma ‘dural tail’
    • Nonenhancing: arachnoid cyst with hypointense ring, cholesteatoma (epidermoids),

Causes of isolated facial nerve palsy (CN VII):

Upper motor neuron lesion:

  • Stroke, most common
  • Vasculitis
  • Syphilis
  • HIV

Lower motor neuron lesion:

  • Bell’s palsy a.k.a. Idiopathic (but HSV-1 is implicated), most common
  • VZV a.k.a. Herpes zoster, Ramsay Hunt Syndrome
  • Otitis media
  • Cholesteatoma
  • Tumours:
    • Cerebellopontine angle, acoustic or facial neuroma
    • Glomus tumour
    • Parotid tumour
  • Temporal bone fracture
  • Diabetes mellitus
  • Lyme disease
  • Sarcoidosis
  • Amyloidosis
  • AIDS
  • Sjogren’s syndrome
  • Lesions of the facial nucleus (usually affects other nerves as well)

Recurrent or bilateral lower motor neuron facial palsy:

  • Base of the skull tumour e.g. Lymphoma
  • Lyme disease
  • Sarcoidosis
  • Gullian-Barre syndrome
  • If immunocompromised, VZV
Related articles:

Mental Neuropathy

Diseases

Synonyms:

a.k.a. numb chin syndrome

Diagnosis:

This is a clinical syndrome diagnosed by signs and symptoms. The underlying cause is determined by investigations and clinical correlation. The distal branches of the trigeminal nerve V3 are affected.

Clinical features:

Unilateral numb chin
+/-anaesthesia of chin & lower lip

Investigations to consider:

Imaging for underlying neoplasm
Mandible X-ray: assess for local disease
CT Mandible: assess for local disease tumors, osteomyelitis
+bone scan if CT is negative

Parinaud Syndrome

Diseases, ,

Synonyms:

Sylvian acqueduct syndrome a.k.a. Koeber-Salus-Elschnig syndrome

Diagnosis:

This syndrome is a clinical diagnosis. The underlying cause is determined by investigations and clinical correlation.

Clinical features:

Slightly dilated fixed pupils (i.e. no light reflex), light-near dissociation, upward gaze palsy.
Lid retraction (Collier’s sign)
Convergence-retraction nystagmus (especially on attempted up gaze)

Investigations to consider:

MRI:

  • Lesion in tectum/superior colliculus
  • E.g. pineal tumors, extending thalamic tumors, gliomas, Wernicke encephalopathy, MS plaque, tuberculoma

RPR: neurosyphilis
Consider investigations for MS

Related articles:

Acquired Oculomotor Apraxia

Diseases, ,

Synonyms:

a.k.a. Roth-Bielschowsky syndrome (supranuclear palsy of gaze due to corticotectal/corticotegmental tract lesions)

Diagnosis:

A form of supranuclear palsy diagnosed clinically and by isolating the underlying cause

Clinical features:

Inability to perform horizontal saccades
Vertical eye movements may be intact
Oculocephalic reflexes are intact
Caloric testing shows slow deviation without saccades
Optokinetic nystagmus remains without saccades
+/-dementia +/-pseudobulbar palsy

Findings on Investigations:

MRI: evidence of severe bilateral cerebrovascular disease (bifrontal or bilateral anterior internal capsule) or suggests a cause of dementia
If congenital this is called Cogan oculomotor apraxia syndrome

Related articles:

Superior Orbital Fissure Syndrome

Diseases, , , ,

Synonyms:

Anterior cavernous sinus syndrome, Rochon-Duvigneaud’s syndrome

Diagnosis:

This is a clinical diagnosis. Underlying causes are identified by investigations and clinical assessment. Dysfunction of cranial nerves oculomotor (III), trochlear (IV), abducens (VI) and first division of the trigeminal nerve (V1). Also sympathetic fibers may be involved causing a Horner syndrome (this becomes cavernous sinus syndrome). Exophthalmos and proptosis may occur. If the ophthalmic nerve (CN II) is involved then this is the orbital apex syndrome.

Investigations to consider:

CT if traumatic, otherwise as below
CT with & without contrast: hemangioma, AVMs
MRI: STIR MRI
Blood tests:

  • FBC, U&E, fasting Glucose
  • Vasculitic screen, ESR, CRP, ANCA, ANA, ENA
  • SPEP, ACE
  • Tests for infections: Borrelia serology, HIV

LP, CSF analysis
Biopsy if no response to steroids or early relapse: Rule out lymphoma

Causes of superior orbital fissure syndrome:

  • Trauma
  • Wegner granulomatosus
  • Neoplastic:
    • Lymphoma, hemangioma,

Related articles:

Cavernous Sinus Syndrome

Diseases, , , , ,

Diagnosis:

This is a clinical diagnosis. Dysfunction of cranial nerves III, IV, and VI, and the superior divisions of cranial nerve V.

Investigations to consider:

Blood tests:

  • FBC, U&E, fasting Glucose
  • Vasculitic screen, ESR, CRP, ANCA, ANA, ENA
  • SPEP, ACE
  • Tests for infections: Borrelia serology, HIV

MRI pre and post contrast:

  • Pituitary tumors, meningioma, metastasis
  • Aneurysms: flow voids, hypointense

If vascular lesion is suspected, CTA:

  • Carotid siphon aneurysm
  • Carotid cavernous fistula CCF: opacification of cavernous sinuses
  • Cavernous sinus thrombosis: filling defects during venous phase

2nd line, Catheter angiography: direct vs. indirect (meningeal feeding) carotid cavernous fistula CCF
LP, CSF analysis
Biopsy

Causes of cavernous sinus syndrome:

  • Cavernous sinus infection
  • Tumor
  • Internal carotid artery aneurysms
  • Wegener’s granulomatosis
  • Tolosa hunt syndrome

Related articles:

Tolosa Hunt Syndrome

Diseases

Diagnosis:

  • Painful opthalmoplegia over days to weeks, usually >40 y.o., causes cavernous sinus syndrome (dysfunction of cranial nerves III, IV, and VI, and the superior divisions of cranial nerve V)
  • Must exclude other causes: trauma, inflammatory, infective, vascular, neoplastic
  • ESR: high i supportive
  • MRI

Findings on Investigations:

MRI:

  • T1 isointense,
  • T2 hyperintense,
  • T1+contrast= enhancement

CT:

  • Enlarged cavernous sinus
  • May enhance with contrast

Investigations to consider:

MRI brain with and without contrast
ESR, CRP, ANA, c-ANCA, p-ANCA,
As per superior orbital fissure syndrome

Treatment:

Corticosteroids: prednisone 100mg/day & slow taper

Related articles:

Internuclear Ophthalmoplegia (INO)

Diseases, , , ,

Diagnosis:

This is a clinical diagnosis. The underlying cause is determined by investigations

Clinical features:

Diplopia
Classic variant, posterior INO:

  • On lateral gaze: Failure of adduction of the contralateral eye, nystagmus of the abducting eye
  • Medial rectus is less weak on testing each eye separately

Anterior INO variant:

  • Divergent eyes bilaterally, paralysis of both medial recti on testing with both eyes open.
  • Medial rectus is less weak on testing each eye separately

Another variant:

  • On lateral gaze: failure of abduction of the ispsilateral eye, adduction of the contralateral eye is not impaired.

Lateral rectus is less weak on testing each eye separately
Note: ipsi- & contra- lateral refer to the direction of gaze

Investigations to consider:

MRI: multiple sclerosis, brainstem glioma, brainstem infarct, brainstem hemorrhage, Wernicke encephalopathy
Further Investigations for MS
B1 thiamine levels

Causes of Internuclear ophthalmoplegia (INO):

  • Multiple sclerosis
  • Brainstem infarct
  • Brainstem glioma
  • Brainstem hemorrhage
  • Wernicke encephalopathy

Related articles:

Abducens (cranial nerve VI palsy)

Diseases, , , , ,

Diagnosis:

This is a clinical diagnosis

Clinical features:

Horizontal diplopia
In neutral gaze, normal appearance or head is slightly turned to the unaffected side (compensation for unopposed medial rectus)
On movement: Affected eye fails to abduct

Investigations to consider:

Blood tests:

  • ESR: giant cell arteritis
  • TFT, glucose
  • ANCA: Wegner’s granulomatosus
  • HbA1c
  • ESR

CT:

  • Out rules hydrocephalus: false localising sign

MRI with and without contrast:

  • Brainstem pontine lesions (multiple sclerosis, glioma)
  • Image base of the skull to exclude nasopharyngeal carcinoma

MRA head or CTA head:

  • ICA aneurysm

Multiple sclerosis investigations
If painful:

  • Consider petrous temporal apex syndrome, superior orbital fissure syndrome & cavernous sinus syndrome,

Treatment:

Treat the cause if found
If painless & idiopathic:

  • Consider conservative management & follow up

Causes of abducens nerve palsy (CN VI):

Nuclear & fasciular:

  • Tumours: glioma
  • Part of a Brainstem stroke syndrome
  • Multiple sclerosis

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Petrous tip area:

  • Raised intracranial pressure ‘false localising sign’
  • Hydrocephalus
  • Mastoiditis
  • Nasophareygeal tumours, paranasal sinus tumours
  • Lateral sinus thrombosis

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis
  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Wegner’s granulomatosus

Related articles:

  • Approach to diplopia,
  • Also see superior orbital fissure syndrome, Tolosa Hunt syndrome, skull base syndromes

Trochlear Nerve Palsy (Cranial IV palsy)

Diseases, , , , ,

Diagnosis:

This is a clinical diagnosis

Clinical features:

Rare in isolation
In neutral gaze: slight head tilted contralateral to the weak superior oblique muscle (loss of in-torsion)
Test with eye adducted and moved inferiorly. This is also the position of worse diplopia
If bilateral: on horizontal gaze, the abducting eye drifts downwards (inferior rectus of the contralateral eye overacts)

Investigations to consider:

CT
MRI brain with and without contrast
TFT, fasting glucose, ESR
CSF: meningitis
Tests for head and neck cancer: transneural spread

Treatment:

Treat underlying disease

Causes of trochlear nerve palsy (CN IV):

Nuclear & fasciular:

  • Tumours: glioma, medulloblastoma
  • Part of a Brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Trauma

Related articles:

Oculomotor Palsy (cranial nerve III palsy)

Diseases, , , , ,

Synonyms:

a.k.a. III nerve palsy

Diagnosis:

This is a clinical diagnosis. The underlying cause requires investigations.

Clinical features:

In neutral gaze: The eye is looking down & out. There is complete ptosis.
On looking downwards torsional (in-torsion) nystagmus of the eye occurs (due to intact IV nerve action)
Note the presence of meiosis:

  • Normal pupil (pupil sparing): the parasympathetics are spared. Occurs in non-compressive causes.
  • Dilated pupil (pupil involving) the parasympathetics are affected. Occurs in compressive cause. Often painful

Investigations to consider:

Fasting blood glucose, HbA1c, ESR, CRP, ANA, anti-dsDNA, c-ANCA, p-ANCA, LDH, VZV serology
MRI:

  • Meningioma
  • Midbrain lesions

MRA head or CTA head:

  • PCOM aneurysm, ICA aneurysm, basilar aneurysm

If no abnormalities on MRI there is a dilated pupil, consider:

  • Catheter angiography of cerebral arteries

Consider other tests:

  • CSF: meningitis
  • Tests for head and neck cancer: transneural spread

Causes of Oculomotor nerve palsy (CN III): think of anatomy

Nuclear & fasciular:

  • Tumours: Glioma
  • Part of a brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar aneurysms
  • Posterior communicating artery PCOM aneurysm
  • Temporal lobe herniation (uncal herniation)

Cavernous sinus area:

  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma
  • Internal Carotid artery aneurysms
  • Cavernous sinus thrombosis
  • Mucormycosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vascular:
    • Vasculopathy: diabetes mellitus, hypertension & atherosclerosis, giant cell arteritis
  • Wegner’s granulomatosus
  • Hodgkin’s disease, VZV, encephalitis, collagen vascular disease, Paget’s disease
  • Trauma

Treatment:

Treat the cause
Diplopia:

  • Fitting prisms to the patients glasses
  • Patching the affected eye

If unresolving diplopia & palsy consider surgery:

  • Restoring binocular vision in primary positions of gaze

 

Related articles:

Horner Syndrome

Diseases, , ,

Synonyms:

a.k.a. occulosympathetic defect

Diagnosis:

This is a clinical diagnosis plus pharmacological tests on occasion

Clinical features:

Miosis, partial ptosis, anhydrosis, illusion of enophthalmos, red eye

Pharmacological test:

Cocaine eye drops 2% in both eyes, failure to dilate diagnoses Horner’s syndrome.
Dilation on adding amfetamine (Paradrine 1% (hydroxyamphetamine, most common) or Pholedrine 5% (n-methyl derivative of hydroxyamphetamine) to the affected eye localises it to 1st or 2nd order neuron (post ganglionic nerve is intact).

Investigations to consider:

CTA head and neck, or MRA Head and neck: to rule out carotid dissection
CXR: lung tumor
CT thorax: lung tumor, neuroblastoma, metastatic breast cancer
MRI brain and MRA cervical spine: central causes
Ultrasound thyroid & carotid: thyroid tumors

Causes of Horner’s syndrome:

Central (1st neuron)

  • Brainstem infarction
  • Cerebral hemorrhage/infarction
  • Multiple sclerosis
  • Intracranial tumour
  • Transverse myelopathy
  • Syrinx

Preganglionic (2nd neuron)

  • Thoracic & neck tumour:
    • Pulmonary apex
    • Thyroid mass
    • Cervical rib
  • Mediastinum disease
  • Trauma
  • Surgery: Endarterectomy

Postganglionic (3rd neuron)

  • Intrancranial tumour
  • Cavernous sinus
  • Cartoid artery aneurysms & dissection
  • Trauma & surgery
  • Headache e.g. Cluster headache
  • Idiopathic

 

Causes ptosis:

Neurogenic ptosis:

  • Horner’s syndrome
  • Oculomotor nerve palsy (unilateral or bilateral)

Myogenic ptosis:

  • Myasthenia gravis (bilateral, but may be asymmetric)
  • Lambert Eaton myasthenic syndrome (bilateral)
  • Chronic progressive external ophthalmoplegia ‘mitochondrial DNA mutations’ (bilateral)
  • Oculopharyngeal muscular dystrophy (bilateral)
  • Myotonic dystrophy (bilateral)
  • Other myopathies (bilateral)

Mechanical ptosis:

  • Saging tissue in elderly
  • Infection etc.
  • Aponeurotic ptosis: stretching or dehiscence of the tendon

 

Cancer-associated retinopathy (CAR)

Diseases, , ,

Diagnosis:

A paraneoplastic syndrome. diagnosed based on clinical features, associated antibodies, perimetry and identification of the underlying neoplasm

Clinical features:

Rapid visual loss
Anti CAR antibodies (VPS, Anti-Recoverin): raised
Goldmann perimetry: ring-like scotoma in each eye

Investigations to consider:

CT chest abdomen & pelvis: lung cancer

Related articles:

Nystagmus

Diseases, ,

Diagnosis:

This is a clinical finding on examination. The corresponding symptom is oscillopsia, although it is often absent. Nystagmus is common in disorders that cause vertigo or ataxia.

Investigations to consider:

Down beat, MRI: cervicomedullary lesions, Chiari Malformation, Multiple sclerosis, brainstem tumor, brainstem stroke, spinocerebellar degeneration
Convergence-Retraction: MRI: dorsal midbrain lesions
Ocular bobbing, MRI: pontine lesions, hydrocephalus,
Periodic alternating nystagmus PAN: anti-GAD antibodies

Related articles:

Ataxia

Diseases, ,

Diagnosis:

This syndrome a clinical diagnosis and has many underlying causes.

Clinical features:

Uncoordinated or inaccurate movement not due to paresis, sensory disturbances, increased tone or involuntary movements. A combination of any of the following features may occur:

  • Gait: broad based, staggering & swaying, unsteady,
  • Truncal ataxia: inability to sit or stand without support
  • Dysmetria: Past-pointing,
  • Asynergia/dyssynergia
  • Intension (kinetic) tremor, postural tremor

Investigations to consider: consider as appropriate depending on clinical assessment

Blood tests:

  • FBC, U&E, LFTs
  • TFT: hypothyroidism
  • B1 thiamine, B12 & methylmalonic acid,

Infectious tests to consider:

  • Syphilis serology: VDRL
  • Serology & cold agglutinins: Mycoplasma pneumoniae,
  • Legionella pneumophilia serology
  • Tests for Rickettsia rickettsii (Rocky mountain spotted fever)
  • CSF: VZV PCR positive,

Other metabolic tests to consider:

  • Ceruloplasmin & slit lamp examination
  • Iron studies: hemochromatosis
  • Vitamin E levels: low in ataxia with vitamin E deficiency AVED
  • Drug levels & toxicology:
  • Lithium levels, Phenytoin PHT levels,
  • Alcohol levels
  • Lead levels
  • Toluene
  • CO poisoning

Autoimmune tests to consider:

  • Coeliac disease antibodies: anti tissue transglutaminase, anti endomysial: Gluten ataxia
  • Antibodies to Purkinje cell antigens (anti-Yo antibodies), Anti-Hu antibodies (ANNA-1), anti-Ri antibodies
  • Anti-GAD antibodies: Cerebellar ataxia, downbeat nystagmus.
  • Anti-GALOP (IgM against central myelin antigen): Gait Disorder, Autoantibody Late-age Onset Polyneuropathy
  • Anti-GD1b antibodies and anti‐GQ1b IgG antibodies: Guillain-Barre syndrome Miller-Fisher variant

Urine amino acids:

  • Maple syrup urine disease, Hartnup disease

MRI +GAD:

  • Brainstem or cerebellar hemorrhage, infarction, multiple sclerosis, neoplasms (medulloblastoma, pilocytic astrocytoma, ependymoma, ATRT, metastasis, glioblastoma, vestibular schwannoma, hemangioblastoma), CJD, abscess, Superficial siderosis, Acute postinfectious cerebellitis
  • Malformations (Chiari-malformation, Dandy-Walker malformation, congenital acquiductal stenosis)
  • Atrophy: cerebellar degeneration, paraneoplastic, alcoholic, Multiple system atrophy

SPECT:

  • Increased perfusion: Acute postinfectious cerebellitis

Genetic tests to consider:

  • Hereditary spinocerebellar ataxias
  • Adult form of Fragile X syndrome (Fragile X tremor ataxia syndrome)
  • Immunoglobulins & alpha fetoprotein: Ataxia telangiectasia

CSF analysis:

  • Pleocytosis: paraneoplastic cerebellar degeneration, postinfectious, viral cerebellar encephalitis,
  • Miller-Fisher syndrome
  • Whipple’s disease a.k.a. Tropheryma whippelli PCR
  • Protein 14-3-3 & S100: CJD

Nerve conduction studies
ECG
Echocardiography: hypertrophic cardiomyopathy in Friedrich’s ataxia, dilated cardiomyopathy in alcoholism
CXR
Endoscopy & intestinal biopsy: Coeliac disease (gluten enteropathy), Whipple’s disease

Causes of ataxia:

Cerebellar ataxia:

  • See causes of cerebellar ataxia

Sensory ataxia:

  • See causes of sensory ataxia

Vestibular ataxia:

  • See ‘vertigo’ peripheral vestibular causes
  • See ‘vertigo’ central vestibular causes

 

Causes of cerebellar ataxia:

Acute:

Chronic:

 

Causes of sensory ataxia:

Peripheral sensory neuropathy:

  • Diabetes
  • Hypothyroidism
  • Diphteria
  • Immune:
    • GALOP syndrome, anti-MAG syndrome, Miller Fisher syndrome (anti‐GQ1b IgG), anti-GD1b antibody syndrome
    • Paraneoplastic anti-Hu antibody
  • Drugs:
    • Isoiazid, Pyridoxine, Cisplatin, Paclitaxel
  • Hereditary:
    • Autosoma dominant sensory ataxic neuropathy
    • HMSN-type III (Dejerine-Sottas disease)
    • Refsum’s disease
  • Those that may also affect the posterior columns, see below
    Sensory nerve root lesions

Myelopathy: (Posterior columns)

Medial lemniscus lesions, rare
Thalamic lesions (hemiataxia or gait ataxia), rare
Parietal lobe lesions (hemiataxia), rare

Related articles:

Chorea, in general

Diseases,

Diagnosis:

This is a clinical diagnosis with various underlying causes

Clinical features:

Involuntary, nonrhythmic, rapid, irregular, jerky, purposeless, unpredictable, non-sustained

Investigations to consider: consider as appropriate

Tests: for Wilson’s disease
Tests: for Huntington’s disease
Blood smear: increased acanthocytes (suggests neuroacanthocytosis)
Uric acid in young: Lesch-Nyhan disease

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Myoclonus

Diseases,

Myoclonus, as a symptom of movement disorders:

Diagnosis:
  • Clinical: Rapid, brief, involuntary, jerk, muscle contraction (positive myoclonus) or inhibition of tone (negative myoclonus)
  • Myoclonus by EMG: bursts <75 msec is diagnostic
Types of myoclonus:

By location:

  • Cortical
  • Subcortical:
    • Brain stem (e.g. opsolonus myoclonus syndrome, hemifacial spasm)
    • Spinal
    • Segmental

By relation to action:

  • Action
  • Postural
  • Reflex

Causes of myoclonus:

Primary:

  • Benign myoclonus (a normal finding, including hiccups)
  • Sleep myoclonus
  • Essential myoclonus
  • Part of idiopathic generalized epilepsy e.g. Juvenile myoclonic epilepsy

Secondary:

  • Systemic conditions:
    • Uremia (renal failure)
    • Liver failure
    • Posthypoxic myoclonus (usually action myoclonus if after recovery, or myoclonic status epilepticus acutely post anoxia)
    • Drug overdose/poisoning
  • Neurodegenerative conditions:
    • Creutzfeldt-Jakob disease
    • Frontotemporal dementia
    • Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis
  • Pure movement disorder:
    • Palatal myoclonus
  • Progressive myoclonus epilepsy (PME), a group of conditions: (see under separate list)
Orthostatic myoclonus:

EMG:

  • Myoclonus= irregular, short duration (less than 100 msec) muscle bursts in the legs
  • +Myoclonus occurring in leg muscles upon standing and not present in the sitting position
  • Or +a marked increase of myoclonic bursting frequency in leg muscles upon standing
  • Also +no myoclonus at rest +non-rhythmic discharges
Negative myoclonus:

EMG: silence

Investigations to consider in patients with myoclonus, on a case by cases basis:
  • Basic metabolic profile creatinine: renal failure,
  • LFTs: liver failure
  • ABG: CO retention
  • EEG: epilepsy e.g. IGE, also CJD, SSPE,
  • Tests for CJD, vCJD
  • Tests for opsoclonus-myoclonus syndrome
  • Tests for SSPE
  • Test for West nile virus WNV
  • Tests for DYT11
  • Tests for Neuronal ceroid lipofuscinosis
  • Tests for Lafora disease
  • MRI: for anoxic brain injury, neuroblastoma, Cerebellopontine angle tumours in hemifacial spasm
Treatment of myoclonus:

If myoclonus is part of an epilepsy syndrome, then treat the myoclonus.
If part of another disease, treat the underlying disease
If due to a mass lesion or compressive lesion, treat the underlying lesion
Midbrain myoclonus:

  • Medications to consider include: Clonazepam. Serotoninergic drugs: clomipramine, fluoxetine.

If localised:

  • Consider botulinum toxin injection
  • Consider above drugs

Related articles:

Dystonia, in general

Diseases,

Diagnosis:

This is a clinical diagnosis. There are many underlying causes

Clinical features:

Simultaneous contraction of agonist & antagonist muscles, involuntary,
Decide on primary vs. secondary
Assess for isolated dystonia or other features e.g. myoclonus, parkinsonism, peripheral neuropathy, etc
Consider:

  • EMG in atypical cases
  • EEG: if necessary to distinguish from seizures

Investigations to consider: consider as appropriate

Trial of levodopa for 2 months: rules out dopamine responsive dystonia
MRI:

  • Previous stroke: putamenal, caudate
  • Brainstem lesions: osmotic demyelination,
  • Caudate atrophy in: Huntington’s disease, neuroacanthocytosis, some GM1 gangliosidoses
  • Eye of the tiger sign or generalised atrophy: Hallervorden-Spatz disease PKAN
  • Putamenal lesions: Wilson’s disease, HIV
  • Putamenal atrophy: Glutaric aciduria
  • Symmetrical basal ganglia lesions: Leigh’s disease
  • Calcifications: Fahr’s disease
  • Thalamic lesions: Wilson’s disease, ADEM with Mycoplasma pneumoniae,
  • Tuberculoma features: TB
  • White matter disease: Krabbe’s disease, metachromatic leukodystrophy

Blood tests:

  • Blood smear: increased acanthocytes (suggests neuroacanthocytosis)

Tests for Wilson’s disease
Mycoplasma pneumoniae serology: if ADEM picture or thalamic lesions
HIV testing
Measles testing: subacute sclerosing panencephalitis SSPE
Carbon monoxide CO testing
Serum lactate, pyruvate: mitochondrial
Uric acid in young: Lesch-Nyhan disease
Glutaric acid, methylmalonic acid, very long chain fatty acids: inherited conditions
Urine amino acids
NCS/EMG:

  • Krabbe’s disease, metachromatic leukodystrophy

Genetic testing:

  • As guided by clinical features & imaging

Causes of dystonia:

Primary:

  • Hereditary, Genetic forms:
    • DYT classification
  • Other primary dystonia genetic forms
  • Sporadic

Secondary:

Related articles:

Leukoencephalopathy (white matter disease)

Diseases, , , ,

Damage to white matter may occur due to may conditions that can affect the brain. The clinical features, prognosis and treatment are related to the underlying condition

Clinical features:

There is a wide range of symptoms:

  • Rapidly progressive dementia/subacute encephalopathy, lower body parkinsonism/gait apraxia, behavioural changes, pseudobulbar speech and pseudobulbar affect may occur
  • Later on the patient is: akinetic mute, spastic quadraparesis
  • Earlier on focal signs may occur and give clues to the diagnosis e.g. peripheral neuropathy, occular movement abnormalities, seizures, myoclonus
  • Systemic features may give clues to the diagnosis: skin changes, systemic disease, e.g. significant hypertension, liver disease in Zellwegar disease,

Findings on Investigations:

+MRI:

  • Diffuse white matter involvement with or without grey matter involvement
  • May be symmetric, asymmetric, enhancing, nonenhancing, associated with hemorrhage or not, associated with DWI restriction or not,
  • May be anterior predominant, posterior predominant, involve or spare the U-fibers
  • May also involve the grey matter
  • In late stages atrophy occurs with gliosis
  • Helps guide DDx & further tests

Grading:

Fazekas grade I, Mild: few small punctate lesions in the white matter.
Fazekas grade II, Moderate: larger white matter lesions that are beginning to become confluent.
Fazekas grade III, Severe: confluent T2 hyper intensity.

Investigations to consider: consider as appropriate

MRI: guides further tests
MRA, CTA, Catheter angiography: as necessary if vasculopathy/vasculitis/cerebral vasoconstriction syndrome is considered
Lumbar puncture for CSF analysis:

  • Cell count, protein, glucose, IgG index, oligoclonal bands, myelin basic protein
  • Microscopy and Cultures
  • Broad tests for infections and inflammation, including viral encephalitis and other encephalitis
  • Features of inflammatory disease (autoimmune encephalitis, multiple sclerosis, ADEM, infectious disease) vs. non-inflammatory profile

Urine toxicology: cocaine, heroin
Serum toxicology
Carboxyhemoglobin: high in CO poisoning
Testing for infections:

  • VDRL, syphilis testing, Lyme disease testing,
  • HSV testing, West Nile virus testing (grey matter involvement initially), CMV testing, HIV testing, see viral encephalitis,
  • Cryptococcus testing, coccidiodes testing

Vasculitis screen:

  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50

Testing for autoimmune or paraneoplastic encephalitis/encephalopathy:

  • anti: Hu (ANNA-1), Yo/PCA1, Ri, MaTa, CV2/CRMP5, amphiphysin, LGI1, CASPR2, VGKC, NMDA (NR1) and GAD65
  • Anti-TPO antibodies

Testing for CADASIL, NOTCH3 mutation
EEG:

  • May provide clues e.g. GPEDs in SSPE,

Tests for mitochondrial disease:

  • Muscle biopsy with biochemical and respiratory chain analysis and electron microscopy
  • Specific testing for individual mitochondrial disease e.g. MELAS, POLG mutation, etc

Selected testing for leukodystrophies:

  • X-linked adrenoleukodystrophy, Metachromatic leukodystrophy, Globoid-cell leukodystrophy (Krabbe’s disease)

Selected testing for perioxisomal disorders:

  • Zellweger disease,

Catheter angiography: if vasculitis is suspected
Brain biopsy

Causes of leukoencephalopathy (diffuse white matter disease):

Vascular:

Infectious:

Inflammatory:

Paraneoplastic:

Neoplastic:

Toxic and drug induced:

Metabolic:

 

References:

  • Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987 Aug;149(2):351-6.

Related articles:

Klüver-Bucy syndrome

Diseases, , ,

Diagnosis:

This is a clinical diagnosis

Clinical features:

Hypersexuality, hyperorality, visual agnosia, and placidity (diminished emotional reactions).

Investigations to consider:

MRI: Lesions in bilateral medial temporal lobes, e.g. Traumatic brain injury, herpes, other infections
Consider tests for dementias (FTLD, Alzheimer’s) & infections

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Alien Limb Syndrome

Diseases,

Synonyms:

a.k.a. alien hand syndrome

Diagnosis:

This is a clinical diagnosis

Clinical features:

Inability to recognise ones limb once visual cues are removed or autonomous movements that are involuntary
Also may have; apraxia, bimanual coordination difficulty, lack of goal directed activities
Localisation: anterior corpus callosum, frontal lobe

Investigations to consider:

MRI: corpus callosum lesions e.g. strokes, bifrontal pathology

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Balint’s Syndrome

Diseases, ,

Diagnosis:

This is a clinical diagnosis

Clinical features:

Ocular apraxia/ sticky fixation: the inability to move the eyes volitionally
Optic ataxia: inability to reach for a target under visual guidance in the absence of primary visual deficits, patients are able to reach under auditory guidance.
Simultinagnosia

Investigations to consider:

MRI: bilateral parietooccipital lesions
Consider testing for CJD

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Mild Cognitive Impairment (MCI)

Diseases,

Synonyms:

a.k.a. Cognitive impairment no dementia CIND:

Diagnosis:

Clinical examination:

  • Impairment of memory without impairment of functions in activities of daily living ADLs
  • May be amnestic type (amnestic MCI) or non-amnestic

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Dementia

Diseases, , , ,

Diagnosis:

Neuropsychological/Psychometric testing
Or Clinical features
The underlying etiology is determined by a combination of clinical features, neuropsychological testing, imaging and laboratory testing
 

Clinical features:

This is an acquired persistent disorder where there is an impairment of the content of consciousness (intellectual function) with compromise in at least 2, e.g.:

  • Memory
  • Language i.e. aphasia
  • Visuospatial skills e.g. apraxia, agnosia, navigation
  • Executive function e.g. impaired abstraction, planning, judgment, reasoning etc.
  • +impairment in functional independence
  • Or pathology evidence of dementia

Severe dementia:

  • MMSE score below 15 (or <10)
  • or a clinical dementia rating CDR of 2 or higher

Differential Diagnosis:

  • Don’t misdiagnose dementia in a patient who is really depressed a.k.a. pseudodementia
  • Reversible causes are: thyroid dysfunction, B12 deficiency, intracranial mass, normal pressure hydrocephalus

Screening:

No single tests is satisfactory
MMSE, mini-mental state examination:

  • If 21-23, suggests mild dementia. +LR= 9
  • If <15 or <10, severe dementia
  • If 24-26, do further testing
  • If >26, suggests dementia is unlikely. –LR= 0.1
  • When monitoring, a change of 4 is considered significant.

Abbreviated mental test AMT:

  • If <6, suggests dementia

Investigations to consider:

Bloods:

  • FBC: macrocytic anemia, infection
  • ESR: chronic infection, vasculitis
  • Complete metabolic panel, Ca++ +phosphate +albumin: hypercalcemia
  • Glucose: a cause of delirium, diabetes as a risk factor
  • Cholesterol +triglycerides
  • TFT: hypothyroidism
  • B12 & Folate levels & blood smear: vitamin B12 deficiency
  • Liver enzymes: early hepatic encephalopathy
  • Syphilis serology: VDRL, FTA-abs
  • HIV serology: AIDS dementia complex
  • Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Ceruloplasmin, Copper: Wilson’s disease
  • HIV serology: AIDS dementia complex
  • PTH: Hyperparathyroidism
  • Short ACTH stimulation test: screening for Addison’s disease

ECG: evaluation of cardiac disease
CXR: paraneoplastic & metastatic
CT:

  • Normal pressure hydrocephalus
  • Chronic subdural hematoma
  • Neoplastic disease (orbitofrontal meningioma, Glioblastoma), multiinfarct dementia

Polysomnogram: obstructive sleep apnea
MRI:

  • Normal pressure hydrocephalus
  • Chronic subdural hematoma
  • Neoplastic disease (orbitofrontal meningioma), multiinfarct dementia, leukoareosis on MRI in Binswanger’s disease, hippocampal atrophy in alzheimer’s, lymphoma
  • CJD findings

EEG
MRI
Lumbar puncture:

  • TB meningitis, cryptococcal meningitis, vasculitis, protein 14-3-3 in CJD, lymphoma,

Thrombophilia screen
Neuropsychological/Psychometric testing: localises affected areas
Screening for Cushing’s disease
Serum toxicology
Urine toxicology
Urine heavy metals
EEG: CJD or nonconvulsive seizures
If is early onset & positive family Hx. genotype for APP PS1 & PS2 mutations
PET Scan
SPECT Scan
Apolipoprotein E
Brain and meningeal biopsy: CJD or vasculitis, various dementias

Monitor:

Regular review for cataract & glaucoma
Regular review for cognitive state
MMSE: a change of 4 is considered significant
Assess nutrition, hydration & skin care

Treatment:

General measures:

  • Influenza vaccination
  • Address hydration, nutrition, skin care, cataract & glaucoma, risk of falls
  • Avoid: Benzodiazepines as they worsen disinhibition & confusion
  • Social: very important
  • Education of family & carers
  • Reality orientation: reinforce name, date, place & time when speaking to the patient
  • Respite for carers
  • Day hospital attendance
  • Involve occupational therapy
  • Involving a community psychiatric nurse
  • See if they are eligible for benefits
  • Address type of accommodation
  • Recommend support from voluntary organisations

Specific Management for underlying cause

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Raised Intracranial Pressure, raised ICP

Diseases, , , ,

This is an abnormality that can occur due to multiple potential causes. It is treated based on the underlying cause and severity.

Diagnosis:

Intracranial pressure monitoring:

  • Ventriculostomy (external ventricular drain EVD)
  • Implantable ICP monitor
  • Lumbar drain

Raised opening pressure on Lumbar puncture (e.g. in cases of pseudotumor cerebri or meningitis). This should not be performed if mass effect is suspected.
May be suspected on clinical grounds based on examination and cross-sectional imaging.
MRI (indirect signs):

  • Optic nerve sheath to optic nerve diameter =or>2.5mm at it’s widest, suggests papilledema and raised intracranial pressure.
  • Used to assess the underlying cause or the consequences.

 

Investigations to consider:

CT head
MRI, MRV
ABG
Complete metabolic panel, Calculate osmolality, Measure osmolality, calculate osmolar gap (gives you a measure of Mannitol)
X-ray skull
Catheter angiography: central venous sinus thrombosis (CVST), aneurysms,
Lumbar puncture: only after CT negative for mass lesion
Isotope cisternography
Intracranial pressure monitor device
Ventriculostomy (external ventricular drain)

Treatment:

Treat the cause
Keep head slightly elevated

Interventions to consider:

Steroids: for neoplastic lesions (tumors) only. Contraindicated in traumatic brain injury (TBI) and not beneficial in stroke
Hyperosmolar therapy:

  • Mannitol:
    • Mannitol initial bolus 1-2g/kg, then 0.25-1g/kg q4-6hr PRN,
    • Keep osmolality 290 to 320mmol/L, Keep it near upper limit, keep Na <155. Calculate Osmolal gap: measured osmolality – calculated osmolality. Keep it <55 to avoid acute renal failure with mannitol.
    • Mannitol onset of action is ~90 min.
  • Hypertonic saline:
  • Hypertonic saline 23.4% NaCl, 30 – 60 mL IV bolus over 3 – 5 minute
  • Hypertonic saline 3% NaCl infusion via central line, titrate 30-50ml/hr, up to 30ml/hr can be done via peripheral IV
  • Hypertonic saline 3% NaCl bolus: 250 mL IV bolus over 20 – 30 minutes q4 – 6h
  • Titrate to Na+ 150-160mmol/l

Hyperventilation (works faster than mannitol):

  • Maintain blood gases within the following ranges:
    • PCO2 4-4.5 Kpa, 30-40 mmHg (or short period of 28-32 if severe)
    • PO2 >70 mmHg

Anelgesia and sedation:

  • Mild to Moderate to deep analgesia and sedation

More advanced interventions:

  • Induced Hypothermia
  • Pharmacological paralysis with NMJ blockers:
    • Atracurium: Loading dose = 0.5 mg/kg IV, Maintenance dose 4 – 25 mcg/kg/min continuous IV infusion
    • Vecuronium: Loading dose = 0.1 mg/kg IV, Maintenance dose 0.8 – 2 mcg/kg/min continuous IV infusion
  • Deep barbiturate coma; pentobarbitone, thiopentone

Surgical interventions:

  • Ventriculostomy (External ventricular drain EVD)
  • Hemicraniectomy, suboccipital craniotomy, wide bilateral craniotomies

Historical:

  • Glycerol 10% solution, 1g/kg NG q6h

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Cerebral Edema

Diseases, , , ,

This is an abnormality that can occur due to multiple potential causes. It is treated based on the underlying cause and severity.

Diagnosis:

CT:

  • Hypodensity
  • Local effacement of sulci and ventricles and cisterns
  • Blurring of the grey-white interface

MRI:

  • DWI: Allows differentiation between vasogenic (no abnormal diffusion restriction) vs. cytotoxic (abnormal diffusion restriction) types of cerebral edema
  • FLAIR: hyperintensity, Local effacement of sulci and ventricles and cisterns
  • T2: hyperintensity, Local effacement of sulci and ventricles and cisterns
  • T1: not very sensitive, may show hypointensity
  • T1 plus contrast: may show enhancement if the Blood brain barrier (BBB) is interrupted

Treatment:

Treat the underlying cause
Consider steroids (dexamethasone for some causes:

  • Steroids useful in brain tumor cerebral edema
  • No steroids for stroke (ischemic or hemorrhagic) cerebral edema
  • No steroids for traumatic brain injury (TBI) cerebral edema

Consider treatment of raised intracranial pressure (ICP) if necessary:

  • see under ICP section

Consider Surgical decompression even if ICP is normal in certain circumstances:

  • Large Middle cerebral artery infarcts
  • Large cerebellar hemisphere infarcts or hemorrhages

Avoid hypotonic fluids

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Chiari Malformation

Diseases,

Synonyms:

Arnold Chiari malformation

Chiari I malforamation:

Diagnosis:

MRI

Clinical features:

  • May be asymptomatic (usually this is the case)
  • In some cases can be associated with headaches and transient brainstem dysfunction

Findings on Investigations:

MRI:

  • Low lying cerebellar tonsils extending below the foramen magnum

Treatment:

Usually no treatment
Medications for headache (but avoid overuse)
In some cases consider surgical decompression

 

Chiari II malformation:

Diagnosis:

By imaging. Chiari 1 malformation features as well as spinal cord syrinx
Prenatal diagnosis:

  • Ultrasound

Findings on Investigations:

MRI, Foramen magnum MRI, sagittal:

  • Tonsillar herniation: Cerebellar tonsils extending >3-5mm into the foramen magnum
  • +/-associated syringomyelia

Pathology:

  • a spinal meningomyelocoele +crowding of the hindbrain i.e. Small posterior fossa
  • Herniation of the cerebellar vermis through the foramen magnum.
  • Aqueductal stenosis or forking of the aquduct.
  • Distortion of the brainstem e.g. beaking of the tectum, Z shaped or kinked medulla,
  • Distortion of the spinal cord e.g. hydromyelia, diplomyelia
  • +hydrocephalus

Microscopically: disorganised Purkinje and granule cell layer in the displaced vermis

Treatment:

Shunt insertion
Consider surgical decompression

JC virus Granule Cell Neuronopathy (JCV GCN)

Diseases, ,

Diagnosis:

Clinical features plus MRI and evidence of JC virus infection

Clinical features:

ataxia

Findings on Investigations:

MRI:

  • Cerebellar atrophy with or without features of PML

CSF:

  • JC virus positive

Pathology, biopsy:

Cerebellum: focal Internal granule cell layer loss, some enlarged granule cell neurons
Special studies:

  • Immunohistochemistry for polyomavirus: positive
  • In situ hybridization ISH for JCV DNA

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Osmotic Demyelination Syndrome

Diseases, , ,

Synonyms:

central pontine myelinolysis, and extrapontine myelinolysis

Diagnosis:

Clinical features plus MRI plus history of rapid change (increase or decrease) in sodium levels

Clinical features:

Encephalopathy, coma, quadriparesis, upper motor neuron signs, dysphagia

Findings on Investigations:

MRI :

  • T2 : high signal in pons, basal ganglia, thalami
  • FLAIR: high signal in pons, basal ganglia, thalami

Treatment:

Supportive care

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Organic-Solvent Related Acute Leukoencephalopathy

Diseases, ,

Diagnosis:

Clincial features, exposure to solvent and MRI

Clinical features:

Solvent exposure
Rapidly progressive dementia, akinetic mute, other features

Findings on Investigations:

MRI:

  • Diffuse symmetric involvement of white matter

Pathology:

PAS-positive macrophages
Electron microscopy EM: membrane-bound lamellar material within macrophage

Treatment:

Supportive care

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Heroin related Acute leukoencephalopathy “chasing the dragon"

Diseases, ,

Diagnosis:

Clinical features plus MRI

Clinical features:

Initially: Ataxia, dysmetria, and dysarthria, gait abnormalities
Later on: akinetic mute, spastic quadraparesis,
After recover: tremor
Inhalation of vaporised heroin (heroin pyrolysate) “chasing the dragon”

Findings on Investigations:

MRI:

  • Involvement of white matter (cerebellum, posterior cerebrum, posterior limbs of the internal capsule, splenium of the corpus callosum, medial lemniscus, and lateral brainstem), and basal ganglia
  • T2: hyperintensity Diffuse, symmetrical in above regions
  • MRS: raised lactate

Pathology:

Spongiform leukoencephalopathy (white matter spongiform degeneration) with relative sparing of U-fibers
Electron microscopy EM: intramyelinic vacuolation with splitting of intraperiod lines

Treatment:

Supportive care

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Hashimoto Encephalopathy

Diseases, ,

Synonyms:

Steroid Responsive Encephalopathy Associated With Autoimmune Thyroiditis SREAT a.k.a. Hashimoto’s encephalopathy

Diagnosis:

A diagnosis by exclusion with the following:

  • Encephalopathy characterised by:
    • Tremor, transient aphasia, myoclonus, gait ataxia, seizures, and sleep abnormalities
  • +no other identifiable cause
  • +Positive antithyroid antibodies: anti-thyroglobulin or anti-thyroperoxidase antibodies
  • +/-abnormal TFTs: usually hypothyroidism, but may be euthyroid to hyperthyroid
  • +response to steroids

Findings on Investigations:

CSF: mildly elevated protein, mild lymphocytic pleocytosis may occur, normal IgG index
EEG: Generalized slowing other findings; focal slowing, triphasic waves, epileptiform abnormalities, and photomyogenic response
MRI: T2 & FLAIR white matter high signal
Catheter angiography: normal

Treatment:

Methylprednisolone 1 g/d intravenously for 5 days followed by predinosolone 60mg/d for 10-30 days.
If it does not respond to therapy, consider investigations for CJD or other subacute encephalopathies

Related articles:

References:

  1. Castillo P, Woodruff B, Caselli R, Vernino S, Lucchinetti C, Swanson J, Noseworthy J, Aksamit A, Carter J, Sirven J, Hunder G, Fatourechi V, Mokri B, Drubach D, Pittock S, Lennon V, Boeve B. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006 Feb;63(2):197-202.

Progressive Multifocal Leukoencephalopathy (PML)

Diseases, , ,

Diagnosis:

Clinical and imaging features plus laboratory findings

Clinical features:

Gradual onset & progressive. Seizures & aphasia may occur
Occurs in the setting of immunosupression: e.g. HIV infection/AIDS, immunosupressant medications,

Findings on Investigations:

JC virus in CSF: by PCR
MRI:

  • White matter lesions, usually asymmetric but bilateral, periventricular and subcortical involvement of U fibres, spares cortex, confluent, usually parieto-occipital, may involve corpus callosum, don’t conform to cerebral territories, lesions may extend from the white matter to the deep grey matter
  • No edema, no mass effect or enhancement
  • T2: increased signal
  • T1: decreased signal
  • T1+gadolinium: no enhancement

CT:

  • Hypodense white matter lesions

Pathology, brain biopsy:

Demyelination: macrophages with myelin
JC oligodendrocytes with intranuclear inclusions (enlarge amphophilic nuclei)
Astrocytic gliosis with bizarre astrocytes
No inflammatory infiltrate unless associated with immune reconstitution syndrome where there are lymphocytes
Special studies:

  • Immunohistochemistry for polyomavirus: positive
  • In situ hybridization ISH for JCV DNA

Treatment:

Treat the underlying cause of immunosuppression

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Disseminated Necrotizing Leukoencephalopathy (DNL)

Diseases,

Synonyms:

a.k.a. Multifocal necrotizing leukoencephalopathy

Diagnosis:

Clinical +MRI +/-biopsy
Occurs after Radiation therapy and/or chemotherapy

Clinical features:

Encephalopathy
Occurs after Radiation therapy and/or chemotherapy

Findings on Investigations:

CT:

  • White matter, Periventricular, centrum semiovale. Spares the U fibres
  • Hypodensity in white matter. Enhancement can occur.

MRI:

  • White matter, Periventricular, centrum semiovale. Spares the U fibres
  • T2 hyperintensity. Enhancement can occur.

Pathology:

Necrosis, reactive gliosis, axonal swelling, demyelination,
White matter necrosis, necrosis & loss of myelin & axons which may calcify, lipid-laden macrophages.
Due to:

  • Radiation therapy and/or chemotherapy
  • Septic shock
  • Other insults

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Acute Disseminated Encephalomyelitis (ADEM)

Diseases, ,

Synonyms:

a.k.a. Acute dissemniated leukoencephalitis a.k.a. Acute postinfectious/post-vaccinial perivenous encephalitis, a.k.a. acute demyelinating encephalomyelitis,

Diagnosis:

Clinical  features plus MRI and supportive tests

Clinical features:

Encephalopathy, focal findings may occur. Often follows an infectious illness or exposure to new antigen to medication

Findings on Investigations:

MRI

  • T2: preferred. High signal intensities (large patchy) in white matter in the brain (subcortical & deep, may extend to ventricles) +/-spinal cord and deep grey nuclei. May or may not enhance with gadolinium.

CT: some areas of hypoattenuation in the white matter and deep grey nuclei
CSF:

  • Protein: mildly elevated 0.5-1.5 g/L (50-150 mg/dL)
  • WCC: lymphocytic pleocytosis usually
  • IgG index: usually normal
  • Myelin basic protein: high

Pathology:

Gross: small lesions in the white matter
Microscopically: perivenous lymphocytes, macrophages & plasma cells. Perivenous demyelination, with relatively spared axons. Usually no inflammation around the arteries. Meningeal inflammatory infiltrates occur.

Acute hemorrhagic leukoencephalitis of Hurst a.k.a Acute hemorrhageic encephalomyelitis AHEM, variant:

Pathology; Grossly, disseminated foci of hemorrhage in the white matter of the cerebral hemispheres, corpus callosum, pons & cerebellum
Microscopically, fibrinoid necrosis of blood veins. Perivenous necrosis, surrounded by hemorrhages. Perivenous mononuclear cells and neutrophils. Some demyelination and axonal loss.

Investigations to consider:

MRI
LP for CSF analysis
Viral screen:

  • Measles, paramyxovirus, varicella, rubella, and Epstein-Barr virus
  • Mycoplasma pneumoniae serology & cold agglutinins

Treatment:

Consider:

  • Corticosteroids
  • IVIG
  • Plasma exchange

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Empty Sella Syndrome

Diseases,

Diagnosis:

An imaging finding that may or may not be associated with clinical features

Clinical features:

Mild headache, CSF rhinorrhea, hypertension, obesity

Findings on Investigations:

CT: empty sella i.e. sella turcica that is completely or partially filled with CSF,
MRI: empty sella i.e. sella turcica that is completely or partially filled with CSF,
TSH, gonadotrophin: low

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Biotin-Responsive Encephalopathy

Diseases, , ,

Diagnosis:

Clinical features, laboratory testing and MRI

Clinical features:

Ophthalmoplegia, nystagmus, ataxia, diplopia and ptosis
Complex partial seizures with status epilepticus.
Thiamine-responsive

Genetics:

Thiamine-Transporter Gene

Findings on Investigations:

MRI:

  • High-intensity signals in the bilateral medial thalamus

Laboratory:

  • Thiamine levels: normal

Treatment:

Thiamine

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Wernicke Encephalopathy

Diseases, ,

Diagnosis:

Clinical features lone or with MRI findings or low B1 levels
+/-Response to thiamine treatment
+/-B1 Thiamine: by functional transketolase assay, thiamine chromatography or urinary thiamine

Clinical features:

Triad:

  • Confusion, ataxia, ophthalmoplegia
  • Not all features are necessary. Occasionally hypothermia occurs.

Findings on Investigations:

MRI features:

  • Hyperintense signals in the periaqueductal gray area, dorsal medial nucleus of the thalamus and the mammilary bodies
  • Hyperintensity of the mammillothalamic tracts.

Investigations to consider:

MRI
B1 Thiamine level

Treatment:

Thiamine, initially 100 mg intravenously multiple times a day, then orally

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Normal Pressure Hydrocephalus

Diseases, ,

Diagnosis:

A combination of clinical features, response to high volume lumbar puncture spinal tap plus imaging

Clinical features:

Gait disorder, the first symptom:

  • Marche a petis pas: wide-based slow shuffling gait
  • Ignition failure: hesitation on starting to walk
  • Magnetic foot: difficulty lifting foot of the ground
  • Poor postural control

Cognitive impairment:

  • Apathy, memory impairment

Urinary incontinence & frequency: late finding
Other findings:

  • grasp reflex, no papilledema, no paresis, no ataxia, normal alternate movements, no rigidity, no tremor,

Findings on Investigations:
CT:

  • Large ventricles, normal sulci.
  • No evidence for CSF flow obstruction

MRI:

  • Large ventricles, normal sulci.
  • No evidence for CSF flow obstruction
  • Transependymal edema (egress of CSF) may occur

+High volume LP with gait testing, a modification of the Fisher test:

  • Opening pressure usually 15-20 cmH2O
  • Walk patient multiple times
  • Remove 30ml CSF,
  • Walk patient multiple times & observe for improvement

Trial of Lumbar drainage with Temporary catheter in lumbar region
Cisternography i.e. Radionucleotide CSF studies: poor predictive value
Cine-MRI (cine phase contrast):

  • Measures cerebral aqueduct CSF stroke volume, if >100 microL suggest shunt responsiveness, if <80 microL suggest shunt unresponsiveness
  • This test is controversial

Investigations to consider:

LP with opening pressure & CSF analysis & Fisher test (lumbar tap test)
Imaging

Treatment:

Consider CSF Shunt placement

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Frontotemporal Dementia (FTD)

Diseases, ,

Synonyms:

a.k.a. Frontotemporal lobar dementia FTLD

Diagnosis:

Clinical features, plus supportive imaging

Clinical features:

Behavioural symptoms:

  • Progressive change in personality
  • Decline of reasoning
  • Social inappropriateness

Primary progressive aphasia:

  • Anomia (inability to retrieve nouns upon demand),
  • Agrammatism (inappropriate word order or use of prepositions),
  • Loss of semantic knowledge about words and objects

Clinical variants: progressive nonfluent aphasia, semantic dementia,

Findings on Investigations:

CT: symmetric lobar atrophy of the temporal +/-frontal lobes
MRI: symmetric lobar atrophy of the temporal +/-frontal lobes
SPECT:

  • Regional hypoperfusion in frontal & anterior temporal lobes

Pathology:

Brain biopsy or autopsy findings: gold standard
See under the following headings
Tauopathies:

  • Tau accumulates (microtubule associated protein tau MAPT gene chr. 17q21)

Pick disease:

  • Pick bodies = tau positive intraneuronal inclusions in frontotemporal cortex & hippocampus.
  • Pick cells = tau positive neurons with swollen eosinophilic cytoplasm.
  • Cortical Neuronal loss & microvacuolation may occur

Multiple system tauopathy FTLD-MST:

  • Also affects substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus
  • Tau positive intraneuronal & glial inclusions
  • Usually familial

Frontotemporal dementia and parkinsonism linked to chromosome 17 FTLDP-17:

  • A rare familial form

Tau negative FTLD
FTLD with ubiquitin only staining FTLD-U:

  • The ubiquinated protein in the inclusions is TAR DNA binding protein 43 a.k.a. TDP-43 (TARDBP gene chr. 1). Normal neurons have TDP-43 in the nucleus, abnormal neurons have cytoplasmic TDP-43 inclusions.

FTLD with motor neuron disease FTLD-MND:

  • Cortical Microvacuolation & neuronal loss.
  • Subcortical gliosis. Basal ganglia atrophy.
  • Ubiquitin +TDP-43 inclusions in cortical neurons & hippocampal dentate granule cells
  • Degeneration of motor neurons
  • Dementia lacking distinctive histology DLDH

Neuronal intermediate filament inclusion disease (NIFID):

  • Neurofilament positive & alpha-internexin positive cytoplasmic inclusions, ubiquitin positive intranuclear inclusions

Genetic/familial forms in FTD:

  • Mutations in PGRN gene chr. 17q21, the protein is progranulin, causes FTLD-U.
  • Mutations in MAPT gene chr. 17q21, the protein is tau, causes: FTDP-17 or FTLD-MST
Pick’s disease:

Diagnosis, Pick’s disease:

  • CT or MRI: symmetric lobar atrophy of the temporal +/-frontal lobes

Pathology:

  • Autopsy findings are the gold standard
  • This is a form of frontotemporal dementia FTD

Treatment for Frontotemporal dementia:

Supportive care

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Vascular Parkinsonism

Diseases, , ,

Diagnosis:

Clinical features plus supportive MRI and poor response to dopamine agonists

Clinical features:

  • Lower body Parkinsonism. Variable cognitive & behavioural deficits.
  • May accompany vascular dementia

Findings on Imaging:

MRI: multiple subcortical infarcts +/-subcortical leukoaraiosis

Treatment:

Supportive care
Address vascular risk factors

Related articles:

Vascular Dementia

Diseases, ,

Diagnosis:

Vascular dementia VaD, NINDS AIREN criteria for probable disease:

Dementia +evidence of cerebrovascular disease +a relationship between them
Evidence of cerebrovascular disease:

  • Clinical features:
    • Exam showing evidence of previous
    • Also, a triad of: short shuffling gait “marche au petit pas”, pseudobulbar palsy, pseudobulbar affect can occur.
  • MRI (1st choice) or CT:
    • Large vessel disease:
      • Bilateral anterior cerebral artery
      • Dominant lobe: inferior medial temporal lobe, parieto-temporal association, tempero-occipital association, paramedian thalamic, angular gyrus, frontal parietal watershed areas,
    • Small vessel disease (subcortical vascular dementia):
      • White matter hyperintensity WMH
      • >25% of white matter, frontal lacunes, multiple basal ganglia or bilateral thalamus
  • Relationship:
    • Dementia <3 months of a stroke
    • Abrupt deterioration or stepwise progression

Vascular cognitive disorder is the umbrella heading that includes vascular dementia, vascular cognitive impairment VCI i.e. without dementia, cerebrovacular disease with Alzheimers disease

Treatment:

General measures for dementia
Vascular risk modification:

  • Control blood pressure e.g. by ACE inhibitor
  • Aspirin
  • Consider: statin

Dementia:

  • Galantamine does not work

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Transient Global Amnesia

Diseases,

Diagnosis:

Clinical features plus supported investigations

Clinical features:

Acute onset. Lasts 1-24 hours.
Complete antrograde amnesia & limited retrograde amnesia (weeks or months).
May be disoriented to time, place but not to self.
Preserved cognitive functions apart from memory & disorientation
No decrease in level of consciousness. Able to interact appropriately during the episode
No other neurological features apart from: headache, dizziness,
No recent trauma or seizure

Findings on Investigations:

MRI:

  • DWI: occasionally punctate hyperintensities in the hippocampus in dominant lobe or bilaterally.
  • May be completely normal

SPECT: hypoperfusion in temporal lobe & hippocampus acutely. Resolves by 1 week.
EEG: normal

Treatment:

No is necessary. This is a self limited condition.

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Gerstmann–Sträussler–Scheinker Syndrome:

Diseases, , ,

Diagnosis:

Clinical features plus imaging

Clinical features:

2-10 years, Progressive ataxia & dementia
Truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria
Supranuclear gaze palsy
Pyramidal signs

Pathology:

Amyloid plaques: PrP positive
Minimal spongiform (vacuolar) change
PRNP gene (GSS102) chr. 20p mutation usually Pro102Leu, octapeptide repeats also occur.

Findings on Investigations:

EEG: slowing
MRI:

  • Normal or cerebellar atrophy
  • T2 hypointensity in basal ganglia (iron)

SPECT: abnormal cerebral SPECT findings.

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Fatal Familial Insomia

Diseases, , ,

Diagnosis:

Combination of clinical features and imaging

Genetics:

Autosomal dominant

Clinical features:

Insomnia, sympathetic over activity, impaired attention
Ataxia, dysarthria,
Memory loss
Hormone abnormalities: increased cortisol,
Polysomnography: reduced total sleep time, absent REM sleep, absent deep nonREM sleep,

Findings on Investigations:

MRI:

  • Normal or cerebral or cerebellar atrophy

PET:

  • Decreased metabolism in the thalami

CSF:

  • 14-3-3. usually negative

Pathology:

Neuronal loss & gliosis: Thalamic (mediodorsal & anteroventral nuclei), inferior olivary nuclei
PrP in cerebellum, olivary nuclei, neocortex
Spongiform (vacuolar) change
PRNP gene chr. 20p mutation usually D178N with methionine at codon 129.

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Variant Creudtzfedt-Jakob Disease (vCJD)

Diseases, , ,

Synonyms:

New variant CJD,

Diagnosis:

Clinical +/-EEG +/-MRI +/-CSF findings +/-brain biopsy

Clinical features:

Abnormal movements (myoclonus, dystonia, chorea), ataxia, slurred speech, tremor, dementia, akinetic mutism
Non-specific sensory symptoms
Psychiatric symptoms: withdrawal, delusions, depression

Findings on Investigations:

MRI:

  • Thalamic hyperintensities: bilateral pulvinar (posterior thalamus) a.k.a. ‘Pulvinar sign’. In some there is also bilateral dorsomedial nucleus involvement creating ‘hockey stick sign’

EEG: Periodic sharp wave complexes PSWC don’t occur
CSF:

  • No inflammatory cells, sometimes increased protein
  • 14-3-3 protein: found sometimes

Pathology, Brain biopsy:

Affects: pulvinar of the thalamus
Spongiform (vacuolar) changes, gliosis,
“florid plaques”: PrP plaques, that are encircled by vacuoles. These are PrP amyloid plaques surrounded by spongiform change, size 5-50 mm, on H&E hyaline eosinophilic core surrounded by a paler halo. Smaller perivascular and pericellular (around neurons, glial cells) plaques occur.
PrP in spleen & lymphoid tissue
PRNP gene chr. 20p codon 129 status: MM

Related articles:

 

Sporadic Creutzfeldt-Jakob Disease (sCJD)

Diseases, ,

Diagnosis:

A type of transmissible spongiform encephalopathy TSE
Clinical +/-EEG +/-MRI +/-CSF findings +/-brain biopsy

Clinical features:

Rapidly progressive, death usually <1 year
Dementia (rapidly progressive), ataxia, myoclonus, rigidity, visual disturbances
Focal cortical symptoms (aphasia, neglect, apraxia, acalculia)
Akinetic mutism (late feature)
Heidenhain variant:

  • Visual symptoms: perception difficulties (colours & structures e.g. metamorphopsia/dysmorphopsia), optical hallucinations, cortical blindness & Anton syndrome (optical anosognosia)
  • Signs:
    • Balint syndrome (simultagnosia, optic apraxia, oculomotor apraxia)
    • Anton syndrome (optical anosognosia)

Findings on Investigations:

MRI, T2 or FLAIR or DW1 or proton density:

  • May be normal
  • Caudate & putamen: hyperintensity (compared with the cortex).
  • Cortical gyral hyperintensity (gyriform) especially on FLAIR, also transient DWI: May be the only finding. Occipital cortex e.g. Heidenhain variant. Subtle cortical atrophy can occur. Also associated with VV1 subtype CJD
  • -Thalamic Pulvinar hyperintensity “pulvinar sign” may occur (more common in variant CJD)
  • Normal T1, and no enhancement post contrast
  • Normal white matter, usually

EEG:

  • Periodic sharp wave complexes PSWC, these are synchronus, 1-2 Hz: may be negative
  • Diffuse slowing: later in the disease
  • Non specific changes in some types

CSF:

  • 14-3-3 protein increased in many subtypes including VV1 subtype: false positives occur
  • No inflammatory cells, sometimes increased protein
  • Tau in CSF: increased >1,300 pg/mL
  • S100b: increased
  • NSE: increased

SPECT: non-specific, hypoperfusion
PET: non-specific, hypometabolism

Pathology and Brain biopsy:

Affects: various areas of the cortex. Occipital in Heidenhain variant, basal ganglia in cases with (rigidity, athetosis, tremor). Minimal gross atrophy
H&E: Spongiform (vacuolar) changes & astrocytic gliosis & granular cell (nerve cell) loss.
Immunohistochemistry: antibody to PrP (amino acid 138 & 152)
Skeletal muscle or spleen western blott for PrP by very sensitive techniques: positive

Classification :

Prion protein PrP western blot migration patterns : type 1 or type 2
PRNP gene chr. 20p codon 129 status : either methionine M or valine V.
Subtypes MM1, MV1, VV1, MM2, MV2, VV2.

Treatment:

Supportive care

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Fungal Intracranial Abscess

Diseases, , ,

Candida abscess:

Diagnosis:

Biopsy or blood culture isolation of organisms

Treatment:

Fluconazole, amphotericin B

 

Cryptococcosis (Cryptococcus neoformans):

See under Cryptococcosis (Cryptococcus neoformans), Cryptococcal meningitis & related

 

Aspergillosis a.k.a. Aspergillus fumigatus or flavus:

Diagnosis:

Suggested by MRI, but confirmed by biopsy

Pathology:

Biopsy:

  • Within distribution of anterior or middle cerebral artery. Multiple. Necrosis, hemorrhage.
  • Microscopy: hyphae branching at acute angles, septate. Vascular invasion, thromobosis & necrosis. Neutrophil or granulomatous infiltrate,

CT: same features of abscess but in a vascular distribution with occasional infarcts
MRI:

  • Well formed capsule, features of infarction may be present,
  • T2/FLAIR: high intensity
  • T1: may have high intensity

Treatment:

Amphotericin +flucytocine
Itraconazole
Surgical debridement

 

Mucormycosis a.k.a. rhinocerebralmucormycosis a.k.a. zygomycosis, Causative agent Rhizopus arrhisus, Absidiacorymbifera:

Diagnosis:

Isolation of organism in setting of appropriate clinical and imaging findings

Pathology and microbiology:

CSF analysis: India Ink stain fungal hyphae
Palate biopsy & culture: HE fungal hyphae invading vessels (broad hyphae). Globular bodies
Fungal RNA analysis: 16s rRNA gene sequence analysis
Causative agent: Rhizopus arrhisus, Absidia corymbifera

Findings on Investigations:

CT/MRI:

  • Strokes
  • Sinusitis, orbital cellulitis

Treatment:

Amphotericin B, itraconazole
Surgical debridement

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Spinal Cord Abscess

Diseases, ,

Diagnosis:

A combination of clinical features, MRI, and biopsy

Clinical features:

Features of myelopathy

Findings on investigations:

MRI: intramedullary ring enhancing lesion,
Spinal cord biopsy & culture: confirmatory of organisms

Treatment:

Antibiotics
Consider surgical drainage

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Epidural Abscess (intracranial or spinal)

Diseases, , , ,

Diagnosis:

Imaging (MRI with and without contrast) plus biopsy for confirmation

Pathology:

Biopsy:

  • Necrosis with inflammation (neutrophils & later macrophages & lymphocytes), rim of fibrosis (if absent this is cerebritis)
  • Surrounding gliosis

Clinical features:

  • Intracranial: focal neurological deficit
  • Spinal: transverse myelopathy and a flexed posture resisting extension, back pain with fever.

Investigations to consider:

FBC, ESR, CRP
Blood cultures
LP for CSF:

  • Pleocytosis & increased protein
  • NB. Not at the site of abscess
  • Gram stain & culture of excised material

MRI, gadolinium enhanced
Consider myelography

Treatment:

Neurological emergency
Surgery, not done in some cases in absence of compression
Antibiotics:

  • Naficillin or vancomycin intravenous empirically
  • Same doses as meningitis

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Brain Abscess

Diseases, , ,

Synonyms:

Intracranial abscess a.k.a. intracerebral abscess:

Diagnosis:

Suggested by imaigng. Confirmed by biopsy and culture

Clinical features:

  • Presents with focal neurological deficits: weakness, aphasia, neglect
  • May present with headache or seizure
  • Meningismus in <30%

Pathology:

Biopsy:

  • Necrosis with inflammation (neutrophils & later macrophages & lymphocytes), rim of fibrosis (if absent this is cerebritis)
  • Surrounding gliosis
  • See fungal section for further details
  • Toxoplasma gondii section for further details

Findings on Investigations:

MRI:

  • Smooth walled, usually thin walled lesion at grey-white interface
  • Surrounding edema
  • Enhances with contrast, ring. Meningeal enhancement may occur
  • DWI: may be bright as opposed to neoplasms

Investigations to consider:

Complete blood count
CT noncontrast & contrast, or MRI:

  • Lesion with enhanced rim a.k.a. ring enhancing lesion
  • +surrounding edema
  • +smooth capsule

MRI:

  • DW: high signal, differentiates central necrosis from necrosis in tumors which is low signal.

If drained: MC&S of the aspirate

Treatment:

Antibiotics to cover appropriate organisms e.g. Penicillin G intravenous +metronidazole intravenous
Decrease edema: glucocoticoids
+/-surgical drainage

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Intracranial Empyema

Diseases, , ,

Diagnosis:

A combination of clinical features, imaging and Growth on cultures from the collection

Clinical features:

seizures, cognitive dysfunction, hemispheric symptoms (aphasia, apraxia, hemiparesis)

Findings on Investigations:

CT: cavity +low density +gas
MRI: resectricted diffusion in an axtra-axial collection
Growth on cultures from the collection

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Subacute Sclerosing Panencephalitis (SSPE)

Diseases, , ,

Diagnosis:

Clinical features, plus EEG

Clinical features:

Previous measles infection. Children or young adults.
Subacute onset of progressive cognitive deficits, behavioural problems, spasticity, rigidity,
Myoclonus, generalised seizures

Findings on Investigations:

EEG: flat with episodic bursts
Anti-measles antibodies
CSF: raised IgG index

Pathology:

Gross: hard brain (gliosis), Microscopic: intracellular (type A) and intracytoplasmic neuronal and glial inclusions

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HIV Associated Neurocognitive Disorders (HAND)

Diseases, ,

Synonyms:

HIV associated dementia HAD, formerly Subacute or Chronic HIV encephalitis a.k.a. AIDS dementia complex formerly AIDS encephalopathy/AIDS encephalitis

Diagnosis:

Acquired impairment in at least 2 cognitive domains:

  • Learning, information processing speed, attention/concentration
  • +Marked impairment of ADLS
  • +No delirium
  • +No other cause for dementia
  • Other features & tests:
    • Limb incoordination, gait ataxia, abnormal smooth pursuit & saccades

Findings on Investigations:

CSF: may be normal, mild leukocytosis, mildly increased protein.
MRI: may be normal, diffuse white matter changes may occur

Pathology:

Multiple patterns may occur
HIV encephalitis: multifocal multinucleated giant cells in white matter & deep grey matter, with rarefaction of white matter (pallor & decreased myelin), and some inflammatory cells (microglial nodules, macrophages, scant lymphocytes) with astrocytosis
HIV leukoencephalopathy: diffuse white matter lesions, with rarefaction of white matter (pallor & decreased myelin) & loss of axons (beta amyloid precursor protein)
Diffuse Poliodystrophy= wasting of grey matter: diffuse astrocytosis & microglia in the cortex with neuronal loss.

HIV associated mild neurocognitive disorder MND

Diagnosis:

Acquired impairment in at least 2 cognitive domains:

  • Verbal/language, information processing speed, attention/working memory, abstraction/executive memory (learning/recall), sensory-perceptual, motor skills
  • +Mild decline (self report or observed) in functioning (home, work or social)
  • +No delirium or dementia
  • +No other cause

HIV associated asymptomatic neurocognitive impairment ANI

Diagnosis:

Deficits in neuropsychological testing
+Cognitive decline doesn’t lead to impairment of ADLS
+No delirium or dementia
+No other cause

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Nonparaneoplastic Autoimmune Limibic Encephalitis

Diseases, ,

Diagnosis:

Clinical features plus antibodies and negative investigations for neoplastic disease

Clinical features:

Subacute impairment, seizures, temporal lobe seizures & hallucinations,

Findings on Investigations:

Associated antibodies:

  • VGKC, voltage-gated potassium channels (Kv1) antibodies:
  • These are positive in patients with limbic encephalitis, Morovan’s syndrome. These have differnet targets.
  • Lgi1: leucine-rich, glioma inactivated 1 protein, a subtype of VGKC found in limbic encephalitis.
  • Caspr2: contactin-associated protein-antibody-2, a subtype of VGKC found in Morovan’s syndrome
  • anti-NMDA receptor antibodies

MRI: may show medial temporal lobe FLAIR hyperintensity & enhancement

Related articles:

Paraneoplastic Encephalomyelitis, Paraneoplastic Encephalitis

Diseases, , ,

Synonyms:

a.k.a. paraneoplastic encephalitis, a.k.a. paraneoplastic limbic encephalits

Diagnosis:

A combination of serology,  clinical features and identification of underlying tumor

Clinical features:

Subacute impairment, seizures, temporal lobe seizures & hallucinations,
Other features may occur:,

Pathology:

Limbic encephalitis (medial temporal lobe, hippocampus, amygdala, cingulate gyrus, inula), thalamus, brainstem encephalitis, cerebellum, spinal cord grey matter, dorsal root ganglia (sensory neuropathy), peripheral nerves, myenteric plexus.
Gross: bilateral necrosis.
Microscopy:

  • CNS: Massive neuronal loss, neuronophagea. Astrocytic gliosis, rod-shaped microglia. Perivascular & intraparenchymal lymphocytic infiltrates.
  • Ganglia: loss of ganglion cells. Prominent inflammatory infiltrates.
  • Peripheral nerves: axonal degeneration with secondary demyelination. Mild perivascular & parenchymal mononclear infltrates.

Findings on Investigations:

MRI: usually bilateral involvement of temporal lobes. Atrophy of the temporal lobe is common. Brainstem or hypothalamic involvement may occur. Hemorrhage is rare. T2 hyperintense, FLAIR hyperintense.
Antibodies:

  • Limbic encephalitis  autoantibodies:
    • Some of these autoantibodies are more strongly associated with neoplasm that others
    • Anti-: Hu (ANNA-1), amphiphysin, CV2/CRMP5, LGI1, CASPR2, VGKC, NMDA (NR1), GAD65, MaTa,
  • Voltage-gated potassium channels VGKC, usually not paraneoplastic
  • Anti-NMDA receptor antibodies: ovarian teratoma. Associated with orolingual dyskinesias & catatonia like state.

Treatment:

Treat the underlying tumor
Consider IVIg, plasma exchange,

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Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)

Diseases, , ,

Diagnosis:

Clinical features, MRI and occasionally biopsy

Clinical features:

Episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and had a favourable initial response to high dose glucocorticosteroids

Findings on Investigations:

+MRI:

  • Symmetric curvilinear gadolinium enhancement peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally spinal cord

Pathology:

white matter perivascular, predominantly T lymphocytic, infiltrate without granulomas

Treatment:

Glucocorticosteroids, if unable to taper add on other immunosuppressants

Idiopathic Hypertrophic Cranial Pachymeningitis

Diseases,

Diagnosis:

Rare, A diagnosis by exclusion
Note: Pachymeningitis is a radiologic pattern

Clinical features:

Severe headache, cranial nerve palsies, ataxia, loss of vision (optic nerve involvement)

Pathology:

Biopsy: Meningeal Polymorphonuclear infiltration

Findings on Investigations:

MRI:

  • T1 +contrast: enhancement of the meninges without enhancement of the sulci. Involves the tentorium, falx, calvarium
  • T2: hypointense dura

Investigations to consider:

LP, CSF analysis:

  • Opening pressure: low in spontaneous intracranial hypotension
  • Routine analysis: infectious meningitis
  • Cytology to rule out leptomeningeal carcinomatosis (carcinomatous meningitis)

Biopsy: sarcoidosis, plasmacytic tumors

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Optic Neuritis

Diseases, ,

Diagnosis:

Clinical features with or without imaging or physiological tests

Clinical features:

Painful, loss of vision, & loss of accurate colour vision (dyschromatopsia)
Fundoscopy: swollen optic disc (optic disc edema, this is not papilledema because pressure is normal),
Relative afferent papillary defect

Findings on Investigations:

MRI: T2 fat suppressed, high signal foci in the optic nerve, minimal or no nerve expansion, enhancement post contrast.
Optical coherence tomography OCT: retinal layer thickness is increased in acute optic neuritis.  Retinal layer thickness is decreased by 3 months.

Investigations to consider:

Those for multiple sclerosis, see multiple sclerosis for more details
Lumbar puncture, CSF electrophoresis
MRI
Blood tests:

  • Anti-NMO antibody,
  • VDRL, FTA-ABS, Lyme serology, CMV serology, VZV serology, cryptococcal antigen, measles serology, mumps serology,
  • B1, B12 levels: nutritional deficiency optic neuropathy
  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • ACE levels: neurosarcoidosis
  • Anti-CRMP5, Anti-CAR (anti-recoverin): cancer associated retinopathy
  • Quantiferon: tuberculosis

Visually evoked response VER: increased latencies, reduced amplitude in >65%
Multifocal VER: more sensitive & specific than VER
CT chest abdomen & pelvis: lung cancer in cancer associated retinopathy
Lymph node biopsy: Bartonella henselae (cat-scratch disease)

Treatment:

Methylprednisolone 1000 mg intravenously daily for 3 -5 days. Some physicians consider following it by prednisolone 1 mg/kg orally X11 days +taper over 4 days.

Causes of optic neuropathy:

Optic neuritis:

  • Multiple sclerosis
  • Neuromyelitis optica
  • Systemic lupus erythematosus, Sjogren’s syndrome, Wegener grandulomatosis, Behcet’s disease inflammatory bowel disease,
  • Neuro-Sarcoidosis
  • Chronic relapsing inflammatory optic neuropathy

Ischemic optic neuropathy:

Infection:

  • Syphilis
  • Lyme disease
  • Tuberculosis
  • Bartonella henselae (cat-scratch disease)
  • CMV
  • VZV
  • Measles, mumps,
  • Cryptococcus

Paraneoplastic:

Noninflammatory:

  • Genetic:
    • Leber’s hereditary optic neuropathy (LHON)
    • Dominant optic neuropathy (Kjers’ type, OPA1 gene, Chr. 3q), Recessive optic neuropathy (X-linked, OPA2),
  • Tobacco-alcohol amblyopia a.k.a. nutritional optic neuropathy
  • B1, B2, B3, B6, or B12 deficiency: nutritional optic neuropathy
  • Compression by internal carotid artery aneurysm at the siphon i.e. infrasellar aneurysm
  • Drugs and toxins: Ethambutol, Chloraphenicol, amiodarone, methanol,
  • Radiation optic neuropathy
  • Traumatic optic neuropathy
  • Neoplastic:

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Neuromyelitis Optica

Diseases, , ,

Synonyms:

a.k.a. Devic’s disease

Diagnosis:

A combination of clinical features, NMO-IgG antibodies and imaging

Clinical features:

simultaneous or sequential occurrence of optic neuritis and myelitis (usually acute complete transverse myelitis).

Findings on Investigations:

MRI:

  • Spinal cord lesion =or> 3 segments long
  • Non-diagnostic for Multiple sclerosis
  • White matter lesions that are long & extend from the ventricle to the cerebrum
  • Periaqueductal lesions
  • Floor of the fourth ventricle lesions

NMO- IgG (targets Aquaporin-4): positive in blood.
Other tests:

  • Other antibodies: occasionally positive
  • CSF: pleocytosis >50 WBC, >5 PMN

Pathology:

Demyelinating plaques
Loss of Aquaporin-4.

Treatment:

Acutely:

  • Plasmaphoresis [case series]
  • IVIg [case reports]

Chronically:

  • Rituximab, Monitor B-cell flow cytometry panel [case series]
  • Azathioprine [case series]

Related articles:

 

Lumbar spinal stenosis

Diseases, , ,

Synonyms:

formerly ‘pseudoclaudication’

Diagnosis:

Any developmental or acquired narrowing of the spinal canal (spinal canal stenosis), nerve root canal, or intervertebral foramina a.k.a. neural foramina, that results in compression of neural elements
Clinical features: (must be present)

  • Pain & numbness in lower back, buttocks & legs on walking or lumbar extension
  • History: Painful gait, Absence of pain while seated (symptoms exacerbated by lumbar extension, relieved by flexion)
  • Physical examination: Wide based gait, flexed posture

NCS/EMG:

  • SNAP: normal
  • CMAP: normal distal latency, conduction velocity & amplitude. In some cases amplitude may be decreased
  • H-reflex: may be absent if S1 is involved
  • F-waves: nonspecific
  • EMG: consistent with radiculopathy in multiple myotomes

CT myelgraphy: if MRI is contraindicated
MRI:

  • Asymptomatic cervical & lumbar stenosis is common. [312]
  • T2: High signal within the cord may occur, nonenhancing
  • Central canal stenosis: the spinal canal is narrowed
  • Lateral spinal stenosis: nerve root canal (from epidural sac through the intervertebral foramen) or intervertebral/neural foramina are narrowed.
  • Subarticular stenosis: area under the facet joints is narrowed
MRI features of Central spinal canal stenosis:
  • Compression of central spinal canal: graded no stenosis, mild stenosis <1 third, moderate stenosis 1 to 2 thirds, severe stenosis >2 thirds.
  • Reduction of anterior CSF space
  • Reduced or absent fluid around cauda equina
  • Hypertrophy of ligamentum flavum
  • Epidural lipomatosis
  • Reduction of posterior epidural fat
  • Nerve root sedimentation sign
  • Redundant nerve roots of cauda equina
MRI features of Lateral recess stenosis:
  • Compression of subarticular zone: graded no stenosis, mild stenosis <1 third, moderate stenosis 1 to 2 thirds, severe stenosis >2 thirds.
  • Visible nerve root compression in lateral recess

Retrolisthesis, may be present:
By definition retrolisthesis is a movement (subluxation) of >=2mm of the vetebral body posteriorly in relation to the vertebral body below it.
Retrolisthesis grading:

  • Can be graded my measuring the retrolisthesis in mm.
  • Can be graded by the intervertebral foramina IVF method:
    • Divide the intervertebral foramina into into 4 equal units.
    • Grade 1 posterior displacement of up to 25% of the IVF
    • Grade 2 posterior displacement of 25% to 50%
    • Grade 3 posterior displacement of 50% to 75%
    • Grade 4 posterior displacement of 75% to 100

Retrolisthesis classification:

  • Complete Retrolisthesis: The body of the subluxed vertebra is is posterior to both the body of the vertebra above as well as the segment below
  • Stair stepped Retrolisthesis: The body of the subluxed vertebra is posterior to the body of the vertebra above but is anterior to the one below.
  • Partial Retrolisthesis: The body of the subluxed vertebra is posterior to the body of the vertebra segment either above or below.

 

Treatment:

Consider surgery

Related articles:

References:

  1. Mamisch N, Brumann M, Hodler J, Held U, Brunner F, Steurer J; Lumbar Spinal Stenosis Outcome Study Working Group Zurich. Radiologic criteria for the diagnosis of spinal stenosis: results of a Delphi survey. Radiology 2012; 264:174–179
  2. Gustav Andreisek G, Imhof M, Wertli M, Winklhofer S, Pfirrmann C, Hodler J, Steurer J; Lumbar Spinal Stenosis Outcome
  3. Study Working Group Zurich.  A Systematic Review of Semiquantitative and Qualitative Radiologic Criteria for the Diagnosis of Lumbar Spinal Stenosis. AJR 2013; 201:W735–W746

Spondylolisthesis and Spondylolysis

Diseases, , ,

Diagnosis:

These are imaging findings. Whether they are the cause of deficits requires clinical correlation plus electrophysiology as necessary
Spondylolisthesis: Slipping of one vertebra upon another
Spondylolysis: a bony defect (fracture) in the pars interarticularis (connects the pedicle and lamina on axial plane, connects superior and inferior articular processes of the facet joints on sagittal plane), incomplete ring. Predisposes to spondylolisthesis

Findings on Investigations:

X-ray: Slipping of one vertebra upon another (spondylolisthesis)
CT:

  • distinguishes spondylolisthesis and spondylolysis
  • If planning surgery or if myelopathy has occurred

MRI:

  • If myelopathy has occurred or if planning surgery
  • For Spondylolysis: STIR (high signal acutely) or T1WI
  • T2: with myelopathy High signal within the spinal cord may occur, nonenhancing

Related articles:

Cervical Spondylosis

Diseases, , ,

Note this can cause myelopathy and radiculopathy

Synonyms:

a.k.a. osteoarthropathy of the cervical spine

Diagnosis:

Imaging confirms the presence of degenerative changes but doesn’t confirm that it is the cause of radiculopathy or myelopathy
X-ray spine:

  • Osteophytes, narrowed disk spaces, narrowed framina
  • This confirms the presence of degenerative changes but doesn’t confirm that it is the cause of radiculopathy or myelopathy

MRI:

  • spondylotic changes in the spine, compression of the spinal cord, T2 increased signal in spinal cord,

EMG:

  • Normal sensory because the lesion is proximal to the dorsal root ganglion
  • May show axonal pattern
  • F waves may help

CT myelography: for myelopathy

Treatment:

Consider:

  • Cervical collar

Consider Surgery if myelopathy or if motor radiculopathy are present

Related articles:

Subacute Combined Degeneration of the Spinal Cord

Diseases, ,

Diagnosis:

Low B12 level or normal lower limit B12 with high methylmalonic acid
MRI T2: expanded spinal cord, high signal in posterior columns

Pathology:

Shrunken thoracic cord, discoloured posterior & lateral columns
Microscopically: Thoracic cord, bilateral symmetrical white matter vacuolar degeneration “spongy appearance” affecting the long tracts, lipid-laden macrophages, Wallarian degeneration of some axons. Gliosis in late stage.
Myelin stain, neurofilament: axonal spheroids
May affect cerebral white matter & optic tracts.

Treatment:

B12 replacement
Address the cause of the B12 deficiency

Related articles:

Syringomyelia

Diseases, ,

Diagnosis:

Clinical features plus MRI

Clinical features:

Suspended sensory level (loss of pain & temperature at a level on both sides),
Later on absent reflexes & weakness
Scoliosis, foot deformity (pes cavus, equinovarus), Charcot joint at the shoulder may occur

Findings on Investigations:

MRI:

  • Cavity within the spinal cord, same signal characteristics as CSF
  • Associated with Chiari Malformation

Treatment:

Treat the cause
If in conus medularis, consider terminal ventriculostomy i.e. resection of the filum terminale

Related articles:

Radiation Myelopathy

Diseases,

Diagnosis:

Clinical features, plus exclusion of other causes

Clinical features:

Recent or distant exposure to radiation
+signs of myelopathy: Lhermitte’s sign, Brown-Sequard lesion is classic
Acute or insidious onset. Transient & progressive forms

Findings on Investigations:

MRI:

  • Radiation change in the vertebra; increased signal
  • Normal initially
  • Later: T1 hypointese, T2/FLAIR hyperintense, enhances,

CSF: raised protein
SSEP: spinal conduction velocity block

Pathology:

Spectrum: demyelination, Wallarian degeneration of axons, necrosis
Fibrinoid necrosis of vessels, hemorrhage

Related articles:

 

Schistosomal Myeloradiculopathy

Diseases, ,

Schistosomal myelopathy and radiculopathy

Diagnosis:

A combination of Schistosoma tests plus MRI and clinical features

Clinical features:

Features of myelopathy & radiculopathy & current or past Schistosomal infection

Findings on Investigations:

MRI: lower thoracic & cona medularis or cauda equina, enlargement, T2 hyperintensity, T1 gadolinium enhancement (linear or micronodular)
Tests for: S. mansoni or S. hematobium serology and stool tests for eggs.
CSF: Pleocytosis, lymphocytosis, eosinophils occur, normal glucose
Peripheral blood eosinophilia

Related articles:

Viral Myelitis

Diseases, ,

Diagnosis:

Clinical +MRI +laboratory studies
+evidence of viral infection

Types:

Herpes viruses:

  • CMV myelitis
  • HSV myelitis
  • VZV myelitis: VZV PCR or antibodies against VZV
  • EBV myelitis
  • HHV6

HIV myelitis
HTLV-1 myelitis: serology
Enteroviruses, Echovirus, coxsackie virus, hepatitis A, hepatitis B, rubella, measles, mumps, lymphocytic choriomeningitis LCM
Poliomyelitis, West nile virus: +/- LMN signs

Treatment:

Treat the underlying cause e.g. aciclovir, antiretrovirals etc.

Related articles:

Idiopathic Acute Transverse Myelitis

Diseases,

Synonyms:

a.k.a. Primary transverse myelitis

Diagnosis:

Clinical +MRI +laboratory studies
+evidence of inflammation by CSF: pleocytosis or raised IgG index, or by MRI enchancement
+exclude secondary disease: including vascular myelopathy

Clinical features:

Acute or subacute onset
Bilateral symptoms and/or signs, usually symmetric i.e. acute complete transverse myelitis ACTM. [142] Acute partial transverse myelitis APTM may occur i.e. incomplete and asymmetric
Sensory, motor or autonomic deficits due to spinal cord involvement. Progresses to a nadir between 4hr and 21 days.
Transverse refers to anterior and posterior parts of the cord.
Back pain may occur

Findings on Investigations:

MRI:

  • T2 High signal over many cord segments
  • Diffuse swelling,
  • T1 +contrast: enhancement

Investigations to consider:

MRI +gadolinium brain and spine: assess for MS, neuromyelitis optica, herniated disc, vertebral fracture, metastasis, tumor, abnormal flow voids of AVM
CSF analysis: Cell count +differential, protein, glucose, oligoclonal bands, IgG index
Viral PCR: HSV, etc
CXR: features of sarcoidosis
Blood tests:

  • FBC, basic metabolic panel, LFT
  • ESR, B12, methymalonic acid
  • Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Serology: Mycoplasma pneumoniae (and cold agglutinins), syphilis, HIV-1, HSV,
  • ANA and ENAs
  • ACE levels
  • NMO IgG: to assess for Devic neuromyelitis optica

Urinalysis
Lip biopsy: Sjogren syndrome
Tests for Brucella spp. (Brucellosis), Schistosomiasis
14-3-3: early rise is associated with poor outcome.

Treatment:

Methylprednisone 1 gram I.V. 5-7 days followed by steroid taper
Consider:

  • Plasmapheresis for steroid unresponsive cases
  • Consider empiric therapy for viral or bacterial causes while tests are pending
  • General measures for myelopathy

Related articles:

Spinal Cord Infarction

Diseases, ,

Synonyms:

a.k.a. anterior spinal artery syndrome:

Clinical features:

Back pain +sudden paraplegia with areflexia & urinary retention, loss of touch, temperature,
Usually spares proprioception & vibration

Findings in Investigations:

+MRI:

  • may be negative initially
  • Hyperintensity in the spinal cord, slightly expanded spinal cord later on

Note: T1-T4 & T5-T7 are the vascular boundary zones

Investigations to consider:

FBC,U&E, creatinine, LFTs, lipid panel, fasting blood glucose
ANA, ANCA, VDRL
ECG, Holter, echocardiogram
MRI

Related articles:

Spinal Cord compression (compression myelopathy)

Diseases,

Clinical features:

Weakness (quadraparisis or paraparesis), sensory level, bowel and bladder dysfunction

Findings on Investigations:

MRI:

  • Compression of the spinal cord
  • T2/STIR: hyperintensity in the spinal cord

Treatment:

Treat the underlying condition
Consider early surgical decompression
If metastatic:

  • Dexamethasone: dose is debatable; initial trials used 100 mg I.V. over 0.5-1 hour, then 4 mg q6 hours
  • Surgery or Radiation therapy or both

Related articles:

Postural orthostatic tachycardia syndrome (POTS)

Diseases

Diagnosis:

15-45 year old, F>M,
Orthostatic symptoms upon standing:

  • Palpitations, light-headedness, blurred vision, anxiety, substernal chest pain, fatigue, and occasionally syncope
  • +increase of heart rate >30 beats/min within 5 minutes standing or tilt up: usually HR =or >120
  • +without a significant drop in blood pressure

Full autonomic nervous function testing: sensitive and specific for diagnosis

Findings on Investigations:

Full autonomic nervous function testing
Noradrenaline (Norepinephrine) plasma levels upon standing: elevated
Adrenaline (epinephrine) Supine & standing: elevated >600ng/ml
Orthostatic tolerance testing:

  • Overnight fast +30 minute supine rest
  • Stand by bed X3-5 minutes or intolerable symptoms

Treatment:

General measures: similar to orthostatic hypotension
Consider:

  • Fludrocortisone
  • Beta blockade

Sinus node ablation doesn’t work

Related articles:

Carotid Sinus Syncope

Diseases

Diagnosis:

A type of neurally mediated syncope
A clinical diagnosis. Occasionally carotid sinus massage is used.
Carotid sinus massage:

  • False positives occur i.e. if positive it is not necessarily the cause of syncope
  • Observe contraindications & procedural care
  • Must have negative results for other causes of syncope

Positive if with 5 seconds of unilateral longitudinal massage:

  • Paroxysmal AV nodal block
  • Asystole for at least 3 seconds
  • BP drop >50 mmHg systolic or >30 mmHg diastolic

Related articles:

Simple Faints

Diseases,

Synonyms:

a.k.a. neurally mediated syncope a.k.a. Vasovagal syncope a.k.a. neurocardiogenic syncope a.k.a. vasodepressor syncope:

Clinical features:

Syncope after emotional stimulus
Syncope after Valsalva & Valsalva like: Cough, defaecation, Micturation, Deglutition, Hyperventilation
Syncope after hemodynamic/orthostatic stress e.g. prolonged standing
Preceded by autonomic activation:
Cold sweat: piloerection, sweating & pallor (vasoconstriction)
Nausea & epigastric discomfort (vagal activation)
Blurred vision (papillary vasoconstriction)
Preceded by lightheadedness & darkening of vision

Findings on Investigations:

+Head up tilt-table testing: positive
After tilt up there is a period of normal BP & HR. Then a sudden drop in BP & HR with recurrence of syncopal symptoms. In contrast in autonomic failure: After tilt up there is a progressive gradual drop in BP & HR.
+excluding heart disease +arrhythmia

Treatment:

Reassurance
Avoidance of precipitants
Increase fluid intake to >2L per day
Exercise training:
Training leg muscles
Stand against a wall for up to 40min, twice daily
Physical countermaneuvers:

  • Leg crossing, squating

If recurrent neurocardiogenic syncope, consider:

  • Salt loading
  • Pacemakers are of no benefit [VPSII RCT]
  • Beta blockers are of no benefit [Randomised crossover trial]

Related articles:

Orthostatic Hypotension

Diseases

Synonyms:

a.k.a. postural hypotension

Diagnosis:

Definition:

  • Drop in BP >30 mmHg systolic or >10 mmHg diastolic when changing from lying to standing (not sitting), after 2-5 minutes of standing
  • Or ≥20 mm Hg (or ≥20%) drop in systolic pressure, either immediately or after 2 min of standing.
  • If negative but symptomatic, do orthostatic stress test:
    • BP lying & then standing after 12 squats

The normal pulse BP response:

  • BP: systolic falls by 5-10 mmHg, diastolic increases by 5-10 mmHg
  • Pulse: increases by 10-25 beats/min.
  • Pulse:
    • If increases >15 beats/min, nonneurogenic causes are suggested.
    • If doesn’t increase by >15 beats/min, autonomic dysfunction is suggested
  • The reason for the wait 2-5 minute is that the baroreceptor response may be sluggish in the elderly, hence sustained drop in BP on standing is what is looked for in orthostatic hypotension

Postural blood pressure & pulse:

  • After ≥5 min in a supine position
  • Immediately after standing
  • 2 min after standing
  • Supine hypertension also suggests autonomic dysfunction

Tilt table testing or formal autonomic nervous system testing can diagnose the condition

Investigations to consider:

Postural BP & pulse
FBC (hematocrit, anemia)
Stool occult blood
U&E
Blood glucose
Syphilis serology (tabes dorsalis)
Physiological & pharmacological autonomic tests
Nerve conduction studies
Tilt table
Autonomic nervous system testing

Treatment:

General measures:
Standing up gradually. Especially in the morning.
Elevate the head of the bed on blocks, 10-20 degrees
Avoid:

  • Hot environment
  • Valsalva manoeuvre
  • High fibre diet +/-Laxatives

If presyncope occurs:

  • Squat, lean forward with head between knees
  • Leg crossing
  • 500-1000ml water ingestion

Diet:

  • High salt,
  • Small meals, lots of fluids, avoid alcohol.

Shave while sitting
Waist high elasticized support hosiery
Stop offending drugs
Treat underlying cause
Medication:

  • Goal is symptom control, not BP control. The risk of complications often out-weighs benefits
  • Fludrocortisone P.O. for idiopathic & diabetic cases. Monitor supine BP, K+, heart failure
  • Midodrine P.O. Monitor supine BP
  • Salt tablets
  • Desmopressin intranasally. Monitor Na+ closely.
  • Erythropoietin subQ Monitor HCT, Hb, iron stores
  • Pyridostigmine P.O.

Related articles:

Subclavian Steal Syndrome

Diseases,

Diagnosis:

Clinical features plus imaging

Clinical features:

Difference in BP between arms

Findings on Investigations:

Vertebral ultrasound:

  • Reversal of flow in vertebral artery

Catheter angiography:

  • Subclavian stenosis or occlusion
  • With reversal of flow in vertebral artery

Treatment:

Treat only if symptomatic
Angioplasty or stenting of subclavian artery
Occlusion of vertebral artery
Carotid subclavian bypass

Related articles:

Chilhood Epilepsy Syndromes

Diseases,

For each syndrome seizure disorder a combination of history, physical examination & EEG are used
Childhood absence epilepsy CAE
Juvenile absence epilepsy JAE
West syndrome a.k.a. Infantile spasms
Aicardi syndrome a.k.a. Aicardi-Goutieres syndrome
Jeavons Syndrome (Eyelid myoclonia with or without absences)
Lennox-Gestuat syndrome
Benign epilepsy with centrotemporal spikes BECTS a.k.a. benign rolandic epilepsy
Juvenile myoclonic epilepsy JME a.k.a. Janz syndrome
Idiopathic generalized epilepsy with Generalized tonic-clonic seizures only
Focal epilepsy (cryptogenic, symptomatic)
Severe myoclonic epilepsy of infancy (SMEI) a.k.a. Dravet’s syndrome
Epilepsy with Continuous spike-waves in slow sleep
Benign epilepsy with occipital paroxysms
Landau-Kleffner syndrome LKS
Myoclonic astatic epilepsy of childhood
Ohtahara syndrome
Early myoclonic encephalopathy
Benign myclonic epilepsy in infancy
Early onset benign childhood occipital epilepsy a.k.a. Early onset benign childhood seizures with Occipital spikes a.k.a. Panayiotopoulos syndrome
Late onset childhood occipital epilepsy (Gestaut type)
Epilepsy with myoclonic absences
Myoclonic-astatic epilepsy of childhood a.k.a. Epilepsy with myoclonic astatic seizures
Idiopathic photosensitive occipital lobe epilepsy
Primary reading epilepsy
Startle epilepsy
Benign familial neonatal seizures a.k.a. Benign Familial neonatal convulsions (benign infantile epilepsy)
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
Generalised epilepsy with febrile seizures plus (GEFS+)
Autosomal dominant partial epilepsy with auditory features a.k.a. Autosomal dominant lateral temporal epilepsy (ADTLE)

Related articles:

Autosomal dominant partial epilepsy with auditory features (ADTLE)

Diseases,

Synonyms:

a.k.a. Autosomal dominant lateral temporal epilepsy

Genetics:

Autosomal dominant
LGI1 gene (leucine-rich glioma inactiated) chr. 10q

Clinical features:

Auditory symptoms (buzzing, ringing, volume changes, songs, voices),receptive aphasia as ictal manifestations, seizures precipitated by sounds

Related articles:

Generalised epilepsy with febrile seizures plus (GEFS+)

Diseases,

Genetics:

Autosomal dominant, familial
Na+:

  • SCN1A chr. 2q24. Alpha 1 subunit
  • SCN1B chr. 19q13.1, Beta 1 subunit (incomplete penetrance)

GABA:

  • GABRG2 chr. 5q31, Gamma2 subunit (incomplete penetrance)

Clinical features:

Febrile seizures >6 y.o. or Generalised seizures without fever:
GTCS, myoclonic, absence & atonic seizures

Related articles:

Benign Familial Neonatal Seizures

Diseases,

Synonyms:

a.k.a. Benign Familial neonatal convulsions (benign infantile epilepsy)

Diagnosis:

A type of channelopathy
Diagnosed clinically

Genetics:

Autosomal dominant.
K+ KCNQ2 or KCNQ3

Clinical features:

Neonatal seizure clearing spontaneously after a few weeks.
Onset on Day 3 remission by week 6
Normal development afterwards
A minority have epilepsy

Related articles:

Myoclonic Astatic Epilepsy of Childhood

Diseases,

Diagnosis:

Clinical plus EEG

Clinical features:

2-5 years old. Initially GTCS occur, then myoclonic seizures & drop attacks develop. Usual attacks have myoclonic jerks followed by drop attacks. Status epilepticus occurs.

Findings on Investigations:

EEG: Background of 4- to 7-Hz rhythm. Regular or irregular bilaterally synchronous 2- to 3-Hz spike-waves and/or polyspike-waves. Sleep increases he spike-wave

Treatment:

Valproate VPA
Topiramate TPM, clonazepam, clobazam
Ketogenic diet

Related articles:

Juvenile Myoclonic Epilepsy (JME)

Diseases,

Synonyms:

a.k.a. Janz syndrome

Diagnosis:

Clinical features plus EEG

Clinical features:

myoclonic jerks, shortly after waking. Generalized tonic clonic seizures triggered by sleep deprivation

Findings on Investigations:

EEG: 4-6 Hz generalized spike wave.

Treatment:

Life long
Valproate VPA orally (except in women of childbearing age)
Lamotrigrine, Levetiracetam LEV, Topiramate TPM, primidone

Related articles:

Benign epilepsy with centrotemporal spikes (BECTS)

Diseases,

Synonyms:

a.k.a. benign rolandic epilepsy

Diagnosis:

Clinical features pluse EEG

Clinical features:

Onset 5-10 years old., < 15 years old Resolves by age 16 years old
Nocturnal seizures with mouth movement & gurgling, may generalise

Findings on Investigations:

EEG: centro-temporal ‘rolandic’ sharp wave activity on normal background, increases during sleep. Has characteristic dipole

Treatment:

Carbamazepine CBZ
Valproate VPA, Lamotrigrine, oxacarbazepine
Remits after 16 years old.

Related articles:

Aicardi Syndrome

Diseases,

Synonyms:

a.k.a. Aicardi-Goutieres syndrome,

Diagnosis:

Triad:

  • Infantile spasms in flexion
  • agenesis of corpus callosum
  • ocular abnormalities

Clinical features:

Birth to childhood, progressive encephalopathy
Seizures: infantile spasms, alternanting hemiconvulsions
Microcephaly, spasticity, dystonia,
Ocular:

  • Visual inattention and abnormal eye movement
    Coloboma, lacunes in the retina,

Fatal or persistent vegetative state

Genetics:

X-linked dominant
Heterogenous

Findings on Investigations:

EEG:

  • Bursts of asynchronous slow waves, spike & sharp waves alternating with suppressed EEG

CT: calcifications, vertebral anomalies
MRI: agenesis of the corpus callosum
CSF: lymphocytosis

Related articles:

West Syndrome

Diseases,

Synonyms:

a.k.a. Infantile spasms

Diagnosis:

Clinical features plus EEG

Clinical features:

Onset 3 months – 3 years, Jack-knifing, myoclonus
+/-mental retardation

Findings on Investigations:

EEG: hypsarrhythmia i.e. chaotic slow-wave high voltage background activity & sharp components
High amplitude (voltage >200 microV)
Slow waves, Sharps waves & spikes in all areas
Sharps & spikes appear randomly from many foci (different areas); also they lack rhythmicity or periodicity
Most pronounced during non-REM sleep & reduced/abolished during REM sleep
Ictally:

  • Electrodecremental peroid i.e. sudden flattening
  • Or Lower amplitude slow waves

Treatment:

Corticosteroids (prednisolone, ACTH)
Vigabatrin

Related articles:

Neuronal Ceroid Lipofuscinosis

Diseases, ,

Synonyms:

Jansky-Bielschowsky, (Spielmeyer-Vogt-Sjogren) Batten, (Parry) Kuf, Santavori

Diagnosis:

A group of lysosomal storage disorders

Types:

Infantile INCL
Type 2: Late infantile LINCL a.k.a. Classic a.k.a. Jansky-Bielschowsky disease
Type 3: Juvenile JNCL a.k.a. Spielmeyer-Vogt-Sjogren disease, or Batten disease
Type 4: Adult ANCL a.k.a. Kuf’s disease, or Parry disease. No visual failure
Type 5: Finish variant
Genetics:
Autosomal recessive, some are Autosomal dominant
Mutation analysis confirms the diagnosis.
CLN1 gene chr. 1p32. Protein= PPT a.k.a. Batten disease. Stored protein= Sphingolipid activator proteins SAP
CLN2 gene chr. 11q15 mutations, protein= lysosomal enzyme tripeptidyl peptidase 1 . TPP1. Stored protein= Subunit c of Mitochondrial ATP synthase (SCMAS)
CLN3 gene chr. 16p12. Stored protein= SCMAS
CLN4 gene, unidentified location. Stored protein= SCMAS. Adult NCL
CLN5 gene chr. 13q21-32, a.k.a. Finish variant. Stored protein= SCMAS
CLN6 gene chr. 15q21-23, late infantile variant. Stored protein= SCMAS
CLN7 gene. Stored protein= SCMAS
CLN8 gene chr. 8p23 N, or a different Northern epilepsy. Stored protein= SCMAS
CLN9 gene. Stored protein= SCMAS
CLN10 gene a.k.a. CTSDgene chr. 11p15.5 Protein= CTSD. Stored protein= SAPs

Clinical features:

Variable from 2-40s years old
Seizure (partial or generalised), myoclonus
Loss of vision, macular degeneration. Except Kuf’s disease
Regression Or Dementia: Loss of motor function & language
Ataxia

Findings on Investigations:

ERG: abnormal.
EEG: photosensitive epilepsy (fast spike-and-wave discharges or posterior spikes) in some e.g. Adult NCL
Visual evoked potentials VEP: giant VEPs in some forms
MRI:

  • Cerebral atrophy (cortical grey matter)
  • T2-hyperintensity of the lobar white matter, and thinning of the cerebral cortex
  • Cerebellar atrophy in Finish variant.

Enzyme analysis:

  • PPT1, TPP1 or CTSD deficiency

Pathology:

Progressive degeneration of the brain and retina.  Apoptosis of neurons and photoreceptors.
Rectal neurons have PAS positive inclusions
Skin biopsy (conjunctival, muscle, biopsy):
Light microscopy: vacuolations in lymphocytes. Occurs in CLN3
EM, especially eccrine secretory cell:
No deposits excludes neuroceroid lipofuscinosis NCL
Intracellular inclusions (most diagnostic feature):

  • Curvilinear bodies CVB, especially late infantile NCL
  • Fingerprint profiles FPP, juvenile and adult NCL
  • Rectilinear profiles RL, especially in CLN3.
  • Granular osmiophilic deposits. Occurs in some types. CLN3, CLN5, CLN6, CLN7, CLN8

Brain biopsy:

  • EM: intracellular inclusions (most diagnostic feature) see above
  • Granules, cytoplasmic: PAS positive, Sudan black B positive, autofluorescent, resistant to lipid solvants
  • Neuronal loss & gliosis may occur

Related articles:

GM2 Gangliosidosis, Hexosaminidase Deficiency

Diseases, ,

Diagnosis:

A type of lysosomal storage disease. Also a sphingolipidosis.

Subtypes:

Tay-Sachs disease: hexosaminidase A gene mutation, HEXA gene chr. 15q, encodes the alpha subunit
Sandhoff disease: hexosaminidase B gene mutation, HEXB gene chr. 5q, encodes the beta subunit
AB variant a.k.a. GM2 activator deficiency: GM2A gene chr. 5q, encodes activator protein

Related articles:

Gaucher Disease

Diseases, ,

Synonyms:

a.k.a. Glucosylcerebrosidase deficiency

Diagnosis:

A type of lysosomal storage disease. A type of sphingolipidosis.
Also a type of Progressive myoclonic epilepsy

Genetics:

Autosomal recessive

Subtypes:

Type 1
Type 2, absent enzyme activity
Type 3, “neurological”:

  • Supranuclera gaze palsy, myoclonus, no dementia
  • Splenomegaly, pancytopenia

Pathology:

Ectopic dendritogenesis, meganeurites

Treatment:

Options as below
Enzyme replacement therapy:

  • Glucocerebrosidase (recombinant) I.V.

Substrate reduction therapy:

  • Miglustat, inhibits glucosylceramide synthase

Related articles:

Myoclonic Epilepsy and Ragged Red Fibres (MERRF)

Diseases, ,

Genetics:

mitochondrial DNA mutation

Diagnosis:

A form of progressive myoclonic epilepsy

Clinical features:

Myopathy, neuropathy
Deafness
Lipomas
Optic atrophy
Myoclonus

Genetics:

Familial, sporadic, maternal
Mitochondrial DNA mutation

Pathology:

Ragged red fibres in muscle. Changes in Dentate nucleus & inferior olive

Related articles:

Sialidosis

Diseases,

A form of progressive myoclonic epilepsy

Type 1:

Clinical features:

Adolescence, severe myoclonus, gradual visual loss, ataxia
Cherry-red spot
No dementia

Genetics:

Autosomal recessive
Chr. 20

Pathology:

Decreased neuraminidase
 

Type 2:

Clinical features:

adolescence, severe myoclonus, gradual visual loss, ataxia
Cherry-red spot
No dementia
Coarse facies, corneal clouding

Genetics:

Autosomal recessive,
Chr. 10

Pathology:

Decreased neuraminidase & beta-galactosidase

Related articles:

Lafora Disease

Diseases,

A form of progressive myoclonic epilepsy

Diagnosis:

Clinical features plus EEG and pathology

Genetics:

EPM2A gene chr. 6q24, protein= laforin (a dual phosphatase),
EPM2B gene chr. 6q22.3 a.k.a. NHLRC1 gene, protein = malin (a E3 ubiquitin ligase)

Clinical features:

Age 10-18 y.o. epilepsy, segmental massive myoclonus, rapidly progressive mental deterioration (dementia), ataxia.

Findings on Investigations:

EEG:

  • Fast spike-wave and poly-spike-wave complexes, photosensitivity, multifocal abnormalities.
  • 50% have occipital spikes

Pathology:

Lafora bodies = intracellular periodic acid-Schiff-positive (PAS) inclusions (abnormal glucose polymer) in CNS (cortex & dentate nucleus), PNS, skin, liver or muscle.

Related articles:

Alcohol Withdrawal

Diseases,

Synonyms and related conditions:

Alcohol withdrawal seizures & delirium tremens DT

Diagnosis:

This is a clinical diagnosis

Clinical features

Within 6-36 hours of cessation of/decrease in alcohol consumption,
Autonomic symptoms: diaphoresis, tachycardia, and hypertension
Neurological symptoms: tremor, anxiety, hallucinations (tactile, visual or auditory), agitation, seizures, headache, insomnia.
Delirium tremens DTs:

  • Alcohol withdrawal
  • +disorientation, confusion, agitation or hallucination

Alcohol hallucinosis:

  • Alcohol withdrawal
  • +Auditory hallucinations, without consciousness disturbance,

Scales & questionnaires:

CAGE questionnaire
Clinical Institute Withdrawal Assessment for Alcohol-Revised CIWA-Ar score:

  • Mild <10
  • Moderate 10-20
  • Severe >20

Investigations to consider:

FBC (megalobastic anemia),
U&E, Mg++: hypokalemia, hypomagnesemia,
Liver enzymes:

  • In hepatitis: AST:ALT ratio > 2:1, AST rarely >300 U/L

B1 Thiamine: by functional transketolase assay, thiamine chromatography or urinary thiamine
Glucose: hypoglycemia

Monitor:

  • Vitals in acute setting
  • Signs of withdrawal

Treatment:

Symptom triggered dosing of Benzodiazepines: diazepam P.O. or chlorediazepoxide P.O., or lorazepam I.V.
Consider Carbamazepine CBZ P.O. if recurrent.
Thiamine repletion, Adequate nutrition & correct electrolyte abnormalities:

  • If liver disease: High calorie & High protein
  • Multivitamin, thiamine B, folate,
  • Correct electrolyte abnormalities & hypoglycemia: routine magnesium sulfate is not indicated.
  • NB. Never give dextrose or glucose before correcting thiamine deficiency in these patients.

Addiction/depedence counselling

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Neurocysticercosis

Diseases, ,

Synonyms:

Taenia solium (pork tapeworm)

Diagnosis:

Imaging plus clinical features

Clinical features:

Seizures,
Meningitis may occur

Findings on Investigations:

MRI:

  • T1 +contrast: multiple ring enhancing lesions with edema
  • T1, punctuate signal void
  • FLAIR: hyperintensity (gliosis) surrounds the lesions

CT:

  • Multiple calcified lesions +/-surrounding edema
  • Migrating intraventricular cyst
  • +positive serology for neurocysticercosis

Treatment:

Albendazole 800mg P.O. daily [RCT]
Antiepileptics for seizures.
Consider steroids

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Rasmussen Encephalitis

Diseases,

Diagnosis:

A combination of clinical, MRI and EEG findings

Clinical features:

Childhood onset
Intractable partial seizures, worsen with time, epilepsia partialis continua, hemiplegia, aphasia

Findings on Investigations:

MRI:

  • White matter hyperintensity and then atrophy

EEG:

  • Focal and multifocal epileptiform discharges and slowing

Pathology:

Cortical atrophy, perivascular lymphocytic infiltrates with vascular injury, astorcytic gliosis, neuronal loss

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Transient Epileptic Amnesia

Diseases,

Diagnosis:

Clincial features plus supporitng EEG

Clinical features:

Older adults
Transient episode of memory loss.
30-60 minutes in duration. Recurs.
+1 of the following 3:

  • Clinical features of epilepsy such as lip-smacking or olfactory hallucinations
  • Epileptiform abnormalities on electroencephalogram (EEG)
  • Clear response to anticonvulsant therapy.

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Heterotopia

Diseases,

Diagnosis:

Pathology is the gold standard, but MRI is an excellent test for diagnosis

Clinical features:

epilepsy

Findings on Investigations:

MRI:

  • Subepindymal, subcortical or band/diffuse
  • Subcortical band heterotopia

FDG-PET:

  • Intertictal: increase uptake in the subcortical band.

EEG: interictal & ictal abnormalities

Genetic forms:

doublecortin (DCX) gene, X-linked. Blood testing available. MRI in affected men: lissencephaly, MRI in affected women: double cortex band heterotopia, subcortical laminar heterotopia, lissencephaly
Human Filamin A gene FLNA mutations, filamin, X-linked. MRI: bilateral perventricular heterotopia
Laminin genes, MRI: Perventricular heterotopia

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Mesotemporal Sclerosis

Diseases,

Synonyms:

a.k.a. mesial temporal sclerosis a.k.a. Amon’s horn sclerosis a.k.a. hippocampal sclerosis

Diagnosis:

Pathology is the gold standard, but MRI is very sensitive

Pathology:

Gold standard
Atrophy, white discolouration of the hippocampal formation, enlarged temporal horn of the lateral ventricle. Fornix atrophy.
Microscopically: loss of neurons (pyramidal & dentate layer) in CA1 (Sommer sector) & CA4 (end-folium). Discontinuity of dentate granular layer. Astrocytic gliosis. Atrophy of white matter efferents (alveus & fimbria).

Findings on investigations:

MRI

  • Hippocampal sclerosis: atrophy on T1, high signal on T2, decreased hippocampal volume

EEG:

  • Absolute interictal spike frequency = or >60spikes/hr is associated with poor surgical outcome, if <60spikes/hr it’s associated with good surgical outcome for amygldalohippocampectomy.

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Status Epilepticus

Diseases,

Diagnosis:

Clinical supported by EEG

Clinical features:

This is an emergency & should be treated as soon as recognised, before EEG or tests
A seizure or multiple seizures without regaining consciousness in between lasting >10 min

Findings on Investigations:

EEG: there is a sequence of EEG findings.
1 discrete seizures
2 merging seizures with waxing and waning amplitude and frequency of EEG rhythms
3 continuous ictal activity
4 continuous ictal activity punctuated by low voltage ‘flat periods’
5 periodic epileptiform discharges PED on a ‘flat’ background

Emergency Treatment:

ABC:

  • Secure airway as necessary
  • Oxygen

Anticonvulsants: if > 10 minutes

  • Lorazepam 0.1mg/kg IV X1 dose favoured over diazepam to interrupt seizures. [VA Cooperative study]
  • Followed by:
    • Fosphenytoin Or Phenytoin PHT 18-20mg/kg IV, aim for level= 20
    • If contraindications or partial status epilepticus, consider: sodium Valproate VPA 25-40mg/Kg IV.

If seizures persist:

  • Propofol 2 mg/kg bolus, followed by infusion
  • Midazolam 0.2 mg/kg bolus IV, 0.1-0.4 mg/kg/hr infusion.(0.75 -11 mcg/kg/min)
  • Some physicians consider Phenobarbital PB 20mg/kg IV X 1 dose, aim for level= 40-60.

For refractory status epilepticus in spite of above measures, consider risk vs. benefit of:

  • Pentobarbital 20 mg/kg bolus, 1-3 mg/kg/hr infusion
  • Thiopentone/thiopental 2-3 mg/kg mg bolus, 3-5 mg/kg/hr infusion

Monitor EEG continuously: aim for burst suppression
Monitor vitals & O2 saturation, alertness
Set up intravenous access
Hyperthermia:

  • Cooling blanket

Treat hypoglycemia +/-thiamine

Further investigations to consider:

Venous blood:
Blood glucose, U&E, Ca++ +PO3–, FBC, ESR, LFTs, antiepileptics levels
toxicology
ABG
ECG
Calculate serum osmolality
CXR: aspiration
Urine toxicology
Consider induction of motor paralysis
Lactic acidosis should not be treated, exclude infection
If >5 minutes intubate & ventilate
EEG monitoring if refractory status i.e. 30-90 minutes
ECG
Calculate serum osmolality
CT head
EEG monitoring
LP
MRI & repeated MRI
Consider:

  • Blood Mitochondrial DNA analysis: Common deletion, POLG mutations
  • Muscle biopsy: mitochondrial disease
  • Brain biopsy
  • CT thorax, abdomen, pelvis: paraneoplastic syndrome
  • Paraneoplastic antibodies

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Congenital Central Hypoventilation Syndrome

Diseases

Synonyms:

Ondine’s curse

Diagnosis:

Adequate ventilation while awake +alveolar hypoventilation while asleep (normal rate +shallow breathing)
+hypoxia +hypercarbia without arousal
+Absence of cardiac, lung, neuromuscular, brain conditions
In some: PHOX2B gene mutation,

Investigations to consider:

ECG, Holter
CXR
Fluoroscopy of the diaphragm
Muscle biopsy
MRI
Blood tests:

  • Carintine

Urine:

  • Carintine

Sleep study:

  • Hb O2 saturation, tidal volume (pneumotachograph), chest & abdomen movement (respiratory inductance plethysmography)

Obstructive Sleep Apnea

Diseases

Diagnosis:

Confirmed by polysomnography

Findings on Investigations:

Polysomnography:

  • The gold standard test
  • =or>5 hypopnea or apneas per hour. +symptoms of hypersomnolence
  • Hypopnea: 10 seconds of decrease in airflow for <10 secons by >50%. Or decrease in airflow <50% with arousal. Or decrease in airflow <50% with 3% desaturation.
  • Apnea: decrease in airflow =or>80% for 10 seconds.
  • Obstructive apnea: apnea that occurs with continued respiratory effort.
  • EEG, electrooculogram, submental EMG, ECG, heart rate monitor, pulse oximetry, oral nasal airflow monitor

Limited sleep study
If pretest probability is high:

  • Overnight pulse oximetry, but this can’t rule out OSA

Investigations to consider:

Epworth sleepiness scale
Evaluation for obesity & metabolic syndrome
Diagnostic tests

Treatment:

Night time CPAP or BiPAP
Weight loss & nutritional education. [small RCT]
Decrease alcohol & sedative drugs
Avoiding sleeping on their back
Consider intraoral devices if mild & the patient is alert in the daytime
If the tonsils are large, a tonsillectomy should be performed

REM Sleep Behaviour Disorder

Diseases

Diagnosis:

A type of parasomnia

Clinical features:

M>F, usually >50 year olds
Vivid and often frightening dreams during REM sleep, but without muscle atonia i.e. act out the dream (behaviour).
Recall of the dream is intact

Finding on Investigations:

Polysomnography: confirms the diagnosis
RSWA: rim sleep without atonia
REM sleep during the episode
EEG: absence of epileptiform activity
EMG (submental or limb): elevated tone

Treatment:

Clonazepam P.O. at night
Melatonin P.O. at night [small nonrandomised study]
Safety education:

  • Removing lamps & other objects from near the bed
  • Placing cushions near the bed

Night Terrors

Diseases

Synonyms:

sleep terror

Diagnosis:

A type of parasomnia, diagnosed by clinical features supported by investigations

Clinically features:

Child appears to awake (vocalisations, fear motor activity) & is disoriented & goes back to sleep
No recall of the episode usually
Difficult to arouse during this

Findings on Investigations:

Polysomnography: confirms it
Occurs during Slow wave sleep (formerly stage 4 non-REM sleep)
Occur ~1.5 hours into sleep i.e. 1st third of the night

Treatment:

Reassure the parents
2nd line:
Wake the child 15 min before expected episode for 1 week

Periodic Limb Movements of Sleep

Diseases

Diagnosis:

Is a polysomnographic diagnosis
Polysomnography:
=or > 15 episodes of periodic, stereotyped jerky movements of legs
Each movement: lasts 0.5-5 seconds in duration
Sequences of Movements are separated by 5-90 seconds. Measured from movement onset to movement onset.
These may occur in normal people and are not significant unless associated with arousals

Treatment:

  • Ropinirole (Level A strong evidence)
  • Pramipexole, rotigotine, cabergoline, or pregabalin (Level B moderate evidence)

Related articles:

Related articles:

  1. Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Nov 16. pii:. PMID:27856776DOI:10.1212/WNL.0000000000003388

Restless Leg Syndrome

Diseases

Diagnosis:

The 4 following are required:

  • An urge to move the legs due to an unpleasant feeling in the legs.
  • Begins or gets worse when at rest or not moving around frequently.
  • Is partly or completely relieved by movement (such as walking or stretching) for as long as the movement continues.
  • Is worse in the evening and at night, or only occurs in the evening or at night.

Investigations to consider:

FBC, U&E, Creatinine
Iron studies: low ferritin

Treatment:

Correct anemia
Pharmacological:

  • Pramipexole, rotigotine, cabergoline (but cardiovascular risk), and gabapentin enacarbil (Level A, strong evidence)
  • Ropinirole, pre-gabalin, and IV ferric carboxymaltose use (Level B moderate evidence)
  • Levodopa (Level C, weak evidence)

Non-pharmacological:

  • Pneumatic compression (Level B moderate evidence)
  • Near-infrared spectroscopy (Level C weak evidence)
  • Transcranial magnetic stimulation TMS (Level C weak evidence)
  • Vibrating pads (Level C weak evidence)
  • Moderate exercise

Related articles:

Related articles:

  1. Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Nov 16. pii:. PMID:27856776DOI:10.1212/WNL.0000000000003388

Narcolepsy

Diseases

Diagnosis:

This is a clinical diagnosis supported by findings on polysomnogram

Clinical features:

Daytime hypersomnolance, wake up refreshed
Cataplexy (sudden loss of muscle tone triggered by emotional situations)
Hypnogogic & hypnopopic hallucinations
Sleep paralysis (patient wakes from sleep but tone is still absent, last 10min)

Findings on investigations:

MSLT (multiple sleep latency test): decreased latency for REM sleep i.e. <8min +2 sleep-onset REM periods
CSF hypocretin-1 (formerly orexin A): low in patients with cataplexy, <110 pg/ml

Treatment:

Amfetamines: Dextroamfetamine P.O.
Antidepressants for cataplexy
 

Insomnia

Diseases

Diagnosis:

Difficulty with sleep initiation or maintenance (staying asleep, waking early) inspite of adequate opportunity to sleep.

Treatment:

Non-pharmacological:

Improve sleep hygiene:

  • Maintain regular sleep-wake cycle: Set to bed time, mid-day Nap less than 1 hour, don’t oversleep in the weekend.
  • Reduce stimulants: no caffiene afternoon, noneducational reading at bed, avoid exercise alcohol & heavy meals close to bedtime. Minimise light, noise, excessive temperatures. Avoid working in the bed room. Remove clock from sight.
  • Exercise but not withing 3 hours of bedtime
  • Don’t lie in bed awake in the morning

Cognitive behavioural therapy CBT: for chronic insomnia

Pharmacological:

For acute insomnia:

  • Melatonin receptor agonist: Ramelteon
  • Benzodiazepine receptor BZR agonist: zolpidem, zopiclone, eszopiclone

For chronic insomnia:

  • Esozopiclone. Ramelteon

 

Enterogenous Cyst

Diseases

Synonyms:

Endodermal cyst,

Diagnosis:

Usually by MRI. Pathology is confirmatory.

Findings on investigations:

MRI:

  • Anterior to the cord
  • Associated with vertebral abnormalities lower than the lesion. Associated with respiratory tract abnormalities if bronchogenic cyst and GIT abnormalities if neuroenteric.

Pathology:

Histology:

  • Well differentiated columnar epithelium, ciliated or nonciliated +/-mucus +/-goblet cells. PAS positive membrane
  • Rarely more developed features occur intestine-like mucosa (Neuroenteric), cartilage (Bronchogenic)

Immunohistochemistry: CEA positive, EMA positive

Epidermoid Cyst

Diseases

Diagnosis:

Usually by MRI imaging

Findings on investigations:

CT: low density, irregularly enhancing rim
MRI:

  • Cerebellopontine angle, suprasellar, infrasellar
  • variable signal (dependent on lipid content)

Pathology:

Histology:

  • Cyst lined by epithelium, keratinisation, no adnexial/dermal tissue (hair & sweat glands) i.e. only top layers of the skin
  • Cyst filled with keratinised material

Treatment:

Surgical resection
 

Arachnoid Cyst

Diseases

Diagnosis:

Usually made by MRI imaging

Findings on investigations:

MRI:

  • Extraaxial. Supratentorial or infratentorial. Supratentorial; middle cranial fossa & third ventricle, perisellar cistern, along the convexities. Infratentorial; retrocerebellar cistern, cerebellopontine angle cistern, quadrigeminal cistern. Rarely intraventricularly. Mild mass effect.
  • isointense with CSF on T1 & T2.
  • Nonenhancing

CT: isodense with CSF
Intrathecal contrast: initially nonenhancing, but takes up enhancement later on.

Pathology:

Histology:

  • Thin walled. Lined by arachnoid cap cells (meningothelial cells)

Immunohistochemistry: positive for= EMA. Negative for =CEA & GFAP.
 

Retinoblastoma

Diseases, ,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

Eye, optic nerve, pineal gland

Pathology:

Grossly: White tan mass
Histology:

  • Small round blue cells, rosette (Homer-Wright around neuritic processes & Flexner-Wintersteiner around a central lumen), necrosis, frequent mitosis

Immunohistochemistry: NSE, NeuN, synaptophysin
Genetics: RB gene mutation 13q14, germline.

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Paraganglioma

Diseases, ,

Synonyms and subtypes:

a.k.a. carotid body tumor, glomus jugulare tumor, glomus tympanicum

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Neck mass (carotid body tumor, glomus jugulare tumor), middle ear canal mass (glomus tympanicum)
  • Filum terminale
  • Enhancing lesion

MRA: blood supply can be assessed.
Catheter Angiogram:

  • To assess vascular supply & embolisation prior to surgery

Pathology:

Histology:

  • Nests of chief cells (Zellballen), surrounded by sustentacular cells, separated by vessels,

Immunohistochemistry: positive for Chromogranin (chief cells), neurofilament (chief cells), synaptophysin (chief cells), NSE (chief cells), S100 (sustentacular cells),
Urine testing: Free catecholamines, metanephrines MTA & vanillylmandelic acid VMA (3-mehoxy-4-hydroxymandelic acid). Metanephrine:creatinine ratio

Treatment:

Consider Presurgical embolisation
Surgical Resection

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Chordoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

Bitemporal hemianopia (chiasm lesion), homonymous hemianopia (optic radiation, pregeniculate)

Findings on Investigations:

MRI:

  • Clivus or sacrum
  • Optic chiasm compression

Pathology:

Histology:

  • Lobulated, fibrovascular septa. Epitheloid cells in chords/rows in mucoid stroma. Physaliphorus Cells (bubble cells)= central nuclei, bubble like vacuolated cytoplasm. Focal cartilage may occur.

Immunohistochemistry: positive for= Vimentin, EMA, cytokeratins, S100

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Intraneural Perineuroma

Diseases,

Synonyms:

formerly localized hypertrophic mononeuropathy

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • MRI neurography (fat saturated T2 or fat saturated T1 post Gadolinium):
  • Hypertrophic nerve, fusiform, several 5-10cm or more.
  • Upper limb: posterior interosseus, radial, ulnar nerves. Or lower limb: sciatic, peroneal, tibial, femoral nerves

Pathology:

Histology:

  • HE: thickened perineurium, Endoneurial “Pseudoonion bulbs”= Whorles of perineurial cells

Immunohistochemistry: EMA positive, S100 negative

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Neurofibromatosis (NF)

Diseases, ,

Diagnosis:

Clinical features:

NF 1, two or more of the following:
  • >5 Café au lait spots
  • Neurofibroma:
    • 2 or more neurofibroma
    • or 1 plexiform neurofibroma
  • Freckles in the axilla or inguinal area a.k.a. Crowe’s sign
  • 2 or more Lisch nodules (iris hamartomas)
  • Optic glioma
  • A distinctive osseous lesion: sphenoid dysplasia, thinning of long bone cortex
  • A parent, sibiling or child with neurofibromatosis
NF 2:
  • Bilateral VIII nerve palsy due to schwannoma
  • A parent, sibling or child with NF 2 plus either:
    • Unilateral VIII nerve mass
    • Or two of the following: neurofibroma, meningioma, glioma, schwannoma or juvenile posterior subcapsular lens opacity

Investigations to consider:

MRI brain and MRI spine
Hearing tests, auditory evoked response
Slit lamp: Lisch nodules in type 1 neurofibromatosis
Monitor:

  • In relatives of those with NF type 2: regular hearing tests, auditory evoked responses

Treatment:

Supportive care
Treat complications
Subcutaneouns neuroma:

  • Excise if painful

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Neurofibroma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

Histology:

  • Spindle cell tumor, densely packed, fascicular appearance. Interstitial axons (sliver impregnation or neurofilament)

Immunohistochemistry: positive for= S100. Neurofilament positive interstitial axons.

Findings on Investigations:

Plexiform type is almost always associated with neurofibromatosis type I
MRI:

  • Widened neural foramina. Erosion of the pedicle. Usually dorsal spinal nerve roots

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Schwannoma

Diseases,

Synonyms:

Vestibular Schwannoma a.k.a. acoustic neuroma (formerly neurilemmoma)

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

Histology:

  • Antoni A pattern: cellular, Spindle cells. Verocay bodies (palisading).
  • Antoni B pattern: less cellular, round nuclei, vacuolated cells, microcysts

Immunohistochemsitry: Positive S100

Findings on Investigations:

MRI:

  • VIII nerve. Extends into the internal auditory canal IAC. May affect cranial nerves VII, V or any other. Cisternal & intracanalicular portions. Cysts may occur. No calcifications, no bony reaction, no dural tail.
  • May occur in spinal nerve roots. Hourglass/Dumbbell shaped mass through the intervetrebal foramen
  • T1 MRI with gadolinium: isointense to hypointense. Enhancement
  • T2: variable signal intensity
  • Fat saturated MRI: distinguishes fat.
  • Associated with arachnoid cyst

Audiological testing: may be impaired
Consider:

  • BAER
  • Electronystagmography ENG

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Meningioma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

CT: hyperdense, uncommonly calcify,
MRI:

  • Extraaxial, parasagittal dura >convexities >sphenoid wing >cerebellopontine angle cistern >olfactory groove >plantum sphenoidale. May encase arteries. May invade bone (hyperostotic or osteolytic).
  • T1: hypointense, enhancement of lesion & dural tail. Vascular flow voids may occur.
  • T2: hypointense, with hyperintense CSF surrounding it ‘cleft sign’,

Catheter angiography: tumor blush and blood supply is noted.

Pathology:

Well circumscribed, attached to dura
Histology: monomorphic cells, round/oval nuclei, syncytium. psammoma bodies, whorls, capsule. Brain invasion defines WHO grade II meningioma
Immunohistochemistry: positive for vimentin, EMA. Negative for GFAP
Associated with neurofibromatosus type 2

Treatment:

Surgical excision
Consider preoperative Catheter angiography

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Lymphomatoid granulomatosis (LG)

Diseases, ,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

  • A type of diffuse large B cell nonHodgkin’s lymphoma
  • B lymphocytis, granuloma involving the vessels (angiocentric & destruction of vessels) & brain parenchyma. Reactive T cells, Histiocytes
  • EBV positive B cells
  • Infarcts

Clinical features:

  • Affects lungs & skin, CNS, Peripheral nervous system (cranial & limbs),
  • Usually affects the lungs before the CNS

Findings on Investigations:

MRI:

  • Infarcts
  • T2/FLAIR: white matter lesions, brainstem or supratentorial
  • Enhancement of lesions: enhancement along perivascular spaces or ring enhancement or punctate enhancement

Catheter Angiogram: appearance of vasculitis

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Intravascular B cell Lymphoma

Diseases, ,

Synonyms:

a.k.a. neoplastic angioendotheliosis a.k.a. angiocentric lymphoma a.k.a. angiotropic malignant lymphoma

Diagnosis:

Suggested by MRI and angiography, and confirmed by pathology (CSF, brain biopsy)

Clinical features:

  • Encephalopathy, dementia, seizures
  • Strokes, myelopathy
  • Can affect any organ: most commonly CNS & Skin or fever of unknown origin

Pathology:

  • NonHodgkin lymphoma, B-cell
  • Confined to blood vessels only, doesn’t extend into brain
  • Blood vessels: in white & grey matter & Subarachnoid vessels
  • Immunohistochemistry: CD20 positive B cells

Findings on Investigations:

CT:

  • May be normal

MRI:

  • Multifocal infarcts
  • Focal parenchymal enhancement may occur, dural enchancement
  • Nonspecific white matter lesions

Catheter Angiogram: may have appearance of vasculitis
CSF:

  • Pleocytosis, increased protein
  • Oligoclonal bands positive
  • Rarely cytology positive

Other tests:

  • ESR: high

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Primary CNS lymphoma (PCNSL)

Diseases,

Synonyms:

a.k.a. CNS lymphoma

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

CT:

  • PCNSL: hyperdense on CT
  • Secondary lymphoma; hyperdense on noncontrast and enhances after contrast.
  • Variable in AIDS.

MRI:

  • Single or multiple lesions. Usually supratentorial, affecting the deep grey matter nuclei and Periventricular. Subependmal spread. Occur at grey-white matter junction. May encase the ventricle. May involve: corpus callosum, septum pellucidum, or encase the ventricles
  • Involves basal ganglia, ependymal spread, corpus callosum
  • T1 +contrast: dense enhancement, ring enhancing lesions, ependymal enhancement. Dural enhancement usually occurs in secondary lymphoma
  • T1: hypointense or isointense
  • FLAIR: hypointense or homogenous, rarely it’s hyperintense
  • DWI: hyperintense but not as bright as a stroke, ADC: hypointense

MR Perfusion: increased perfusion. Differentiates it from toxoplasmosis.
Thallium scan: increased. Differentiates it from toxoplasmosis.

Pathology:

Histology:

  • Pleomorphic, Small round blue cells without cytoplasmic processes. Perivascular lymphocytes. Necrosis may occur.

Immunohistochemistry: CD20 B cell marker.
–      Primary CNS lymphoma is associated with AIDS with EBV. Mainly a B cell lymphoma.

Treatment:

Omya reservoir:

  • Intraventricular methtrexate

Radiation therapy
Steroids
Radiation therapy
Steroids

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Pineoblastoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

Parinaud syndrome
Hydrocephalus

Findings on Investigations:

MRI:

  • Pineal mass
  • Contrast enhancement
  • CSF leptomeningeal metastasis can occur

CSF analysis:

  • leptomeningeal metastasis can occur

Pathology:

Histology:

  • Small round blue cell tumor, high nuclear cytoplasmic ratio. Homer-Wright (around neuritic processes) & Flexner-Wintersteiner Rosettes (around lumen). Necrosis & mitosis may occur.

Immunohistochemistry: positive for= synaptophysin, NSE, neurofilament, Class III beta tubulin, chromogranin, retinal S antigen. Rarely GFAP positive

Treatment:

Options:

  • Surgery
  • Radiation therapy
  • Chemotherapy

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Pineocytoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

Parinaud syndrome
Hydrocephalus

Findings on Investigations:

MRI:

  • Pineal region mass
  • Contrast enhancement

Pathology:

Histology:

  • Small round blue cell tumor. Rosettes may occur. Mitosis & necrosis are rare.

Immunohistochemistry: positive for= synaptophysin, NSE, neurofilament, Class III beta tubulin, chromogranin, retinal S antigen. Rarely GFAP positive

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Germinoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

Parinaud syndrome
Hydrocephalus

Findings on Investigations:

CT:

  • Pineal region mass
  • Calcified

MRI:

  • Pineal region mass
  • isointense with brain

Pathology:

Histology:

  • Large round blue cells, vesicular nuclei, abundant cytoplasm. With lymphocytic infiltrate.

Immunohistochemisty: PLAP positive

Treatment:

Radiation therapy

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Rathke Cleft Cyst

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

Visual problems, headache, Hypopituitarysm,

Findings on Investigations:

CT:

  • Intrasellar or suprasellar
  • Variable density (based on mucus content)

MRI:

  • Intrasellar or suprasellar
  • T1: cyst is hyperintense
  • T1 +GAD: pituitary enhances, lesion remains hyperintense

Pathology:

Histology:

  • Epithelial lined cavity, cuboidal or columnar epithelium, +/-cilia, serous mucous or gelatinous contents.
  • Occasional squamous metaplasia occurs.

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Craniopharyngioma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

  • Hypopituitarism, visual field cuts,
  • Chemical meningitis on rupture

Findings on Investigations:

Usually suprasellar. The following features may occur: Cysts. Calcified (rim or nodular). Enhancement (solid or nodular).
CT: Calcied rim. Enhancing nodule. Hypodense cysts
MRI:

  • T1: variable intensity cysts
  • T2: usually hyperintense
  • PD: hyperintense.

Pathology:

Histology:

  • Pseudostratified columnar cells, squamous cells rimmed by basaloid cells. Palisading. Keratin nests. Calcifications. Foreign body giant cells.

Treatment:

Surgical resection

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Pituitary adenoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

  • Non-secreting tumors: present with visual field defects commonly bitemporal hemianopsia. Also present with headaches or are incidentally found
  • Hormonal syndromes with secreting tumors: amenorrhea and infertility with prolactinomas, acromegaly, Cushing’s disease with other hormones
  • Pituitary apoplexy: Severe headache, Sudden visual loss or sudden collapse, multiple ocular nerve plasies

Findings on Investigations:

Microadenoma: <10 mm.

MRI T1, hypointense, doesn’t enhance unlike normal pituitary.
CT. hypodense, erosion of sellar floor, upward convexity of diaphragm sellae,

MacroAdenoma :

>1 cm. Hemorrhage may occur, may invade cavernous sinus, extend into suprasellar space (Michellin Man appearance)
MRI:

  • T1, hypointense lesion, if present hypointense cysts
  • T2, if present hyperintense cysts

Pathology:

Histology:
Small round blue cells. Further classification based on other stains & immunohistochemistry.

Hormonal tests:

Raised prolactin: Prolactinoma or compression of the stalk. In prolactinoma, Prolactin >200 ng/ml
Insulin stimulation tests: hypopituitarism
OGTT with GH +clinical features: acromegaly
TSH secreting pituitary adenoma: high TSH, high free T4, high free T3. TRH sitimulation test: flat TSH response

Treatment:

Depends on presence & absence of hormonal secretion & neurological deficits
If nonsecreting:

  • Surgery:
    • Transfrontal or trasphenoidal approach, or subfrontal craniotomy if there is intracranial extension beyond the pituitary fossa
    • If +Hypohpysectomy: need hormonal & steroid replacement

Radiation therapy

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Atypical teratoid rhabdoid tumor (ATRT)

Diseases

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

Posterior fossa > supratentorial

Pathology:

Histology:

  • Small round blue cell tumor, with rhabdoid cells= eccentric nucleus with prominent nucleolus, eosinophilic cytoplasmic inclusions,
  • Immunohistochemistry: INI1 negative (distinguishes it from choroid plexus carcinoma which is INI1 positive, but this is not a perfect test), EMA positive, smooth muscle actin positive, Cytokeratin positive, GFAP= positive

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Neuroblastoma, Olfactory

Diseases,

Synonyms:

a.k.a. olfactory neuroblastoma a.k.a. esthesioneuroblastoma:

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

CT: for bone erosion, homogenous mass
MRI:

  • Mass beneath the cribriform plate in the nasal cavity, extending into the nasal sinus, orbit (via lamina papyrecea) or frontal lobe (via cribriform plate). Superior cystic component
  •  T1: hypointense
  • T2: iso- or hyper-intense
  • Homogenous or inhomogeneity
  • Moderate enhancement
  • Dumbbell shape around the cribriform plate

Pathology:

Histology:

  • Small round blue cell tumor
  • Arranged in nests, Homer Wright pseudorosettes (around neuritic processes) & Flexner Wintersteiner rosettes (around a lumen) may be seen.

Immunohistochemistry:

  • NSE, synaptophysin & chromogranin positive. Some S100 positivity in the periphery.
  • Negative for: cytokeratin, CLA, HMB45, GFAP, desmin, vimentin,

Treatment:

Treatment modalities:

  • Surgical resection
  • Radiation therapy
  • chemotherapy

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Primitive Neuroectodermal Tumor (PNET)

Diseases,

If supratentorial= PNET. If cerebellar= medulloblastoma.

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • If cerebellar= medulloblastoma. If supratentorial= PNET
  • PNET: supratentorial (frontal, parietal, occipital lobes), large, homogenous, well circumscribed. Enhance heterogeneously. Calcifications, cysts & hemorrhage are common. Minimal oedema.
  • Medulloblastoma: midline cerebellar, may occur in cerebellar hemispheres, grow into 4th ventricle with distortion of the ventricles shape, uncommonly calcify, cysts are uncommon. Minimal oedema. Moderate enhancement.
  • T1, hypointense
  • T2, intermediate intensity, isointense,
  • FLAIR, hyperintense tumor, hyperintensities in subarachnoid space= seeding, with gadolinium it’s more sensitive to seeding, seeding can occur anywhere along the craniospinal axis.
  • TI with contrast: Leptomeningeal enhancement indicates CSF seeding

CT: homogenous, hyperdense, well circumscribed,

Pathology:

Small round blue cells. Homer Wright rosettes.
Desmoplastic medulloblastoma nests of cells arranged in nodules (surrounded by fibrous bands). Medulloepitheliomas= cells arranged in cords or papillae.
Immunohistochemistry: positive for synaptophysin, Trk, nerve growth factor. Variable positivity for NSE, GFA, vimentin, S100

Treatment:

Treatment modalities:

  • Surgery
  • Radiotherapy (craniospinal)
  • Chemotherapy

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Medulloblastoma

Diseases,

If cerebellar= medulloblastoma. If supratentorial= PNET

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • If cerebellar= medulloblastoma. If supratentorial= PNET
  • Medulloblastoma: midline cerebellar, may occur in cerebellar hemispheres, grow into 4th ventricle with distortion of the ventricles shape, uncommonly calcify, cysts are uncommon. Minimal oedema. Moderate enhancement.
  • PNET: supratentorial (frontal, parietal, occipital lobes), large, homogenous, well circumscribed. Enhance heterogeneously. Calcifications, cysts & hemorrhage are common. Minimal oedema.
  • T1, hypointense
  • T2, intermediate intensity, isointense,
  • FLAIR, hyperintense tumor, hyperintensities in subarachnoid space= seeding, with gadolinium it’s more sensitive to seeding, seeding can occur anywhere along the craniospinal axis.
  • TI with contrast: Leptomeningeal enhancement indicates CSF seeding

CT: homogenous, hyperdense, well circumscribed,

Pathology:

Small round blue cells. Homer Wright rosettes.
Desmoplastic medulloblastoma nests of cells arranged in nodules (surrounded by fibrous bands). Medulloepitheliomas= cells arranged in cords or papillae.
Immunohistochemistry: positive for synaptophysin, Trk, nerve growth factor. Variable positivity for NSE, GFA, vimentin, S100

Treatment:

Treatment modalities:

  • Surgery
  • Radiotherapy (craniospinal)
  • Chemotherapy

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Choroid Plexus Papilloma

Diseases,

 

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Interaventricular mass: fourth ventricle > lateral ventricles > third ventricle
  • Homogenous mass, prominent flow voids (vascular), calcification
  • Lateral ventricle trigone. In adults it occurs at the 4th ventricle.
  • Calcification, hemorrhage may occur
  • Enhance intensely
  • Pathology:

Pathology:

Histology:

  • Hyperplasia of bland looking (Minimal atypia) choroid plexus cells. Fibrovascular stalks. Mitosis are rare.
  • Choroid plexus, epithelium

Immunohistochemistry: positive for= vimentin, keratin, S100.

Treatment:

Surgical resection, with or without radiation therapy

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Central Neurocytoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Occur anywhere in the ventricular system. Septum pellucidum, temporal & frontal horns of the third ventricle.
  • Calcification, cystic component may occur. Variable contrast enhancement

Pathology:

Round cells, fibrillary background, Speckled chromatin, scant cytoplasm,
Prominent vasculature sometimes,
Immunohistochemistry: Positive for synaptophysin, NSE, taur, MAP2, class III beta tubulin

Treatment:

Surgical resection

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Hemangioblastoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Cerebellar, less commonly brainstem or spinal cord
  • Cyst with enhancing mural nodule

Other features:
Associated with von Hippel-Lindau syndrome, 3p25-26
FBC: high Hb & HCT
Pancreatic cysts, renal cyst
Retinal hemangioblastoma

Pathology:

Histology: Well circumscribed, cystic with nodule
Microscopically: 2 parts; prominent vascular capillaries & stromal cells. Stromal cells have vacuolated cytoplasm. Adjacent gliosis.
Immunohistochemistry: vimentin= focally positive, GFAP= weakly positive in some areas. Stromal cells negative for: factor VIII, EMA, neurofilament, keratin
Oil red O stain: foamy cells

Treatment:

Surgical resection with or without pre-operative embolization

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Desmoplastic infantile ganglioglioma (DIG) and desmpolastic infantile astrocytoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Clinical features:

occur in children < 2 years old

Findings on Investigations:

MRI:

  • Supratentorial, superficial cortical
  • Large cystic lesion with solid nodule, displacing normal brain
  • Enhancing nodule
  • May have dural attachment

Pathology:

May have dural attachment
Histology:

  • Spindle cells in fascicles or storiform pattern. Large neurons in DIG. Also gemistocyte-like cells
  • Dense reticulin network (reticulin or trichorme stains).

Immunohistochemistry: positive for GFAP, synaptophysin (in ganglion cells),

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Dysembryoplastic neuroepithelial tumor DNET

Diseases,

WHO grade I

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI: Intracortical lesions, commonly in the temporal lobe, may have a small cystic component

Clinical features:

Associated with intractable seizures in some cases

Pathology:

Histology: Nodular or multinodular. Mucin rich cortical nodules
Oligodendroglial-like areas (halos without satellitosis) and neurocytic areas. ‘specific glioneuronal element’: oligodendroglial-like cells  with axons around microcystic spaces with ganglion cells.  Floating neurons= ganglion cells in a pool of mucin
Dysplastic adjacent cortex. Calcifications & cysts may occur.
Immunohistochemistry: synaptophysin positive, S100 oligodendroglial-like cells positive, GFAP negative, MIB low.

Treatment:

Surgical resection

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Gangliocytoma and Ganglioglioma

Diseases,

Synonyms and classification:

  • Gangliocytoma, WHO grade I
  • Ganglioglioma WHO grade I or II a.k.a. ganglion cell tuomur

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

May occur through out the CNS. Commonly temporal lobe. Circumscribed solid mass or cyst with mural nodule.
CT: hypodense or isodense. Calcification may occur.
MRI:

  • T1: hypointense
  • T2: hyperintense
  • Enhancement: variable

Pathology:

Histology: Neoplastic mature ganglion cells (abnormal e.g. binucleate, lack of polarity, nuclear pleomorphism, clustered in groups). If alone= gangliocytoma. If with neoplastic glial cells= ganglioglioma. Eosinophilic granular bodies, Perivascular lymphocytic cuffing, cystic spaces & calcifications may occur.
Gangliocytoma: groups of large, irregular multipolar neurons. Non-neoplastic glial stroma. Reticulin fibre network.
Ganglioglioma: as in gangliocytoma except there is a neoplastic glial component, usually astrocytic. Necrosis is absent.
Immunohistochemsitry: GFAP usually positive in ganglioglioma. Ganglion cells are positive for neural markers e.g. synaptophysin, neurofilament, chromogranin. Neoplastic neurons are NeuN negative. MIB low.

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Astroblastoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Usually cystic, intraaxial, well demarcatd
  • Enhancing

Pathology:

Histology: Oval nuclei, cytoplasm fibrillary or cuboidal
Perivascular pseudorosette with broad processes`. Vascular hyalinisation.
Immunohistochemistry: positive for GFAP, S100. Negative for Synaptophysin, neurofilament, NeuN, chromogranin

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Ependymoma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

Histology: perivascular pseudoresettes (tumor cells surrounding a vessel), ependymal tubules ‘canals or rosettes’ (tumor cells lining central lumens)
Immunohistochemistry: GFAP positive, EMA dot positivity, CD99 dot positivity

Findings on Investigations:

Ventricular system infratentorial (fourth ventricle) >supratentorial >spinal (lumbosacral expansion of the cord, +/-associated syrinx, common in adults, conus medularis/filum terminale), CSF spread
Heterogenous solid mass. Cysts may occur (esp. if supratentorial).  Hemorrhage & calcification may occur. Hydrocephalus.
CT:

  • hypodense mass. Calcifications. Cysts may occur. Enhancement.

MRI:

  • T1: hypointense.
  • T2: intermediate intensity. Calcifications may be hypointense.

Treatment:

Surgical resection
Consider radiation therapy

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Oligodendroglioma

Diseases,

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

Histology: small round blue nucleus, halo of cytoplasm ‘fried egg or honey comb’ appearance on formalin fixed tissue. Thin walled branching capillaries ‘chicken wire or wishbone’ appearance. Minigemistocytes, perineuronal satellitosis & Microcalcifications may occur. In higher grade; endothelial proliferation, mitosis & necrosis are present.
Immunohistochemistry: GFAP classic cells are negative, minigemistocytes are positive, some cells have a perinuclear rim= gliofibrillary oligodendrocytes. S100 positive. The following are negative: CLA, Cytokeratins, EMA, HMB45.
FISH: deletion of 1q & 19p.

Findings on Investigations:

Involvedment of the frontal lobes or temporal lobes. Rare in spinal cord, brain stem & posterior fossa
CT:

  • hypodense mass, serpentine calcification, cystic areas. Hemorrhage can occur. Usually no oedema. Variable enhancement

MRI:

  • T1: hypointense
  • T2/FLAIR: hyperintense tumor, hypointense calcification. But calcification is easier to see on CT

Treatment:

Oligodendroglioma:
  • Surgical resection
  • Consider Chemotherapy:
    • Procarbazine +Lomustine CCNU+Vincristine PCV if 1p/19q deletion. Increases progression free survival PFS but doesn’t increase overall survival. Toxicity overweighs benefit in grade III.
    • Temozolamide TMZ if 1p/19q codeletion & low grade (200 mg/m2/day for 5 consecutive days, repeated every 28 days).
Mixed Oligoastrocytoma, WHO grade II & grade III:

If grade II:

  • Surgical resection
  • Consider Chemotherapy: Temozolamide TMZ if 1p/19q codeletion (200 mg/m2/day for 5 consecutive days, repeated every 28 days).

If grade III:

  • Surgical resection
  • Consider radiotherapy

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Gliomatosis Cerebri

Diseases,

This is different than leptomeningeal gliomatosis:

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Pathology:

Gross: enlarged brain, diffusely. Involving white matter more than grey matter, may involve any part of the neuroaxis, diffuse tumor without a single large mass
Histology: infiltration of grey & white matter by undifferentiated cells. Elongated cells, forming parallel rows when infiltrating tracts. No microvascular proliferation.
Immunohistochemsitry: GFAP positive variably.

Findings on Investigations:

CT:

  • Homogenous, hypodense, loss of grey white junction, swollen hemispheres. Low sensitivity.

MRI:

  • Involvement of the grey matter and some of the white matter, swollen hemispheres with sulcal effacement
  • T1: hypointense or isointense.
  • T2: hyperintense. Better than T1.
  • Minimal enhancement.
  • Overall low sensitivity.

Treatment:

Radiation therapy

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Brain Tumor

Diseases,

Neoplastic brain disease can be divided into primary brain neoplasms and metastatic (or secondary) brain neoplasms. Another way of classifying brain tumors is by whether they are intra-axial (within the substance of the brain) or extra-axial lesions. Furthermore, it is useful to note the general and specific locations of the tumor. Brain tumors in adults are more likely to be supratentorial, whereas in children they are usually infratentorial. Specific locations for the brain tumors also narrow the differential diagnosis; for example pituitary region tumors, pineal region tumors, cerebellopontine angle (CP angle) brain tumors and leptomeningeal metastasis all have very different causes.
This section gives a general overview on brain tumors. Other topics in neurooncology include spinal cord tumors and paraneoplastic syndromes
 

Causes of Brain tumours by location:

Extraaxial:

  • Intradural:
    • Meningioma
    • Sarcoma: meningosarcoma, angiosarcoma etc.
    • Metastasis:
      • Lung, breast, prostate, melanoma
  • Extradural:
    • Schwannoma
    • Neurofibroma
    • Metastasis: Subarachnoid seeding a.k.a. Carcinomatous meningitis:
      • Adults: Lymphoma, leukemia, Glioblastoma, breast, lung, GI, melanoma
      • Children: lymphoma, leukemia, Choroid plexus papilloma, ependymoma, PNET, astrocytoma, neuroblastoma

Intraaxial Infratentorial:

Intraaxial Supratentorial Hemispheric:

Pituitary fossa/suprasellar cistern:

Pineal region:

Intraventricular & periventricular region:

Cerebellopontine angle:

 

Primary Brain tumors:

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)
See individual pages for each type of brain tumor

Investigations to consider:

CT
MRI with & without contrast
Chest X-ray
Catheter angiography: for very vascular tumors like hemangioblastoma or meningioma
CSF analysis: Medulloblastoma & pinealoma can metastasis to the CSF
Stereotactic Biopsy
MRI for operative planning:

  • Image guidance
  • Intraoperative MRI
  • DTI/Tractography
  • fMRI for language and motor function

CT chest, abdomen, pelvis: for primary tumor in suspected metastatic disease
Obsolete tests, historical:

  • Skull X-ray
  • Pituitary view X rays

Treatment:

Treat cerebral edema and Raised intracranial pressure:

  • Dexamethasone (as dexamethasone sodium phosphate): if emergent start with 10mg intravenously. In non emergent cases oral regimen is preferred
  • Consider PCP prophylaxis if on long term steroids

If acute hydrocephalus (noncommunicating or communicating), consider shunting
Consider definitive treatment modalities depending on the tumor:

  • Surgical resection
  • Radiotherapy:
    • External beam: whole brain radatiation therapy, or stereotactic radiosurgery
    • Implanted beeds or wafers
  • Chemotherapy

If Pulmonary embolism or DVT occur, consider:

  • Anticoagulation: heparin, [small retrospective studies]
  • IVC filter [small retrospective studies]

Seizures:

  • Treat only after seizures occur
  • Antiepileptic drugs
  • Treatment of tumor: surgery, radiotherapy

 

 
 

Brain metastasis, a.k.a. secondary brain tumor:

Parenchymal brain metastasis:

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations parenchymal brain metastasis:

Small, often multiple, at grey-white interface. Well defined. Variable oedema.
CT: hypodense unless hemorrhage, calcification, or hypercellular or hyperproteinaceous.
MRI: T2 oedema is hyperintense, the lesion may be isointense or hyperintense. T1 the lesion is usually hypointense. Enhancing, ring enhancement.

Pathology, in parenchymal brain metastasis:

Histology:

  • Features of primary tumor. Lung, breast, melanoma, renal & GIT cancer.

Immunohistochemsitry may help:

  • AE1/AE3

Treatment of parenchymal brain metastasis:

Options:

  • Surgery, if single metastasis.
  • Radiation therapy
  • Chemotherapy
  • Palliative therapy

Supportive care:

  • Control of seizures, cerebral edema, hydrocphalus and systemic complications such as deep venous thrombosis and pulmonary embolism

 

Leptomeningeal carcinomatosis:

Synonyms:

Leptomeningeal carcinomatosis a.k.a. carcinomatous meningitis a.k.a. neoplastic meningitis, similar to dural metastasis

Diagnosis in leptomeningeal carcinomatosis:

  • Suggested by clinical findings and MRI and confirmed by pathology (biopsy/resection, CSF analysis)

Pathology, meningeal biopsy in leptomeningeal carcinomatosis:

  • Tumor infiltrating the meninges, peripheral nerves, cranial nerves

Clinical features in leptomeningeal carcinomatosis:

Multiple cranial or peripheral neuropathies (polyradiculopathy pattern)
Decreased level of consciousness, encephalopathy, nausea, vomiting (hydrocephalus pattern)

Findings on Investigations in leptomeningeal carcinomatosis:

LP, CSF analysis:

  • 50% positive on 1st tap, 85% on 3rd tap
  • Malignant cells, increased protein, increased cells
  • Low glucose
  • Opening pressure: High with blocked CSF drainage

CT:

  • Communicating hydrocephalus
  • Leptomeningeal deposits (pia, arachnoid),
  • Dural deposists
  • Meningeal enhancement,

MRI:

  • Communicating hydrocephalus
  • Dural metastasis:
    • Dural deposits, T1/T2 variable, FLAIR: hyperintense
    • T1+contrast or FLAIR +contrast: Dural tail enhancement
  • Subarachnoid seeding/Leptomeningeal carcinomatosis:
    • Leptomeningeal deposits (pia, arachnoid) “subarachnoid seeding”, basal cisterns, interpeduncular cistern, cerebellopontine angle cistern, convexities, cranial nerves.
    • FLAIR: hyperintense
    • T1+contrast or FLAIR +contrast: leptomeningeal enhancement, cerebellar or cerebral surface enhancement, nerve root enhancement,

Treatment of leptomeningeal carcinomatosis:

Consider the following options:

  • Intrathecal chemotherapy
  • Radiation therapy
  • Palliative care

Treatment of secondary complications
 

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Glioblastoma

Diseases,

WHO grade IV

Synonyms:

formerly glioblastoma multiforme, GBM

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

MRI:

  • Cerebral hemispheres, corpus callusum. Rarely brainstem, spinal cord
  • Large, irregular, ring enhancing or irregular enhancing. ‘butterfly pattern’ if it spreads via the corpus callosum. Oedema.
  • T1: low signal
  • MRI T2,FLAIR: high signal vasogenic oedema

Pathology:

Histology: marked nuclear atypia, mitosis, microvascular proliferation, +/-necrosis. Also, pseudopalisading of cells around necrosis, some have giant cells
Tumor genetics:

  • Primary GBM: EGFR chr. 7p12 overexpression, PTEN (MMAC1) mutation, CDKN2A chr. 9p21(p16=INK4a) deletion. Occasionally MDM2 amplification
  • Secondary GBM: p53 17p13.1mutation,

Treatment:

Surgery
Radiation therapy:

  • Fractionated focal irradiation in daily fractions of 2 Gy 5 days/week X 6 weeks, for a total of 60 Gy.
  • Or focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy.

Consider chemotherapy:

  • Temozolamide TMZ.
  • Bevacizumab after extensive surgery, radiotherpy & temozolamide

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Anaplastic Astrocytoma

Diseases,

WHO grade III

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

Ill defined, homogenous lesion. Some enhancement within the mass, but not a ring

Pathology:

Histology:

  • Nuclear atypia, mitosis, no microvascular proliferation, no necrosis

Treatment:

Radiotherapy
Consider surgery or chemotherapy in some cases

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Diffuse Astrocytoma

Diseases,

WHO grade II

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

Ill defined, homogenous lesion, cystic degeneration may occur. Usually non-enhancing. Enhancement suggests anaplasia
CT: hypodense. May be unapparent.
T2/FLAIR: high signal

Pathology:

Histology:

  • Nuclear atypia, extremely rare mitosis, no microvascular proliferation, no necrosis
  • Variants: fibrillary, gemistocytic, protoplasmic
  • FISH: deletion of 1q & 19p.
Treatment:

Surgery
Consider Chemotherapy:

  • Temozolamide TMZ if 1p/19q codeletion (200 mg/m2/day for 5 consecutive days, repeated every 28 days).

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Pleomorphic Xanthoastrocytoma PXA

Diseases,

WHO grade II

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

Supratentorial. Superficial, may involve meninges i.e. meningocerebral mass. Associated with a cyst.
T1: hyperintense mural nodule. Hypointense cyst

Pathology:

Histology:

  • Pleomorphic cells, lipidized cells i.e. Lipid-laden astrocytes, cellular atypia, spindle cells, multinucleated giant cells. Xanthomatous (foamy/clear) astrocytes.
  • Often, eosinphilic granular bodies (PAS positive), Lymphocytic infiltrates may occur.
  • Silver impregnations: cells surrounded by reticulin network
  • Immunohistochemistry: GFAP positive, S100 positive

Treatment:

Surgical resection

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Subependymal Giant Cell Astrocytoma SEGA

Diseases,

WHO grade I

Synonyms:

a.k.a. SGCA

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on Investigations:

CT: Near foramina of Monro, may block it, extends intraventricularly, enhances, may calcify
MRI: Near foramina of Monro, may block it, extends intraventricularly, enhances
Pathology:
Histology: large cells resembling gemistocytic astrocytes with neuron-like nuclei & astrocyte-like cytoplasm, calcifications may be present. Perivascular pseudorosettes.
Immunohistochemistry: Positive for GFAP, S100
Associated with tuberous sclerosis

Treatment:

Surgical Resection
Stereotactic radiotherapy: Gamma knife
mTOR inhibitors:

  • Everolimus
  • Rapamycin (sirolimus)

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Pilocytic Astrocytoma

Diseases,

WHO grade I neoplasm

Diagnosis:

Suggested by MRI and confirmed by pathology (brain biopsy/resection)

Findings on investigations:

MRI:

  • Cerebellar (commonest site). May occur in optic nerves, hypothalamus, thalamus. Brain stem-tectal plate. Ill defined cystic tumor with solid component. Occasionally without cyst.
  • T1: low signal, enhancement of wall and solid components
  • T2: high intensity

Pathology:

Histology: astrocytes with bipolar processes, eosinophilic processes (long tapering), oval nuclei, Rosenthal fibres (eosinophilic irregular fibres), eosinophilic granular bodies (PAS positive). Vessels are prominent. Compact areas & loose (microcyts) areas. Oligodendrocyte-like cells & infarct like necrosis may occur.
Immunohistochemistry: GFAP positive, S100 positive,

Treatment:

Surgical resection

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Fahr disease

Diseases, , , ,

Synonyms:

a.k.a. idiopathic basal ganglia calcification

Diagnosis:

A combination of clinical features, imaging and other testing

Clinical features:

  • 30-60 y.o.
  • Progressive dystonia, dysphagia, neuropsychiatric symptoms, ataxia

Genetics:

  • Autosomal dominant
  • Chr. 14q,

Findings on investigations:

CT: calcification in the globus pallidus, but also occurs in putamen, caudate, dentate, thalamus and cerebral white matter
Serum calcium & phosphate: Normal
Investigations for hyperparathyroidism: negative

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Neuroacanthocytosis

Diseases, , ,

A group of disorders with the following general features

Neuroacanthocytosis general features

Neurologic symptoms +blood smear with increased acanthocytes (spiky appearing RBCs). Note: wet preparation with a 1:1 dilution with normal saline, i.e. one drop of blood with one drop of saline.

Choreoacanthocytosis:

Diagnosis:

Clinical features:

  • Chorea, orofaciolingual dyskinesia
  • Dysphagia, dysarthria,
  • Seizures
  • Dementia
  • Areflexia (peripheral neuropathy), myopathy

Genetics:

  • CHaC gene,

Other tests:

  • +Blood smear: Increased acanthocytes
  • Elevated CK

MacLeod’s syndrome:

Diagnosis:

Clinical features:

  • Chorea
  • Psychiatric symptoms
  • Areflexia (peripheral neuroathy), myopathy

Genetics:

  • X-linked, KX gene,

Other tests:

  • +Blood smear: Increased acanthocytes Elevated CK
  • Kell blood group, hemolytic anemia

Abetalipoproteinemia a.k.a.Bassen-Kornzweig Syndrome:

Diagnosis:

Clinical features:

  • Spinocerebellar ataxia, peripheral neuropathy and retinitis pigmentosa
  • Malabsorption

Genetics:

  • Autosomal recessive, loss of serum apolipoprotein B

Other tests:

  • loss of serum apolipoprotein B, fat soluble vitamin deficiency,
  • Lipid profile: very low cholesterol
  • +Blood smear: Increased acanthocytes

Neurodegeneration with brain iron accumulation type 1 NBIA1 a.k.a. Pantathenate kinase PANK deficiency, formerly Hallervorden-Spatz disease:

See separate page.

Related articles:

Dentatorubropallidoluysian atrophy DRPLA

Diseases,

Diagnosis:

Genetics:

  • Autosomal dominant
  • DRPLA gene chr. 12. CAG repeat expansion (normal repeat number is 6-35). Protein= atrophin-1 protein.

Clinical features:

  • Chorea, ataxia, dementia, myoclonus

Pathology:

Gross: diffuse brain atrophy, worse in pons and cerebellum. Atrophy & discolouration of the globus pallidus, dentate nucleus, subthalamus & pontine tegmentum.
Microscopic: neuronal loss of dentate nucleus with grumose degeneration (eosinophilic granular material near the bodies of dentate neurons, it consists of preterminal axons). Neuronal loss & astrocytosis of external globus pallidus.
Neuronal loss also in: red nucleus, caudate, putamen, substantia nigra, subthalamus.
White matter degeneration of: cerebellar/olivary complex, superior cerebellar complex, posterior columns, spinocerebellar tracts.
Eosinophilic neuronal inclusions. Cytoplasmic inclusions in dentate nucleus neurons.
Immunohistochemistry: atrophin-1 positive intranuclear inclusions, ubiquitin positive intranuclear inclusions & cytoplasmic inclusions.

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Hypoxanthine-guanine phosphoribosyltransferase HPRT deficiency

Diseases, ,

Synonyms:

Hypoxanthine-guanine phosphoribosyltransferase HPRT deficiency a.k.a. Lesch-Nyhan disease

Diagnosis:

Genetics:

  • X-linked
  • Protein= hypoxanthine-guanine phosphoribosyltransferase HPRT

Clinical features:

Dystonia, athetosis,
Self mutilation (lip & finger biting)
Mental retardation (learning disability)
Severe gout, renal failure

Findings on investigations:

Uric acid: high

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Hereditary ferritinopathy and neurodegeneration with brain iron accumulation type 2 NIBA2

Diseases, ,

Synonyms:

Neuroferritinopathy a.k.a. Hereditary ferritinopathy and neurodegeneration with brain iron accumulation type 2 NIBA2

Diagnosis:

Genetics:

  • Autosomal dominant
  • Genetic: gene = FTL1, ferritin light chain gene. 460InsA mutation

Clinical features:

  • Focal dystonia, chorea, Parkinsonism. Cognitive effects occur later on.

Iron studies, etc:

  • Ferritin: low in men & post menopausal women. Normal in premenopausal women
  • Fe levels: normal
  • Hb, FBC & blood film: normal

Findings on investigations:
MRI:

  • Gradient echo: loss of T2 signal in red nuclei, substatia nigra, dentate nuclei, globus pallidi, thalami, cuadate nuclei. If severe cystic degeneration of globus pallidi and putamen.
  • Conventional spin echo MRI: signal loss in red nuclei and substatia nigra
  • T1: in severe disease high signal in dentate nuclei, thalami, caudate nuclei. Cystic degeneration of globus pallidi and putamen.

Other tests:

  • Muscle biopsy:
    • COX deficient fibres
    • Respiratory chain defects
  • FBC, U&E, lactate: normal
  • CSF: protein might be elevated
  • Electroretinogram: normal
  • NCS/EMG: normal
  • EEG: normal
  • Slit lamp: normal

Related articles:

Pantathenate kinase deficiency Associated Neurodegeneration

Diseases,

Synonysms:

Pantathenate kinase associated neurodegeneration PKAN a.k.a. Pantathenate kinase PANK deficiency a.k.a. Pantathenate kinase PANK deficiency a.k.a. Neurodegeneration with brain iron accumulation type 1 NBIA1, formerly Hallervorden-Spatz disease, rare:

Diagnosis:

Genetics:

  • Sporadic or autosomal recessive
  • PANK2 gene Chr. 20p13. Protein= pantothenate kinase (involved in coenzyme A biosythesis, panthothenate= vitamin B5)

Clinical features:

  • Childhood onset usually but may present in adulthood
  • Ridigity, difficulty walking, dysarthria, dementia,
  • Psychiatic symptoms: depression, behavioural problems

Findings on investigations:

MRI:

  • T2: external globus pallidus bilateral hyperintensities with surrounding hypointensity a.k.a. “eye of the tiger sign”
  • Generalised atrophy
  • Other tests:
    • Blood smear: increased acanthocytes

Pathology:

Gross: discolouration of the medial globus pallidus & substantia nigra. Atrophy of cerebral cortex, brain stem & cerebellum
Microscopically: axonal spheroids, neuronal loss & astrocytosis in the medial globus pallidus & substatia nigra. Spheroids also occur in the cerebral cortex, thalamus, subthalamus, striatum, brainstem & spinal cord,
Iron deposition in spheroids, neurons, microglia & vessels.
Immunohistochemistry: spheroids are positive for ferritin, ubiquitin, amyloid precursor protein, neurofilament and alpha synuclein.

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Chronic Carbon Monoxide CO poisoning

Diseases,

Diagnosis:

A combination of clinical features, MRI findings and carboxyhemoglobin testing

Clinical features:

  • Symmetric Parkinson like symptoms

Findings on investigations:

MRI: bilateral globus pallidus necrosis & lesions in the putamen, patchy white matter demyelination= Grinker myelinopathy
Carboxyhemoglobin: high

Pathology:

Acute, not movement disorder: Cerebral oedema, Cherry red colour
Chronic:

  • Pallidal necrosis: Bilateral, asymmetrical, gross necrosis, microscopic necrosis
  • Neocortical & hippocampal necrosis can occur
  • Cerebellum: loss of Purkinje cells & granlar layer
  • White matter a.k.a. Grinker myelinopathy demyelination & necrosis, relative sparing of axons.

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Opsoclonus Myoclonus

Diseases,

Synonyms:

a.k.a. dancing eyes dancing feet syndrome

Diagnosis:

This is a clinical syndrome

Clinical features:

  • Age: 18 months to 6 years. Can occur in adults
  • Opsoclonus: rapid, involuntary, repetitive disorganised congugate eye movements in all directions of gaze. Can be confirmed by oculography: absent intersaccadic interval

Investigations to consider:

  • MRI: neuroblastoma
  • CT: lung cancer, Hodgkins disease/Hodgkins lymphoma, thyroid cancer
  • US thyroid: thyroid cancer
  • Mammography: breast cancer
  • LP & CSF analysis:
    • Brainstem encephalitis
    • PCR for whipple’s disease
    • Pleocytosis, raised IgG, increased protein
  • Other tests for whipple’s disease
  • Paraneoplastic antibodies: anti-Ri

Treatment:

Treat the underlying disorder
Steroids

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Hemifacial Spasm

Diseases, ,

Diagnosis:

Clinical features:

  • Episodic unilateral twitching of the face. May lead to eye closure, but is distinguished from blepharospasm by being unilateral and often having an upgoing forhead muscle ipsilateral to the facial twitch
  • A type of segmental myoclonus involving the muscles supplied by the facial nerve (cranial nerve VII)

Investigations to consider:

Consider if atypical:

  • MRI & MRA: cerebellopontine angle tumors (including epidermoid tumors, meningioma), basilar artery aneurysm.

Treatment:

  • Botulinum toxin injection
  • Consider: microvascular decompression (usually PICA, AICA or VA)
  • Consider: carbamazepine, gabapentin or baclofen

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Stiff Person Syndrome

Diseases, ,

Synonyms:

formerly stiff man syndrome a.k.a. Moersch-Woltmann syndrome

Diagnosis:

Clinical  and electrophysiological features, supplemented by antibody tests
Diagnosis by exclusion: Absence of any other neurologic disease or chronic pain syndromes that could explain stiffness and rigidity.
This condition is often mis-diagnosed as psychogenic dystonia

Clinical features:

Rigidity: Insidious onset, Limbs and axial (trunk) muscles, most prominent in the abdominal and thoracolumbar paraspinals. Difficulty in turning or bending
+Continuous co-contraction of agonist and antagonist muscles. With inability to relax:

  • Confirmed clinically and electrophysiologically
  • +Episodic spasms:
    • Superimposed on rigidity
    • Precipitated by unexpected noises, tactile stimuli, or emotional upset

+Diagnosis by exclusion: Absence of any other neurologic disease or chronic pain syndromes that could explain stiffness and rigidity

Electrophysiology, EMG:

Continuous motor-unit activity:

  • & limbs
  • Disappears with IV diazepam, sleep, and local or general anesthesia
  • Note: preservation of silent period after muscle contraction
  • Abnormal co-contractions of antagonistic muscles
  • Intermittent superimposed contractions: Continue into drowsiness & interfere with sleep
  • Spasmodic reflex myoclonus

Antibody tests:

  • Anti-glutamic acid decarboxylase GAD antibodies, anti-amphiphysin antibodies, anti-Gephyrin antibodies
  • Associated with other autoimmune disorders e.g. diabetes, thyroid disease

Treatment:

Symptomatic:

  • 1st line: diazepam orally qid
  • 2nd line: baclofen
  • Others:
    • vigabatrin, Valproate VPA, Gabapentin GBP

Disease altering:

  • Treat underlying tumor if present
  • IVIg
  • Steroids
  • Plasmaphoresis

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Tardive Dyskinesia

Diseases, ,

Diagnosis:

Hyperkinetic movements due to use of dopamine receptor blocking drugs
Types:

  • Orofacial stereotypy
  • Dystonia

Treatment:

  • Stop the offending drug
  • Consider:
    • Valbenazine [KINECT3 RCT]
    • Reserpine
  • If tardive dystonia:
    • Anticholinergics: trihexyphenidyl
    • Botulinum toxin injection
  • If dystonia:
    • Diphenhydramine
  • Benzatropine
  • Consider deep brain stimulation DBS of globus pallidus interna GPi

Related articles:

References:

  1. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry 2017;174:476-484. PMID: 28320223. https://doi.org/10.1176/appi.ajp.2017.16091037

Genetic Dystonia

Diseases, ,

These are a group of dystonias

Oppenheim’s dystonia a.k.a. dystonia musculorum deformans 1 a.k.a. DYT1:

Diagnosis:

Genetics:

  • Autosomal dominant
  • Torsin A gene, chr. 9q34

Clinical features:

  • <26 y.o. starts as a focal dystonia (usually foot) then generalises

Lubag a.k.a. X-linked dystonia Parkinsonism a.k.a. DYT3:

Diagnosis:
  • X-linked, Xq13.1, TAF1 gene, protein= transcription factor,
  • Adults, 30y.o. (large spectrum 12-52y.o.), starts as Dystonia, Parkinsonism may develop latera

Dystonia 4 a.k.a. DYT4:

Diagnosis:
  • Autosomal dominant
  • Laryngeal & cervical dystonia +/-psychiatric symptoms

Dopa responsive dystonia a.k.a. DYT5 a.k.a. GCH1 a.k.a. Segawa syndrome:

Diagnosis:

Trial of levodopa, 2 months long. This should be tried in all childhood onset dystonias

Genetics:

Autosomal dominant
GTP cyclohydrase I gene (GCH1) mutation, protein= GTP cyclohydrase I, causes dopa responsive dystonia

Treatment:

Levodopa

Dystonia 6 a.k.a. DYT6:

Diagnosis:

Autosomal dominant
Chr. 8p21-p22. THAP1= gene, protein= thanatos-associated protein [THAP] domain-containing apoptosis-associated protein 1 = a transcription factor

Dystonia 7 a.k.a. DYT7:

Diagnosis:

Autosomal dominant
Chr. 18p

Paroxysmal nonkinesigenic dyskinesia a.k.a. Dystonia 8 a.k.a. DYT8, formerly paroxysmal dystonic choreoathetosis, Mount–Reback syndrome:

Diagnosis:

Genetics:

  • Autosomal dominant
  • Chr. 2q33-q35

Clinical features:

  • childhood to adulthood, episodes 2 min- 4 hours, dystonia, chorea or dyskinesia

Dystonia 9 a.k.a. DYT9:

Diagnosis:

Genetics:

  • Autosomal dominant
  • Chr. 1p13.3-1p21
Clinical features:

Childhood, chronic spastic paraplegia, dystonia, choreoathetosis, paraesthesia, diplopia

Dystonia 10 a.k.a. DYT10:

Diagnosis:

Autosomal dominant
Chr. 16p11.2-q12.1

Myoclonus-dystonia syndrome a.k.a. DYT11:

Diagnosis:

Genetics:

  • Autosomal dominant
  • SGCE gene Chr. 7q21-7q31, epsilon sarcoglycan protein

Clinical features:

  • myoclonus, dystonia, seizures, depression, OCD, alcohol responsive in some patients

Rapid onset dystonia parkinsonism RDP a.k.a. DYT12:

Diagnosis:

Genetics:

  • Autosomal dominant, variable penetrance.
  • ATP1A3 gene. Protein= Na+/K+-ATPase alpha three (a3) subunit

Clinical features:

  • Adolescents, young adults. Abrupt onset of dystonia and parkinsonism, a rostrocaudal gradient, prominent bulbar findings. Psychological triggers. Minimal/no response with dopaminergic drugs.

Dystonia 13 a.k.a. DYT13:

Diagnosis:

Genetics:

  • Autosomal dominant
  • 1p36.13-1p36.32,

Clinical features:

  • focal dystonia, craniocervical, children to adulthood,

Deafness-dystonia syndrome 1 a.k.a. Mohr-Tranebjaerg syndrome a.k.a. DFN-1/MTS:

Diagnosis:

Genetics:

  • X-linked, Xq22

Clinical features:

  • childhood, dystonia, sensorineural hearing loss, spasticity, mental retardation, cortical blindness,

Leber’s hereditary optic neuropathy plus dystonia:

  • See under Leber’s hereditary optic neuropathy/mitochondrial disorders

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Paroxysmal Dyskinesia

Diseases, ,

Synonyms:

a.k.a. paroxysmal dystonia

General points:

There are two subtypes:

  • Kinesiogenic paroxysmal dystonia
  • Non-Kinesiogenic paroxysmal dystonia

Kinesiogenic paroxysmal dystonia:

Diagnosis:

Precipitated by sudden movements
Lasts <5 minutes, recurs up to 100/day

Treatment:

Carbamazepine CBZ, Phenytoin PHT

Non-kinesiogenic paroxysmal dystonia (formerly paroxysmal dystonic choreoathetosis, Mount–Reback syndrome):

Diagnosis:

This condition is DYT8 a form of genetic dystonia

Related articles:

 

Generalised Dystonia or Segmental Dystonia

Diseases, ,

Diagnosis:

Clinical features:

  • Segmental: to adjacent regions
  • Mutifocal: nonadjacent regions
  • Hemidystonia: ipsilateral arm & leg
  • Generalised: leg +trunk +another region

Trial of levodopa, 2 months long to rule out dopa responsive dystonia.

Treatment:

Trial of levodopa, 2 months long. This should be tried in all childhood onset dystonias
Anticholinergics: e.g. Trihexyphenidyl
Others:

  • Clonazepam, Baclofen or Carbamazepine CBZ
  • Diazepam
  • Phenothiazines: haloperidol, tetrabenazine

Consider:

  • Local Botulinum toxin injection
  • Bilateral pallidal deep-brain stimulation [SPIDY, small prospective]

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Focal Dystonia

Diseases, ,

Diagnosis:

Clinical
Focal dystonia: i.e. dystonia involving 1 region

Types:

  • Blepharospasm: involuntary bilateral eye closure
  • Oromandibular dystonia
  • Spasmodic dysphonia
  • Cervical dystonia:
    • Spasmodic (intermittent) or sustained
    • Torticollis: turned/rotated
    • Retrocollis: extended
    • Anterocollis: flexed
    • Laterocollis: tilted
  • Focal hand dystonia
  • Task specific dystonia:
    • Writers cramp (graphospasm), piano players cram, guitar players cramp, golf, running

Investigations to consider:

Consider:

  • MRI if accompanied by other signs
  • EMG/nerve conduction studies in equivocal cases

Treatment:

  • Trial of levodopa (for dopa responsive dystonia)

1st line, for cervical dystonia, blepharospasm, oromandibular dystonia, spasmodic dysphonia & hand dystonia:

  • Botulinum toxin A injection every 3 months
  • Into forarm muscles for hand dystonia
  • 2nd line:
    • Anticholinergics: e.g. Trihexyphenidyl or benztropine
  • Others:
    • Clonazepam, Baclofen or Carbamazepine CBZ
    • Diazepam
    • Phenothiazines: haloperidol, tetrabenazine
  • Consider nerve section in very refractory cases of spasmodic torticolis

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Tourette’s syndrome

Diseases,

Synonyms:

Gilles de la Tourette’s syndrome

Diagnosis:

Clinical criteria:

  • Onset < 21 y.o.
  • Lasts >1 year.
  • Multiple motor tics. At least 1 vocal tick. Fluctuating course.
  • Corprolalia is not necessary for diagnosis
  • Consider associated:
    • Attention deficit hyperactivity disorder ADHD
    • Obsessive compulsive disorder OCD

Treatment:

Educate patient, family members, teachers.
Decide on if treatment is warranted
Social: Extra breaks at school & additional test taking time.
Motor Tics:

  • 1st line: Fluphenazine
  • Pimozide, [Metanalysis].
  • Haloperidol, trifluoperazine
  • Consider: botulinum toxin injection

If attention deficit is present: treat it

  • Clonidine orally, then patch
  • Haloperidol

If obsessive compulsive:

  • Clomipramine P.O. or others

If impulsive:

  • Carbamazepine CBZ or lithium.

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Periodic Alternating Nystagmus PAN

Diseases

Diagnosis:

Primary position of gaze: Horizontal jerk nystagmus to one direction for 2 minutes, this then changes/alternates to the opposite direction every 2 minutes
May be associated with Anti-GAD antibodies

Clinical features:

Oscillopsia
Nystagmus

Findings on investigations:

MRI: hemorrhage or stroke of the nodulus of the cerebellum, Chiari-Malformation, Arachnoid cyst, Multiple sclerosis
Anti-GAD antibody

Treatment:

Baclofen orally

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Paraneoplastic Cerebellar Degeneration

Diseases, ,

Diagnosis:

A combination of clinical features, identification of underlying cancer and occasionally other tests

Clinical features:

Symmetric subacute progressive cerebellar ataxia with dysarthria & nystagmus

Pathology:

Histology: massive loss of Purkinje cells. Dentate nucleus: Pallor of myelin fleece (amiculum). Sometimes mononuclear perivascular infiltrates or microglial nodules

Findings on investigations:

Antibodies:

  • anti-Yo a.k.a. anti-PCA-1 (ovarian & breast cancer), anti-Hu a.k.a. ANNA-1 (lung cancer), Tr-Ab (Hodgkin lymphoma), anti-mGluR1 (Hodgkin’s lymphoma), Anti-Ma1 (lung cancer), anti-CRMP5 a.k.a. anti-CV2 (small cell lung cancer, thymoma)

CSF:

  • Raised IgG index, lymphocytic pleocytosis, increased protein in some

Treatment:

Consider:

  • Plasmapharesis, IVIG, steroids, cyclophosphamide

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Fragile X Tremor Ataxia syndrome

Diseases, ,
Diagnosis:

Genetic testing: expansion of CGG repeat on FMR1 gene on chr. X.
55-200 repeats = premutation range, associated with tremor/ataxia syndrome and premature ovarian failure
>200 repeats = Fragile X syndrome

Findings on investigations:

MRI: T2 white matter hyperintensities in the middle cerebellar peduncles or brain stem. Cereberal white matter hyperintensities and atrophy may occur.

Pathology:

In white matter enlarged astrocytes with inclusions. Inclusion bodies in neurons and astrocytes occur in the CNS and in autonomic neurons.

Related articles:

Episodic Ataxia type 2

Diseases, ,

Genetics:

Autosomal dominant
Ca++ CANA1A chr. 19p13.1

Clinical features:

2nd decade. Paroxysmal cerebellar ataxia
Lasts hours: Vertigo, diplopia, nystagmus
Progressive signs
Associated with absence seizures in some

Findings on investigations:

MRI: vermian atrophy

Treatment:

Responds to acetazolamide

Related articles:

Episodic Ataxia type 1

Diseases, ,

Genetics:

Autosomal dominant
Kva1.1 KCNA1 chr. 12q13

Clinical features:

Paroxysmal cerebellar ataxia, seconds-minutes
Triggers: exertion, stress, startle
Associated with:

  • Myokymia/neuromyotonia
  • Cramps

Findings on investigations:

Electrophysiology/Pathogenesis:

  • EMG: spontaneous discharges (Myokymia/neuromyotonia)

Treatment:

Acetazolamide or Carbamazepine CBZ

Related articles:

Spinocerebellar Ataxias

Diseases, ,

Synonyms:

Spinocerebellar ataxias (SCAs) a.k.a. spinocerebellar degeneration, formerly olivopontocerebellar ataxia (OPCA)

Spinocerebellar ataxias (SCAs) in General:

This  is a group of disorders characterized by ataxia and other findings such as hypotonia. The various subtypes are outlined below
Clinical features:

  • Hypotonia and ataxia

MRI:

  • Atrophy of Cerebellum & pons

SCA1:

Diagnosis:

Autosomal dominant
CAG repeat, ataxin-1 gene on Chr. 6p23

SCA2 a.k.a. olivopontocereberllar atrophy of Menzel.

Diagnosis:

Autosomal dominant
CAG repeat on chr. 12q24 (normal repeat number is 14-31). Protein= ataxin-2

Pathology:

SCA2: gross; severe atrophy of basis pontis, cerebellum & cervical spinal cord.
Microscopically: Neuronal loss in pons, inferior olivary nucleus, cerebellar cortex & substatia nigra.
Immunohistochemistry: IC2 (binds polyglutamine repeats) positive  intranuclear inclusions.

SCA3 a.k.a. Machado-Joseph disease MJD:

Diagnosis:

Autosomal dominant
CAG repeat on chr. 14q32 (normal repeat number is 12-40). Protein= ataxin-3,

Pathology:

SCA3: gross; mild atrophy of the spinal cord & posterior fossa structures.
Microscopically: Neuronal loss in cerebellar dentate nucleus with grumose degeneration (eosinophilic granular material near the bodies of dentate neurons, it consists of preterminal axons). Also neuronal loss in basis pontis, Clarke’s column, LMNs and substatia nigra.
Immunohistochemsitry: Ubiquitin positive intranuclear inclusions, ataxin-3 positive intranuclear inclusions.

SCA4:

Diagnosis:

Autosomal dominant
Chr. 16q22

SCA5:

Diagnosis:

Autosomal dominant
Chr. 11p

SCA6:

Diagnosis:

Autosomal dominant
CAG repeat in human alpha-1a calcium channel subunit gene chr. 19p13. a type of channelopathy. Commoner in Japan. Clinical features: Progressive ataxia (10-30 yrs), all extremities, dysarthria, nystagmus, impaired vibration & position sense. No pyramidal signs

SCA7:

Diagnosis:

Autosomal dominant
CAG repeat, ataxin-7 gene Chr. 3p

SCA8:

Diagnosis:

Autosomal dominant
CTG repeat Chr. 13q21,

SCA9:

Diagnosis:

Autosomal dominant

SCA10:

Diagnosis:

Autosomal dominant
Chr. 22q13,

SCA11:

Diagnosis:

Autosomal dominant
Chr. 15q15,
TTBK2 gene, Protein= tau tubulin kinase-2

SCA12:

Diagnosis:

Autosomal dominant
CAG repeat Chr. 5q31-33

SCA13:

Diagnosis:

Autosomal dominant
Chr. 19q

SCA14:

Diagnosis:

Autosomal dominant
Chr. 19q

SCA15:

Diagnosis:

Autosomal dominant. chr. 3p, ITPR1 gene, protein= type 1 inositol 1,4,5-triphosphate receptor.

SCA16:

Diagnosis:

Autosomal dominant
Chr. 8q

SCA17:

Diagnosis:

Autosomal dominant
Chr. 6q27, CAG repeat >44, TATA-binding protein gene

SCA18:

Diagnosis:

Autosomal dominant
Chr. 7q22-q32

SCA19:

Diagnosis:

Autosomal dominant
Chr.1p21-q21

SCA20:

Diagnosis:

Autosomal dominant

SCA21:

Diagnosis:

Autosomal dominant
Chr.7p21.3-p15.1

SCA22:

Diagnosis:

Autosomal dominant
Chr.1p21-q23
Findings on investigations SCA22:

  • Electroretinography ERG: Retinal degeneration in SCA1 & 7

Related articles:

Friedreich’s Ataxia

Diseases, , ,

Diagnosis:

Genetics:

  • Autosomal recessive
  • Frataxin gene chr. 9. Protein= Frataxin. GAA nucleotide repeat (normal repeat number is 6-27). Compound heterozygotes occur in 5%.

Clinical features:

  • Ataxia & dysarthria
  • Areflexia, extensor plantars
  • Hammer toes arched foot, scoliosis

Pathology:

Gross: atrophy of spinal cord. Grey discolouration of posterior & lateral aspects of the spinal cord. Small sensory nerve roots.
Microscopically: Brain stem: atrophy of the dentate nucleus and superior cerebellar peduncle. Neuronal loss in vestibular and cochlear nuclei. Spinal cord: degeneration of posterior columns, spinocerebellar tracts and corticospinal tracts. Neuronal loss in Clarkes column. Dorsal root ganglia: neuronal loss.

Findings on investigations:

Echocardiogram: cardiomyopathy
Fasting blood glucose: diabetes mellitus
ECG: conduction defects

Treatment:

Supportive care
Consider Co-enzyme Q, Vitamin E

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Gluten Ataxia

Diseases, ,

Synonyms:

Gluten ataxia a.k.a. ataxia associated with Coeliac disease antibodies

Diagnosis:

A combination of clinical features and testing for coeliac disease

Clinical features:

Ataxia
+Coeliac disease antibodies: anti-TTG (especially anti-TTG6), anti-Endomysial antibody
+exclusion of other causes

Findings on investigations:

MRI: cerebellar atrophy, T2 white matter hyperintensities

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Acute Post-Infectious Cerebellitis

Diseases, ,

Diagnosis:

This is diagnosed by a combination of clinical features, imaging finding and sometimes associated laboratory tests

Clinical features:

Prodrome e.g. Upper respiratory tract infection
Then Headache
Then cerebellar ataxia
Then improvement

Findings on investigations:

MRI +GAD:

  • Normal,
  • Then cerebellar enhancement of folia & hemispheres, swelling of hemispheres, tonsillar ectopia
  • Then mild cerebellar atrophy, resolution of enhancement & tonsillar ectopia

SPECT:

  • Hyperperfusion of the cerebellum

CSF:

  • Lymphocytosis, normal to mildly increased protein, normal glucose

Other tests:

  • EBV serologies: positive in some cases

Treatment:

Consider plasmapheresis if persistent. [case reports]

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Progressive Ataxia and Palatal Tremor

Diseases,

Synonyms:

PAPT= Progressive ataxia and palatal tremour

Diagnosis:

This is a diagnosis of exclusion

Clinical features:

Soft ear clicks heard by patient & examiner
Symmetrical palatal tremour (levator veli palatini muscle)
Ataxia

Findings on investigations:

MRI, MRA:

  • Absence of lesion in dentato-rubro-olivary pathway (Guillain-Mollaret triangle) which lies in the brainstem tegmentum
  • Hypertrophic olivary degeneration
  • Atrophy of the cerebellum

Related articles:

Oculopalatal Tremor

Diseases,

Synonyms:

OPT, formerly oculopalatal myoclonus a.k.a. palatal tremour formerly palatal myoclonus

Diagnosis:

Clinical diagnosis

Clinical features:

  • Soft ear clicks heard by patient & examiner. Oscillopsia
  • Symmetrical palatal tremour (levator veli palatini muscle)
  • +Ocular nystagmus: pendular (same speed in both phases), usually vertical (may be tosional) & sometimes horisontal. May be bilateral or unilateral i.e. dissociated.

MRI & MRA:

  • Lesion in dentato-rubro-olivary pathway (Guillain-Mollaret triangle) which lies in the brainstem tegmentum
  • Hypertrophic olivary degeneration (unilateral or bilateral): high signal on T2 or proton density, this may return to normal
  • Typically develops 2–49 months after the initial insult

Related articles:

Rubral Tremor

Diseases,

Synonyms:

Holmes tremor

Diagnosis:

This is a clinical diagnosis in the correct clinical context (damage to the midbrain)

Clinical:

Mainly unilateral tremor, low frequency (3–5 Hz)
Occurs at rest, in posture and during movement
Exacerbation by goal-directed movements.
Disappears during sleep

Findings on investigations:

  • MRI: lesions in brain stem, cerebellum or thalamus

Treatment:

Consider Levetiracetam LEV

Related articles:

Wilson's disease

Diseases,

Synonyms:

a.k.a. hepatolenticular degeneration:

Diagnosis:

  • Slit lamp examination: Kayser Fleischer rings Golden Brown Corneal deposits
  • Neurological: wing-beathing tremor & facial dystonia (sardonic smile), cognitive deficits, neuorpsychiatirc symptoms
  • Ceruloplasmin: low, <20 mg/dL
  • 24 hr Urinary copper excretion: increased >100 micrograms

MRI:

  • T2: Increased signal (but variable) in striatum, Midbrain, Pons, dentate nucleus, white matter lesions
  • T1: usually bright signal

Genetics:

  • Autosomal recessive
  • ATP7B gene,

Pathology:

  • Alzheimer type 1 astrocytes (large abundant cytoplasm)
  • Oplaski cells in basal ganglia

Investigations to consider:

Blood tests: FBC, U&E, LFTs
Ceruloplasmin: low
Copper: low, 24 hr Urinary copper excretion: increased
Slit lamp examination
Liver biopsy: increased copper weight
MRI
Penicillamine challenge +urinary copper

Monitor:
  • FBC
  • Slit lamp examination
Screening:

1st line:

  • Slit lamp examination
  • Ceruloplasmin

2nd line:

  • Copper: low
  • Urinary copper excretion: increased

3rd line:

  • Consider Liver biopsy: copper

Treatment:

Genetic counselling
1st line:

  • D-Penicillamine oral monitor FBC +pyridoxine B6
  • Others:
    • Tetrathiomolybdate or trientine
    • Zinc sulfate P.O.

Restrict copper intake:

  • Shell fish, internal organs, legumes
  • Liver transplant

Screen siblings

Related articles:

Neurofilament inclusion body disease NIBD

Diseases,

Diagnosis:

A combination of clinical and MRI
Clinical:

  • Age <65yo
  • Parkinsonism: Rigidity, bradykinesia, falls
  • Dopamine resistant
  • Cortical features: Hand clumsiness, apraxia, language dysfunction, Mute,

MRI:

  • Frontal atrophy, caudate atrophy, temporal atrophy,

Pathology:

  • Gross: frontal atrophy, caudate atrophy, Nigral pallor,
  • Superficial Spongiosis in frontal lobes, Purkinje cell loss
  • Intraneuronal inclusions (cytoplasmic) in frontal lobes, see below

Immunohistochemsitry:

  • Intraneuronal Inclusions (cytoplasmic & intranuclear) are neurofilament positive, ubiquitin positive.
  • Inclusions are negative for alpha synuclein, tau, amyloid, prion protein

Related articles:

Argyrophilic grain disease AGD

Diseases,

Diagnosis:

  • A debatable neurodegenerative condition. Considered a tauopathy.

Pathology:

  • Argyrophilic grains (silver staining grains by Gallyas silver iodide method) in neuropil of the cortex of elderly patients with cognitive symptoms. Shape: spindle shaped, rod-like, button-like or round bodies.
  • Ballooned neurons (a nonspecific finding, silver negative) & coiled bodies in oligodendrocytes (a nonspecific finding) also occur.
  • Commonly occur in: entorhinal cortex, hippocampus CA1 area, amygdala and neighbouring temporal cortex
  • Commonly associated with other pathologies e.g. Alzheimers disease, Pick’s disease, progressive supranuclear palsy PSP, corticobasal degeneration, CJD, Lewy body disease, Parkinson’s disease with dementia

Immunohistochemistry:

  • Argyrophilic grains & coiled bodies in oligodendrocytes are tau positive
  • Ballooned neurons are B-crystallin positive

Clinical:

Mainly memory impairment.
Behaviour abnormalities, mood changes

Related articles:

Corticobasal Degeneration

Diseases,

Synonyms:

a.k.a. Cortical basal ganglionic degeneration CBGD formerly corticodentatonigral degeneration with neuronal achromasia a.k.a. corticonigral degeneration:

Diagnosis:

Clinical:

  • Cortical signs: apraxia, visuospatial impairment, executive dysfunction, language dysfunction, spared memory function.
  • +Basal ganglia signs: asymmetric rigidity, dystonia, myoclonus, alien hand,
  • Relative Sparing of memory

Pathology:

Gross:

  • Perisagittal atrophy of frontal & parietal lobes. Substantia nigra pallor

Microscopic:

  • Cortical Microvacuolation, neuronal loss, gliosis. Neuronal loss in the substantia nigra & basal ganglia.
  • Relatively spares the hippocampus & parahippocampal gyrus.
  • Balloon neurons (chromatolytic-like)= large achromatic neurones (neuronal achromasia) in affected cortex (frontal & parietal) & basal ganglia.

Immunohistochemistry:

  • Tau positive: Intraneuronal inclusions in cortical layer II.
  • Astrocytic plaques
  • Thread-like processes
  • Oligodendroglial coiled bodies
  • Neurofilament positive ballooned neurons
  • Western blott: 4R type of Tau (4 microtubule repeats)

Related articles:

Progressive Supranuclear Palsy

Diseases,

Synonyms:

a.k.a. PSP, a.k.a. -Richardson-Olszewski syndrome

Diagnosis:

Clinical:

  • Symmetric parkinsonism, vertical gaze palsy, eyelid opening apraxia, axial rigidity (axial dystonia), retrocollis, dementia (executive dysfunction, impaired abstraction & planning, relatively preserved memory), pseudobulbar palsy, pseudobulbar affect,

Clinically two syndromes:

  • Richardson syndrome: postural instability with falls, supranuclear vertical gaze palsy, cognitive deficits/dementia.
  • PSP-Parkinsonism: unilateral tremor, transient levodopa response.

Pathology:

  • Definite diagnosis possible at autopsy
  • Basal ganglia, diencephalon, brain stem, prefrontal cortex are affected
  • Globose neurofibrillary tangle, neuronal loss, gliosis
  • Tau positive (4 repeat Tau).

Findings on investigations:

MRI:

  • DWI MRI, ADC: increased regional ADC, rADC in putamen. [312]
  • Atropy in midbrain tegmentum, pons, striatum & frontal cortex

Treatment:

Rigidity & hypokinesia:

  • Dopaminergic therapy

Speech, gait & pathologic crying/laughing:

  •  Amitriptyline
  • or benzotropine orally

Dysphagia:

  • Consider Methysergide

Related articles:

References:

  1. Williams DR, de Silva R, Paviour DC, et al; Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain. 2005 Jun;128(Pt 6):1247-58.
  2. Litvan I, Agid Y, Calne D, et al; Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996 Jul;47(1):1-9.
  3. Williams DR, Lees AJ; Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009 Mar;8(3):270-9.
  4. Rafal RD, Grimm RJ. Progressive supranuclear palsy: functional analysis of the response to methysergide and antiparkinsonian agents. Neurology. 1981 Dec;31(12):1507-18.

 

Multiple System Atrophy

Diseases,

Synonyms:

formerly Shy-Drager syndrome/Striatonigral degeneration, formerly included under olivopontocerebelar atrophy OPCA

Diagnosis:

This is based on clinical features supported by consistent investigations

Clinical features:

Parkinsonism
+other features:

  • Ataxia
  • Early falls forward
  • Autonomic failure:
    • Othostatic hypotension, syncope
    • Impotence, urinary retention, constipation
    • Axial rigidity
  • Laryngeal stridor
  • Hypometric saccadic eye movements
  • Coat hanger sign: a sensation of being suspended from a coat hanger when standing upright.

Subtypes:

2 subtypes: MSA-P (parkinsonian predominant), MSA-C (cerebellar predominant).
Debated (old terminology):

  • Shy Drager syndrome SDS: +dysautonomia
  • Sporadic Olivopontocerebellar atrophy OPCA: +
  • Striatonigral degeneration SND

Pathology:

Gross:

  • Both; pallor of substantia nigra. MSA-P discolouration & atrophy of the Putamen, atrophy of the caudate nucleus. MSA-C atrophy of the cerebellum, middle cerebellar peduncle and pons.

Microscopically:

  • Both; neuronal loss and astrocytic gliosis in pons, accessory and inferior olivary nuclei, locus ceruleus, medulla, arcuate nucleus and in hypothalamus and intermediolateral cell column.
  • MSA-P neuronal loss and astrocytosis in putamen and caudate nucleus;
  • MSA-C; Purkinje cell loss in cerebellar vermis>hemispheres.

Immunohistochemistry:

  • Alpha-synuclein and ubiquitin positive oligodendroglial Glial Cytoplasmic Inclusions GCI in pyramidal, extrapyramidal, limbic, corticocerebellar and supraspinal autonomic systems.
  • Variable tau immunoreactivity.
  • Sliver stain: also stains alpha-synuclein.
  • Epicardial space nerve fibres: Tyrosine hydroxylase staining is normal (no cardiac denervation, sympathetic)

Findings on investigations:

  • Intact Cardiac innervation by:
  • Cardiac SPECT 123I –labeled MIBG, reduced uptake
  • PET scan

MRI:

  • DWI MRI, ADC: increased regional ADC, rADC in middle cerebellar peduncle. This is normal in Parkinson disease and in progressive supranuclear palsy PSP.
  • Autonomic nervous system testing: panautonomic failure.

Related articles:

Post-Encephalitic Parkinsonism

Diseases,

Synonyms:

Encephalitis lethargica a.k.a. postencephalitic parkinsonism a.k.a. Von Economo encephalitis:

Diagnosis:

Clinical:

  • Prodrome: pharyngitis
  • Subacute sleep disturbance (hypersomnolence, reversal of diurnal sleep pattern or insomnia), ophthalmoparesis, lethargy
  • Followed by: Parkinsonism, dyskinesia, oculogyric crisis, neuropsychiatric symptoms and central respiratory abnormalities

Pathology:

  • Midbrain and basal ganglia: lymphocyte (predominantly plasma cell) infiltration

Investigations to consider:

CSF:

  • Oligoclonal bands
  • Protein: Elevated

MRI:

  • FLAIR hyperintensity: Midbrain & periaqueductal grey. Also in Thalamus & putamen

Related articles:

 

Serotonin Syndrome

Diseases,

Diagnosis:

Clinical features:

  • Hyperthermia, muscle rigidity, abdominal cramping, hypertension, myoclonus, agitation, coma, life-threatening

Investigations to consider:

  • FBC, metabolic panel, creatinine, CK

Treatment:

  • Discontinue the drug
  • Hyperthermia: Active cooling, entubation & muscle relaxants
  • Lorazepam intravenously
  • 5HT2 antagonist: cyproheptadine orally
  • If severe: intensive care & observation

Related articles:

Neuroleptic Malignant Syndrome

Diseases,

Diagnosis:

Clinical:

  • Hyperpyrexia +autonomic instability + muscle rigidity +tachycardia +fluctuation of consciousness

Investigations to consider:

  • FBC: leukocytosis, LFTs: AST & ALT are high, U&E, creatinine
  • Creatine kinase: high,, plasma myoglobin: high
  • Urinalysis for myoglobin: myoglobinuria

Treatment:

  • Discontinuing the offending drug/drugs
  • Cooling
  • Dantrolene
  • Dopamine agonist e.g. bromocriptine

Related articles:

Complex Regional Pain Syndromes CRPS

Diseases

Synonyms:

Former/other names: Causalgia, Reflex sympathetic dystrophy RSD, Shoulder-hand syndrome, Sudeck’s atrophy, algoneurodystrophy

Types:

CRPS type I: occurs following soft tissue injury, formerly reflex sympathetic dystrophy (RSD)
CRPS type II: occurs following nerve injury, formerly causalgia

Clinical features:

Pain, allodynia, hyperalgesia after the injury
Oedema, skin blood flow changes, or abnormal sweat gland (sudomotor) activity
Exclusion of other conditions that would account for the degree of pain or dysfucntion

Neck-tongue syndrome

Diseases

Diagnosis:

Clinical:

  • Neck pain after sudden turning of the head in distribution of C2 & lateral aspect of tongue +/-dysesthesia/numbness

Investigations to consider:

  • MRI C-spine: cervical spondylosis or lesions involving C2
  • Flexion-extension X-rays of the neck: atlantoaxial instability
  • CT flexion-extension views of the neck or right-left rotational views: atlantoaxial instability

 

Temoporomandibular joint TMJ syndrome

Diseases

Diagnosis:

Clinical:

  • Pain around the TMJ
  • +one of the following:
    • Noise from TMJ on jaw opening
    • Tenderness at TMJ joint capsule
    • Pain occurs with chewing or moving the jaw
    • Reduced jaw range or irregular opening

+Imaging:

  • CT
  • X-ray
  • MRI
  • Bone scintigraphy

Treatment:

Nocternal bite guard
Local heat application
Jaw exercises
NSAIDs

Related articles:

Post-Herpetic Neuralgia

Diseases

Synonyms:

Post zoster neuralgia VZV:

Diagnosis:

Persistence of the pain of herpes zoster more than 3 months after resolution of the rash.
Zoster-associated pain: the continuum of pain from acute herpes zoster to the development of postherpetic neuralgia.

Treatment:

Best medications:

  • Tricyclic antidepressants:
    • Nortriptyline, amitriptyline, desipramine, and maprotiline
  • Antiepileptics:
    • Gabapentin GBP, pregabalin
  • Opioids:
    • Oxycodone or morphine sulfate sustained release
  • Topical lidocaine patches

Others:

  • Capsiacin topical, but takes longer to act

If the above fail:

  • Consider preservative free methylprednisolone intrathecally

Prevention:

  • Use of antivirals within 72 hours of onset of VZV infection

Related articles:

Glossopharyngeal Neuralgia

Diseases

Diagnosis:

Clinical:

  • Pain in: ear, base of tongue, tonsillar fossa, beneth the angle of the jaw
  • +Pain <2 minutes
  • +reproducing the pain through trigger zone stimulation

Primary or secondary

Investigations to consider:

MRI+contrast, MRA

Treatment:

  • Treat the cause if identified
  • Carbamazepine CBZ, three times a day, controls the pain & syncope
  • or Phenytoin PHT

Related articles:

Trigeminal Neuralgia

Diseases

Synonyms:

formerly tic douloureux

Diagnosis:

Clinical:

  • Brief electric shock like pains or stabbing
  • +last 1 second to 2 minutes
  • +in the distribution of the trigeminal nerve
  • +attacks are stereotyped
  • May be triggered by light touch of areas supplied by the trigeminal nerve
  • Primary (classic) or secondary forms

Electrophysiology: trigeminal nerve reflexes can distinguish between primary & secondary causes

Investigations to consider:

If young investigations for MS
If not young MRI for posterior fossa tumour
Consider electrophysiology for trigeminal nerve reflexes

Neuralgias due to Trigeminal nerve branches:

Superior laryngeal neuralgia
Nasociliary neuralgia, formerly Charlin’s neuralgia
Supraorbital neuralgia
Infraorbital, lingual, alveolar and mental nerves.
Occipital neuralgia

Treatment:

First line:

  • Carbamazepine CBZ 200-1200mg
  • Oxcarbazepine OXC 600-1800mg/day

Second line:

  • Lamotrigine LTG, Baclofen, Pimozide (no longer used)

If refractory, Consider surgery:

  • Dorsal root entry zone lesion DREZ
  • Posterior fossa microvascular decompression

Related articles:

Idiopathic Stabbing Headache

Diseases

Synonyms:

a.k.a. primary stabbing headache a.k.a. idiopathic Ice pick pain a.k.a. jabs and jolts syndrome:

Diagnosis:

Clinical:

  • Sharp ice pick like pain, lasting less than 1 second
  • Within the distribution of trigeminal nerve, especially V1 division. Rarely it is outside this distribution
  • May cause flinching & may occur in a series

Note:

  • Ice pick like pain also occurs in Migraine, Cluster headache & giant cell arteritis.

Treatment:

  • If repetitive: Indomethacin TID

Related articles:

Chronic Daily Headache

Diseases

Diagnosis:

  • >15 days per month for >6 months.
Subtypes:

Chronic tension type headache
Chronic migraine (see under migraine)
Transformed migraine: chronic daily headache that has evolved from migraine not meeting criteria for chronic migraine. Believed to be the late stage of chronic migraine.

Treatment:

Behavioural psychotherapy
Physical therapy for myofascial symptoms
Consider trigger point botulinum toxin injection or occipital nerve block
Prevention & acute treatment for underlying headache: migraine or tension

Related articles:

Hemicrania Continua

Diseases

Diagnosis:

Clinical:

  • Unilateral headache,
  • +Unremitting (no pain free periods) daily for >3months, but with exacerbations
  • +1 autonomic feature:
    • Conjunctival injection or lacrimation
    • Nasal congestion or rhinorrhea
    • Ptosis or miosis
    • +response to indomethacin

Treatment:

Indomethacin 25 mg TID up to 200 mg/day (strong evidence base)

Related articles:

Paroxysmal Hemicrania

Diseases

Diagnosis:

  • Clinical, similar to cluster headache (character & associated symptoms) except:
  • No male predominance
  • Attacks are shorter, more frequent
  • Complete resolution with Indomethacin
  • Episodic & chronic forms

Treatment:

Prophylaxis:

  • Indomethacin up to 200mg (strong evidence base)
  • Verapamil (weak evidence base)
  • NSAIDs (weak evidence base)
  • Topiramate (weak evidence base)

Related articles:

Cluster Headache

Diseases

Diagnosis:

Clinical:

  • Always unilateral. Usually periorbital pain. M>F
  • +15-180 minutes, multiple times per day for weeks
  • +long (month) headache free period
  • +associated with ipsilateral autonomic features:
    • Conjunctival injection or lacrimation
    • Nasal congestion or rhinorrhea
    • Ptosis or miosis
    • Eyelid or forehead swelling

Treatment:

Acutely:

  • 100% Oxygen inhaled, 7-10 L/min for 15 min (strong evidence base)
  • Sumatriptan 6 mg, sc (strong evidence base), Sumatriptan 20 mg nasal (strong evidence base, but has side effects)
  • Zolmitriptan 5 mg nasal (strong evidence base), Zolmitriptan 10 mg oral (moderate evidence base but has side effects)
  • Lidocaine nasal (moderate evidence base)
  • Octreotide (moderate evidence base)
  • Dihydroergotamine
  • Consider Prednisolone 60 mg & taper (then 40mg, 20mg over two days or over 3 weeks)
  • Avoid pizotifen and intranasal capsaicin because of side effects

Prophylaxis:
 

  • Verapamil (strong evidence base)
  • Steroids (strong evidence base)
  • Lithium carbonate TID, monitor levels (moderate evidence base)
  • Methysergide (moderate evidence base)
  • Topiramate (moderate evidence base)
  • Ergotamine tartrate or Dihydroergotamine (moderate evidence base)
  • Valproic acid (weak evidence base)
  • Melatonin (weak evidence base)
  • Baclofen 15-30 mg(weak evidence base)

if chronic rather than episodic consider diagnosis of hemicrania continua.

Related articles:

Spontaneous Intracranial Hypotension

Diseases

Synonyms:

a.k.a. sinking brain syndrome a.k.a. Spontaneous CSF leak

Diagnosis:

Clinical:

  • Orthostatic headache a.k.a. postural headache (improves on lying down):
  • Worsened by standing in <15 minutes
  • Associated symptoms: tinnitus, hypacusia, photophobia, nausea, neck stiffness
  • May present with thunderclap headache
  • Later stages: drowsiness, coma
  • No history of dural puncture or LP

MRI:

  • Postcontrast: enhancement of thickened dura i.e. Pachymeningeal enhancement.
  • Brain sagging (effacement of the suprasellar cistern, bowing of the optic chiasm over the pituitary fossa, flattening of the pons against the clivus and obliteration of the prepontine cistern) & pseudo-Chiari malformation (hindbrain herniation)
  • Dilation of veins & venous sinuses. Subdural fluid collections.
  • Also enlarged pituitary gland, dilation of the spinal peridural plexus

If with nasal discharge:

  • Test for Beta 2 Transferrin by immunofixation, present in CSF

Lumbar Puncture, LP:

  • Low opening pressure (<6 cmH2O) or dry tap
  • Protein: usually high,
  • Pleocytosis: occurs
  • Xanthochromia may occur

CT myelography:

  • Study of choice for defining the leak
  • Myelography with water-soluble contrast followed by CT scan

Radionuclide cisternography:

  • 111 Indium-diethylenetriamine pentaacetic acid
  • Not as sensitive as CT myelography

Meningeal biopsy:

  • A thin layer of fibroblasts in the subdural zone
  • Small thin-walled dilated blood vessels
  • No evidence of inflammation
  • Meningeal fibrosis in longstanding cases

Treatment:

Epidural blood patch 20mL. [312] This may be repeated 20-100mL.

Related articles:

Idiopathic Intracranial Hypertension

Diseases

Synonyms:

a.k.a. Benign intracranial hypertesion a.k.a. Pseudotumor cerebri

Diagnosis:

Clinical:

  • Headache
  • +Visual disturbances e.g. peripheral visual field loss or diplopia, “transient visual obscurations”.
  • +Papilloedema, +/-VI palsy

+Imaing MRI, MRV or CTV:

  • No ventricular dilation
  • No venous sinus thrombosis
  • Transependymal oedema may occur

+lumbar puncture opening pressure: 25—40 cm H2O
Visual fields, by perimetry: nasal step defect, arcuate scotoma,

Findings on other investigations:

MRI:

  • Increased CSF space around optic nerve, empty sella turcica, protrusion of optic nerve head (into the globe), Posterior flattening of the globe,

MRV:

  • Venous stenosis

Lars Frisen grades of papilloedema:

Grade 0: normal disc, mild nasal disc blurring
Grade I: C-shaped halo of oedema (elevation) around the optic disc; nasal, superior & inferior aspect
Grade II: circumferential halo of oedema (elevation) around the optic disc
Grade III: above +involvement of vessels leaving the disc
Grade IV: above +involvement of vessels on the disc +/-hemorrhages

Monitor:

Visual fields by Perimetry

Treatment:

  • Acetazlamide orally TID

If refractory:

  • Repeated lumbar punctures
  • Lumboperitoneal shunting

Consider:

  • Transorbital optic nerve sheath fenestration
  • Venous sinus stenting [case series]

Related articles:

Primary Thunderclap Headache

Diseases

Diagnosis:

Clinical +exclude secondary causes (see list below e.g. subarachnoid hemorrhage, venous sinus thrombosis & others):

  • Sudden onset, maximum intensity within 1 minute
  • Lasts 1hr to 10 days
  • Doesn’t recur within months

Note:

  • Secondary causes to exclude: SAH, intracranial hematoma, arterial dissection, venous sinus thrombosis, reversible cerebral vasoconstriction syndrome (RCVS),
  • Other primary headaches to exclude: primary headache associated with sexual activity, primary cough headache, primary exertional headache,

Investigations to consider:

CT: rule out SAH, intracranial hematoma, pituitary apoplexy, colloid cyst
Lumbar puncture if CT is negative: rule out SAH, Spontaneous intracranial hypotension SIH
Catheter angiography: Reversible cerebral vasoconstriction syndrome RCVS

Related articles:

Cerebral Palsy

Diseases

The term cerebral palsy is a broad term for multiple conditions that share in common that there is a non-progressive disorder of power, movement or posture due to damange of the immature brain.

Diagnosis:

Clinical:

  • A non progressive disorder of power, movment or posture due to damage of the immature brain
  • Patients may have a wide range of cognitive ability: ranging from completely normal cognition to severe cognitive disability. It is non-progressive.

Investigations to consider:

EEG if history of seizures
Other tests to determine aetiology or assess comorbidities:

  • MRI
  • Tests for inborn errors of metabolism
  • Infectious agents tests

Treatment:

Physical therapy
Bracing
Consider antispasticity treatment:

  • Diazepam, baclofen or dantrolene orally
  • Consider botulinum toxin
  • Consider selective posterior rhizotomy

Education
Consider surgical release of contractures
Treat comorbidities

Dolichoectasia of intracranial arteries

Diseases,

Synonyms and related terms:

Vertebrobasilar dolichoectasia, Vertebral artery dolichoectasia, basilar artery dolichoectasia, internal carotid artery dolichoectasia

Diagnosis:

Clinical:

  • Asymptomatic, or nerve palsies e.g. XII,
  • Associated with longstanding uncontrolled hypertension or family history

CTA:

  • Ectatic and elnongated intracranial arteries, may be confused with fusiform aneurysms, may be associated with aneurysm in the same patient,
  • Typically in Vertebral artery or basilar artery

MRI, MRA:

  • Ectatic and elnongated intracranial arteries, may be confused with fusiform aneurysms, may be associated with aneurysm in the same patient,
  • Typically in Vertebral artery or basilar artery

Related articles:

Vertebral Artery Stenosis, Extracranial

Diseases,

This section refers to extracranial vertebral artery stenosis due to atherosclerotic disease

Diagnosis:

Must exclude other etiologies of stroke: including intracranial atherosclerotic disease
Catheter angiography:

  • Gold standard test
  • Allows accurate determination of degree of stenosis and collateral pathways
  • Allows determination of intracranial disease

MRA
CTA
Ultrasound: is if insufficient sensitivity to exclude the diagnosis

Treatment:

Antiplatelet therapy and risk factor control in all patients with extracranial vertebral artery stenosis
Asymptomatic disease:

  • Very low stroke risk in asymptomatic disease on antiplatelet therapy

Address risk factors
Antiplatelets:

  • Aspirin with or dipyridamole
  • Or clopidogrel

Consider endovascular intervention (angioplasty +stenting):

  • Consider if failing medical therapy
  • Heparin during procedure
  • Aspirin +clopidogrel for 3 months

Related articles:

Vertebral Artery Stump Syndrome

Diseases,

Diagnosis:

  • Ongoing ischemic events in the territory supplied by the vertebral artery despite occlusion of the vertebral artery
  • Must be differentiated from intracranial atherosclerotic disease (ICAD), small vessel disease and other competing stroke mechanisms

Pathophysiology:

  • Emboli travel to the posterior circulation in the distribution of the affected vertebral artery via collaateral pathways.

Treatment:

Medical therapy:

  • This is first line therapy with antiplatelets

Consider Endovascular therapy:

  • Consider if recurrent events in spite of medical therapy
  • Coiling of the distal segment of the vertebral artery
  • Or Endovascular occlusion of collaterals

Related articles:

Carotid Stump Syndrome

Diseases,

Diagnosis:

  • Ongoing ischemic events in the territory supplied by the internal carotid artery despite occlusion of the internal carotid artery
  • Must be differentiated from intracranial atherosclerotic disease (ICAD), small vessel disease and other competing stroke mechanisms

Pathophysiology:

  • Emboli travel to the ipsilateral brain or retina in the distribution of the affected internal carotid artery via collaateral pathways from the ipsilateral external carotid artery. External carotid artery stenosis can be a responsible cause

Related articles:

Ischemic Stroke with Patent Foramen Ovale

Diseases,

This section will summarize ischemic stroke with Patent foramen ovale (PFO) or atrial septal aneurysm

Diagnosis:

This Patent foramen ovale is associated with cryptogenic stroke, but is not the major cause of cryptogenic stroke. Consider this potential etiology in patients with non-lacunar stroke after investigations for intracranial atherosclerosis, extracranial atherosclerosis, atrial fibrillation (including long term cardiac monitoring), other causes of cardioembolism and other determined stroke etiologies such as dissection and vasculitis.

Diagnosis of Patent foramen ovale:

Tansoesophageal echocardiography with bubble study:

  • Right-to-left transit of contrast microbubbles within 3 to 4 cardiac cycles of right atrial opacification
  • May occur with or without atrial septal aneurysm

Trancranial doppler ultrasound (TCD) with bubble study is the most sensitive test for right to left shunt. This shunt may be due to PFO or other causes

Diagnosis Atrial septal aneurysm:

TTE, Transoesophageal echocardiography: >10-mm excursions of the interatrial septum with the cardiac cycle.

Treatment:

If associated with stroke:

  • Antiplatelet therapy: long term prognosis is excellent on aspirin ~2% stroke rate in NOMAS study
  • Anticoagulation if evidence of venous thrombosis
  • Consider closure if recurrent despite medical therapy and no other cause can be identified (including testing for paroxysmal atrial fibrillation)

Related articles:

Varicella Zoster Virus VZV vasculopathy

Diseases, ,

Diagnosis:

Clinical: large artery or small vessel ischemic stroke, recurrent, protracted course. Rash may be absent or occur months before
MRI, CT: large artery or small vessel ischemic stroke, typically at grey-white junction. Imaging is sensitive but not specific
Anti-VZV IgG & VZV PCR: IgG is more sensitive for VZV vasculopathy, also reduced serum/CSF ratio of VZV IgG
CSF: pleocytosis occurs but isn’t sensitive,

Pathology:

  • Multinucleated giant cells, lymphocytes & histiocytes in the artery walls
  • Avidin-biotin-peroxidase staining: VZV antigen staining in Cowdry A inclusions (large with halo) in cytoplasm of histiocytes in the artery walls
  • Immunohistochemistry: Anti-VZV Ig, stains positive in the arterial wall
  • EM: viral particles

Treatment:

  • Acyclovir for 3 weeks

Related articles:

Bell's Palsy

Diseases,

Synonyms:

Idiopathic facial nerve palsy (CN VII)

Diangosis:

Bell’s palsy is a diagnosis by exclusion
Clinical diagnosis:

  • Unilateral Lower motor neuron pattern facial palsy (the forehead muscles are involved)
  • Bell’s phenomenon: the eyes will roll upwards and backwards when eyelid closure is attempted. This is a normal response that occurs in everyone, but it is visible to the examiner in Bell’s palsy. Patients who are not making an effort to close their eyes will not have Bell’s phenomenon.

Electrodiagnosis: nerve conduction studies, electromyography:

  • Normal for 3 days, excitation decreases for 4-10 days. Therefore is done at least 3 days after complete paralysis, best done at 14 days
  • If excitation is present, 90% recover, if abscent 20% recover
  • If less than 90% degeneration 80% recover, if 90% degeneration 50% recover

Pathology:

  • Edema, lymphocytic infiltrate, nerve fibre degeneration

Investigations to consider:

Consider electrodiagnosis if complete paralysis
To exclude other causes (if any atypical features):

  • Syphilis serology
  • HIV tests
  • Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • CSF analysis

If recurrent or bilateral:

  • MRI, base of the skull
  • Borrelia serology: Lyme disease
  • Sarcoidosis tests

Treatment:

Protect the cornea:

  • Artificial Tears while awake every 4 hours & tape eyes closed while sleeping

Steroids:

  • Prednisolone orally days & taper over 7 days.

+some people consider antivirals P.O. [weak evidence] e.g. valacyclovir BD
If no recovery:

  • In 3-6 weeks: Reconsider the Dx
  • Permanent: Consider cross-facial grafting or hypoglossal facial anastomosis, consider tarsorrhaphy

Related articles:

References:

  1. Sullivan, F.M., et al., Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med, 2007. 357(16): p. 1598-607.
  2. Gilden, D.H., Clinical practice. Bell’s Palsy. N Engl J Med, 2004. 351(13): p. 1323-31.

Diffuse Axonal Injury

Diseases, ,

Diagnosis:

Neuroimaging +Clinical features

Clinical features:

  • Coma after head trauma: low GCS <8, with or without features to suggest structural cause (dilated pupills, disconjugate gaze, asymmetric posturing)
  • Raise intracranial pressure (ICP ) often occurs

Neuroimaging:

CT:

  • May be normal
  • May show petechial hemorrhages in the whitematter (corpus callosum, corona radiata, cerebral peduncles)
  • May show diffuse cerebral edema

MRI

  • Mirrors findings on CT but is more sensitive
  • GRE: very sensitive for associated hemorrhages and diffuse axonal injury
  • DWI: may show diffuse axonal injury (abnormally restricted diffusion)

Pathology:

  • Petechial hemorrhage (diffuse vascular injury) in corpus callosum, superior cerebellar peduncle & other white matter
  • Microscopically: eosinophilic dystrophic (swollen) axons, beaded axons
  • Immunohistochemistry: positive for beta amyloid precursor protein BetaAPP

Treatment:

  • Supportive care
  • Management of raised intracranial pressure

Related articles:

Cerebral Contusion

Diseases, ,

Diagnosis:

CT:

  • Cerebral edema (hypodensity on CT) in the cortex or lobe at  the site of injury or opposite location (counter-coup) or distant site where impact occurs at areas of the skull
  • Hemorrhage (hyperdensity on CT) within the areas of contusion are typical. They involve the cortex and extend subcortically to a variable extent
  • Frontal lobes (orbitofrontal) and temporal lobes (anterior temporal) are common locations
  • Associated with other features of traumatic brain injury such as traumatic subarachnoid hemorrhage (common), subdural hematoma or extradural hematoma

MRI:

  • Mirrors above findings on CT, but is more sensitive
  • GRE: very sensitive for associated hemorrhages and diffuse axonal injury
  • DWI: may show diffuse axonal injury in addition
  • T2/FLAIR: cortical and subcortical cerebral edema with hemorrhage

Pathology:

  • Disruption of cortex with adherent blood acutely. Tan grey if old. Inferior frontal & temporal lobes usually. Gliding contusions occur in parasagittal white matter.
  • Microscopically: acutely hemorrhage, perpendicular to cortex. Chronically hemosiderin, macrophages, disrupted cortex.

Treatment:

  • Medical treatment of ICP and osmolar agents as necessary for cerebral edema
  • Uncommonly requires surgery: if so usually decompressive craniotomy to allow for space as the edema progresses then resolves

Subdural Hematoma

Diseases, ,

Synonyms:

Subdural haematoma

Diagnosis:

CT:

  • Crescent shaped, diffuse covering a large part of the hemisphere
  • Can be biconvex in shape
  • Can be of mixed density: e.g. Fluid-fluid level
  • Cross suture lines but not the midline
  • Variation with time:
    • Acute, hyperdense, homogenous
    • Middle, isodense with brain
    • Chronic: hypodense
    • Acute on chronic: heterogenous, fluid-fluid levels

Pathology:

  • Acute: nonadherent gelatinous blood. Red blood cells
  • Chronic: fluid adherent to meninges, fibrous tissue if old. Microscopically: macrophages, capillaries, hemosiderin or fibrous tissue

Treatment:

  • If Acute Surgical: craniotomy & evacuation under direct vision
  • If subacute or chronic: consider burr-hole drainage or a case by case basis

Related articles:

Epidural Hematoma

Diseases, ,

Synonyms:

  • Extradural hematoma

Diagnosis:

CT or MRI:

  • Biconvex shape a.k.a. ‘lentiform’, usually over the temporal lobe
  • Can cross the falx, tentorium, can cross the midline, but doesn’t cross the suture lines
  • Associated with skull fracture

Clinical features:

  • Usually there is a history of trauma
  • Often the patient is knocked unconscious with the initial trauma. They may regain consciousness (lucid period) and then become unconscious again
  • Neurological examination may reveal features suggesting a structural cause of coma: asymmetric weakness or posturing response, disconjugate gaze or dilate pupil ipsilateral to the hematoma

Pathology:

  • Acute: gelatinous clotted blood. Microscopically, red blood cells +/-macrophages +/-hemosiderin
  • Chronic: Dark brown clot adherent to the skull or dura. Or replaced by fibrous tissue. Microscopically: Fibrous tissue, venules & membrane.

Treatment:

  • Surgical: craniotomy & evacuation under direct vision

Related articles:

Concussion

Diseases, ,

Diagnosis:

Clinical

Classification:

Grade 1: Transient confusion; no loss of consciousness; concussion symptoms clear in less than 15 minutes.
Grade 2: Transient confusion; No loss of consciousness; concussion symptoms or mental status abnormalities last longer than 15 minutes.
Grade 3: Any loss of consciousness, either brief (seconds) or prolonged (minutes).

Treatment:

Return to play (quick guidelines, see updated guidelines for up to date evidence based recommendations):

  • Most important:
    • No return to play if athelete is still experiencing symptoms
    • Must be assessed by a Neurologist or physician with proper training (e.g. sports medicine) before return to play
  • Grade 1: same day
  • Multiple grade 1: 1 week
  • Grade 2 concussion: 1 week
  • Multiple Grade 2 concussions: 2 weeks
  • Grade 3:
    • Grade 3- brief loss of consciousness (seconds): 1 week
    • Grade 3- prolonged loss consciousness (minutes): 2 weeks
    • Multiple Grade 3 concussions: 1 month or longer, based on clinical decision of evaluating physician

Related articles:

 

Traumatic Brain Injury

Diseases, ,

Synonyms and related terms:

Head trauma a.k.a. head injury a.k.a. traumatic brain injury TBI

Diagnosis:

Clinical
With or without neuroimaging: CT more commonly than MRI,

Classification, the Glasgow coma scale GCS was designed for this:

Mild: GCS 13-15
Moderate: GCS 9-12
Severe: GCS = or <8
Critical: GCS 3-4

Treatment:

If mild:

  • Consider discharge or observation

ABCD drill (Airway, Breathing, Circulation, Deficits)
Treat surgically correctible lesions
If not mild, consider prophylactic antiepileptic drugs:

  • Phenytoin PHT or levetiracetam, only for 1 week
  • If open skull fracture or Gun shot wound, consider 3 months prophylaxis

In severe trauma:

  • ICP monitoring if abnormal CT or high risk
  • Keep cerebral perfusion pressure CPP  >50 mmHg, but avoid >70 mmHg by:
    • Cerebral perfusion pressure CPP= mean arterial pressure MAP – intracranial pressure ICP
    • Noradrenaline I.V. infusion
    • Fluids: Saline. Avoid albumin. [SAFE]
    • Corticosteroids should not be used routinely

Related articles:

Subcortical Arteriosclerosis Encephalopathy

Diseases, ,

Now considered a subtype of Subcortical Vascular Dementia when cognitive dysfunction is present. It is the result of longstanding small vessel disease, particularly due to uncontrolled hypertension.

Synonyms:

Binswanger disease a.k.a. subcortical arteriosclerosis encephalopathy:

Diagnosis:

MRI

  • T2/FLAIR: subcortical white matter hyperintensities in confluent areas (initially multifocal), more prominant periventricularly, usually with evidence of previous lacunar infarctions
  • GRE: often there are microhemorrhages
  • T1 plus GAD: White matter disease does not enhance

Pathology:

  • Affects: subcortical white matter bilaterally more severe periventricularly

Microscopically:

  • Hypertensive lacunes, myelin loss, oligodendroglial loss, microcystic cavities, myelin sheath swelling, gliosis.
  • Hyaline arteriolosclerosis= concentric thickening of small arteries & arterioles +widening of perivascular space.
  • Lipohyalinosis (fibrinoid necrosis & hyalinisation)= vessens between 40-300 mm in diameter.

Related articles:

Primary Angiitis of the Central Nervous System

Diseases,

Synonyms:

Primary angiitis of the central nervous system PACNS a.k.a. Granulomatous angiitis of the CNS GANS a.k.a. isolated CNS vasculitis

Diagnosis:

Brain +Meningeal biopsy:

  • 1 cm wedge biopsy with meninges, grey & white matter
  • Small or medium sized vessels. Parenchymal or meningeal
  • Transmural destruction. Granulomatous (multinucleated cells) or lymphocytic infiltrate. Sometime macrophages. Intimal proliferation may occur
  • Infarcts may be present as well as reactive astrocytosis

Findings on Investigations:

MRI features:

  • May be normal
  • Infarcts: cortical & subcortical
  • T2,FLAIR: nonspecific High intensity lesions. Involves white matter, cortex & basal ganglia
  • Hemorrhage may occur: SAH, IPH, Subdural

MR perfusion: perfusion defects
MRA: false negatives occur
Catheter Angiogram:

  • May be normal (false negative, resolution is 0.5mm (500microm) in diameter), low specificity
  • Symmetric (circumferential & long segments) narrowing of the distal or proximal arteries & dilatation.
  • Beading

CSF:

  • Abnormal in 80-90% of cases
  • Leukocytosis
  • Raised protein

Transcranial Doppler TCD:

  • Low sensitivity
  • increased velocities in intracranial vessels

Investigations to Consider:

ESR: typically normal
CSF: pleocytosis, mainly lymphocytes & elevated protein. Oligoclonal bands occasionally. Culture & testing for (Lyme, Syphilis, Hemophilus influenzae, TB, VZV, Cryptococcus, Coccidiodes)
MRI
Angiogram
Toxicology screen: methamfetamine, cocaine
Rule out other types of vasculitis:

  • Autoimmune:
    • Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50: SLE, Sjogren’s syndrome and others.
    • Complement C3, C4 & CH50: screens for consumptive process
    • ANCA: Wegener granulomatosus
    • Hepatitis panel: HBSAg in polyarteritis nodosa
    • Anticardiolipin antibody, lupus anticoagulant: Sneddon syndrome
    • ACE level, CXR: CNS sarcoid angiitis
    • Pathergy test: Behcet syndrome
  • Infectious:
    • Lyme serology, Hemophilus influenzae (blood culture & serology)
    • RPR, VDRL, TB PCR (other TB testing)
    • VZV IgG, VZV PCR, HIV testing
    • Cryptococcus antigen, Coccidiodes serology,
    • Thick & thin smears for Malaria
  • Consider, CT chest, abdomen and pelvis:
    • Paraneoplastic vasculitis (very rare)

Brain biopsy:

  • Confirms diagnosis
  • Rules out intravascular lymphoma & lymphomatoid granulomatosis

Treatment:

  • Corticosteroids
  • Cyclophosphamide

Related articles:

Reversible Cerebral Vasoconstriction Syndrome

Diseases,

Synonyms:

Reversible cerebral vasoconstriction syndrome RCVS a.k.a. Call-Fleming syndrome a.k.a. benign angiopathy of the CNS a.k.a. thunderclap headache with vasoconstriction

Diagnosis:

Clinical:

  • Female >Male, thunderclap headache with out without neurological symptoms.
  • Hemiplegia, visual field defects,
  • May be postpartum
  • +Imaging

Findings on investigations:

CT: infarcts usually posterior/watershed or hemorrhagic transformation, no SAH
MRI: infarcts usually posterior/watershed or hemorrhagic transformation or similar to posterior reversible leucoencephalopathy
+CTA, MRA or Catheter Angiogram:

  • Segmental vasoconstriction, multifocal.
  • +Resolution within 12 weeks.
  • Catheter angiography is the gold standard
  • CTA, MRA have poor sensitivity

Transcranial Doppler TCD: increased velocities
CSF: normal, no SAH, no pleocytosis (helps differentiate from PACNS)
Brain biopsy: no vasculitis, may have reactive gliosis (helps differentiate from PACNS)

Investigations to consider:

Vasculitis screen: ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA, Complement C3, C4 and CH50
Catheter angiogram
MRI brain with and without contrast
Consider lumbar puncture and CSF analysis

Treatment:

Calcium channel blockers:

  • Verapamil
  • Or Nimodipine

Related articles:

Cervical Artery Dissection

Diseases,

Synonyms:

Cervical artery dissection: Internal Carotid artery dissection ICAD a.k.a. carotid dissection AND Vertebral artery dissection VAD

Diagnosis:

A combination of MRI dissection protocol and catheter angiography is best

Findings on Investigations:

MRI axial T1:

  • False lumen= intermural hematoma (high signal, appears after 48hrs) compressing the true lumen (signal void). [274]
  • Conventional spin echo MR: Fat suppressed T1 and T2 axial images are best
  • SAH may occur if intracranial dissections.

MRA shows length of dissection
CTA:

  • ICA: Usually in 2-3cm distal to common carotid bifurcation, less commonly at the base of the skull. May occur intracranially.
  • VA: Usually at C1-C2 junction, but may occur at any level. May occur intracranially

Ultrasound:

  • False negatives occur.

Catheter angiography:

  • The false lumen usually does not fill
  • True lumen is compressed or tapered
  • Evaluates patency vs. occlusion
  • Rarely double lumen (contrast in false lumen)
  • Contrast retention in vessel wall
  • Intimal flap
  • Ripple appearance
  • Evaluates for pseudoaneurysm

Pathology:

  • Subintimal hemorrhage in the media or adventitia
  • Superficial temporal artery biopsy: microhematoma in media, defects in the wall integrity & smooth muscle cell breakdown at the media-advantitia junction, degraded RBCs/hemosiderin near vasa vasorum. [case report] [275]
  • Associated with cystic medial necrosis in some cases

Treatment:

Acutely:

  • Antiplatelet therapy or anticoagulation are both associated with low recurrent rate of stroke [CADISS]

Antiplatelt therapy:

  • Single or combination antiplatelet therapy. [CADISS]

Anticoagulation:

  • Heparin intravenously followed by warfarin for 3-6 months

Consider:

  • Stent placement in true lumen if symptoms recur despite medical therapy
  • Note: surgery is not an option unless high risk & other therapies are contraindicated due to 10% perioperative minor stroke risk 2% perioperative death rate.

Lifestyle modification:

  • Avoid: chiropractic neck manipulation, neck hyperextension, contact sports, weight lifting, labor related to child birth.

Related articles:

Radiation Vasculopathy

Diseases,

Diagnosis:

MRI:

  • Infarcts
  • Enhancing mass lesion
  • Cavernous marlformations

Angiogram/Catheter angiography:

  • Stenosis in MCA, ICA
  • Can also cause accelerated atherosclerosis in the extracranial internal carotid artery

Treatment:

Depends on presentation:

  • Enhancing mass, typically treated with steroids
  • Infarcts are treated with antiplatelets, but data is limited
  • Extracranial accelerated atherosclerosis is treat with antiplatelets, risk factor control and carotid artery stenting if severe stenosis

 

Fibromuscular Dysplasia

Diseases,

Synonyms:

Fibromuscular dysplasia FMD,

Diagnosis:

Catheter angiography:

  • Affects: extracranial vessels e.g. carotid artery
  • Dilated portions (larger than normal parent vessel) & stenotic portions
  • +/-Pseudoaneurysm

Type 1: ‘string if pearls’ beaded appearance
Type 2: tubular stenosis (focal or multifocal)
Type 3: limited to part of the arterial wall
False negatives with MRA, CTA and ultrasound but CTA is a useful screening test

Pathology:

  • Tunica media: smooth muscle cell hyperplasia, proliferation of fibroblasts, fibrosis
  • Dilated portions (larger than normal parent vessel) & stenotic portions
  • +/-dissection, +/-pseudoaneurysm, +/-berry aneurysm, +/- CCF, +/-rare VA arteriovenous fistula,

Vessels affected:

  • Extracranial ICA (usually mid-portion), VA (mid-distal)
  • Less commonly, Intracranial ICA, VA
  • Renal arteries
  • Other vessels may be affected

Investigations to consider:

Catheter angiography:

  • Exclude other mechanisms e.g. atheroma
  • Evaluate for presence of aneurysms

Treatment:

Depends on complications e.g. stroke, pseudoaneurysm, dissection etc.
No randomized controlled trials are available.

Related articles:

Intracranial Atherosclerotic Disease

Diseases,

Synonyms:

Intracranial atherosclerotic disease ICAD a.k.a. Intracranial stenosis & intracranial atherosclerosis

Diagnosis:

Catheter angiography:
WASID intracranial stenosis criteria:

50% stenosis by WASID criteria:

  • Measure the diameter of the residual lumen
  • Measure the normal reference diameter (one of the following in descending order of preference):
    • 1 Same artery proximal to the stenosis
    • 2 Same artery distal to the stenosis
    • 3 Feeding artery
  • % stenosis= [1-(residual lumen/normal diameter)]X 100

The location has to have normal vessel segment with parallel walls free of atherosclerosis
Good interobserver and intraobserver agreements

Classification of intracranial stenosis: Mori et al

Type A: <5mm short, concentric or moderately eccentric
Type B: 5-10mm long, tubular configuration, eccentric or moderately angulated
Type C: >10mm long, tortuous configuration, angulated >90 degrees.

Sites of stenosis:
  • ICA: supraclinoid, cavernous, peterous segments
  • Anterior cerebral artery ACA, middle cerebral artery MCA, Basilar artery, posterior cerebral artery PCA

Treatment:

Optimize medical therapy:

  • Dual Antiplatelets (aspirin plus clopidogrel) for at least 3 months, then single antiplatelet agent afterwards
  • BP control <140/85mmHg
  • Cholesterol control LDL <70mg/dl
  • Smoking cessation

Angioplasty plus stenting is contraindicated for first episode [SAMMPRIS]. If recurrent, no evidence to support or refute further intervention

Related articles:

References:

  1. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Torbey MT, Zaidat OO, Rumboldt Z, Cloft HJ; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011 Sep 15;365(11):993-1003. doi: 10.1056/NEJMoa1105335. Epub 2011 Sep 7.
  2. Samuels OB, et al. AJNR Am J Neuroradiol2000; 21:643–4
  3. Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS, Montgomery J, Nizam A, Lane BF, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Lynch JR, Zaidat OO, Rumboldt Z, Cloft HJ; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial Investigators. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet. 2014 Jan 25;383(9914):333-41. doi: 10.1016/S0140-6736(13)62038-3. Epub 2013 Oct 26.
  4. Fiorella D, Derdeyn CP, Lynn MJ, Barnwell SL, Hoh BL, Levy EI, Harrigan MR, Klucznik RP, McDougall CG, Pride GL Jr, Zaidat OO, Lutsep HL, Waters MF, Hourihane JM, Alexandrov AV, Chiu D, Clark JM, Johnson MD, Torbey MT, Rumboldt Z, Cloft HJ, Turan TN, Lane BF, Janis LS, Chimowitz MI; SAMMPRIS Trial Investigators. Detailed analysis of periprocedural strokes in patients undergoing intracranial stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS). Stroke. 2012 Oct;43(10):2682-8. Epub 2012 Sep 13.
  5. Derdeyn CP, Fiorella D, Lynn MJ, Barnwell SL, Zaidat OO, Meyers PM, Gobin YP, Dion J, Lane BF, Turan TN, Janis LS, Chimowitz MI; SAMMPRIS Trial Investigators. Impact of operator and site experience on outcomes after angioplasty and stenting in the SAMMPRIS trial. J Neurointerv Surg. 2013 Nov;5(6):528-33. doi: 10.1136/neurintsurg-2012-010504. Epub 2012 Sep 12.
  6. Lutsep HL, Barnwell SL, Larsen DT, Lynn MJ, Hong M, Turan TN, Derdeyn CP, Fiorella D, Janis LS, Chimowitz MI; SAMMPRIS Investigators. Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial: subgroup analysis. Stroke. 2015 Mar;46(3):775-9. doi: 10.1161/STROKEAHA.114.007752. Epub 2015 Jan 15.
  7. Waters MF, Hoh BL, Lynn MJ, Kwon HM, Turan TN, Derdeyn CP, Fiorella D, Khanna A, Sheehan TO, Lane BF, Janis S, Montgomery J, Chimowitz MI; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial Investigators. Factors Associated With Recurrent Ischemic Stroke in the Medical Group of the SAMMPRIS Trial. JAMA Neurol. 2016 Jan 4:1-8. doi: 10.1001/jamaneurol.2015.4315.

Carotid Artery Stenosis, Extracranial

Diseases,

This section discusses extracranial internal carotid artery stenosis due to atherosclerotic disease.

Diagnosis:

Catheter angiography DSA digital subtraction angiography:

  • Gold standard test
  • NASCET measurement:
    • N= narrowest diameter of residual lumen
    • D= diameter of ICA well beyond the bulb
    • Percentage stenosis= (1-N/D) X 100
  • Useful for:
    • Suspected Total occlusion, Difficult anatomy, Fibromuscular dysplasia, Dissection, Disconcordant tests, Very calcified carotid stenosis

Carotid artery duplex ultrasound (B mode ultrasound +doppler):

  • Moderate stenosis 50-70%
  • Severe stenosis 70-99%
  • Differentiates between atheroma and thrombosis/acute plaque change:
    • Lucent areas in the plaque: corresponding to necrosis or hemorrhage
    • Thickness of fibrous cap: thin cap is associated with ulceration & necrosis
  • Can assess Carotid Intima-Media Thickness

MRA:

  • Time of flight TOF method: over-estimates the occlusion
  • High spatial resolusion CE MRA: for stenosis >70% & for occlusion. Thrombosis may be mistaken for atherma

CTA:

  • Narrowest portion of internal carotid artery correlates to NASCET-style measured stenosis:
  • 2.2mm to 50% NASCET-style stenosis
  • 1.3 mm to 70% NASCET-style stenosis

Transcranial Doppler  ultrasound TCD:

  • Absence of microemboli confers lower risk.

Investigations to consider:

  • Lipid panel: Cholesterol, triglycerides
  • Fasting glucose, HbA1c
  • ECG
  • MRI or CT: silent infarcts for baseline

Treatment:

Address risk factors:

  • BP, Cholesterol, diabetes

Asymptomatic Carotid Artery Stenosis:

  • Antiplatelet:
    • Clopidogrel, or Aspirin +/-dipyridamole, or Cilostazol
  • +/-Revascularization (carotid artery stenting or Endarterectomy) if >70% (debatable but supported by current evidence in spite of high NNT, ACST)

Symptomatic: also see TIA, or stroke section

  • Antiplatelet:
    • Clopidogrel, or Aspirin +/-dipyridamole, or Cilostazol
  • +Revascularization (carotid artery stenting or Endarterectomy) if >70% by NASCET criteria within 2 weeks of symptoms at the latest

Carotid artery stenting (CAS):

  • best done under local anesthesia with consciouss sedation (angioplasty +stenting) [CAVATAS,SAPHIRE,EVA-3S,SPACE, ICSS]
  • Heparin during procedure, protection device is used
  • Aspirin +clopidogrel for 3 months afterwards

Carotid endarterectomy (CEA):

  • Mostly under general anaesthetic, +patch: synthetic or veinous +intraoperative shunt +/-transcranial ultrasound
  • With antiplatelets [Mayo clinic trial]

Things that don’t work:

  • Extracranial-intracranial bypass [EC/IC]

 

Related articles:

Cardioembolic Stroke

Diseases,

Diagnosis:

  • Ischemic stroke with cardiac source found on investigations.

Treatment:

No use for anticoagulation  if not cardioembolic [TOAST]
Choice of anticoagulant:

  • Apixaban
  • Dabigatran
  • Warfarin orally, goal INR= 3.0-4.0 monitor every 2 weeks. Start Warfarin therapy without bridging [retrospective review]
  • Other options: edoxaban, rivaroxaban

Anticoagulate if:

  • Atrial fibrillation [EAFT]
  • Prosthetic valve: If recurrent on anticoagulation add Aspirin 100mg P.O.
  • <3 months post MI
  • Some patients with dilated cardiomyopathy

In acute phase without thrombolysis:

  • In Atrial fibrillation: No difference between aspirin & dalteparin. [HAEST]
  • In unselected stroke group: No difference in efficacy between Aspirin & tinzaparin, more symptomatic intracranial hemorrhages with tinzaparin up to 14 days. [TAIST]

Related articles:

References:

  1. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet, 1993. 342(8882): p. 1255-62.
  2. Berge, E., et al., Low molecular-weight heparin versus aspirin in patients with acute ischemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet, 2000. 355(9211): p. 1205-10.
  3. Wallmann, D., et al., Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: an opportunity for a new diagnostic strategy. Stroke, 2007. 38(8): p. 2292-4.
  4. Hallevi, H., et al., Anticoagulation After Cardioembolic Stroke: To Bridge or Not to Bridge? Arch Neurol, 2008.

Small Vessel Disease

Diseases, ,

This section will cover ischemic stroke due to small vessel disease

Synonyms:

Microangiopathic stroke a.k.a. microangipathic infarct ~Lacunar infarct

Diagnosis:

Clinical lacunar/thalamic syndrome:

  • +HTN or DM
  • +negative cardiac evaluation
  • +negative large artery disease evaluation

Note that cardiac embolism and large artery disease can cause imaging features consistent with lacunar infarcts
Extensive work up is still necessary in Lacunar stroke.
Lacune: <1.5mm (<2mm in some definitions) areas of volume loss in territory of perforating small vessels, surrounded by T2/FLAIR white matter hyperintensity gliotic rim.

Findings on investigations:

CT:

  • Lacunar infarct: Hypodensity in putamen, globus pallidus, internal capsule, thalami, periventricular white matter

MRI:

  • Putamen, globus pallidus, internal capsule, thalami, periventricular white matter
  • T1: low signal intensity white matter change,
  • T2: high signal intensity white matter change, Lacunes with surrounding peri-lacunar high signal gliosis, enlarged perivascular spaces may co-exist and follow CSF signal,
  • GRE/SWI: cerebral microbleeds may be present, old intracerebral hemorrhage may co-exist

Pathology:

  • Lacunar stroke: lipohyalinosis

Genetics:

Most cases of small vessel disease are not a Mendelian genetic disorder. However, Mendelian genetic forms exist:
Mendelian genetic cerebral SVD:

  • CADASIL=NOTCH3 for Neurogenic locus notch homolog protein 3,
  • CARASIL=HTRA1 gene for Serine protease,
  • COL4A1/2 syndrome=COL4A1 and COL4A2 genes for collagen,
  • RVCL=TREX1 gene for Three prime repair exonuclease 1 enzyme.

Treatment:

Antiplatelets:

  • Single antiplatelet agent is best for ischemic stroke due to small vessel disease. Choose one of: aspirin, clopidogrel, cilostazol

Control vascular risk factors:

  • Hypertension
  • Cholesterol
  • Diabetes mellitus
  • Sedentary lifestyle
  • Smoking cessation

Rehabilitation services as appropriate

Related articles:

Transient Ischemic Attack

Diseases, , ,

Diagnosis:

  • Sudden neurological focal deficit of vascular origin lasting <24 hrs (usually lasts <1 hr), with normal diffusion weighted MRI (DWI).
  • PWI: may show decreased perfusion.
Investigations to Consider:

Blood tests:

  • FBC, Coagulation screen, Blood Glucose, Blood chemistry panel,
  • Fasting: Cholesterol, Lipids, glucose
  • ESR: vasculitides, giant cell arteritis.
  • Consider Homocystein, vasculitic screen, thrombophilia screen

Extracranial vascular evaluation:

  • CTA, MRA
  • Or carotid ultrasound if carotid territory (too  low sensitivity in posterior ciruclation TIA)

Intracranial vascular evaluation:

  • CTA, MRA: good screening tests, particularly CTA
  • Cathetera angiography: confirmatory test for intracranial stenosis

Cardiac evaluation:

  • ECG: Exclude AF
  • Transthoracic echocardiogram
  • Transoesophageal Echocardiogram TOE, especially if other tests don’t reveal the mechanism.
  • Consider implantable cardiac monitor or prolonged external monitor (>or=60 days) if clinically definite TIA

Consider:

  • DWI MRI: high signal indicates high risk of stroke

Treatment:

  • Emergent or urgent evaluation & treatment. [EXPRESS]
  • If admitting to the hospital, admit the patient to the stroke unit

Antiplatelets: Choose one

  • Aspirin +/-dipyridamole
  • Clopidogre
  • Cilostazol
  • Don’t use aspirin +clopidogrel, use single antiplatelt agent investigations confirm intracranial atherosclerotic disease with stenosis

Anticoagulation: if cardioembolic stroke (see cardioembolic stroke)
Manage risk factors for stoke & atheroma:

  • Hypertension control
  • Statin
  • Others: smoking, diabetes mellitus, diet, exercise

Revascularization if meets crteria for extracranial symptomatic carotid stenosis: by carotid artery stenting or carotid endarterectomy

Related articles:

Cerebral Amyloid Angiopathy

Diseases,

Patholgy:

Brain Biopsy:

  • Involves the cortex & overlying meninges, sparing the deeper structures.

Histology:

  • Congophilic angiopathy: amyloid in medium & small sized arteries. Dyshoric angiopathy: amyloid leaking from capillaries.
  • Media & advantitia infiltration. H&E: eosinophilic acellular amorphous material (media & adventitia). Sometimes double barrel vessels (loss of smooth muscle & preservation of endothelium). Congo red stain: apple green birefringence under polarized light. Secondary changes: microaneurysm, fibrosis, chronic inflammation, surrounding hemosiderin
  • Associated perivascular lymphocytic infiltrate may occur, B-cells & T-cells
  • Immunohistochemistry: beta-amyloid positive in the arteriolar wall, diffusely

Diagnosis:

Combination of clinical findings (age), MRI findings and pathology if present. The Boston criteria is used.

Findings on investigations:

MRI:

  • Hemorrhages: usually lobar, rarely SAH or subdural
  • Silent infarcts
  • Gradient echo GRE: multiple hemorrhages

 

Related articles:

Cavernous Malformation

Diseases,

Synonyms:

a.k.a. Cavernous hemangioma a.k.a. Cavernous angioma a.k.a. cavernoma

Pathology:

Dilated thin walled veins, without intervening brain tissue, surrounding gliosis & hemosiderin, no elastin in the walls

Diagnosis:

MRI:

  • TI, T2 & FLAIR: Heterogenous mass (blood at different ages) with high signal on TI, T2 & FLAIR, low signal rim (hemosiderin) on T2 & FLAIR
  • DWI: normal
  • Contrast: no enhancement or minimal enhancement especially if with associated developmental venous anomaly
  • Usually in the brain, rarely occur in the spinal cord
  • Giant if >6 cm

MRA: normal
Catheter angiography:

  • Usually Normal
  • Capillary blush may occur especially on repeated injection, also suggests a draining vein or venous malformation
  • Mass effect if hemorrahge has occurred

CT:

  • Round densities with Central Calcification with mild enhancement & without oedema or sulcal effacement.
  • Usually negative

CTA: usually negative

Zabramski classification:

Type 1: subacute hemorrhage
Type 2: mixed signal with hemorrhage of various ages
Type 3: chronic hemorrhage
Type 4: punctate microhemorrhages

Genetic forms:

CCM1 gene chr. 3,7q, KRIT1 protein
CCM2 gene
CCM3 gene

Treatment:

  • Antiepileptics if seizures occur
  • Consider surgery if previously ruptured, and further rupture risk is estimated to be higher than surgical risk

Related articles:

Spinal Vascular Lesions

Diseases, , ,

Classification:

Neoplastic vascular lesions:

  • Hemangioblastoma
  • Cavernous hemangioma

Spinal aneurysms, rare
Spinal Arteriovenous fistula, AVF

  • Extradural
  • Intradural: a.k.a. Foix-Alajouanine
    • Ventral intradural:
      • A. Small shunt
      • B. Medium shunt
      • C. Large shunt
  • Dorsal intradural:
    • A. single feeder
    • B. multiple feeders

Spinal Arteriovenous malformation AVM:

  • Extradural-intradural
  • Intradural:
  • Intramedullary:
    • Compact
    • Diffuse
    • Conus medullaris

 

 

Spinal Arteriovenous Fistula, spinal-AVF:

Spinal extradural arteriovenous fistula AVF, rare:

Diagnosis:

Catheter angiography: Fistula point is entirely external to the dura
 

Spinal dural arteriovenous fistula SDAVF, a subtype Foix-Alajouanine, rare:

Pathology:

A fistula between an extradural artery and vein, high flow, leads to enlargement of the extradural venous plexus and compression of the spinal cord or vascular steal.
 

Spinal intradural arterivenous fistulas:

Classification:

Ventral:

  • A: Small, B: Medium, C: Large

Dorsal:

  • A: Single arterial feeder, B: Multiple arterial feeders
Diagnosis:

Catheter angiography

Pathology:

Ventral type: A fistula between the anterior spinal artery and enlarged venous system, high flow.
Dorsal type: A fistula between radicular artery and corresponding radicular vein within the dural root sleeve, low flow. Usually thoracolumbar
Enlarged Veins outside the spinal cord. Thickened intima and media. Widened lumen. Infarction/necrosis of the lower spinal cord grey>white matter. Secondary long tract degeneration.

Clinically:

Middle age men >women, lower limb ascending motor or sensory lower motor neuron symptoms, then spinal cord symptoms regardless of the level. This is because congestion of the cord affects the lower segements first.

Findings on investigations:

Catheter angiography: demonstrates fistula, arterial feeders and venous drainage
MRI: Cord Swelling. T2: hyperintensity within the cord over 5-7 segments. Flow void (hypointensity) dorsal to the cord: tortuous veins. T1: hypointensity. Contrast enhancement especially 40-45 min post injection.
MRA: Serpentine perimedullary structures. False positives occur.
Myelography: dilated lumbar veins =’postage stamp’ appearance of lumbar roots,

Treatment of spinal intradural arteriovenous fistula:

Consider:

  • Endovascular therapy
  • Surgical closure of the fistula

 

Related articles:

References:

  1. Spetzler, R.F., et al., Modified classification of spinal cord vascular lesions. J Neurosurg, 2002. 96(2 Suppl): p. 145-56

Capillary telangiectasia

Diseases,

Diagnosis:

Clinical:

  • Usually an incidental finding, very rarely [case reports] of bleeding.

MRI:

  • Pons
  • ~3cm diameter
  • T1 +contrast: Nodular enhancement after contrast
  • Gradient echo GRE: hypointense,
  • T2 isointense

CT: invisible
Angiography:

  • Usually nothing is visible

Pathology:

  • Pons is the commonest location
  • Microscopic Ectatic thin walled vascular channels (Capillaries) with interspersed normal appearing brain matter. Usually, no surrounding blood products, but hemosiderin has been reported.
  • Rarely associated with Hereditary hemorrhagic telangiectasia a.k.a. Osler-Weber-Rendu disease

Treatment:

  • No treatment is necessary, this is a normal variant
  • Avoid surgery or radiation therapy, this will lead to complications
  • Clinical relevance: easily confused with small enhancing lesions

Related articles:

Sinus pericranii

Diseases,

Diagnosis:

Clinical:

  • Scalp mass that increases with valsalva or lying down & reduces with standing

CT:

  • Focal bone defect may be present
  • Extracranial venous malformation that enhances heterogenously
  • Cortical varix that strongly enhances

CTV shows this well
MRI:

  • T1, T2: signal based on flow
  • Contrast: Cortical Varix enhances well. Extracranial Venous malformation enhances heterogeneously

MRV shows this well
Catheter Angiogram/angiography:

  • Normal arterial phase
  • No early draining vein
  • Allows classification

Percutanseous venography:

  • Shows extracranial venous component & draining scalp veins

Classification:

  • Closed: blood originates from & drains into dural venous sinus
  • Open: blood comes from dural venous sinus & drains into scalp veins

Treatment:

No treatment is necessary, this is a normal variant

Developmental Venous Anomaly

Diseases,

Synonyms:

a.k.a. Venous malformations a.k.a. venous angioma

Diagnosis:

MRI:

  • Linear structures with flow voids
  • Dilated medullary veins: Around the ventricles, transcerebral course
  • One large vein may drain into dural sinus or deep vein
  • Enhance with contrast: caput medusae or umbrella shaped
  • Features of associated cavernous malformation may be present

Catheter Angiography:

  • Normal arteries in size & number
  • Persistence of normally filling abnormal aberrant veins, sometimes blush occurs
  • Paraventricular, but also occur subcortically
  • One large vein may drain into dural sinus or deep vein

Pathology:

  • Ectatic venous channels.
  • No surrounding blood products.
  • No gliosis

Treatment:

  • No treatment is necessary, this is a normal variant
  • Avoid surgery or embolization, this will lead to ischemic stroke

Related articles:

Vein of Galen malformation

Diseases,

Synonyms:

a.k.a. vein of Galen aneurysm a.k.a. Galenic varix
 

General points:

This is a type of direct arteriovenous fistula AVF. It’s a misnomer because it involves the Median prosencephalic vein of Markowski. It is not an AVM because there is no nidus. It is not a dural arteriovenous fistula because it does not involve the dural primarily.

Diagnosis:

Catheter Angiogram/angiography:

  • Shows arterial feeders & dilated draining median prosencephalic vein
  • Arterial feeders:
    • Choroidal (associated with neonatal presentation): pericallosal, anterior choroidal, thalamoperforating
    • Mural (associated with infant presentation): collicular or posterior choroidal arteries
  • Shows associated venous sinus abnormalities

CT:

  • Hyperdense venous pouch
  • +/-calcification of thrombus in venous wall
  • +/-parenchymal calcification
  • Hydrocephalus & parenchymal atrophy may occur
  • Enhancement: of arteries & vein

CTA:

  • Shows the features well

MRI:

  • Arterial feeders: seen on T1 or flow voids on T2
  • Thrombus in the venous wall: hyperintense on T1
  • Mixed intensity in the draining vein: T2 & T1
  • Features of ischemia/infarction in surrounding brain

Other tests:

  • In neonates: CXR: cardiomegaly, oedema
  • Ultrasound head:
    • Mildly echogenic midline mass (draining vein)
    • Doppler: arterial feeders, fast flow in draining vein
  • Echocardiogram: features of CHF

Related articles:

Vertebral arteriovenous fistula

Diseases,

This section refers to Vertebral arteriovenous fistula (without dural involvement):

Diagnosis:

Clinical:

  • Vertebrobasilar insufficiency, lower cranial nerve compression, neck pain, or asymptomatic
  • Usually post trauma.
  • Spontaneous fistula occur in fibromuscular dysplasia and neurofibromatosis. i.e. usually a complication of dissection

Catheter angiography DSA:

  • Arterial supply: Vertebral artery directly fills veinous plexus. Fistula point is usually at the level of C1, C2 or C3
  • Venous drainage: variable, depends on the fistula point

Treatment:

Endovascular embolisation:

  • Arterial or venous approach
  • Coil embolization
  • Occationally covered stents or multiple overlapping stents
  • Occationally fistula point occlusionw with concurrent vessel sacrifice

 

Related articles:

Carotid Cavernous Fistula

Diseases,

Carotid cavernous fistulas are a type of dural arteriovenous fistula that involves the cavernous sinus. There are two types of carotid cavernous fistula (CCF):

  • Direct carotid-cavernous fistula
  • Indirect carotid-cavernous fistula

 

Classification (by catheter angiography):

  • Barrow Type A i.e. direct CCF: direct ICA to Cavernous sinus shunt. i.e. no dural arterial branches are involved
  • Type B: dural ICA branches to cavernous sinus shunt
  • Type C: dural ECA (meningeal feeding via external carotid) to cavernous shunt
  • Type D: ECA/ICA dural branches to cavernous sinus

 

 

Direct carotid-cavernous fistula (direct CCF):

Diagnosis:

Clinical:

  • Days or weeks post trauma or post rupture of cavernous ICA aneurysm
  • Cavernous sinus syndrome w pulsatile exophthalmos
  • Ischemic and hemorrhagic complications

Catheter angiography DSA:

  • Arterial supply: Rapid direct filling of cavernous sinus from ICA, on ICA injection. Uncommonly, ECA feeders (internal maxillary artery, APhA)
  • Venous drainage via: ophthalmic veins (superior and inferior). +/-Other drainange: contralateral cavernous sinus, petrosal sinuses (superior & inferior), ponto-mesenscephalic veins, basal vein of Rosenthal, middle cerebral veins (deep & superficial).
  • If severe ICA laceration, no distal ICA flow
  • Examine both ICA, ECA and VA injections

CTA:

  • Opacification of cavernous sinuses

MRI:

  • Dilated superior ophthalmic vein or other draining veins
  • Cerebral edema in some cases with extensive venous hypertension

 

Treatment, Type A, (direct CCF):

It is important to get a baseling neuro-ophthalmological examination and to measure intraocular pressure
Endovascular treatment:

  • Arterial approach via Internal carotid artery
  • Venous approach via jugular vein and inferior petrosal sinus, or via facial vein or superior ophthalmic vein
  • Embolization agents:
    • Detachable balloons
    • Balloon assisted coil embolization

 

 

Indirect carotid-cavernous fistula (indirect CCF):

Diagnosis:

Clinical:

  • Gradual onset of carotid cavernous syndrome: ophthalmoplegia, conjunctival injection, raised intraocular pressure, proptosis
  • Cavernous sinus syndrome with pulsatile exophthalmos
  • Ischemic and hemorrhagic complications

Catheter angiography DSA:

  • Arterial supply: Dural arterial branches (from external carotid artery or from dural branches of the internal carotid artery)
  • Fistula point: within the cavernous sinus
  • Venous drainage: any of the outlet drainage of the cavernous sinus; the superior ophthalmic vein, the pterygoid plexus, the inferior petrosal sinus, the bridgeing veins to the brainstem etc.
  • Typical arterial feeders:
    • Distal IMA, APhA, MMA, cavernous ICA branches (uni- or bi-lateral)
    • Rarely only ECA or ICA branches
  • Typical venous drainage:
    • Variable: one or both of the patterns below:
    • Superior & inferior ophthalmic veins if anterior fistula
    • Inferior petrosal sinus & superior petrosal sinus if posterior fistula
  • Typical pial vein involvement:
    • Usually none
    • directly to Superficial & deep middle cerebral veins, or via paracavernous sinus via connection with pterygoid plexus
    • to bridging vein to ponto-mesencephalic vein to peduncular vein to Basal vein of Rosenthal
    • to Superior petrosal sinus to petrosal vein to lateral mesencephalic vein to basal vein of Rosenthal
    • to petrosal vein to cerebellar veins

CTA:

  • Opacification of cavernous sinuses

MRI:

  • Dilated superior ophthalmic vein or other draining veins
  • Cerebral edema in some cases with extensive venous hypertension

Treatment indirect CCF:

It is important to get a baseling neuroophthalmological examination and to measure intraocular pressure
Type B, C, D (indirect CCF)

  • Consider Carotid-jugular compression for diagnosis if not contraindicated
  • or Endovascular treatment

Endovascular treatment:

  • Venous approach via jugular vein and inferior petrosal sinus, or via facial vein or superior ophthalmic vein
  • Arterial approach via dural branches of the external carotid artery or dural branches of the internal carotid artery
  • Embolization agents:
    • Detachable balloons
    • Balloon assisted coil embolization

 

Related articles:

Dural Arteriovenous Fistula, Cranial

Diseases,

Clinical features:

  • Wide range including: asymptomatic, pulsatile tinnitus, headache, cranial nerve palsy, cognitive deficits, hydrocephalus, focal deficits, seizures\
  • Pulsatile tinnitus, pulsatile exophthalmos
  • Cranial neuropathy
  • Encephalopathy, dementia, Parkinsonism
  • In neonates/infants: heart failure

Diagnosis:

Catheter Angiogram:

  • Use superselective catheterisation of 4 vessels, +external carotid
  • Abnormal arteries and veins with shunting contained entirely within the dura (dural leaflets)
  • Multiple feeding arteries are usually present. Usually external carotid artery.
  • Early opacification of venous structures after dye administration. Flow reversal in veins may occur. Cortical drainage is associated with poor prognosis (high rupture rate).
  • Associated with thrombosed venous sinus (especially transverse & cavernous) or with the tentorium.
  • Named based on involved dural sinus.

Pathology:

  • Direct connection between artery and vein (pial vein i.e. cortical vein or dural sinus) without capillaries or nidus
  • Venous drainage may be directly into the dural sinus or via pial veins “cortical vein”
  • Feeding arteries are usually branches of the extracranial carotid artery but ICA and VA meningeal branches may supply the fistula. Dural arteries supply dural AVFs.
  • May cause infarct, hemorrhage, venous thrombosis, cranial nerve palsy

Findings on Investigations:

CT:

  • May be normal
  • Enhancement: may be normal or show enlarged arterial feeder, enlarged sinus or enlarged vein

CTA:

  • False negatives occur
  • Shows some of the angioarchitecture

MRI:

  • False negatives occur
  • T1: normal or abnormal vessels or thrombosed sinus
  • T2: flow voids, Retrograde leptomeningeal venous drainage (hyperintensity in adjacent brain)
  • FLAIR: thrombosed sinus, +/-brain oedema,
  • GRE: normal or hemorrhage
  • DWI: normal or restricted in infarct
  • Enhancement: enhanced thromosed sinus

MRA:

  • False negatives occur
  • TOF
  • Contrast enhanced TOF MRA may show detail

MRV:

  • False negatives occur
  • Thrombosed sinus
  • Flow reversal in draining veins

DSA, catheter angiography: perform ECA, ICA, VA injections

Classifications:

Sites (6-7 locations):
  • Transverse and sigmoid sinus DAVF
  • Torcula herophili DAVF (considered by some subtype of transverse sinus DAVF)
  • Cavernous sinus, indirect CCF
  • Superior sagittal sinus DAVF
  • Ethmoidal (anterior fossa) DAVF
  • Tentorial DAVF
  • Foramen magnum DAVF
Sites (feeders & drainage in detail):

Transverse and sigmoid sinus DAVF:

  • Typical arterial feeders:
    • ECA branches: occipital a., APhA, MMA, (unilateral or bilateral)
    • Sometimes: Meningeal ICA (cavernous segment) branches, meningeal VA branches
  • Typical venous drainage:
    • Transverse sinus
    • Typical pial vein involvement:
    • None or minimal

Torcula herophili DAVF (considered by some subtype of transverse sinus DAVF):

  • Typical arterial feeders:
    • ECA branches: occipital a., APhA, MMA, (unilateral or bilateral)
    • Sometimes: Meningeal ICA (cavernous segment) branches, meningeal VA branches or cerebellar pial arteries
  • Typical venous drainage:
    • torcula herophili. But if thrombosed, then to straight sinus to vein of Galen to basal vein of Rosenthal then to deep cerebral veins +venous congestion
    • Typical pial vein involvement:
    • none, but congestion in deep cerebral and cerebellar veins

Cavernous sinus, indirect CCF:

  • Typical arterial feeders:
    • Distal IMA, APhA, MMA, cavernous ICA branches (uni- or bi-lateral)
    • Rarely only ECA or ICA branches
  • Typical venous drainage:
    • Variable: one or both of the patterns below:
    • Superior & inferior ophthalmic veins if anterior fistula
    • Inferior petrosal sinus & superior petrosal sinus if posterior fistula
  • Typical pial vein involvement:
    • Usually none
    • directly to Superficial & deep middle cerebral veins, or via paracavernous sinus via connection with pterygoid plexus
    • to bridging vein to ponto-mesencephalic vein to peduncular vein to Basal vein of Rosenthal
    • to Superior petrosal sinus to petrosal vein to lateral mesencephalic vein to basal vein of Rosenthal
    • to petrosal vein to cerebellar veins

Superior sagittal sinus DAVF:

  • Typical arterial feeders:
    • ECA branches: MMA (often bilaterally), Superficial temporal artery (transosseous), Occipital artery (transosseous)
    • Occasionally: Ophthalmic supply (Anterior meningeal artery), VA meningeal branches
  • Typical venous drainage:
    • Typical pial vein involvement: long tortuous pial cortical veins

Ethmoidal (anterior cranial fossa) DAVF:

  • Typical arterial feeders:
    • Ophthalmic artery branches (Anterior and posterior ethmoidal arteries, anterior meningeal artery), anastomosis with internal maxillary artery IMA (IMA ethmoidal branches from sphenopalatine artery)
  • Typical venous drainage: cortical veins to Superior sagittal sinus. Uncommonly to the cavernous sinus.
  • Typical pial vein involvement: cerebral veins (frontal convexity veins)

Tentorial DAVF:

  • Anterior (petrotentotial), posterior (ie. Posterior or lateral) subtypes
  • Typical arterial feeders:
    • Many feeders: ECA (MMA branches), artery of foramen rotundum, Occipital artery, APhA. Cavernous ICA branches. SCA (Leptomeningeal branches).
    • In posterior subtype same arterial feeders +more SCA, PCA branches, artery of the falx cerebelli. Also +meningeal branch of PCA
  • Typical venous drainage:
    • Petrosal vein then mesencephalic vein, then posterior mesencephalic vein then vein of Galen then straight sinus. If thrombosed, then to Basal vein of Rosenthal, then to internal cerebral vein.
    • In posterior subtype: very variable, same as anterior +transverse sinus, superior sagittal sinus,
  • Typical pial vein involvement: cerebellar and cerebral (occipital) especially in posterior subtype

Foramen magnum DAVF:

  • Typical arterial feeders:
    • APhA (uni-or bilaterally), Occipital artery, VA. Rarely internal maxillary artery or ICA branches.
  • Typical venous drainage: variable, inferior petrosal sinus, jugular vein, sigmoid sinus, anterior condylar vein, marginal sinus
  • Typical pial vein involvement: brainstem veins, Spinal perimedullary venous drainage
Cognard classification (intracranial dAVF):

Type I:

  • AVF in sinus wall, antegrade flow
  • Benign course

Type IIA:

  • AVF in main sinus, reflux into sinus, no reflux into cortical veins

Type IIB:

  • Reflux into cortical veins
  • High hemorrhage rate

Type III:

  • Direct cortical drainage, no venous ectasia
  • High hemorrhage rate

Type IV:

  • Direct cortical drainage, +venous ectasia
  • High hemorrhage rate

Type V:

  • Spinal perimedullary venous drainage

See classification of spinal vascular lesions separately
 

Classification (Borden):

Type 1:

  • Shunting into dural sinus (or meningeal vein) with only antegrade flow

Type 2:

  • Shunting into dural sinus (or meningeal vein) with retrograde flow into subarachnoid veins

Type 3:

  • Direct shunting into subarachnoid veins without dural drainage
    Each may be subtype A (single hole), subtype B (multiple holes)

Treatment:

Observation, endovascular (venous or arterial approach), surgical or combined treatment
Transverse and sigmoid sinus dAVF:

  • Usually endovascular (arterial or venous approach). Consider surgery if thrombosis has caused an isolated sinus.

Cavernous sinus (indirect CCF):

  • Consider Carotid-jugular compression for diagnosis if not contraindicated
  • Usually endovascularly via venous approach
  • Arterial approach via external carotid artery
  • Venous approach via jugular vein and inferior petrosal sinus
  • Venous approach via facial vein & superior orbital vein

Superior sagittal sinus dAVF:

  • Usually surgically
  • Embolization is sometimes possible.

Ethmoidal (anterior cranial fossa) dAVF:

  • Usually surgically

Tentorial dAVF:

  • Difficult. Usually endovascular +/-surgery

Foramen magnum dAVF:

  • Usually Surgically

Torcula herophili DAVF:

  • Endovascular option:
    • Embolization via arterial route: Onyx or glue
      Or if at least one transverse sinus is open, transvenous embolization with coils
  • Surgical excision vs. endovascular embolization

Related articles:

Arteriovenous Malformations

Diseases,

Findings on Investigations:

CT:

  • Tangle of blood vessels: Serpentine or punctate high density on noncontrast
  • Enhance with contrast
  • Calcification may occur, hemorrhage may occur
  • Hydrocephalus may occur with Vein of Galen malformation

CTA:

  • Arteries & draining veins are visible well, but angiography is still necessary

MRI:

  • Localises the lesion well.
  • T1: curvilinear vessels
  • T2: curvilinear Signal voids indicate the patent vessels, no intervening brain tissue
  • FLAIR: vascular flow voids & high signal surrounding gliosis
  • Gradient echo GRE: assess for hemorrhage, hypointense
  • Strong enhancement
  • False negatives if small

MRA:

  • Useful but doesn’t show detailed architecture AVM

Catheter Angiogram:

  • Gold standard test
  • Useful for mapping of AVM, use selective catheterisation of 4 vessels, +external carotid arteries
  • Cardinal features:
    • Enlarged arteries, 1 or more. With or without feeding artery aneurysms.
    • Nidus, with or without intra-nidal aneurysms
    • Draining vein, 1 or more early draining vein
  • Arteries: May have associated aneurysm: Cortical “pial” supply (supplied by arteries that would normally supply brain tissue i.e. branches of circle of Willis). Much more rarely, dural supply (rare supply from arteris that normally supply dura)
  • Nidus= core= a cluster of entangled blood vessels this drains into the enlarged veins. May have associated aneurysm
  • Draining veins: These are early draining veins (i.e. present on arterial phase). They may be deep or superficial drainange.
  • Associated features: Aneurysm of the feeding artery (pedicle) may be present. Aneurysm of the nidus intranidal aneurysm may be present

Pathology:

  • Gross: tangled mass of blood vessels, wedge shaped
  • Microscopy: thick walled arteries (elastic stains), thick walled veins (arterialised), +/-thrombosis +/-recanalisation, gliosis between blood vessels.
  • Perinidal capillary network= Abnormal large capillaries in 1-7mm surrounding the nidus.

Classification:

Spetzler Martin Grading 1-5 system for surgical difficulty:

Size:

  • <3cm, score =1
  • 3-6cm, score =2
  • >6cm, score =3

Location:

  • Non-Eloquent, score =0
  • Eloquent, score =1

Deep drainage:

  • No, score =0
  • Yes, score =1

Treatment:

Options:

  • Observation: this is the best approach for unruptured AVMs
  • Surgery: Excision en bloc resection +ligation of feeding vessels
  • Endovascular Emoblisation to reduce size to allow radiosurgery, to reduce flow to allow surgical resection or rare to cure very small AVMs.
  • Gamma radiotherapy (stereotactic radiosurgery STRS)
  • Annualized rupture rate 2.1% per year [Based on ARUBA trial]

For ruptured AVMs consider treatment:

  • Grade 1 & 2: surgery
  • Grade 3: surgery or radiosurgery +embolization
  • Grade 4 & 5: multidisciplinary, usually conservative management for grade 5

Related articles:

 

Cerebral Pseudoaneurysms

Diseases,

Subtypes:

These can be Intracranial or extracranial

  • Intracranial Pseudoaneurysm (Cerebral Pseudoaneurysm)
  • Extracranial cervical artery pseudoaneursym (cervical pseudoaneurysm):

Diagnosis:

  • Focal dilation of a vessel wall that is not outlined by the layers of normal arterial wall. Usually, a hematoma that communicates with the vessel lumen.

CT:

  • Hematoma adjacent to vessel. Enhancing focus within a hematoma.

CTA:

  • Contrast may fill the pseudoaneurysm

MRI:

  • T1: hyperintense hematoma
  • T2: typical for hematoma age
  • FLAIR: hyperintense hematoma, acutely
  • GRE: hypointense
  • DWI: foci of restriction may occur (ischemia)

Catheter Angiogram:

  • Pseudoaneurysm slowly fills and empties with contrast
  • Mass effect on parent vessel from hematoma

Treatment:

Options are:

  • Observation
  • Endovascular therapy: coiling (unassisted), stent-assisted coiling, multiple overlapping stents, liquid embolic agents, vessel sacrifice

Related articles:

Blister Like Pseudoaneurysm

Diseases,

Synonyms:

Blood blister-like aneurysm a.k.a. blister-like pseudoaneurysm a.k.a. trunk aneurysm

Pathology:

  • Atherosclerosis with ulceration & hematoma
  • A small defect in the vessel wall covered only with overlying fibrous tissue
  • Atherosclerosis in parent vessel

Diagnosis:

Catheter Angiography:

  • Small lateral wall bulge (asymmetric i.e. only one side of the lateral wall), hemispherical in shape
  • Usually <10mm
  • May be read as negative
  • Usually in internal carotid artery, but can occur in Posterior communicating artery PCOM

CT: SAH may occur
CTA:

  • Asymmetrical bulge of arterial wall
  • Often false-negative on CTA

MRI: features of SAH
MRA: may show it or be negative

Treatment:

Very difficult and controversial. Treated if they rupture, options:

  • Endovascular:
    • Multiple overlapping flow diverting stents
    • Stent assisted coiling
    • Parent vessel sacrifice
  • Surgical:
    • Surgical wrapping

Related articles:

Cerebral Aneurysms, Fusiform

Diseases,

Subtypes:

There are two main subtypes:

  • Non-atherosclerotic fusiform cerebral aneurysms (some authors include dissecting aneurysms here)
  • Atherosclerotic fusiform cerebral aneurysms
  • These are different from saccular cerebral aneurysms

These are discussed in the two sections below:

Non-Atherosclerotic fusiform cerebral aneurysms:

Diagnosis of non-atherosclerotic fusiform aneurysms:

Catheter Angiography:

  • Long segment fusiform dilatation in absence of atherosclerosis, +ectatic vessel, +/-focal outpouching
  • Common locations:
    • Posterior circulation (BA, VA) more common than anterior (supraclinoid ICA, MCA)

MRI:

  • T1: ectatic vessel. +/-high signal with thrombus or slow flow
  • T2: Flow void. +/-low signal with thrombus
  • FLAIR: +/-hyperintense thrombus in vessel
  • DWI: restricted if associated with ischemia

MRA:

  • TOF may be inaccurate due to abnormal flow
  • Contrast enhanced dynamic MRA for accurate delineation

 

Classification & pathology:

Type 1: typical dissecting aneurysm:

  • Acute widespread disruption of the internal elastic lamina
  • Without intimal thickening
  • Rebleeds are common

Type 2: segmental ectasia:

  • Extended and/or fragmented internal elastic lamina with intimal thickening
  • Benign course

Type 3: dolichoectatic dissecting aneurysms:

  • Fragmentation of the internal elastic lamina
  • Multiple dissections of thickened intima
  • Organized thrombus in the lumen
  • Symptomatic progressive enlargement

Type 4: atypically located saccular aneurysm i.e. not at branching point e.g. lateral wall:

  • Minimally disrupted internal elastic lamina
  • Without intimal thickening
  • High rerupture risk

Associated with Ehlers-Danlos type IV, Neurofibromatosis 1, HIV associated vasculopathy, VZV associated vasculopathy, SLE

Treatment of non-atherosclerotic fusiform cerebral aneurysm:

  • Consider observation
  • If anterior circulation: endovascular therapy using flow diversion (flow diverting stent) e.g. Pipeline stent. Consider balloon-test occlusion followed by endovascular vessel sacrifice
  • If posterior circulation:
    • Vertebral artery (segment without perforators):endovascular therapy using flow diversion (flow diverting stent) e.g. Pipeline stent. Consider balloon-test occlusion followed by endovascular vessel sacrifice
    • Basilar artery (segment with perforators): observation. Consider surgical wrapping
  • Note, if Ehlers-Danlos type IV catheter angiography is contraindicated because of risk of dissection

 

Diagnosis:

Catheter Angiogram:

  • Ectatic vessel with atherosclerosis with focal out-pouching
  • Common locations:
    • Posterior circulation (BA, VA) more common than anterior (supraclinoid ICA, MCA)
    • Basilar artery

CT:

  • Hyperdense due to calcium
  • Enhancing lumen

CTA:

  • Ectatic vessel +atherosclerosis +focal outpouching/dilatation

MRI:

  • T1,T2: depend on presence of hematoma or thrombus
  • Enhancement of lumen.

MRA:

  • TOF is inadequate because slow flow in the lumen gives heterogenous signal
  • Dynamic Contrast enhanced MRA is useful
Treatment of atherosclerotic fusiform cerebral aneurysms:
  • Medical management of atheroslcerosis
  • In selected cases consider endovascular treatment

 

Related Articles:

Cerebral Aneurysms, Saccular

Diseases,

Please see other articles for fusiform cerebral aneurysms

Synonyms:

Saccular Intracranial aneurysms, Saccular Cerebral aneurysms, saccular aneurysms

Diagnosis:

Catheter angiography is the gold standard
MRA and CTA can also be used as good screening tests

Clinical features:

  • Asymptomatic
  • SAH signs and symptoms
  • Occulomotor nerve palsy
  • Trigeminal neuralgia
  • Visual field cut (optic nerve compression)
  • Cavernous sinus syndrome
  • Epistaxis (very rare, may occur in cavernous aneurysms)
  • Hydrocephalus signs and symptoms (typically with unruptured giant aneurysms or ruptured aneurysms)
  • Headache

Features on investigations:

Angiography, rotational angiography: gold standard

  • Round lobulated outpouching from an artery.
  • Assess for:
    • Location
    • Bifurcation vs. sidewall morphology
    • Neck: May have narrow or broad base (neck) i.e. <4mm or >4mm
    • Relationship to parent vessels and near by branches
    • Collateral circulation
    • Single lobe vs. multilobed
    • Aspect ratio: height of aneurysm/neck width. If >3, very high risk of rupture.

CTA:

  • Good for intracranial aneurysms >5mm in diameter

MRA:

  • Mycotic aneurysm are usually more peripheral i.e. in the smaller branches
  • Good for intracranial aneurysms >5mm

CT:

  • May show hyperdense aneurysm (mural calcium +/-thrombus)
  • Enhances in the patent area. Rim enhancement if thrombosed
  • Insufficient as a screening test on its own

MRI:

  • T1: out pouching in artery, may show laminated thrombus
  • T2: flow void, hypointense
  • Rim enhancement if thrombosed
  • Insufficient as a screening test on its own

Pathology:

  • Thin-walled sac attached to a vessel
  • Microscopically: fibrocollagenous wall +/-thrombus. Loss of elastic fibres & smooth muscle at junction between sac & vessel (neck).

Grading:

  • Giant >25 mm
  • Large 12-24 mm
  • Medium 5-11 mm
  • Small < 5 mm
  • Very small <3mm
  • Usual size 5-7mm

Classification/naming of Saccular aneurysms:

Common locations:

  • Anterior circulation more common than posterior circulation
  • Internal carotid ICA-posterior communicating artery PCOM junction “posteriorly directed”
  • Anterior cerebral artery ACA-Anterior communicating artery ACOM junction
  • M1-M2 division of MCA
  • Basilar artery BA-posterior cerebral artery PCA junction
  • Other locations:
    • PICA, especially PICA-VA junction, distal PICA aneurysms may occur (usually dissecting, not saccular)
    • ICA Paraclinoid aneurysms (cavernous, ophthalmic “directed upward a.k.a. carotid-ophthalmic”, superior hypophyseal “directed downward and medially towards the sella turcica” groups)
    • AChA aneurysms “posteriorly and laterally directed”
    • Petrous ICA (very rare, extra-dural)
Locations and names:
  • ICA aneurysm (terminus/bifurcation, PCOM aneurysms, AChA aneurysms , paraclinoid the following; cavernous, ophthalmic, superior hypophyseal), MCA aneurysm (M1 bifurcation), ACA aneurysm (A1-A2 junction, pericallosal-callosomarginal junction “less common”, A1 segment “rare”), ACOM aneurysm,
  • Basilar artery aneurysm (tip/bifurcation, BA-SCA junction, BA-AICA junction, BA-VA junction), Vertebral artery aneurysm (VA-PICA junction), PCA aneurysm (rare),
Giant aneurysms locations (>25 mm):
  • Anterior circulation (cavernous ICA aneurysm, supraclinoid ICA aneurysm, ACA aneurysm, MCA aneurysm)
  • Posterior circulation (BA aneurysm, PCA aneurysm)

Monitor:

  • Initially by catheter angiography, subsequently by MRA or CTA if small and stable over time

Treatment:

If ruptured:

If un-ruptured:

  • Options are:
    • Observation: catheter angiogram initially, subsequently by MRA or CTA if small and stable over time
    • Endovascular treatment options: coiling (unassisted), balloon-assisted coiling (balloon remodeling technique), stent-assisted coiling, flow diversion (flow diverting stent), parent vessel occlusion (vessel sacrifice)
    • Surgical treatment options: surgical clipping, bypass with vessel sacrifice.
  • Risk vs. benefit of treatment:
    • Decide if the aneurysm needs treatment based on size, location, life-expectancy and risk factors for rupture, technical ease vs. difficulty of treatment
    • If <10mm, low risk of rupture ~0.05% per year. But risk is determined on length of follow up, smoking status & other factors.
    • If =or>25mm (giant aneuryms), high risk of rupture ~6% in 1st year
  • Choice of therapy:
    • Basilar tip aneurysms: Endovascular rather than surgery.
    • Cavernous internal carotid artery: Endovascular rather than surgery
    • MCA territory: traditionally, surgery rather than Endovascular. Although this is changing as endovascular treatment has improved.
    • Neck <5mm & Neck:largest aneurysm diameter ratio (neck to dome ratio) <0.5: suggests good outcome with unassisted coiling. If these features are not present than balloon-assisted coiling, stent-assisted coiling or flow diverting stent or other techiques is necessary

Related articles:

References:

  1. Unruptured intracranial aneurysms–risk of rupture and risks of surgical intervention. International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med, 1998. 339(24): p. 1725-33.

Superficial Siderosis

Diseases,

 Synonyms:

Central nervous system siderosis:

Diagnosis:

MRI:

  • T2: dark outlining similar to GRE of all affected structures
  • T2 gradient echo GRE: dark outlining to cerebellum, cerebellar folia, VIII cranial nerve & meninges & rest of the brain or spinal cord
  • FLAIR: dark outlining similar to GRE of all affected structures
  • T1: high signal on CNS surfaces
  • T1+C: no enhancement of brain surfaces
  • May show source of bleeding

CSF:

  • High protein
  • Xanthochromia

Clinical features:

  • Bilateral sensorineural hearing loss & ataxia

 

Pathology:

  • Thickened brown stained meninges
  • Hemosiderin laden macrophages near the surface
  • Loss of cerebellar Purkinje cells, gliosis

Treatment:

  • Treat source of bleeding

Related articles:

Perimesenchphalic Subarachnoid Hemorrhage

Diseases, ,

Diagnosis:

CT or MRI: blood in CSF space around the midbrain i.e. peri-mesencephalic. Usually in prepontine cistern or quadrageminal cistern.
+Catheter Angiography: that excludes any cause of SAH. Especially posterior circulation aneurysm.
+absence of trauma

DDx.

  • Aneurysmal subarachnoid hemorrhage due to ruptured posterior  inferior cerebellar artery (PICA) aneurysms
  • 7% of Posterior circulation aneurysms may present this way

 

Related articles:

References:

  1.  van Gijn J, van Dongen KJ, Vermeulen M, et al. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985;35:493–97
  2. Kallmes DF, Clark HP, Dix JE,  et al. Ruptured vertebrobasilar aneurysms: frequency of the nonaneurysmal perimesencephalic pattern of hemorrhage on CT scans. Radiology 1996;201:657–60
  3. Brinjikji W, Kallmes DF, White JB, Lanzino G, Morris JM, Cloft HJ. Inter- and intraobserver agreement in CT characterization of non-aneurysmal perimesencephalic subarachnoid hemorrhage. AJNR Am J Neuroradiol. 2010;31:1103–1105

 

Anoxic Brain Injury

Diseases,

Synonyms:

Global cerebral ischemia a.k.a. global/diffuse cerebral hypoxia ischemia a.k.a. hypoxic ischemic encephalopathy a.k.a. Postanoxic Encephalopahty

Diagnosis:

Clinical features with or without MRI

Clinical features:

  • Coma after pulseless cardiac arrest or after significant hypoxia
  • Episode of brain anoxia/global ischemia. Myoclonic status epilepticus may occur (may involve face, trunk, limbs)

Findings on investigations:

MRI:

  • T2/FLAIR hyperintensity symmetrically both globus pallidi, & caudate nuclei, sometimes cortical.
  • Diffusion: restricted in both globus pallidi symmetrically, sometimes cortical.
  • T1 hyperintensity in the cortex (laminar necrosis), hyperintensity in both globus pallidi,

EEG features suggesting poor prognosis:

  • Burst suppression pattern,
  • Periodic discharges associated with myoclonus
  • Invariant monorhythmic pattern
  • Electrocerebral silence

Pathology:

Gross:

  • Diffuse swelling (cytotoxic oedema)
  • Softening & discolouration of hippocampus (Somer sector= CA1), watershed areas

Microscopically:

  • Hyperacute <12 hours: no changes
  • Acute 12-24 hrs: eosinophilic neurons “ischemic change a.k.a. red-dead a.k.a. acute neuronal cell change” especially pyramidal cells of the hippocampus & cerebellum, hyperchromatic nucleus, pyknosis (shrunken nucleus), pallor of neuropil
  • Subacute 2 days-2 weeks: macrophages, capillary proliferation, astrocytes
  • Chronic months- years: cavitation, macrophages

Investigations to consider:

  • CT: to rule out competing diagnosis
  • MRI: to rule out competing diagnosis
  • EEG: isoelctric pattern, burst-suppression pattern
  • Somatosensory evoked potentials SSEP:Bilateral absence of cortical SSEP (N20 component with median nerve stimulation), within 1st week.

Treatment

Therapeutic hypothermia if post Ventricular fibrillation arrest & meets other criteria
Supportive care

Related articles:

Posterior Reversible Leukoencephalopathy Syndrome PRES

Diseases, ,

Synonyms:

Reversible posterior leukoencephalopathy syndrome RPLS

Diagnosis:

CT:

  • Hypodensity in affected areas, MRI is better.

MRI:

  • T2: Hyperintensity in the occipital and sometimes parietal areas bilaterally. Involves the white matter and sometimes the grey matter. Other affected areas; basal ganglia, cerebellum, brain stem, frontal lobes. Areas usually spared: calcarine cortex, paramedian occipital lobe
  • DWI: hyperintense restricted diffusion, ADC: hyperintense initially
  • T1 +contrast: enchancement may occur
  • MRA: Normal

Clinical:

  • Encephalopathy with or without headache or homonymous hemianopsia or hemiparesis
  • Hypertension is not required for diagnosis but is often present

Pathology:

  • White matter oedema, in some cases microinfarcts and fibrinoid necrosis.

Degos disease

Diseases,

Synonyms:

Malignant atrophic papulosis

Diagnosis:

Clinical:

  • Skin, brain & bowel vasculitis
  • Skin: initially red papules then, umbilicated papules, +white centre & telangiectatic rim
  • Bowel: GI bleed, bowel perforation

MRI:

  • Infarcts
  • T2 hyperintensities, +small hemorrhagic areas
  • T1 +GAD: dural enhancement may occur

Cather Angiogram/angiography:

  • Vasculitis features
  • Peripheral aneurysms
  • Also stenosis in GI arteries e.g. coeliac artery

Eales Disease

Diseases,

Diagnosis:

Clinical:

  • Retinal hemorrhages, retinal vasculitis, stroke

Fundoscopy/slit lamp exam:

  • Bilateral
  • +Vascular sheathing (thin white lines along either side of the vessel)
  • +Peripheral nonperfusion
  • +Neovascularisation
  • Microaneurysms, retinal hemorrhages, chorioretinal scars, tortuous vessels,
  • Branch retinal vein occlusion
  • Macular oedema
  • Vitreous hemorrhages & debris,

Fluorescein angiography:

  • Leakage of dye in areas of vascular sheathing

MRI:

  • White matter lesions

Angiogram/angiography:

  • Features of vasculitis

Susac’s syndrome

Diseases, ,

Synonyms:

Retinocochleocerebral vasculopathy

Diagnosis:

Clinical:

  • Encephalopathy (including psychosis), monocular vision loss, hearing loss
  • Headache
  • Branch retinal artery occlusion

MRI:

  • T2 hyperintensity in basal ganglia, thalamus, white matter (almost always involving corpus callosum). May involve brainstem & cerebellum
  • T1 +contrast: leptomeningeal enhancement & parenchymal enhancement

Ophthalmic fluorescein angiography:

  • Retinal vasculitis: narrowing, occlusion, vessel wall hyperfluorescence, contrast outflow

Audiogram:

  • Sensorineural hearing loss

Angiogram/angiography:

  • Normal as the affect vessels are very small <100 micrometer

Pathology, brain biopsy:

Microangiopathy in cortex & white matter:

  • Infarcts, Capillary hyaline thrombi, Perivascular inflammatory cells

 

Alagille syndrome

Diseases,

Synonyms:

Arteriohepatic dysplasia

Diagnosis:

Genetics:

  • Autosomal dominant
  • JAG1 gene Chr. 20p, jagged1

Clinical features and investigations:

Syndrome of involvement of Liver:

  • LFTs: cholestasis,

Ultrasound, MRCP: intrahepatic bile duct paucity
+other systems including:

  • Heart: coarctation of the aorta, aortic aneurysm
  • Eyes: anterior chamber defects, posterior embryotoxon
  • Face: frontal bossing, deep set eyes, bulbos nose tip, pointed chin
  • Skeleton: butterfly vertebra

Other test:

  • CTPA: pulmonary artery abnormalities
  • Ultrasound: Renal stenosis
  • MRI, MRA brain: moyamoya syndrome, aneurysms (basilar, MCA), asymptomatic hemorrhages,

 

Cerebral Autosomal Dominant Arteriopathy and Subacute Infarcts with Leukoencephalopathy

Diseases,

Cerebral autosomal dominant arteriopathy and subacute infarcts with leukoencephalopathy (CADASIL)

Diagnosis:

  • Genetic testing: Notch 3 gene mutation on chromosome 19.
  • Clinical including family history plus biopsy (skin or brain)
  • +MRI:
    • Diffuse white matter lesions including frontal lobes, temporal lobes (especially anteriorly), insula, deep & periventricular white matter.
    • T2 hyperintense
    • T1 hypointense

Pathology:

Skin biopsy:

  • Electron microscopy: tunica media of arteries showing granular osmiophilic material GOM between degenerating smooth muscle cells
  • Light microscopy: thickened arterioles with PAS positive granular material in tunica media
  • Immunohistochemistry Notch 3 positive smoothe muscle cells.

Brain biopsy:

  • Parenchymal arteries are involved. Thickened arterioles with PAS positive granular material in tunica media. Necrosis

Postpartum Cerebral Angiopathy

Diseases,

Synonyms:

Postpartum cerebral vasculopathy:

Diagnosis:

There are two forms:

  • Idiopathic postpartum angiopathy a.k.a. Call-Fleming postpartum angiopathy
  • Secondary postpartum cerebral angiopathy:
    • Due to bromocriptine (used for lactation suppression), ergot alkaloids (used for control postpartum hemorrhage), sympathomemimetics, nasal decongestants

Clinical features:

  • Headache, seizure, encephalopathy within 1 month of delivery
  • Normotensive (normal BP), no proteinuria

MRI:

  • In the idiopathic form: intraparenchymal hemorrhage (intracerebral hemorrhage).
  • T2 hyperintensities in white or grey matter, reversible
  • May have features of posterior reversible leukoencephalopathy syndrome PRESS.

Catheter Angiography:

  • Reversible multifocal stenosis
  • Beaded appearance of medium & small calibre arteries in the anterior circulation

Transcranial doppler ultrasound TCD:

  • Increased velocities= vasoconstriction. Reversible.

Pathology:

  • Non-specific: findings of ischemia.

 

Treatment:

  • Consider:
    • Nimodipine, other calcium channel blockers
    • Induced hypervolemia for vasospasm
    • Corticosteroids
  • Treat seizures if they occur
  • Angioplasty if refractory

Cerebral Venous Sinus Thrombosis

Diseases,

Synonyms:

Cerebral venous thrombosis CVT or cerebral venous sinus thrombosis/dural sinus thrombosis CVST and also Cortical cerebral venous thrombosis:
 

Diagnosis:

By neuroimaging including CT venography, MR venography or catheter angiography revealing thrombus in the cerebral venous sinuses. May be clinically symptomatic or asymptomatic
 

Pathology:

Any combination of the following may be involved:

  • Venous sinuses (sagittal sinus, torcula herephili, transverse sinus, straight sinus, sigmoid sinus, internal jugular vein, cavernous sinus)
  • Deep veins
  • Superficial (cortical) veins
  • Note. in carvernous sinus thrombosis the vasavasorum of the ICA may be involved causing infarction in ICA territories, especially if due to infectious thrombosis

 

Clinical features:

  • Headache, seizure, decreased consciousness
  • Fluctuating symptoms
  • Focal symptoms & signs including papilloedema

 

Findings on Investigations:

  • LP: Raised opening pressure

MR venography MRV, (Time-of-flight TOF, contrast-enhanced MRV, Phase-Contrast PC MRV):

  • Absence of filling in the sinus or veins
  • Phase contrast MRV: shows flow only but not thrombus
  • False positives occur in: Variant anatomy: high bifurcation of torcula, asymtrical bifurcation of torcula, atresia/hypoplasia of transverse sinus, arachnoid granulations
  • TOF: flow gaps

MRI with contrast:

  • Thrombus features:
    • T1: Thrombus is initially isointense & hyperintense (methemoglobin) later on
    • T2:- Thrombus is hypointense “pseudo flow void”, later on hyperintense (methemoglobin),
    • FLAIR: Thrombus=hyperintense
    • T2 gradient echo GRE: Thrombus= hypointese
    • T1 +contrast: Clot= periclot enhancement early, all structures enhance later on.
  • Brain parenchyma effects, oedema/Infarct /hemorrhage:
    • DWI: may have hyperintense areas ADC map: high (vasogenic oedema) or low (cytotoxic oedema)
    • T1: brain= hypointense & swollen, Hemorrhage that starts from the center of the lesion
    • Venous infarcts: irregular edges
    • T2: brain= hyperintense & swollen
    • FLAIR: brain= hyperintense
    • Gradient echo GRE: Brain= hypointense venous hemorrhage
    • T1 +contrast: Brain= no enhancement, or patchy enhancement

Catheter angiography DSA:

  • Occluded sinuses or Occluded cortical veins.
  • Opacified draining veins. corkscrew appearance of rerouting veins.
  • Enlarged collateral veins e.g. pterygoid veins

CT venogram CTV

  • CT:
  • Hemorrhagic infarction: irregular borders
  • Hypodensity in one or both thalami (internal cerebral vein, straight sinus)
  • Posterior temporal lobe oedema and petechial hemorrhage or large hemorrhage (transverse sinus, middle cerebral veins, vein of Labbe)
  • Parasagittal lesion with superior sagittal sinus thrombosis
  • Subarachnoid hemorrhage SAH blood over the cortex
  • Thrombus: Hyperdensity in the sinus
  • Delta sign (enhancement around a clot in the sagittal sinus)
  • Cord sign= dense vessel sign= hyperdense veins e.g. in internal cerebral veins, cortical veins
  • Prominent medullary veins: collateral circulation
  • Hydrocephalus, hypodensity (venous infarction) with hemorrhagic conversion,

 

Investigations to consider:

  • CT
  • CTV or MRV
  • LP: IIncreased opening pressure, Pleocytosis if septic
  • Thrombophilia screen
  • Monitor:
    • No need for aggressively repeating imaging if no change in clincial status. However low threshold for imaging if clinical changes occur

 

Treatment:

Anticoagulation even if intracerebral hemorrhage is present [RCT of 20 patients, RCT 60 patients] :

  • Heparin I.V.
  • LMW heparin: enoxaparin, nadroparin or others
  • Followed by warfarin for 3-6 months

If refractory consider endovascular therapy:

  • Mechanical thrombectomy
  • Local thrombolysis via venous approach

Moyamoya disease

Diseases,

Synonyms:

Moyamoya disease a.k.a. idiopathic progressive arteriopathy of childhood a.k.a. spontaneous occlusion of circle of Willis:

Diagnosis:

Moyamoya syndrome is an angipathic pattern, not a specific disease. It has primary & secondary causes
Moyamoya disease referes to the idiopathic condition that represents primary moyamoya syndrome
 

Clinical features:

  • Bimodal age of onset: children ~5 years old & adults ~40 years old.
  • TIA, Ischemic stroke, intraparenchymal hemorrhage (basal ganglia), Subarachnoid hemorrhage, seizures, migraine-like headaches.
  • Ophthalmoscopy: “morning glory disk,” an enlargement of the optic disk with concomitant retinovascular anomalies

 

Findings on Investigations:

CT:

  • With contrast shows punctate dots in the basal ganglia & net like vessels in cisterns
  • Intraventricular hemorrhage may occur
  • Atrophy anterior> posterior in children
  • Features of Complications (stroke, intraparenchymal hemorrhage, subarachnoid hemorrhage)

MRI:

  • T1: Basal ganglia flow voids
  • T2: white matter disease
  • Reduced flow voids in the internal, middle, and anterior cerebral arteries
  • Prominent flow voids through the basal ganglia and thalamus (from collateral vessels)
  • FLAIR: Cortical flow= high signal in sulci = “ivy sign”
  • T2 Gradient echo: prior hemorrhage
  • DWI: acute stroke if acute on chronic disease
  • T1+C: shows punctate dots in the basal ganglia & net like vessels in cisterns. Enhanced “Ivy sign”

CTA:

  • Narrowed intracranial internal carotid arties & proximal ACA & MCA.
  • Collaterals from internal carotid artery (basal ganglia) and external carotid artery.
  • Aneurysms (circle of Willis, basal ganglia, collateral vessels)

Catheter Angiography:

  • Gold standard test
  • Stenosis of distal ICA bilaterally or proximal circle of Willis arteries
  • Enlargement of lenticulostriate/thalamostriate arteries “puff of smoke” appearance.
  • Dilated anterior choroidal artery
  • Transdural & transosseous ICA ECA collaterals
  • See Suzuki grade. Also do ECA angiograms to evaluate collaterals.
  • Aneurysms may occur (circle of Willis, basal ganglia, collateral vessels).

EEG, in children:

  • Posterior or centrotemporal slowing
  • Hyperventilation: build up (monophasic slow waves during hyperventilation), re-build up (monophosic slow waves after hyperventilation) indicates diminished cerebral reserve.

 

Pathology:

  • It affects Large vessels: Narrowed vessels
  • Hyperplasia of smooth-muscle cells and luminal thrombosis
  • Tunica Media: attenuated, with irregular elastic lamina
  • Collaterals: fragmented elastic lamina, thinned tunica media, microaneurysms
Suzuki Grade:
  • I: Narrowing of ICA apex
  • II: Initiation of “puff of smoke” moyamoya collaterals
  • III: Narrowing of internal carotids with prominent moyamoya collaterals (puff of smoke). Diminished cortical perfusion.
  • IV: Development of ECA collaterals
  • V: prominent ECA collaterals & reduction of moyamoya collaterals
  • VI: Occlusion of ICAs & disappearance of internal carotid artery collaterals (persistence of ECA collaterals)

 

Treatment:

Atherosclerotic moyamoya syndrome should be treated like high grade intracranial atherosclerotic disease ICAD. The rest of the discussion refers to non-atherosclerotic moyamoya syndrome:

  • Aspirin in adults presenting with ischemic stroke unless intraparenchymal hemorrhage is present
  • Revascularisation in non-atherosclerotic moyamoya syndrome
  • Indirect methods ECA branch to brain:
    • ECA (dura, temporalis muscle, or superficial temporal artery)
    • Examples:
      • Encephalo-dural-arterio-synangiosis EDAS
      • Encephalomyoarteriosynangiosis
      • Pial synangiosis
  • Direct methods ECA branch to ICA branch:
    • Superficial temporal artery- Middle cerebral artery anastomosis, STA-MCA anastomosis

References:

  1. Kawaguchi, S., et al., Characteristics of intracranial aneurysms associated with moyamoya disease. A review of 111 cases. Acta Neurochir (Wien), 1996. 138(11): p. 1287-94.
  2. Fung, L.W., D. Thompson, and V. Ganesan, Revascularisation surgery for Pediatric moyamoya: a review of the literature. Childs Nerv Syst, 2005. 21(5): p. 358-64.

Posterior Cortical Atrophy

Diseases, ,

Synonyms:

Visual variant of Alzheimer’s disease, Benson’s syndrome
 

Clinical features:

  • Features of Gerstmann’s syndrome (Alexia, Acalculia, Agraphia, Left-right agnosia/disorientation, Finger agnosia)
  • Features of Balint’s syndrome (simultanagnosia, oculomotor apraxia, optic ataxia),
  • Apperceptive visual agnosia, dressing apraxia, environmental disorientation, hemianopia, transcortical sensory aphasia
  • Less commonly: memory or language disturbances

Localises to visual association cortex bilaterally, usually due to Alzheimer’s disease. If visual hallucinations are present, diffuse Lewy body disease is the likely cause (thalamocortical & ascending midbrain pathways).
 

Pathology:

Usually neurofibrillary tangles and neuritic plaques similar to Alzheimer’s disease but localized to parieto-occipital cortex or temporo-occipital cortex. Rarely features of diffuse Lewy body disease
 

Findings on Investigations:

CT/MRI: posterior atrophy (parieto-occipital cortex or temporo-occipital cortex)
SPECT/PET: hypometabolism in parieto-occipital cortex or temporo-occipital cortex
 

References:

  1. Benson, D.F., R.J. Davis, and B.D. Snyder, Posterior cortical atrophy. Arch Neurol, 1988. 45(7): p. 789-93.

Polymyositis

Diseases, ,

Clinical features:

Proximal muscle weakness; may be asymmetric. Muscle wasting is late
Shoulder girdle tenderness (may be absent)
Dysphagia & neck muscle weakness may occur
Spares face muscles & ocular muscles

Muscle biopsy:

Endomysial (within the fascicles): muscle fibre necrosis, lymphocytes (absence of eosinophils & plasma cells). Absence of rimmed vacuoles. Surrounding healthy fibres.
If chronic: increased connective tissue, positive reactivity with alkaline phosphatase
Immunohistochemistry: CD8+ T cell lymphocytes that are associated with myofibres that express MHC-1. MHC-1 expression persists even after corticosteroids.

Other points:

Part of antisynthetase syndrome (anti-tRNA synthetase): polymyositis, associated with:

  • Interstitial lung disease, Raynaud’s phenomenon, nonerosive arthritis, skin rash (mechanic’s hand)

Antisynthetase syndrome antibodies:

  • Anti-Jo1 (dermatomyositis or polymyositis), anti-PL-7, anti-EJ,

May be a Primary disease or secondary to:

  • Retroviral infections e.g. HIV
  • Overlap syndromes:
    • Limited cutaneous SSc +polymyositis: Anti-PM/Scl formerly anti-PM1
  • Anti-Ku

Polymyositis rarely affects children
CK, follows disease activity: Elevated

Nerve conduction studies/electromyography NCS/EMG:

MUAP Myopathic recruitment On activation: Short duration, low amplitude polyphasic units
Spontaneously: increased activity with fibrillations, complex repetitive charges & positive sharp waves PSW

Investigations to consider:

  • FBC, blood chemistry panel
  • CK: usually increased, marker of activity
  • EMG: myopathic changes
  • Antibodies:
    • Anti-Jo-1: dermatomyositis
    • Anti PM/Scl: polymyositis systemic sclerosis overlap syndrome
  • HIV testing
  • Muscle biopsy
  • CT chest, abdomen & pelvis

Monitor:

  • Weakness not CK

Treatment:

General measures:

  • Physical therapy to prevent contractures
  • Rest during exacerbations

Glucocorticoids:

  • Prednisolone +/- potassium supplements +/- antacids
  • High dose, then taper over 10 weeks, Maintenance for 2-3 yrs
  • If resistant (>3 months on glucocorticoids) or rapid:
  • Azathioprine P.O.
  • Methotrexate weekly

Plasmapharesis
IVIG
 

Causes of Polymyositis:

Idiopathic
Secondary:

  • Zidovudine
  • Penicillinamine
  • Overlap syndrome with other connective tissue disease

DDx. of polymyositis:

Chronic weakness:

  • Dermatomyositis
  • Inclusion body myositis
  • Motor neuron disease (amyotrophic lateral sclerosis and others)
  • Spinal muscular atrophy
  • Endocrine myopathy:
    • Cushing’s syndrome
    • Hyper or hypo- thyroidism
    • Hyper- or hypo- parathyroidism
  • Drug induced myopathy:
    • True myositis:
      • Penicillamine, Procainamide
      • Zidovudine (mitochondrial myopathy)
    • Glucocorticoids
    • Statins: Lovastatin, simvastatin
    • Fibrates: Clofibrate
  • Metabolic myopathy:
    • Some Glycogen storage diseases, Some Lipid storage diseases, Some mitochondrial myopathy
  • Fascioscapulohumeral muscular dystrophy
  • Paraneoplastic neuromyopathy

Acute weakness:

  • Alcoholism
  • Neuropathy
  • Some Glycogen storage diseases
  • Parasitic polymyositis
  • Pyomyositis a.k.a. Tropical polymyositis
  • Other bacteria:
    • Borrelia burgdorferi ‘Lyme disease’
    • Legionella pneumophila ‘Legionnaire’s disease’
  • Pain and muscle tenderness:
    • Polymyalgia rheumatica
    • Fibromyalgia
    • Chronic fatigue syndrome

 

Related articles:

Dermatomyositis

Diseases, ,

 Clinical features:

  • Heliotrope ‘lilac/purple blue’ rash around the eyelids, malar region, extensors, knuckles, trunk
  • Gottron’s papules on hand dorsum
  • Nailfold telangiectasia & erythema
  • Nail changes; thickening, cracking
  • Proximal Muscle weakness

Findings on investigations:

Nerve conduction studies/electromyography NCS/EMG:

MUAP Myopathic recruitment On activation: Short duration, low amplitude polyphasic units
Spontaneously: increased activity with fibrillations, complex repetitive charges & positive sharp waves
Muscle Biopsy, is diagnostic:

  • Myofibres: Perifascicular atrophy (myofibres at the periphery of the fascicle). ‘punched out’ vacuoles. Microinfarcts (contiguous necrotic or regenerating fibres.
  • Inflammation: Perivascular, interfascicular/septal, endomysial. Mainly lymphocytes but plasma cells & eosinophils occur. Perivascular lymphocytes in capillaries DDx.
  • Systemic vasculitis involves larger arteries.
  • Immunohistochemistry: T cells & B cells in lymphocytes, complement activation on capillaries

Notes:

  • 15% of dermatomyositis is a/w neoplasia:
  • Ovarian, breast, melanoma, colon cancer
  • Dermatomyositis may affect children,
  • CK, follows disease activity: Elevated or normal
Other tests:

Anti-Mi-1 antibodies, anti-Mi-2 antibodies

Findings on investigations:

  • FBC, blood chemistry panel,
  • CK: usually increased, marker of activity
  • Antibodies:
    • Anti-Jo-1: dermatomyositis or polymyositis
    • Anti PM/Scl: polymyositis systemic sclerosis overlap syndrome

Search for neoplasm in dermatomyositis:

  • CT thorax abdomen & pelvis
  • Colonoscopy

Monitor:

  • Pelvic, breast, rectal examinations
  • Weakness not CK

Treatment:

General measures:

  • Physical therapy to prevent contractures
  • Rest during exacerbations

Glucocorticoids:

  • Prednisolone +/- potassium supplements +/- antacids
  • High dose, then taper over 10 weeks, Maintenance for 2-3 yrs

If resistant (>3 months on glucocorticoids) or rapid:

  • Azathioprine P.O.
  • Methotrexate weekly

Other options:

  • Intravenous immunoglobulin IVIg
  • Cyclophosphamide, ciclosporin or mycophenolate

Treat the underlying tumour if one is present

Causes of dermatomyositis:

Idiopathic
Secondary:

  • Neoplasia in 15%:
  • Ovarian, breast, melanoma, colon cancer
  • Penicillinamine
  • Overlap syndrome with other connective tissue disease
  • Associates vasculitis in children

Related articles:

Huntington Disease

Diseases, ,

Genetics:

Autosomal dominant

  • HD gene chr. 4p16.3, expansion of CAG trinucleotide repeat. Protein= huntingtin, mutation= expansion of polyglutamine segment. Norma repeat is <26 repeats, Hungtingtons disease if = or >36 repeats
  • Genetic testing for CAG repeat expansion in the huntingin gene

Clinical:

Chorea, personality change, dementia
Chorea: initially as fidgety movements, then it affects fingers, arms, legs, face, trunk
Westphal variant: onset before 20 y.o. Presents with bradykinesia, rigidity, dystonia, epileptic seizures

Features on Investigations:

MRI: atrophy of the caudate nucleus, bilateral striatum hyperintensity in juvenile Huntington disease

Pathology:

Gross: Atrophy of caudate nucleus (flattened or concave), also some atrophy of parietal & occipital lobes. At end stage; atrophy of globus pallidus, thalamus, brain stem & cerebellum.
Microscopic:

  • Neuronal loss, astrocytosis affecting the caudate nucleus, putamen & nucleus accumbens. Neuronal loss in cerebral cortex & mesial temporal structures. In the juvenile form it also affects the cerebellum with loss of Purkinje & granular cell layers.
  • Immunohistochemistry: huntingtin positive intraneuronal inclusions & neurites, ubiquitin positive intraneuronal inclusions & neurites. These occur in the neostriatum, cortex & hippocampus.

Treatment:

Chorea:

  • Tetrabenazine. [RCT]
  • Or Haloperidol or chlorpromazine
  • or reserpine

Related articles:

Approach to cognitive impairment,

References:

  1. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology, 2006. 66(3): p. 366-72.

 

Diffuse Lewy Body Disease

Diseases, , ,

Synonyms:

Dementia with Lewy bodies, a.k.a. Lewy body dementia a.k.a. Diffuse Lewy body disease DLBD, formerly Lewy body varient of Alzheimers:

Clinical features:

  • Dementia: deficits in attention, executive function, visuospatial ability and later on in memory. This is a subcortical dementia i.e. cortical features are spared early in the disease

Core features:

  • Dementia that develops before or within two years after the onset of motor symptoms of parkinsonism.
  • Visual hallucinations
  • Fluctuations in level of consciousness i.e. moments of clarity & moments of confusion

Other features:

  • REM sleep behaviour disorder
  • Severe neuroleptic sensitivity
  • Autonomic dysfunction

Histology:

Gross: pallor of the substantia nigra & locus ceruleus
Microscopically:

  • Affects: Classical types: brainstem, limbic, and diffuse cortical types,
  • Brain stem: Substantia nigra, Amygdala, raphe nuclei, pedunculopontine nuclei, dorsal vagal nucleus
  • Limbic (transitional) i.e. subcortical structures: anterior cingulate, entorhinal, basal forebrain/nucleus basalis of Meynert. Sometime amygdala
  • Diffuse cortical; neocortex (frontal, temporal, insular), sometimes hippocampus.
  • Lewy bodies (see under parkinson disease) in the cortex & brainstem. Levels of involvement brainstem predominant, limbic (transitional) & cortical.
  • Lewy neurites occur.
  • Vacuolar change in the parahippocampal gyrus. Coexisting Alzheimers pathology is frequent.

Immunohistochemistry: Lewy bodies and extracellular Lewy neurites are alpha synuclein positive and also ubiquitin positive.

Findings on Investigations:

SPECT:

  • DAT SPECT (123I-FP-CIT SPECT): images presynaptic dopamine transporters
  • Reduced uptake in putamen & caudate in DLB, normal in Alzheimer’s disease

Other tests:

  • MIBG cardiac scintigraphy: reduced uptake in the myocardium, a sign of postganglionic disease

PET, DAT scan dopamine transporter scan: reduced uptake in the striatum.
FDG PET: reduced uptake in the occipital lobes

Treatment:

General measures of dementia care
Treatment is dependent on presentation
Psychiatric symptoms:

  • Acetylcholine esterase inhibitors e.g. rivastigmine
  • Typical antipsychotics are contraindicated. Avoid anticholingergics including amantadine.

Motor symptoms:

  • Dopamine therapy

Related articles:

References:

  1. McKeith, I.G., et al., Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology, 2005. 65(12): p. 1863-72.
  2. McKeith, I., et al., Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet, 2000. 356(9247): p. 2031-6.
  3. McKeith, I., et al., Neuroleptic sensitivity in patients with senile dementia of Lewy body type. Bmj, 1992. 305(6855): p. 673-8.

Essential Tremor

Diseases

Synonyms:

Benign essential tremor

Clinical features:

Postural and action tremor, present during the following activities:

  • Pouring water, using a spoon to drink water, drinking water, finger-to-nose maneuver, and drawing a spiral

Head titubation may occur

Findings on Investigations:

MRI brain: usually normal
DAT SPECT (123I-FP-CIT SPECT) “DaTscan”:

  • Images presynaptic dopamine transporters
  • Helps differentiate between PD (abnormal, reduced in putamen) and essential tremor (normal)

Investigations to consider:

  • Thyroid Function Tests TFT
  • If < 40 y.o. serum ceruloplasmin: <20 mg per decilitre +/-slit lamp examination
  • DAT SPECT (123I-FP-CIT SPECT) “DaTSCAN”: if atypical or to distinguish between esstential tremor and Parkinson disease

Treatment:

1st line:

  • Propranolol BID or prn, especially long acting
  • Primidone start at low dose

2nd line:

  • Topiramate TPM P.O.
  • Alprazolam P.O., lorazepam.
  • Gabapentin GBP, Nimodipine P.O., Theophylline

Consider, selected cases:

  • Deep brain stimulation:
  • Contralateral thalamus

Surgery:

  • Thalamotomy

Related articles:

Parkinson’s disease,

Chronic Inflammatory Demyelinating Polyradiculopathy

Diseases, , ,

Synonyms:

Chronic inflammatory demyelinating polyradiculoneuropathy a.k.a. Chronic inflammatory demyelinating polyneuropathy, CIDP

Diagnosis:

Is by clinical findings supported by +NCS/EMG and occasionally nerve biopsy

Clinical features:

Clinical: >2 months, gradual onset, usually sensorimotor, arms & legs, proximal weakness & distal weakness, usually spares the cranial nerves, thickened nerves may occur.

NCS/EMG Nerve conduction studies:

Key features: Evidence of demyelination, rarely secondary axonal degeneration
CMAP:

  • Conduction block, Temporal dispersion
  • Decreased conduction velocities & prolonged distal latencies.
  • Amplitude: normal apart from conduction block

SNAP:

  • Decreased conduction velocities & prolonged distal latencies.
  • Amplitudes: normal or decreased
  • Prolonged F latencies.

EMG: normal or mild denervation changes, decreased recruitment (neuropathic recruitment)

Pathology, nerve biopsy:

  • Endoneurium: Inflammation: Infiltrate of macrophages & lymphocytes, Perivascular
  • Luxol fast blue: Onion bulb formation: demyelination & remyelination
  • Demyelinated or thinly myelinated fibres, they are variable within a fascicle
  • Axonal degeneration if longstanding
  • Immunohistochemsitry: macrophages, CLA for lymphocytes

Teased fibres:

  • Demyelination
  • Features more prominent in nerve roots (autopsy specimen),

 

CSF analysis, Albuminocytological dissociation:

Protein75-200 mg/dL
Raised IgG
Normal WCC

CIDP Variants:

  • CIDP, idiopathic
  • CIDP with paraproteinemia, includes:
    • MGUS, Waldenstrom’s macroglobulinemia, multiple myeloma, plasmacytoma, POEMS syndrome, B cell lymphoma, CLL,
  • CIDP with SLE, inflammatory bowel disease, sarcoidosis, chronic active hepatitis,
  • CIDP with HIV
  • CIDP with hepatitis B, hepatitis C
  • CIDP with Diabetes mellitus, thyrotoxicosis
  • CIDP with hereditary demyelinating neuropathies
  • CIDP with bone marrow & organ transplantation

Investigations to consider:

Blood tests:

  • FBC, blood chemistry panel, Creatinine, Mg, Phosphate
  • Fasting blood glucose & HbA1c
  • HIV testing
  • TFTs, LFTs: chronic active hepatitis
  • SPEP with IFE: paraproteinemia
  • If MGUS noted on SPEP: immunofixation, UPEP, uric acid, beta 2 – microglobulin, lactate dehydrogenase, rheumatoid factor, serum cryoglobulins,
  • If signs of POEMS syndrome (peripheral lymphadenopathy, hepatosplenomegaly, macroglossia) then serum VEGF levels.
  • ANA, ESR, CRP, complement
  • LP, CSF analysis, including cytology
  • Hepatitis serology
  • ACE level, Ca++: sarcodosis
  • Anti-MAG, anti-GM1
  • Heavy metal screen
  • Porphyria testing

Nerve biopsy in atypical cases
Abdominal ultrasound: in POEMS syndrome
Skeletal survey or low dose CT whole body: if paraproteinemia is present

Treatment:

  • Intravenous immunoglobulin IVIg 2g/kg divided over 5 days & repeat monthly & then space out treatment
  • or plasma exchange and repeat:
    • One plasma volume (40-50 mL/kg) X5 exchanges (i.e. total 200-250 mL/kg) over 7-14 days.
  • or Prednisolone high dose 60-80mg (or 1.5mg/Kg in children) for 2-4 weeks and switch to alternate day therapy, then taper to maintenance dose after maximum response is achieved. Prophylaxis & treatment of steroid complications

If unresponsive to treatment, consider:

  • Azathioprine p.o. 1mg/kg X2 weeks then increase to 2-3mg/kg.monitor FBC & LFTs
  • or cyclophosphamide 50mg/kg I.V. for 4 days, then G-CSF on day 10
  • or interferon Beta 30 microg/kg I.M.
  • or Rituximab 375 mg/m-2 I.V. every 4 weeks
  • or etanercept 25 mg SubQ twice a week

Related articles:

Epilepsy

Diseases, ,

This section will not cover all of epilepsy as it is a major subspeciality within neurology. But here is an introduction to get you started.
Epilepsy is a clinical diagnosis supported by electoencephalography (EEG) evidence of seizure or certain inter-ictal findings. Epilepsy is a disorder of recurrent unprovoked seizures. Classically, it requires at least 2 seizure to make the diagnosis and the seizures must be unprovoked. This distinguishes epilepsy from provoked seizures due to another medical condition such as hyponatremia for example. Furthermore, there are many different types of epilpesy syndromes; well beyond the scope of this article. There are other important topics that are not discussed here such as the approach to new onset seizure, the management of status epilepticus and childhood febrile seizures.
Epilepsy has many different types and can be classified in many ways. Idiopathic epilepsies, such as idiopathic generalized epilepsy and juvenile myoclonic epilepsy, are disorders on to themselves. Epilepsy may also be a consequence of previous injury to the brain such as in post stroke epilepsy, and in epilpesy post traumatic brain injury; two common types of epilepsy in adults. Another way to look at epilepsy is by presence of a seizure focus or a lesion. Some types of lesional epilepsy include epilepsy due to mesial temporal sclerosis, epilepsy due to cortical dysplasia and epilepsy due to arteriovous malformations (AVMs). Lastly, brain tumors may present with seizures or with epilepsy.
Type of epilepsy and seizure type are different things. Seizure may be simple partial, complex partial, secondarily generalized or primary generalized. There are other types of seizures too. A patient with a given type of epilepsy may have one seizure type e.g. absence epilepsy. Or in other cases multiple seizure types for example in Lennox-Gestuat syndrome. The names can be confusing initially but this will make sense as you read through and you practice classifying your patients.
Brief note on some seizure types:
Partial seizures are seizure that begin in one part of the brain. The patient often will experience symptoms related to activation of that part of the brain e.g. hand jerking. If the seizure does not spread this is called a simple partial seizure. If the seizure occurs or spreads to limbic structures or temporal lobe structures it can impair consciousness or memory. Seizures with interruption of memory or consciousness are called complex partial seizures. If the seizure spreads to involve both hemispheres this will lead to generalized tonic-clonic seizures. This is called secondarily generalized seizure. Some patients with secondarily generalized seizures will have asymmetry of movement with one side of the body being stiff and the head turned to that side (head version). Some patients will have a Jacksonian march; where the partial seizure activity spreads along the body from the lips to the hand to the arm to the shoulder then the leg and generalizes. This mirrors the electrical seizure activity spreading along the motor homunculus. In partial seizures there may be warning that the patient experiences before a seizure; called an aura. Auras may include an experience of de ja vu;  the patient feels that they have already experienced what is going on. They feel as if they are reliving the events that are currently occurring. Other auras including a rising epigastric sensation. These clues in partial seizures can tell us where the seizures start.
In some patients there is no partial seizure but the seizures appear to involve both hemispheres from the outset. This is called primary generalized seizure. With generalized seizure, the patient often has tongue or cheek biting and bladder or bowel incontinence. During the tonic phase the limbs stiffen up, and in the clonic phase they jerk. The patients eyes are typically open but the patient is unaware of what is going on. Post ictal symptoms include feeling fatigue, lethargy, confusion, and a mild to moderate headache.

Diagnosis:

Epilepsy is a clinical diagnosis supported by electoencephalography (EEG) evidence of seizure or certain inter-ictal findings.
Epilepsy is a disorder of recurrent unprovoked seizures. Classically, it requires at least 2 seizure to make the diagnosis and the seizure must be unprovoked.
 

Clinical features of epilepsy,  in general:

The clinical features of epilepsy are usually described in 3 phases depending on whether they occur before, during or after a seizure. Pre-ictal (auras or prodromal) features, ictal features and post-ictal features. Not all patients will have pre-ictal or post-ictal features. Auras may suggest partial epilepsy and some of the other features may suggest the epilepsy syndrome. We refer to the clinical description of the seizures as the seizure semiology. It is valuable to interview both the patient and the person witnessing the seizures to obtain the information.
Try to describe the seizure types the patient experience (see the discussion above). Is it one seizure type or multiple seizure types? Is it partial or generalized? Was there an aura or prodrome? The aura may give a clue to where in the brain the seizure originates.
Also determine the frequency of seizures and the duration of the event. The duration of the ictal phase and the post ictal phase.

Epilepsy syndromes, by affected lobes:

Temporal lobe epilepsy:

Clinical features:

  • Prodrome & aura.
  • Ictal: automatisms (oral, motor, ipsilateral arm), contralateral dystonic posturing, versive head movements contralaterally
  • Postictal phase.
Frontal lobe epilepsy:

Clinical features:

  • Rare prodrome, unusual to have aura
  • Ictal: brief, tonic gaze contralateral, contralateral head version, hypermotor
  • Genital manipulation may occur, facial expression of fear may occur
  • Rarely postictal
Occipital lobe epilepsy:

Clinical features:

  • Unusual to have aura
  • Icta: visual hallucination (elemental or formed), twinkling, pulsing lights,
Parietal lobe seizures:

Clinical features:

  • Contralateral paraesthesia, contralateral pain
Catamenial epilepsy:

Epilepsy with seizures occurring more frequently around the menstrual cycle

EEG in epilepsy:

EEG notes:

  • Specificity is better than sensitivity
  • A normal EEG doesn’t exclude partial epilepsy
  • Abnormal interictal epileptiform discharges IEDs can occur in people who never develop epilepsy e.g. normal people or people with other pathology.
  • Standard EEG should include hyperventilation & photic stimulation.

EEG types:

  • Standard EEG (routine EEG)
  • Sleep EEG
  • Prolonged EEG
  • Repeated standard EEG do 4 serial but not more
  • Long term video EEG monitoring
  • Ambulatory EEG

 

EEG findings related to seizure type:

Absence seizures:

Generalised 3 Hz spike and wave discharges, exacerbated by hyperventilation
Background: usually normal

Atypical absence seizures:

Generalised spike & wave discharge 1.5-2.5 Hz (<3Hz).
Background: usually abnormal

Tonic-Clonic seizures:

Generalised 10 Hz activity in tonic phase
Then:

  • Rhythmic spike and wave
  • Slow wave
  • or sharp slow wave.
Atonic seizures:

Low voltage fast activity, polyspike and wave, or electrodecrement
 

Investigations in Epilepsy, in general:

The purpose of investigations in epilepsy is to exclude other causes of seizure, classify the type of epilepsy and to determine if there is an underlying lesion. All patients should get basic blood tests, EEG and MRI. The exception is children with febrile seizures or neonates, MRI may be done at a later stage if indicated. Consider other testing as necessary.
EEG:

  • See section above

Indications for MRI in epilepsy or seizures:

  • If focal features are present
  • Or If onset after 25 y.o. or before 1 y.o.
  • Or if considering surgery
  • Or if seizures continue in spite of medications

MRI:

  • May be entirely normal or reveal other abnormalities
  • DWI: may be abnormal after a seizure in the hippocampus, cerebral cortex, or thalamus
  • May reveal Hippocampal sclerosis
  • Malformations of cortical development:
    • Focal cortical dysplasia: focal cortical thickening, simplified gyration, blurred White-grey junction, prolonged T2, especially frontal lobe
  • Atrophy
  • Heterotopia: subepindymal, subcortical or band/diffuse
  • Vascular malformations, small tumours
  • Neurocysticercosis: see under neurocysticercosis
  • Tuberculomas

Blood tests:

  • FBC, ESR, blood chemistry panel, Syphilis serology, Liver enzymes

 

Treatment of epilepsy, in general:

Epilepsy requires expertise and referral to neurologist is the standard of care.
General issues:

  • Address driving advise according to medical and local legal criteria. There are some work implications for certain professions: pilots, commercial drivers
  • Sudden unexplained death in epilepsy SUDEP may occur in patients with poor control
  • Address advice regarding medication use in pregnancy, teratogenicity and pregnancy planning
  • Most patients achieve seizure control. Consider investigation for medication refractory epilepsy if 2 adequate trials of medications fail. However, this should not prevent further medication trials. This should occur in parallel.

Antiepileptics drugs (AEDs):

  • Please see the neuropharmacology notes and clinical trials notes
  • AEDs are selected based on epilepsy syndrome, seizure type, patient co-morbidities, fertility status, side effect profile and socio-economic factors
  • Certain medications work better for generalized epilepsy e.g. valproic acid or topiramate. Others work well for partial epilepsy such as lamotrigine or carbamazepine. There are medications to avoid in women of child-bearing potential e.g. valproic acid and others. Other types of epilepsy syndrome have specific medications such as ethosuximide and lamotrigine in absence epilepsy and ACTH in infantile spasms. There are some medications with good side effect profiles and broad spectrum of efficiacy with very few drug interactions such as levetiacetam.
  • After seizure freedom for 2 years, in some cases of epilepsy at attempt at medication withdrawal may be considered. This is dependant on epilepsy syndrome, imaging variables and EEG findings. This is another reason that epilepsy treatment is specialized.

Factors involve in antiepileptic drug choice:

  • Epilepsy syndrome
  • Seizure type
  • Patient co-morbidities
  • Potential drug-drug interactions
  • Fertility status
  • Side effect profile
  • Socio-economic factors and access to medications
  • Pharmacogenetics

 

Medically refractory epilepsy:

Diagnosis:

Epilepsy is considered medically refractory once the patient has continued seizures in spite of adequate trial of 2 anti-epileptic medications. This diagnosis is designed as a trigger to initiate investigations to determine if the patient is a candidate for non-pharmacological therapy such as epilepsy surgery or vegal nerve stimulator insertion.
This does not mean that the patient will not achieve seizure freedom with subsequent medication trials. However, in patients meeting the above criteria the benefits vs. risk favor initiating investigations for medically refractory epilepsy in parallel with further medication trials. Another consideration is evaluation for possible non-epileptic attacks (or pseudoseizures) as a reason for medication non-response. This often requires video-EEG monitoring. Also note, that some patients may have both epilepsy and non-epileptic attacks.

Investigations in medically refractory epilepsy:

Video EEG monitoring in an epilepsy monitoring unit:

  • Absolute interictal spike frequency = or >60 spikes/hr is associated with poor surgical outcome, if <60 spikes/hr it is associated with good surgical outcome for amygldalohippocampectomy. [182]

MRI:

  • T1,T2, proton density, FLAIR

fMRI:

  • to localise cognitive functions including language, and motor & sensory areas. Not as good as WADA test

Neuropsychological assessment: IQ (verbal & nonverbal), learning disability, memory, speech.
SPECT Single photon emission CT, interictal & Ictal:

  • Seizures must be frequent enough
  • Increased blood flow to seizure focus ictally
  • Decreased blood flow to focus interictaly
  • Good for temporal lobe epilepsy & frontal lobe epilepsy

Positron emission tomography PET scans:

  • Hypometabolism/decreased glucose intake at seizure focus interictally
  • Hypermetabolism/increased glucose uptake during a seizure
  • More useful for lateralisation than localisation

Wada test: presurgery to lateralise memory and speech.
Invasive monitoring:

  • Subdural leads
  • Depth electrodes

Treatment:

Consider treatment as appropriate. This is a multidisciplinary effort
Left vagal nerve stimulation VNS:

  • Especially for partial seizures

Surgery:

  • Lesionectomy
  • Selective hippocampalectomy for Mesotemporal sclerosis
  • Removal of cortical dysplasia
  • Unilateral anterior temporal lobectomy
  • Corpus callosum section

Related articles:

Approach to Transient (paroxysmal) loss of consciousness,

References:

  1. Harden CL, Hopp J, Ting TY, et al. ; American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy–focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009 Jul 14;73(2):126-32. doi: 10.1212/WNL.0b013e3181a6b2f8. Epub 2009 Apr 27.
  2. Morris GL 3rd, Gloss D, Buchhalter J,  Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 Oct 15;81(16):1453-9. doi: 10.1212/WNL.0b013e3182a393d1. Epub 2013 Aug 28.
  3. EO3 study. Ben-Menachem E et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Epilepsia. 1994 May-Jun;35(3):616-26.
  4. EO3 study. Ramsay RE et al. Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects, and tolerability. First International Vagus Nerve Stimulation Study Group. Epilepsia. 1994 May-Jun;35(3):627-36.
  5. EO3 study. George R et al. Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. First International Vagus Nerve Stimulation Study Group. Epilepsia. 1994 May-Jun;35(3):637-43.
  6. Handforth A et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1998 Jul;51(1):48-55.
  7. D’Onofrio G, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med. 1999 Mar 25;340(12):915-9.
  8. Daeppen JB et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002 May 27;162(10):1117-21.
  9. Hessen E, et al. Influence of major antiepileptic drugs on attention, reaction time, and speed of information processing: results from a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy. Epilepsia. 2006 Dec;47(12):2038-45.
  10. Marson AG, et al; SANAD Study group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007 Mar 24;369(9566):1016-26.
  11. Marson AG et al; SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007 Mar 24;369(9566):1000-15.
  12. Lossius MI, et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia. 2008 Mar;49(3):455-63. Epub 2007 Sep 19.
  13. Neal EG et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008 Jun;7(6):500-6. doi: 10.1016/S1474-4422(08)70092-9. Epub 2008 May 2.
  14. Silbergleit R, et al; RAMPART NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012 Feb 16;366(7):591-600. doi: 10.1056/NEJMoa1107494.
  15. Trinka E et al; KOMET Study Group. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1138-47. doi: 10.1136/jnnp-2011-300376. Epub 2012 Aug 29.
  16. Berkovic, S.F., et al., Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology, 2007. 69(18): p. 1751-60.

 

Lumbosacral Plexopathy

Diseases, ,

Diagnosis:

This is a clinical diagnosis supported by neurophysiological (electrophysiology NCS/EMG) tests

Clinical features:

Weakness and sensory loss in lumbosacral distribution that spares the paraspinal muscles and is usually asymmetric in a distribution localizing to the plexus.

Lumbar plexopathy:
  • Loss of knee reflex
  • Weakness: hip flexors, hip adductors, knee extensors,
  • Reverse straight leg sign may occur: pain in anterior thigh with thigh hyperextension
Sacral plexopathy:
  • Loss of ankle reflex
  • Weakness of: hip extensors, hip abductors, ankle plantar flexors
  • S2,3 sensory loss
  • Lasegue’s sign: pain in posterior thigh during straight leg raise

Findings on investigations:

Electrophysiology NCS/EMG:

SNAP:

  • More sensitive than CMAP
  • Normal conduction velocity and distal latency
  • Decreased amplitude in affected nerve (may be normal initially).

CMAP:

  • Indicates more severe injury
  • Decreased amplitude (however normal side to side differences are common, >50% difference is significant)

F-wave: nonspecific
H-reflex: not helpful
EMG:

  • Fibrillations and Positive Sharp Waves PSW in denervated muscles.
  • Iliopsoas must be evaluated for lumbar plexus
  • Gluteal muscles must be evaluated for sacral plexus
  • If reinnervation has occurred: MUAP shows decreased recruitment, long duration, increased amplitude, polyphasia
  • Paraspinal muscles are normal (dorsal rami supply these, distinguishes this form radiculopathies)

Pattern by nerve:

Femoral nerve:

SNAP: Decreased amplitude in femoral nerve
EMG:

  • involved muscles, quadriceps, sartorius, iliacus, pectinous
  • Spared muscles: paraspinal muscles
Obturator nerve:

SNAP: Decreased amplitude in obturator nerve
EMG:

  • Involved muscles, adductor longus, adductor brevis, adductor magnus (dual supply), gracilis, obturator internis
  • Spared muscles: paraspinal muscles
Superior gluteal nerve (pure motor):

EMG:

  • Involved muscles, gluteus medius and gluteus minimus, tensor fascia lata
  • Spared muscles: paraspinal muscles
Inferior gluteal nerve (pure motor):

EMG:

  • Involved muscles, gluteus maximus
  • Spared muscles: paraspinal muscles
Sciatic nerve (peroneal):

SNAP: decreased amplitude in peroneal nerve
EMG:

  • involved muscles, short head of biceps femoris, tibialis anterior, extensor digitorum brevis EDB, peroneus teritus, brevis and longus
  • Spared muscles: paraspinal muscles
Sciatic nerve (tibial):

SNAP: decreased amplitude in tibial nerve
EMG:

  • Involved muscles, long head of biceps femoris, semitendinosus, semimembranosus, adductor magnus (dual supply), plantaris, popliteus, gastrocnemius, soleus, tibialis posterior, flexor digitorum longus, flexor hallucis longus
  • Spared muscles: paraspinal muscles

Investigations to consider:

Fasting blood glucose, HbA1c
HIV serology
CT abdomen and pelvis: retroperitoneal tumour or haematoma
MRI lumbosacral plexus: tumour infiltration
CTA abdomen: abdominal aortic aneursym
NCS/EMG: rule out radiculopathy
CSF analysis: raised protein in some cases e.g. diabetic amyotrophy
 

Causes of lumbosacral plexopathy:

Diabetic amyotrophy
Idiopathic Lumbosacral plexitis a.k.a. lumbosacral plexitis a.k.a. idiopathic neuralgic amyotrophy a.k.a. Lumbosacral plexopathy
HIV lumbosacral plexopathy
Compressive/trauma/radiation injury:

  • Retroperitoneal hematoma
  • Retroperitoneal tumor
  • Radiation lumbosacral plexopathy
  • Abdominal aortic aneurysm

Neoplastic:

Related articles:

Subarachnoid Hemorrhage

Diseases, , , ,

Synonyms:

Subarachnoid haemorrhage

Diagnosis:

Findings on Investigations:

Diagnosis is established by neuroimaging (CT or MRI) or by lumbar puncture
Non-contrast CT:

  • Demonstrates subarachnoid hemorrhage in the acute phase.
  • May be negative, but is positive in the majority of cases. If CT is negative LP is indicated.
  • Blood in CSF spaces: sulci & cisterns. May also be associated with blood in ventricles (intraventricular hemorrhage IVH) especially the occipital horns of the lateral ventricles
  • Obscured sulci & sylvian fissures
  • Mild hydrocephalus especially temporal horns of the lateral ventricles
  • Diffuse cerebral oedema
  • Hypodensities: secondary ischemia in; perisylvian, pericallosal interfrontal, inferior frontal areas
  • Contrast CT shows up most medium to large AVMs

Lumbar puncture after 12hr from onset if CT is negative:

  • Negative LP combined with negative CT rules out SAH. [prospective large].  This is provided the LP is not delayed for weeks. Best timing is 6-12 hours from symptom onset.
  • Markedly elevated opening pressure
  • RBC/mm3:
    • Usually 100,000- over 1 million:
    • Occurs early in SAH
    • Clearing if RBCs from tube 1 to 3 (or 4) is occurs in traumatic taps. In traumatic taps it should approach zero. 25% reduction in RBCs is not enough.
  • Supernatant of centrifuged CSF: xanthochromia due to Bilirubin and oxyhemoglobin
  • Xanthochromia by Visual inspection may occur before 12 hrs and may miss SAH.
  • Xanthochromia analysis by spectrophotometry (spectroscopy) timed from 12 hrs to 2 weeks post onset helps exclude ruptured aneurysm.
  • WCC: raised or in chemical meningitis markedly raised with reduced glucose

MRI:

  • If > 4 days consider MRI especially gradient echo GRE (hypointense).
  • If >3 weeks, MRI (especially FLAIR: hyperintense CSF spaces) & MRA: shows hemosiderin deposition.
  • T1: isointense CSF, T2/FLAIR: hyperintense CSF, GRE: hypointense CSF
  • DWI: foci of restriction (vasospasm, ischemia)
Cerebro-Vascular imaging:

CTA or MRA:

  • After diagnosis is confirmed, to diagnosed the cause. Aneurysm, AVM, intracranial dissection
  • CTA helps more so later in the hospital course to detect vasospasm
  • Detects aneurysms =or> 2mm. Catheter angiogram is more sensative and specific.

Cerebral Angiography:

  • After diagnosis, to diagnose underlying cause
  • Both carotids & vertebral arteries
  • Best sensitivity and specificity. This is further improved if catheter rotational angiography is also performed
  • Repeat if negative, false negatives with vasospasm or thrombosis or very small causative lesion. Occurs in 5% of patients.
  • Repeat once if negative, especially if CT shows hemorrhage & more so if it is outside perimesencephalic region

Cerebral Vasospasm:

This can occur as a complication of subarachnoid hemorrhage. It may occur  from other conditions as well. It may be clinical vasospasm if this occurs with symptoms  or infarction. It also may be radiological vasospasm where there is evidence of vasospasm on imaging without clinical deficits or infarction.
Clinical features of cerebral vasospasm:

  • Confusion, motor deficit, aphasia or seizure

Radiological vasospasm, determined by:

  • Cerebral angiography
  • CT angiography (CTA)
  • Transcranial ultrasound (trancranial doppler ultrasound, TCD): shows increased mean flow velocity (MFV) if proximal vasospasm is present, increased pulsatility index if distal vasospasm is  present
  • MR Angiography (MRA)

Scales & Grading:

Hunt-Hess scale:

Grade 1: Asymptomatic, mild headache, slight nuchal rigidity
Grade 2: Moderate to severe headache, nuchal rigidity , no neurologic deficit other than cranial nerve palsy
Grade 3: Drowsiness / confusion, mild focal neurologic deficit
Grade 4: Stupor, moderate-severe hemiparesis
Grade 5: Coma, decerebrate posturing

World federation of neurosurgeons WFNS grading:

Grading is done after the patient is stable
Grade 1, GCS 15, no focal signs
Grade 2, GCS 13-14, no focal signs
Grade 3, GCS 13-14, with focal signs
Grade 4, GCS 7-12
Grade 5, GCS 3-6

Fischer grading:

Grade 1: no SAH on CT
Grade 2: diffuse SAH or vertical layers <1mm thick
Grade 3: diffuse clot or vertical layer >1mm thick
Grade 4: intracerebral/intraparenchymal or intraventricular clot with diffuse SAH or no blood

Modified Fisher grade

0 None evident, no IVH either
1 Thin without IVH
2 Thin with IVH
3 Thick without IVH
4 Thick with IVH
 

Findings on other investigations:

  • Chemistry panel: hyponatremia often occurs
  • Urine drug screen: for cocaine in some cases
  • Non-contrast CT: see above
  • LP: see above
  • MRI: see above
  • CTA, catheter angiogram: see above
  • Transcranial doppler ultrasound: see above
  • ECG, continuous monitoring
  • ECG Changes with SAH: ST depression, peaked T waves, flat T waves or T wave inversion, tall U waves, long QT interval (VT, VFib, Torsades), PSVT. Most go away within 48-72 hours. T wave inversion may persist.
  • ECG Changes with nemodipine: bradycardia, AV block
  • Consider Troponin if ECG changes
  • Echocardiogram: stress induced cardiomyopathy may occur

Treatment:

For aneurysmal subarachnoid hemorrhage (aSAH). There are two periods to consider depending on whether the aneurysm is secured:

  • Initial period: ruptured aSAH or re-ruptured aSAH
  • Second period, secured aSAH, vasospasm & medical complications

Goals & targets:

  • Optimise Cerebral perfusion pressure CPP, MAP and ICP
  • Ruptured aSAH, unsecured: avoid high systolic mmHg (<140), keep EVD open at 20cm (to avoid reducing ICP too much, theoretical temponade effect of higher ICP)
  • Ruptured aSAH, secured: use MAP as primary BP target rather than Systolic BP, drop EVD to 10cm, allow patient to ambulate

 
Treatment of underlying lesion:

  • Aneurysmal SAH: Endovascular treatment (coiling or assisted techniques) is the standard of care. However some aneurysm are not suitable for endovascular treatment. Surgery should be considered for those cases.
  • AVM: definitive treatment is usually performed at a later stage unless there is venous outflow obstruction. Treatment may involve a combination of endovascular therapy, surgery or radiosurgery.

Consider hematoma evacuation if large
Contraindications:

  • Avoid antiplatelets until aneurysm is secured

Prevent raise in intracranial pressure:

  • Absolute bed rest, until aneurysm is secured. Then early ambulation
  • Tilt the bed head 15-20 degrees
  • Analgesia for headache
  • Antiemetic

Consider Antifibrinolytic therapy:

  • Avoid after treatment of aneurysm or delayed administration. [Metanalysis]
  • Avoid antifibrinolytic therapy after 48 hours or for >3 days
  • Consider Tranexamic acid 1g I.V. STAT & 1g q6h until aneurysm treatment or 72hrs. [RCT]

Neuroprotection:

  • Nimodipine 60 mg P.O. every 4 hours, after BP is corrected, X 21 days +monitor BP & heart rate [RCT]

 

Prophylaxis of complications:

Delayed cerebral ischemia DCI, Avoid:

  • Hypovolemia, hypotension, and hyponatremia (see below)
  • Hyperthermia: paracetamol & cooling blankets. Hyperglycemia: insulin therapy

Seizures:

  • Only use prophylaxis prior to aneurysm being secured
  • Avoid phenytoin as it is associated with poor cognitive outcomes in observational studies
Mx. Of complications:

Raised intracranial pressure ICP:

  • Ventriculostomy= External ventricular drain EVD

If vasospasm occurs:

  • Increase MAP by 30%, EVD 0 and open, CPP goal >60
  • Induce hypertension with phenylephrine or dopamine
  • Euvolemia: NaCl 0.9% 200ml/hr, consider albumin infusion if electrolyte abnormalities develop
  • Consider optimizing cardiac output: i.e. Cardiac index CI.
  • Consider endovascular therapy (balloon angiopasty if proximal, intraarterial verapamil if distal)

If hyponatremic:

  • Treat the cause: usually syndrom of inappropriate anti-diuretic hormone (SIADH) or cerebral salt wasting
  • Sodium replacement with NaCl P.O. or 3% normal saline I.V.
  • D not use fluid restriction as hypovolemia can be harmful

Neurogenic pulmonary oedema:

  • Supportive care

Stress-induced cardiomyopathy:

  • Supportive care

Related articles:

References:

  1. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012 Jun;43(6):1711-37. doi: 10.1161/STR.0b013e3182587839. Epub 2012 May 3.
  2. van Gijn, J. and G.J. Rinkel, Subarachnoid hemorrhage: diagnosis, causes and management. Brain, 2001. 124(Pt 2): p. 249-78.
  3. van Gijn, J. and G.J. Rinkel, Subarachnoid hemorrhage: diagnosis, causes and management. Brain, 2001. 124(Pt 2): p. 249-78.
  4. Brouwers, P.J., et al., Serial electrocardiographic recording in aneurysmal subarachnoid hemorrhage. Stroke, 1989. 20(9): p. 1162-7.
  5. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg, 1988. 68(6): p. 985-6.
  6. Roos, Y.B., et al., Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage. Cochrane Database Syst Rev, 2003(2): p. CD001245.
  7. Heasley, D.C., M.A. Mohamed, and D.M. Yousem, Clearing of red blood cells in lumbar puncture does not rule out ruptured aneurysm in patients with suspected subarachnoid hemorrhage but negative head CT findings. AJNR Am J Neuroradiol, 2005. 26(4): p. 820-4.
  8. Perry, J.J., et al., Is the combination of negative computed tomography result and negative lumbar puncture result sufficient to rule out subarachnoid hemorrhage? Ann Emerg Med, 2008. 51(6): p. 707-13.
  9. MacDonald, A. and A.D. Mendelow, Xanthochromia revisited: a re-evaluation of lumbar puncture and CT scanning in the diagnosis of subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry, 1988. 51(3): p. 342-4.
  10. Vermeulen, M., et al., Xanthochromia after subarachnoid hemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry, 1989. 52(7): p. 826-8.
  11. Mitchell, P., et al., Detection of subarachnoid hemorrhage with magnetic resonance imaging. J Neurol Neurosurg Psychiatry, 2001. 70(2): p. 205-11.
  12. Imaizumi, T., et al., Detection of hemosiderin deposition by T2*-weighted MRI after subarachnoid hemorrhage. Stroke, 2003. 34(7): p. 1693-8.
  13. Fisher, C.M., J.P. Kistler, and J.M. Davis, Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery, 1980. 6(1): p. 1-9.
  14. Jung, J.Y., et al., Spontaneous subarachnoid hemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci, 2006. 13(10): p. 1011-7

 

Intracerebral Hemorrhage

Diseases, , , , ,

This section will discuss intracerebral hemorrhage; the commonest type of hemorrhagic stroke. Hemorrhagic stroke is a broad category of stroke and includes intracerebral hemorrhage and subarachnoid hemorrhage. Together these two conditions represent 13-20% of stroke cases with the rest being due to ischemic stroke. Intracerebral hemorrhage is more common than subarachnoid hemorrhage with the later representing approximately 5% of all strokes.
Intracerebral hemorrhage presents with sudden onset focal neurological deficit. This may be accompanied by a headache and nausea. The main differential diagnosis is ischemic stroke. Subarachnoid hemorrhage presents with sudden severe headache. In more severe cases patients with either condition may present in coma.
The conditions are separate with different etiology and management strategies. Please see other sections if necessary.
The overall commonest cause of intracerebral hemorrhage is hypertension. In patients older than 70 years, cerebral amyloid angiopathy is the commonest cause. The commonest cause in children is cerebral arteriovenous malformations (AVM).

Synonyms:

Intraparenchymal hemorrhage (IPH), intracerebral hematoma, intracerabral haemorrahge

Causes of intracerebral hemorrhage ICH: ‘hemorrhagic stroke’:

Arterial:

  • Hypertension
  • Small vessel disease
  • Cerebral amyloid angiopathy CAA (hemorrhagic)- Arteriovenous malformations AVM
  • Reversible cerebral vasoconstriction syndrome (RCVS)
  • Cerebral vasculitis
  • Posterior reversible encephalopathy syndrome (PRESS)

Venous:

  • Cavernous malformations a.k.a. Cavernous hemangiogma a.k.a. cavernoma
  • Cerebral Venous sinus thrombosis (venous sinus, deep veins, cortical veins)
  • Venous thrombosis

Others:

  • Coagulopathy: Systemic bleeding disorders, Anticoagulant therapy

Hemorrhagic tumours (intra-tumoural hemorrhage):

  • Metastasis: melanoma, renal cell carcinoma, choriocarcinoma, thyroid, bronchogenic carcinoma
  • High grade astrocytoma: anaplastic astrocytoma, glioblastoma
  • Others: schwannoma, pituitary adenoma, meningioma, hemangioblastoma

Diagnosis:

CT:

  • Hyperdense, sharp margin
  • Surrounding hypodensity: oedema
  • Possible mass effect
  • Single or multiple
  • If traumatic CT appearance might be delayed >24hrs
  • Variation with time:
    • Acute: hyperdense +oedema
    • Weeks: isodense
    • Months: hypodense, dilated adjacent sulci & ventricle

ABC/2 method of measuring hemorrhage volume:

  • A= greatest hemorrhage diameter
  • B= diameter 90 degrees to A
  • C= number of CT slices with hemorrhage X slice thickness.
  • Slices with hemorrhage:
  • Slices with hemorrhage >75% of A count as 1 slice
  • Slices with hemorrhage 25-75% count as 0.5 slice

MRI:

  • Gradient echo MRI: Best to detect old hemorrhage in stroke with delayed presentation. Acute or old Hemorrhage: low signal
  • Assesses causes: AVM, Cavernous malformation, underlying neoplasm, features of cerebral amyloid angiopathy (old hemorrhages), hemorrhagic PRESS, cerebral venous thrombosis CVT, cerebral vasculitis

ICH score:

Add scores for the follwoing parameters:

  • Glasgow coma scale
  • Age ≥ 80
  • ICH Volume ≥ 30ml
  • Presence of intraventricular hemorrhage IVH
  • Infratentorial origin of hemorrhage

Glasgow Coma Score:

  • +2 points for GCS 3-4
  • +1 points for GCS 5-12
  • 0 points for 13-15

Age ≥ 80

  • 1 point for YES
  • 0 points for NO

ICH Volume ≥ 30ml

  • 1 point for YES
  • 0 points for NO

Intraventricular Hemorrhage

  • 1 point for YES
  • 0 points for NO

Infratentorial Origin of Hemorrhage

  • 1 point for YES
  • 0 points for NO

Pathology:

  • Depends on cause, see cerebral amyloid angiopathy, cavernoma, AVM, cerebral aneurysms
  • Acute: hemorrhage (RBC), disruption of brain tissue,
  • Charcot-Bouchard aneurysms in hypertensive intracerebral hemorrhage. Not true aneurysms but represent tortuous perforator blood vessels
  • Genetic forms: COL4A1 gene mutations are associated with small vessel disease & hemorrhagic stroke

Investigations to consider:

MRA:

  • To assess for underlying vascular malformation
  • May be negative in dural arteriovenous fistula DAVF
  • MRV: to rule out venous sinus thrombosis CVST, deep cerebral vein thrombosis, cortical vein thrombosis

CTA:

  • To assess for underlying vascular malformation
  • May be negative in dural arteriovenous fistula DAVF
  • CT venogram, or MRV: to rule out venous sinus thrombosis CVST, deep cerebral vein thrombosis DCVT, cortical vein thrombosis

Catheter angiography, Digital Subtraction Angiography DSA:

  • Repeat or delayed Angiography may be needed to rule out AVMs as angiography can be false-negative in acute hemorrhage
  • Best test for AVM
  • Best test for dural arteriovenous fistula DAVF
  • Helps evaluate cerebral venous sinus thrombosis CVST, Reversible cerebral vasoconstriction syndrome (RCVS), Cerebral vasculitis

Blood tests:

  • FBC, blood chemistry panel, coagulation screen
  • Blood cultures X3: if suspecting infective endocarditis
  • Tests for coagulopathy as appropriate

Speech and language therapy assessment:

  • Dysphagia Screening: 10 ml water swallow: coughing, choking or wet quality of voice
  • Test feeds

Videofluroscopy: be aware of normal aging changes
Echocardiogram:

  • May demonstrate features of chronic hypertension, LVH, cardiomyopathy.
  • Infective endocarditis with septic embolism ‘mycotic aneurysm’

Brain Biopsy: cerebral amyloid angiopathy

Treatment:

  • Avoid do not resuscitate (DNR) orders for the first 24-48 hours
  • The maintain treatment is medical and supportive care. There is a small role for surgery
  • Treat the underlying condition if present: AVM, DAVF, coagulopathy, cerebral venous sinus thrombosis,

Medical:

  • Temperature: Acetaminophen/paracetamol if >37 degrees. [post hoc of RCT]
  • Blood pressure control:
    • Keep BP<140 mmHg systolic [INTERACT RCT]
    • Consider using nicardipine IV infusion, labetalol IV infusion, nitroglycerin paste
    • Avoid: Nitroprusside may raise ICP [theoretical concerns]
  • Medical management of cerebral edema as necessary: hyper-osmolar therapy
  • Airway management, mechanical ventilation as necessary
  • Swallow assessment and feeding with efforts to avoid aspiration pneumonia
  • Glycemic control: by insulin sliding scale or if necessary insulin infusion
  • DVT prophylaxis with enoxaparin or heparin subcutaneously is safe on day 2. [Prospective study]

Consider Surgery:

  • Limited role. Not useful in deep hemorrhages. Not useful in most cortical hemorrhages either. [STICH, STICH2] Minimally invasive surgery (MIS) techniques are promising but require further study in randomized controlled trials.
  • For cerebellar hemorrhage, consider cerebellar decompression: craniotomy +evacuation under direct vision
  • Consider external ventricular drain (EVD) for intraventricular hemorrhage. No benefit for additional intra-ventricular alteplase. [CLEAR-IVH]

Rehabilitation:

  • Safe to start day 2 after ICH
  • Core components:
    • Early mobilization
    • Speech & language therapy
    • Physical therapy
    • Occupational therapy

Oral Anticoagulant associated ICH:

Diagnosis:
  • Expand over a long period, up to 7 days
  • Hemorrhage is common
  • Fluid-fluid level may occur
Treatment:
  • Same as spontaneous ICH except reverse the agent.
  • Prothrombin complex concentrate (PCC) for warfarin induced ICH
  • Idarucizumab (trade name= Praxbind) for dabigatran induced ICH

 

Related articles:

Approach to weakness, approach to abnormal speech,

References:

  1. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015 Jul;46(7):2032-60. doi: 10.1161/STR.0000000000000069.
  2. Kothari, R.U., et al., The ABCs of measuring intracerebral hemorrhage volumes. Stroke, 1996. 27(8): p. 1304-5.
  3. Boeer, A., et al., Early heparin therapy in patients with spontaneous intracerebral hemorrhage. J Neurol Neurosurg Psychiatry, 1991. 54(5): p. 466-7.
  4. Geocadin, R.G., et al., Intracerebral hemorrhage and postpartum cerebral vasculopathy. J Neurol Sci, 2002. 205(1): p. 29-34.
  5. Hemphill et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001, 32:891-897

Hemorrhagic Stroke

Diseases

Hemorrhagic stroke is a broad category of stroke and includes intracerebral hemorrhage and subarachnoid hemorrhage. Together these two conditions represent 13-20% of stroke cases with the rest being due to ischemic stroke. Intracerebral hemorrhage is more common than subarachnoid hemorrhage with the later representing approximately 5% of all strokes.
Intracerebral hemorrhage presents with sudden onset focal neurological deficit. This may be accompanied by a headache and nausea. The main differential diagnosis is ischemic stroke. Subarachnoid hemorrhage presents with sudden severe headache. In more severe cases patients with either condition may present in coma.
The conditions are separate with different etiology and management strategies. Please see dedicated sections; intracerebral hemorrhage or subarachnoid hemorrhage.
 

Ischemic Stroke

Diseases, , , , ,

Ischemic stroke is the commonest form of stroke. It represents infarction of the brain or spinal cord due to interruption of blood supply. There are many causes including embolism of material such as thrombus, cholesterol or rarely other material. Other mechanisms include thrombosis and miscellaneous causes of interruption of blood flow.
The symptoms vary depending on which blood vessels are affected. Occlusion of proximal blood vessels such as the internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA), basilar artery (BA) and posterior cerebral artery (PCA) cause large areas of infarction. These infarcts affect cortical areas as well as subcortical tracts and structures. Perforator blood vessel occlusion such as the lenticulostriate arteries, the recurrent artery of Heubner, thalamic perforators and brainstem perforators cause smaller areas of infarction that spare the cortical structures. These are lacunar strokes and have typical syndromes. However, the clinical deficits are often disabiling regardless of the blood vessel size. Occasionally, the cortical branches of the main arteries may be affected without involvement of the proximal portions. In these cases cortical infarcts that spare the subcortical structures occur.
By understanding the functional neuroanatomy of the central nervous system and the patterns of blood supply, stroke syndromes allow localization of the area of infarction in most cases. This is important in emergency settings when dealing with acute stroke to be able to distinguish between ischemic stroke and stroke mimics.
Here are the main goals of assessment of patients with ischemic stroke:

  1. Identification of ischemic stroke patients who may be candidates for emergent reperfusion therapies.
  2. Identification of mechanism of stroke and underlying etiology to guide secondary prevention strategies. This helps prevent early and late stroke recurrence.
  3. Identification of potential complications to prevent them and to institute early therapy.
  4. Identification of rehabilitation needs.

Synonyms:

Cerebral infarction, ischaemic stroke.

Diagnosis:

Diagnosis is confirmed by imaging demonstrating areas of infarction.

Clinical features:

  • The clinical spectrum of ischemic stroke ranges through a spectrum from silent infarction to disabiling focal neurological deficits, coma and death. Symptoms with stroke may be transient but are usually persistant.
  • Typically there is sudden onset focal neurological deficit attributable to a vascular territory. Symptoms may be stuttering. Progression may occur.
  • Malignant middle cerebral artery (MCA) syndrome:
    • Infarction =or> 2 thirds MCA territory +/-ACA infarction
    • With decreased consciousness, GCS=or <13
    • NIHSS =or>16 for non-dominant hemisphere & =or>20 for dominant hemisphere.

Causes of ischemic stroke (ischemic stroke, focal cerebral ischemia, infarction, TIA):

Vascular disorders:

  • Vasculopathy:
    • Atherosclerosis
    • Fibromuscular dysplasia
    • Carotid or vertebral artery dissection
    • Post radiation syndrome
    • Cholesterol emboli syndrome
    • Reversible cerebral vasoconstriction syndrome RCVS
    • Progressive intracranial occlusions: moyamoya syndrome
    • Aortic dissection
    • Lacunar infarction
  • Vasculitidis (cerebral vasculitis a.k.a. cerebral vasculitidis):
    • Autoimmune Vasculitis:
      • Granulomatous angiitis of the CNS, primary angiitis of the CNS
    • Large vessels:
      • Giant cell arteritis
      • Takayasu arteritis
    • Connective tissue disease:
      • Systemic lupus erythematosus
      • Sjogren syndrome
      • Microscopic Polyarteritis
      • Wegener granulomatosis
      • Churg-Strauss syndrome
    • Kawasaki syndrome
    • Behcet disease
  • Infectious Vasculitis:
  •  Bacterial:
    • Lyme disease
    • Syphilitic arteritis (meningovascular syphilis)
    • Rickettsial
    • Meningovascular TB,
    • Viral: Varicella-Zoster Virus VZV, EBV
    • Fungal: Mucormycosis,
    • Parasitic: malaria, Schistosomiasis
    • Malignancy associated
    • Drug induced
    • Cerebral autosomal dominant angiopathy with subcortical infarcts & leukoencephalopathy CADASIL
    • Migraine
    • Drug abuse:
      • Cocaine, amfetamine
      • – Venous or venous sinus thrombosis
    • Mitochondrial encephalomyopathy lactic acidosis & stroke MELAS

Cardiac disorders

  • Arrhythmias
  • Mural thrombus
  • Rheumatic heart disease
  • Endocarditis
  • Mitral valve prolapse
  • Prosthetic heart valves
  • Paradoxic embolus
  • Atrial myxoma

Hematologic disorders:

  • Sickle cell disease
  • Thrombocytosis: >1,000,000/microL
  • Polycythemia: Hematocrit >46%
  • Leukocytosis >150,000/microL
  • Hypercoagulable states
  • Intravascular lymphoma

Causes of deterioration after an ischemic stroke:

  • Cerebral edema of the stroke
  • Hemorrhagic transformation of the stroke
  • Metabolic
  • Infection

DDx. ischemic stroke ‘focal cerebral ischemia, ischemic stroke’:

  • Migraine
  • Vascular:
    • Intracerebral hemorrhage
    • Subdural hematoma
    • Extradural hematoma
    • Subarachnoid Masses:
    • Brain abscess
    • Tumor
  • Metabolic:
    • Hypoglycemia
    • Hyperosmolar nonketotic hyperglycemia

Findings on Investigations:

CT noncontrast:

  • Rules out hemorrhage
  • In the early phase, initial few hours: no changes on CT
  • Extensive hypodensity e.g. >1/3 area of MCA territory, is considered a contraindication to TPA
  • Early, after a few hours:
    • Loss of grey-white matter differentiation e.g. loss of insular ribbon
    • Effacement of sulci: vasogenic oedema.
    • +/-hemorrhage
    • Hyperdense arteries e.g. proximal MCA, basilar artery, vertebral arteries: thrombosis
  • By 24 hours:
    • Hypodensity that matches the territory of the involved artery. Typically wedge shaped in cortical infarcts
    • Posterior circulation: ‘tiger eye’ hypodensity of small part of the thalamus due to perforators, occipital area hypodensity
    • Lacunar infarct: Hypodensity in basal ganglia, thalami, periventricular white matter
  • By day 2-4:
    • Features of oedema +mass effect
    • Acute oedema: area hypodense to white matter but hyperdense to CSF
    • Mass effect: effacement of the cerebral sulci, sylvian fissure or other basal cisterns, or compression of the ventricular system (this lasts <4 weeks)
    • If CT with contrast: Gyral enhancement (enhancement of the gyri) occurs.
  • Chronic:
    • Focal volume loss +dilation of the adjacent ventricle: evidence of encephalomalacia

CT angiography (CTA):

  • Shows major vessel occlusion (ICA, MCA M1 M2, basilar) or dissections
  • Shows atherosclerosis & stenosis (carotid, MCA, PCA, Basilar)
  • Shows anatomic variations
  • Shows leptomeningeal collaterals

CTP, CT perfusion:

  • e.g. by TTP time-to-minimum-perfusion (Time to peak)
  • e.g. by MTT mean transit time: prolonged in affected area (core infarct+penumbra).
  • Cerebral blood volume CBV: reduced in core infarct
  • Shows the core infarct+ischemic penumbra
  • Uses contrast
  • CTP, MR perfusion PWI criteria for anterior circulation LVO stroke:
    • The core infarct lesion measured 50 ml or less,
    • The volume of tissue with a time to maximum delay of more than 10 seconds was 100 ml or less
    • And the mismatch volume was at least 15 ml
    • And the mismatch ratio was more than 1.8:1.0

MRI:

  • Early: shows areas of infarction within minutes
  • Edema in gyri on T2
  • Effacement of adjacent subarrachnoid space
  • Loss of signal void in vessels a.k.a. Arterial enhancement (high signal in artery on noncontrast T1, T2): slow flow vs. thrombus
  • Lacunar infarct:
    • T1: low signal intensity
    • T2: high signal intensity
  • T1 +contrast: Gyral enhancement occurs at <6 weeks, nhancement of adjacent meninges with gadolinium
  • FLAIR: Distal Hyperintense vessels may indicate collateral perfusion.
  • Hemorrhagic transformation/Hemorrhagic conversion (HT): petechial or confluent hemorrhage within the ischemic lesion starts in the periphery
  • Parenchymal hemorrhage (PH): blood clots in the infarcted area with at least slight space-occupying effect.
  • DWI MRI (diffusion weighted MRI)
  • Shows the core infarct & shows it the earliest
  • Lasts up to 10 days
  • High signal on DWI within a vascular territory. On apparent diffusion coefficient ADC map it is low signal
  • Nonspecific
  • False negatives occur in brain stem strokes & vertebrobasilar strokes <24hrs. [312]

PWI MRI (Perfusion weighted MRI)

  • e.g. by TTP time-to-minimum-perfusion (Time to peak)
  • Shows the core infarct+ischemic penumbra
  • With gadolinium contrast reduce signal in areas with slow or no flow.
  • Diffusion/perfusion mismatch shows ischemic penumbra. [DIFFUSE]
  • CTP, MR perfusion PWI criteria for anterior circulation LVO stroke:
    • The core infarct lesion measured 50 ml or less,
    • The volume of tissue with a time to maximum delay of more than 10 seconds was 100 ml or less
    • And the mismatch volume was at least 15 ml
    • And the mismatch ratio was more than 1.8:1.0

MRA:

  • Shows major vessel occlusion e.g. loss of signal void.
  • Can exclude 50-99% stenosis of large vessels. [SONIA]
  • Turbulant flow can look like stenosis
  • Tight focal stenosis can look like 2-3 cm stenosis because of turbulance

MRI vessel wall imaging:

  • T1 +fat saturated: hyperintense serpentine hemorrhage within the vessel wall

Transcranial dopper TCD:

  • Can exclude 50-99% stenosis of large vessels in some patients but other tests are preferable. [SONIA]

Catheter Angiography:

  • Demonstrates areas of occlusion. Occlusion of blood vessel, bare areas in capillary phase
  • Increased Capillary blush if a few hours from onset
  • Demonstrates collateral flow
  • Luxury perfusion (also seen on SPECT/angiography): early venous drainage, +transient blush. Occurs at 2-4 weeks

SPECT, acetazolamide for rCBF, IMP iodine amphetamine: [234]

  • Central area:
    • Acutely: Reduced uptake & blood flow rCBF
    • Subacute: Luxury perfusion (nonnutritional perfusion): increased perfusion rCBF of the infracted area after a stroke that disappears later on.
    • Chronic: decreased rCBF
  • Peripheral area (surrounds the infarct):
    • Slight decrease in rCBF & IMP uptake ~contrast enhancement.
  • If tPA is used:
    • Increased perfusion in areas that remain reperfused (nutritional perfusion) ~recovered tissue
    • Luxury perfursion (nonnutritional perfusion) occurs in areas that then become unperfused i.e. infarct

Pathology:

  • Acute 12-24 hrs: pallor, eosinophilic neurons “ischemic change a.k.a. red dead neurons”
  • Subacute 2 days- 2 weeks: macrophages, capillary proliferation, reactive astrocytes
  • Chronic months- years: cavitation, macrophages, reactive astrocytes
  • Lacunar stroke: lipohyalinosis

Useful scales and classifications:

National Institutes of Health Stroke Scale NIHSS:

0 is normal
1a. LOC Level of consciousness Alertness 0-3
1b. LOC responses 0-2
1.c LOC Following commands 0-2
2. Best Gaze 0-2

  •  Normal
  • Gaze palsy
  • Forced deviation or Gaze paralysis

3. Visual fields 0-3

  • Normal
  • Partial hemianopia
  • Completel hemianopia
  • Bilateral hemianopia or  cortical blindness

4. Facial palsy 0-3
5a. Motor arms drift in 10s left 0-4

  • Normal
  • Some drift
  • Some effort against gravity
  • No antigravity movement
  • No movement

5b. Motor arms drift in 10s right 0-4

  • Same scale as left arm

6a. Motor legs in 5s left 0-4

  • Same scale as left arm

6b. Motor legs in 5s right 0-4

  • Same scale as left arm

7. Limb ataxia 0-2

  • Finger-nose, heel-shin

8. Sensory 0-2

  • Pin-prick

9. Best language 0-3
10. Dysarthria 0-2
11. Extinction & hemi-inattention 0-2

  • Sensory & Visual stimulation
Modified Rankin scale:

0, No symptoms at all
1, No significant disability despite symptoms; able to carry out all usual duties and activities
2, Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
3, Moderate disability; requiring some help, but able to walk without assistance
4, Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
5, Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6, Dead

Oxfordshire Community Stroke Project Classification:
  • Total anterior circulation infarction
  • Partial anterior circulation infarction
  • Posterior infarction
  • Lacunar infarction
TOAST classification:
  • Large-artery atherosclerosis
  • Cardioembolism
  • Small-vessel occlusion
  • Stroke of other determined aetiology
  • Stroke of undetermined aetiology

 

Investigations in Ischemic Stroke

General points:

  • Basic investigations in every patient include vascular imaging of extracranial and intracranial blood vessels, ECG, echocardiogram and at least 24 hours of monitoring for paroxysmal atrial fibrillation
  • Extensive work up is still necessary in Lacunar stroke
  • In the ER CT non-contrast and CTA are necessary emergently to exclude intracerebral hemorrhage and identify large vessel occlusion respectively. This helps identify patients who may be candidates for emergent reprefusion therapies

Blood tests:

  • FBC, Coagulation screen, Blood Glucose, blood chemistry panel,
  • Fasting: Cholesterol, Lipids, glucose
  • ESR in some cases: vasculitides, giant cell arteritis.

Cardiac evaluation:

  • Necessary even in lacunar stroke
  • Initial evaluation includes ECG, echocardiogram and at least 24 hours of cardiac rhythm monitoring
  • ECG: assess for Atrial fibrillation, and signs of cardiac ischemia
  • Cardiac monitor for at least 24 hours. But subsequent trials show higher yield of detecting paroxysmal atrial fibrillation with longer monitoring

Holter monitor:

  • 24-48hrs. Detects additional patients with AF
  • If =or> 70 atrial premature beats/24hr, higher risk of Paroxysmal AF: 7 day event recorder
  • If no other cause on vascular imaging and echocardiogram and >45 years old consider long-term holter monitor or implantable recorder

Transthoracic echocardiogram:

  • Valvular disease, left atrial thrombus, mural thrombus, aortic arch atheroma, patent foramen ovale

Transesophageal Echocardiogram TEE +bubble study:

  • Especially if other tests don’t reveal the mechanism
  • Valvular disease, left atrial thrombus, mural thrombus, aortic arch atheroma, patent foramen ovale
  • If there is contrast in right atrium & left atrium: shunt is present

Vascular evaluation:

  • Necessary in every patient. Must evaluate extracranial and intracranial vascular anatomy

CTA:

  • Allows rapid evaluation of extracranial and intracranial circulation
  • Good screening test for extracranial internal carotid artery stenosis, vertebral artery stenosis, intracranial stenosis and for large vessel occlusion

MRA:

  • Allows evaluation of extracranial and intracranial circulation
  • Good screening test
  • May mistakenly show high grade stenosis as occlusion

Carotid artery duplex ultrasound (B mode ultrasound +doppler)

  • Good for extracranial internal carotid artery atherosclerotic stenosis if validated in the insitution against catheter angiography
  • Poor test for vertebral artery disease
  • Poor test for intracranial stenosis
  • Difficult to interpret with multiple occlusion and with dissection

Catheter Angiography:

  • Useful if there are discrepencies between non-invasive tests
  • Useful if planning therapy
  • Useful in intracranial atherosclerotic disease
  • Useful in non-atherosclerotic stenosis

CXR:

  • For cardiomegaly (chronic hypertension), aortic dissection
  • Not necessary prior to thrombolysis

Speech and language therapy assessment:

  • Dysphagia swallowing screen: can be performed by nurses
  • Test feeds
  • Formal evaluation by speech and language pathologist if positive screen or brainstem stroke
Investigations to consider if relevant:

Blood tests:

  • Homocysteine level
  • Vasculitic screen [ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50],
  • Antiphospholipid antibodies: Anticardiolipin antibodies [APASS], lupus anticoagulant.
  • Serum protein electrophoresis SPEP, B2 microglobulin,
  • Plasma hemoglobin electrophoresis: Sickle cell disease
  • Cryoglobulins
  • Consider Thrombophilia screen (see below, except anticardiolipin antibodies): if young, not if old. Repeat test regardless of result and assess for venous thromboembolism
  • If suspecting vasculitis: lyme serology.

Thrombophilia screen in selected patients:

  • Factor V Leiden Mutation
  • Anticardiolipin antibody
  • Lupus-anticoagulant:
    • aPTT is usually prolonged. Also do a manual aPTT screen (different phospholipid composition), or hexagonal PL screen (uses very dilute aPTT reagent making it sensitive to phospholipids)
    • Do a mixing study aPTT (immediate and delayed mixing study) or dRVVT (see below): 1:1 (patient plasma:control plasma) Failure to correct indicates an inhibitor, Correction with mixing indicates factor deficiency. Delayed mixing study is to look for slow inhibitors (e.g. factor VIII inhibitor).
    • dilute Russelll Viper Venom Test (dRVVT) mixing study is prolonged in lupus anticoagulant or factor inhibitor. It’s a type of mixing study using snake venom (activates factor X).
    • Do Phospholipid (PL) dependence confirmatory test (adding phospholipid shortens/corrects the clotting time): e.g. dRVVT confirm ratio (i.e. dRVVT screen/dRVVT confirm). Or hexagonal PL confirm (basically hexagonal screen+PL, then calculate, Delta=hexagonal PL screen – hexagonal PL confirm). Or platelet neutralization (PNP).
    • Then Rule out inhibitors including factor VIII inhibitor
    • Then recheck panel in 12 weeks
  • Thrombin Time: necessary for lupus anticoagulant interpretation in some cases
  • Protein S: deficiency
  • Protein C antigen & activity: deficiency
  • Antithrombin (formerly Antithrombin III): deficiency
  • Prothrombin gene variant G20210A
  • Activated protein C ratio (APC ratio) i.e. effect of APC on PTT: poor response =Activated protein C resistance
  • Homocysteine levels
  • HITS antibody (IgG antibody against heparin-platelet factor 4 complex)
  • Also do: FBC, coagulation screen, fibrinogen levels
  • Consider:
    • Plasminogen activator inhibitor PAI-1 levels: PAI-1 deficiency

Urine toxicology: cocaine, amfetamines
CSF analysis, LP:

  • Subarachnoid hemorrhage, syphilis
  • Pleocytosis in VZV vasculopathy vasculitis
  • Anti-VZV IgG, serum/CSF ratio of VZV IgG & VZV PCR: IgG is more sensitive, VZV vasculopathy

Cardiac:

  • Troponin T: associated with increase mortality.
  • 3 blood cultures: Infective Endocarditis even though hemorrhagic stroke is more common in infective endocarditis
  • Stress testing for coronary artery disease

Transcranial Doppler ultrasound TCD:

  • Decreased flow: proximal stenosis
  • Increased flow: spasm of the artery e.g. middle cerebral artery
  • Confirm crossfilling of MCA from contralateral carotid
  • With contrast: confirms Right to left shunt.

CT thorax, abdomen & pelvis::

  • for underlying cancer, Pulmonary AVM
  • for underlying neoplasm in paraneoplastic hypercoaguable states and paraneoplastic vasculitis

Videofluroscopy: for swallow assessment, be aware of normal aging changes

Treatment:

Assess for emergency reperfusion therapies:

This is an emergency, activate the stroke team protocol and proceed per local institution guidelines. Here are some points:

  • Emergent CT head and CTA head and neck to assess for emergency reperfusion therapies
  • Finger stick glucose test
  • Obtain IV access for CTA and potential thrombolysis

BP management prior to reperfusion:

  • Do not lower BP unless it is outside parameters for thrombolysis avoid hypotension
  • Non-thromboysis candidates:
    • Treat if >220/120 mmHg, but lower it slowly. consider Labetalol, or Nicardipine or other agents
  • Thrombolysis candidates:
    • Goal <185/110 mmHg. consider Labetalol, or Nicardipine or other agents

If patient meets criteria for thrombolysis proceed to thrombolysis without delay. [Multiple RCT and meta-analysis, standard of care]
If patient meets criteria for neuroendovascular stroke therapy proceed to endovascular therapy without delay. [Multiple RCT and meta-analysis, standard of care]
 

Reperfusion strategies:
  • Intravenous thrombolytic therapy I.V.: [NINDS-rtPA, ECASS-3, SITS-MOST, Meta-analysis]
  • Alteplase intravenously within 4.5 hours. Review indications, contraindications & post procedure care
  • Avoid Aspirin or anticoagulants for 24 hours

NeuroEndovascular stroke therapy:

  • Mechanical thrombectomy is proven efficacious for patients with proximal large vessel occlusion (LVO) ischemic stroke [multiple RCTs, MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME, REVASCAT, and meta-analysis]
  • Stent-retrievers are more efficacious than MERCI device. [SWIFT, TREVO]. Studies using MERCI device along did not show benefit. [IMS3, MR RESCUE]
  • Intraarterial therapy with alteplase alone is probably not effective compared to intravenous alteplase. [IMS3, Synthesis]
  • Indicated for patients with large vessel occlusion LVO strokes in anterior circulation (ICA, MCA) within 6 hours of last known well (LKW) with CT/CTA selection [HERMES metaanalysis, MRCLEAN, ESCAPE, SWIFT PRIME, EXTEND IA, REVASCAT]
  • Indicated for patients with large vessel occlusion LVO strokes in anterior circulation (ICA, MCA) within 6-24 hours of last known well (LKW) with CT/CTA/CTP or MRI/PWI/DWI selection [DAWN trial].
  • Indicated for patients with posterior circulation LVO strokes within 24 hours depending on clinical-imaging criteria [observational studies]

 

Admit to stroke unit:

General measures:

  • Nurse head-down (flat) initially (<24hours) to improve perfusion vs. >30 degrees later to prevent pneumonia
  • Nothing by mouth & cough/gag/swallow assessment, then restart feeding
  • Temperature control: Acetaminophen/paracetamol if >37 degrees. [post hoc of RCT]
  • Monitor BP
  • Treat Hyperglycemia:
    • Insulin to prevent worsening of the pathology of the ‘ischemic penumbra’ [Theoretical basis]
    • GIK (GKI, glucose potassium insulin infusion) may be used safely. [GIST]
    • Insulin sliding scale is also an acceptable option and easier for most cases
  • Skin care, mobilize to prevent pressure ulcers
  • Early mobilization. Safe to start 24 hours after stroke onset. Safe to start rehabilitation 24 hours after stroke onset.
  • Prevention of contractures, range of motion exercise by nurses and care-givers
  • DVT prophylaxis:
    • Graduated compression stockings/thromboembolic deterrent stockings TED stockings are inefficacious. [CLOTS1].
    • LMW heparin rather than heparin [PROTECT, RCT]
    • Early mobilisation

 

Secondary prevention:

Antiplatelets VS anticoagulation depending on mechanism
Extracranial carotid artery stenosis:

  • Antiplatelets: Aspirin, clopidogrel, cilostazole. [IST,CAST, UK-TIA, NINDS-rtPA, ESPRIT,]
  • Statin
  • Blood pressure control
  • Smoking cessation if smoker
  • Diabetes mellitus control if diabetic
  • Plus revascularization with carotid artery stenting or carotid endarterctomy if stenosis is >70 % per NASCET criteria. [NASCET, ECST, CREST, ICSS, SAPPHIRE]

Extracranial vertebral artery stenosis:

  • Antiplatelets: Aspirin, clopidogrel, or cilostazole. [IST,CAST, UK-TIA, NINDS-rtPA, ESPRIT,]
  • Statin
  • Blood pressure control
  • Smoking cessation if smoker
  • Diabetes mellitus control if diabetic

Intracranial Atherosclerotic disease (ICAD):

  • Antiplatelets:
    • Aspirin, clopidogrel, or cilostazole. [WASID, IST,CAST, UK-TIA, NINDS-rtPA, ESPRIT,]
    • Consider aspirin plus clopidogrel for 3 months, then single antiplatelet after that. [SAMMPRIS]
    • Aspirin as effective as warfarin in this subtype but with lower hemorrhage risk. [WASID]
  • Statin
  • Blood pressure control
  • Smoking cessation if smoker
  • Diabetes mellitus control if diabetic

Small vessel disease:

  • Antiplatelets: Single antiplatelet therapy. Aspirin, clopidogrel, or cilostazole. [SPS3, MATCH]
  • Statin
  • Blood pressure control
  • Smoking cessation if smoker
  • Diabetes mellitus control if diabetic

Cardioembolic due to atrial fibrillation:

  • Anticoagulation:
    • Timing is controversial but should be initiated by 2 weeks at the most. Usually prior to guided by risk of hemorrhagic transformation
    • Apixaban, dabigatran, warfarin, rivaroxaban, or edoxaban. [ARISTOTLE, AVERROS, RE-LY, BAFTA, ACTIVE-W, ACTIVE-A, ROCKET-AF, RCTs]
    • Avoid therapeutic enoxaparin. [Meta-analysis shows NNT and NNH are similar 33 and 35]
  • Statin
  • Blood pressure control
  • Smoking cessation if smoker
  • Diabetes mellitus control if diabetic

Extracranial cervical artery dissection (carotid artery or vertebral artery):

  • Antiplatelets or anticoagulation are both effective. [CADISS]

Paradoxical embolism:

  • Anticoagulation or antiplatelets
  • No benefit to closure of patent foramen ovale (PFO)

 
Infective endocarditis:

  • Intravenous antibiotics
  • Avoid anticoagulations
  • Surgery in some patients

 

Risk factor optimization:

Blood pressure control:

  • No benefit to early rapid reduction of blood pressure, but significant benefit from long-term treatment of hypertension. [WASID, SAMMPRIS, PROGRESS]
  • Gradually reduce the blood pressure during the subacute phase of stroke.
  • Agents:
    • ACEi +thiazide: Perindopril P.O. +indapamide P.O. [PROGRESS]
    • Calcium channel blockers
    • Beta blockers
    • Direct vasodilators
    • Other agents

Lipid management:

  • Goal: LDL <1.8mmol/l (70mg/dl), or high does statin regardless of LDL.
  • Statin pravastatin P.O. to reduce coronary events & secondary prevention [HPS]
  • Agents: Atorvastatin P.O. [SPARCL]

Diabetes & hyperglycemia:

  • Acutely, avoid hyperglycemia
  • Chronically, screen for & treat diabetes

Smoking cessation
Alcohol: reduce if heavy alcohol consumption
Obesity: targets BMI of 18.5 to 24.9 kg/m2 and a waist circumference of <88cm (35inch) for women and <102cm (40 inch) for men
Diet, exercise

Complications and related issues:

Malignant MCA syndrome (space occupying middle cerebral artery infarction cerebral edmea) with hemispheric infarct & patients 18-60 years old within 48hrs and in some patients older than 60 years old:

  • Hemicraniectomy.[HAMLET, DECIMAL, DESTINY & metanalysis] [312]
  • Adjuncts to decompression:
    • Osmotherapy: 3% NaCl &/or Mannitol (see under cerebral oedema for dosing etc)
    • Hyperventilation, very temporary measure
    • Corticosteroids are not used

Impending herniation with cerebellar infarct:

  • Posterior fossa decompression, Suboccipital craniotomy
  • Osmotherapy: 3% NaCl &/or Mannitol 20% or 25%

 

Rehabilitation:

Safe to start 24 hours after stroke onset
Core compoennts:

  • Early mobilization
  • Speech & language therapy
  • Physical therapy
  • Occupational therapy

3-9 months post stroke: Consider intensive 2-week program of constraint-induced movement therapy CIMT [EXCITE]:

  • Up to 6 h each weekday of using the paretic limb for functionally relevant repetitive tasks,including shaping procedures.
  • +Restraint of the less affected wrist & hand during most waking hours.

 

Primary prevention of stroke:

Risk factor control:

  • Blood pressure control
  • Smoking cessation if smoker
  • Lipid control [HPS, LIPID]
  • Diabetes mellitus control if diabetic
  • Physical activiy

Antiplatelet agents in selected patients.
Rapid evaulation and treatment of transient ischemic attacks (TIA) [CHANCE]

Related articles:

References:

  1. Statins after ischemic stroke and transient ischemic attack: an advisory statement from the Stroke Council, American Heart Association and American Stroke Association. Stroke, 2004. 35(4): p. 1023.
  2. Adams, H.P., Jr., et al., Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke, 2003. 34(4): p. 1056-83.

Listeria Rhombencephalitis

Diseases, ,

Synonyms:

Listeria brainstem encephalitis, neurolisteriosis, Listeria meningitis if without parenchymal involvement

Diagnosis:

  • Positive CSF gram stain & culture: gram positive bacillus, Listeria monocytogenes
  • Or Positive blood culture: growing Listeria monocytogenes
  • Listeria meningitis if without parenchymal involvement

Clinical features:

  • Fever +headache, then brainstem signs, then coma & respiratory failure

Findings on Investigations:

MRI:

  • lesion in brainstem (pons & medulla). T2 hyperintense lesion. T1 plus contrast small ring enhancing.

CT: usually normal
CSF analysis:

  • Lymphocytic pleocytosis (Polymorphonuclear PMN pleocytosis may occur), raised protein, normal glucose

Treatment:

  • Ampicillin
  • Sometimes combined with aminoglycoside e.g. gentamicin

Viral Encephalitis

Diseases, , ,

Viral encephalitis is the commonest cause of encephalitis. The general features and causes of encephalitis are described in a separate section. Here we discuss the various viral encephalitides.
 

HSV Encephalitis:

Diagnosis:

Clinical findings combined with MRI features and isolation of virus by PCR or pathology

Findings on investigations:

CT:

  • Low density in: Insular regions, hippocampus, cingulated gyrus

MRI:

  • T2 high signal intensity, especially in the temporal lobes or orbitofrontal lobe
  • May cause Rhombencephalitis

Electroencephalography, EEG:

  • Temporal lobe disease
  • Periodic lateralised epileptiform discharges (PLEDs),
  • Temporal spikes at 2-3Hz

CSF PCR: false negatives can occur
Lumbar puncture & CSF analysis:

  • White cell counts: high,
    • Lymphocytes or monocytes, can be very high
  • RCC: raised in HSV encephalitis
  • Opening pressure: Normal or mildly elevated 100-350 mmH2O
  • Glucose normal or slightly decreased
  • Protein: normal or slightly increased 0.2-0.8 g/L (20-80 mg/dL)
  • Oligoclonal bands & electrophoresis abnormalities may occur

Pathology, Biopsy:

  • Perivascular lymphocytes
  • Lymphocytic infiltrate
  • Microglial proliferation
  • Intranuclear & cytoplasmic inclusions, Cowdry A inclusions (large with halo)

 

Treatment:

  • Acyclovir I.V. for at least 3 weeks

 

West Nile Virus encephalitis, WNV meningoencephalitis & WMV neuropathy WNV:

Clinical features:

  • –      Meningeal symptoms: fever, headache, neckstiffness, rash
  • Encephalopathy, seizures may occur
  • Myoclonus, tremour, rigidity, postural instability, bradykinesia, Cranial nerve palsies, vertigo, cerebellar ataxia
  • Flaccid paralysis syndrome may occur (with or without encephalitis)
  • Optic neuritis & chorioretinitis

Diagnosis:

  • Clinical features plus CSF antibody tests or isolation of the virus

Findings on Investigations:

+CSF IgG & IgM for West nile virus:

  • Microspheric immunoassay (MIA): if serology is positive to exclude a heterologous response to other flaviviruses

+CSF PCR for WNV:

  • False negatives occur

+Serology: IgG & IgM for West nile virus: not 100% specific, negative test doesn’t rule out infection
CSF analysis:

  • CSF: lymphocytic pleocytosis (rarely normal), raised protein, normal glucose,

CT: is usually normal
MRI:

  • leptomeningeal or pervascular enchancement. T2: normal initially, high signal in caudate nuclei, thalami, brainstem, spinal cord,
  • MRI brachial plexus: Thickened brachial plexus on T2 in WNV neuropathy

EEG: non-specific features of encephalopathy
NCS/EMG:

  • normal SNAPs, reduced CMAPs

 

 

Rabies encephalitis:

Clinical features:

  • Prodrome: headache, fever, malaise, anxiety
  • Dysphagia,
  • Hydrophobia: laryngeal spasm on swallowing liquids
  • Seizures

Pathology, biopsy:

  • Negri bodies: eosinophilic intracytoplasmic inclusions in pyramidal cells & Purkinje cells
  • Babes nodules: microglial nodules

Treatment:

  • Clean the wound
  • Human rabies Ig
  • Human diploid cell vaccine

Tension-Type Headache

Diseases

Tension-type headache (TTH) is the commonest headache. It has a very high incidence with most people experiencing a tension-type headache at some point in their lives. There are many subtypes of Tension-type headache. The commonest one is the infrequent episode variant which tends to be mild and self-limiting. However, other people may experience more frequent or chronic tension-type headache and this can be severe. These variants can lead to decreased quality of life and disability.

Synonyms:

  • Formerly known as: Tension headache, ordinary headache, muscle contraction headache, stress headache, essential headache, idiopathic headache, psychogenic headache, psychomyogenic headache

Clinical features:

  • The headaches are typically bilateral, have a tension (pressure or tightening) character and may last from minutes to days.
  • The headache is non-pusating and not aggravated by routine physical activity such
    as walking or climbing stairs. There is no vomiting with the headaches. Usually there is no nausea but in severe cases mild nausea may occur. Photophobia or phonophobia may occur but not both.
  • There are no auras or focal neurological signs.
  • Increased pericranial tenderness may occur in tension-type headache. This is often present even when the patient is not experiencing a headache. The pericranial tenderness occurs in the following muscles:  frontalis, temporalis, masseter, pterygoid, sternocleidomastoid, splenius and trapezius.
  • The neurological examination is normal.

Diagnosis:

International Headache Society IHS criteria:

At least 10 previous headache episodes fulfilling criteria below:

  • Number of days with such headache is < 180/yr (< 15/mo)
  • Headache lasting from 30 min to 7 days
  • At least two of the following pain characteristics:
    • Pressing or tightening (nonpulsating) quality
    • Mild or moderate intensity (may inhibit but does not prohibit activities)
    • Bilateral location
    • No aggravation by walking stairs or similar routine activity
  • Both of the following:
    • No nausea or vomiting (anorexia may occur)
    • Photophobia and phonophobia are absent, or one but not the other is present
  • No evidence of another illness that can explain the headache

Other notes:

Migraine without aura is the commonest differential diagnosis

Treatment:

Treatment is usually with simple analegics like acetaminophen and education to avoid medication over-use headache. In some cases, especially more frequent or chronic variants, other medications may be indicated.

Acutely:
Prophylaxis:
  • Medications in selected patients with frequent headaches:
    • Amitriptyline
    • Mirtazapine and venlafaxine
    • Some consider: SSRI (sertraline, fluoxetine), Propranolol
  • Acupuncture for prophyaxis, at least 6 sessions [good evidence, by multiple RCTs, and 2014 Cochrane systematic review]
  • Address psycho-social stressors
  • Cognitive behavioural therapy and relaxation techniques training for selected patients
  • Electromyography (EMG) biofeedback in selected patients

Related articles:

References:

  1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658. PMID: 23771276
  2. Linde K, Allais G, Brinkhaus B, Fei Y, Mehring M, Shin BC, Vickers A, White AR. Acupuncture for the prevention of tension-type headache. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD007587. DOI: 10.1002/14651858.CD007587.pub2. PMID: 27092807
  3. Bendtsen L1, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J; EFNS. EFNS guideline on the treatment of tension-type headache – report of an EFNS task force. Eur J Neurol. 2010 Nov;17(11):1318-25. doi: 10.1111/j.1468-1331.2010.03070.x PMID: 20482606

Encephalitis

Diseases, , , ,

Encephalitis is the term used to describe an inflammatory process of the substance of the brain. This distinguishes it from meningitis which is an inflammatory process of the coverings of the brain. There are patients who have inflammation of both areas and this is described as meningo-encephalitis. Patients with encephalitis and those with meningitis present differently. The underlying causes of encephalitis are different from causes of meningitis. Encephalitis has many causes, as outlined below. The inflammatory process may be infectious in origin or non-infectious. Viral encephalitis is the commonest cause of infecious encephalitis. Non-infectious causes of encephalitis include autoimmune and paraneoplastic diseases.

Clinical features:

The cardinal symptom of encephalitis is confusion. In other words, encephalitis presents as a cause of encephalopathy. There is loss of attention, disorientation and in severe cases decreased level of consciousness. The encephalopathy is often accompanied by a fever, headache or a seizure. As a clinical pearl: the presence of fever in a patient with encephalopathy should always raise encephalitis in the differential diagnosis even though the eventual diagnosis may be a systemic infection.
When there is a high enough clinical suspicion of encephalitis, empiric therapy is often started with acyclovir for Herpes Simplex Virus (HSV) encephalitis while the investigations are being obtained for confirmation and for competing diseases. This is a clinical decision that is individualized based on potential benefits vs. risks.

Investigations to consider:

MRI:

  • Patterns of disease on MRI may help narrow down the cause of encephalitis
  • To assess for competing causes (diseases other than encephalitis) in the differential diagnosis

CSF analysis:

  • Often abnormal, raised WCC, mildly elevated protein
  • Gram stain & culture
  • VDRL: syphilis
  • PCR: HSV, VZV, EBV, CMV, enterovirus, WNV, TB
  • Serology: WNV, VZV, measles
  • AFB & culture: TB
  • India ink: Cryptococcus
  • Cryptococcal antigen
  • CSF wet mount: Naegleria fowleri
  • IgG index

Electroencephalography, EEG:

  • May demonstrate slowing of background, dysregulation, Periodic Lateralized Epileptiform Discharges (PLEDs) or seizures

Blood tests:

  • LFTs: EBV, herpes viruses, Alpers syndrome
  • Amylase: mumps
  • Tests for infections:
    • Blood smear: atypical lymphocytes in EBV
    • Heterophil antibody: EBV
    • Cryptococcal antigen
    • Toxoplasma serology
  • Paraneoplastic antibodies/autoimmune antibodies: Anti-Hu (ANNA-1), CV2 (CRMP5), Ma2/Ta, amphiphysin, Yo, Ri, Zic4, voltage gated potassium channel (VGKC), anti-NMDA antibodies
  • Voltage-gated potassium channels (VGKC): autoimmune or paraneoplastic limbic encephalitis
  • POLG mutation analysis: mitochondrial disease

Brain biopsy in some cases
Muscle biopsy:

  • Mitochondrial DNA analysis for mitochondrial disease

Causes of encephalitis:

  • Viral encephalitis:
    • HSV1, HSV2, VZV, CMV, EBV
    • Measles, mumps
    • Polio, Rabies
    • Arboviruses: West nile virus, Japanese B encephalitis, St. Louis encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, and Venezuelan equine encephalitis virus, tick borne encephalitis viruses
    • Influenza A virus
  • Bacterial encephalitis:
    • Listeria monocytogenes (Listeria rhombencephalitis)
    • Mycobacterium tuberculosis
    • Other bacteria: Borrelia burgdorferi (Lyme disease), Mycoplasma pneumoniae, Leptospirosis, Brucellosis, Leptospirosis, Legionella, Tropheryma whippeli (Whipple’s disease), Nocardia actinomyces, Treponema pallidum, Salmonella typhi,
    • Rickettsial, Rickettsia rickettsia (Rocky Mountain spotted fever), Rickettsia typhi (endemic typhus), Rickettsia prowazeki (epidemic typhus), Coxiella burnetti (Q fever), Ehrlichiosis (Ehrlichia chaffeensis—human monocytic ehrlichiosis)
  • Fungal encephalitis:
    • Cryptococcus, Aspergillosis, Candidiasis
    • Coccidiomycosis, Histoplasmosis
    • North American blastomycosis
  • Parasitic:
    • Toxoplasma gondii
    • Cerebral malaria
    • Trypanosomiasis (sleeping sickness)
    • Echinococcus granulosus, Schistosomiasis
  • Non-infectious:

Related articles:

Fungal Meningitis

Diseases, , ,

There are various fungi that may cause meningitis. The manifestations vary by causative organism and host immune status. Some organisms are more common in certain geographical locations. Patients may present acutely with headache and encephalopathy or may have a much more indolent course.
 

 

Cryptococcal meningitis:

Synonyms:

Cryptococcosis (Cryptococcus neoformans)

Diagnosis:

Clinical findings plus isolation of the cryptococcus neoformans organism or identification of cryptococcal antigen

Findings on investigation:

CSF analysis:

  • Cryptococcus antigen: positive. 95% sensitive
  • India Ink stain: positive, 50% sensitive, white capsule, pale nucleus
  • WCC: high opening pressure, lymphocytosis in low counts, reduced glucose but may be normal, elevated protein,

Blood, in disseminated infection:

  • Blood cryptococcal antigen: positive, false positive in patients with positive rheumatoid factor RF
  • Isolator cultures: positive
  • Fungal culture:
    • For 6 weeks at 37 degrees

CT:

  • Hypodensity suggest infarcts
  • Hydrocephalus

MRI:

  • Findings of infarcts may occur
  • Hydrocephalus
  • T2: Basal ganglia hyperintense cysts (gelatinous pseudocysts), T1 +GAD: mildly enhancing
  • Gyral enhancement

MRA:

  • Findings of vasculitis may occur

Angiography:

  • Findings of vasculitis may occur

Other tests:

  • CXR: pulmonary infiltrates +/- lymphadenopathy may occur. May be negative in pulmonary disease. Bronchoalveolar lavage (BAL) culture or cryptococcal antigen positive

Pathology, Biopsy:

  • Immunocompetent patients: Focal granuloma, macrophages, microglia
  • Immunodeficient patient: no or minimal inflammation
  • H&E: clear capsule, blue nucleus, involves Virchow-Robin spaces. More organisms in immunodeficient patients.
  • Meninges: GMS stain, Cryptococcus organisms
  • India ink CSF: white capsule, pale nucleus

Cryptococal meningitis treatment:

  • Amphotericin B
  • Fluconazole

Related articles:

Tuberculous Meningitis

Diseases, , , , ,

Synonyms:

Mycobacterium tuberculosis meningitis, TB meningitis, tuberculoma, tuberculous meningovasculitis

Diagnosis:

Clinical features plus confirmatory CSF analysis or TB studies

Findings in Investigations:

  • Findings remain after 10 days treatment
  • White cell count: moderately high,
    • Usually <500/microL, (100-300/mm3)
    • Mainly lymphocytes
  • Protein: High, >0.8g/L
  • Glucose: Low ,<2.2 mmol/l
  • Or atypically:
    • Neutrophilia if early, normal protein, normal glucose
    • Eosinophilia may occur
  • Acid fast stain positive in 20%
  • Culture is positive in 80%
  • CSF PCR: for TB

MRI:

  • Tuberculomas: gadolinium enhancement, nodular
  • Infarctions in vasculitis

MRA:

  • In vasculitis diffuse narrowing of the arteries. However, affected blood vessels are typically small and may not be abnormal on MRA

Angiogram/angiography:

  • Proximal carotid artery & basilar artery stenosis: vasculitis of “basilar meningitis”
  • May be normal

Pathology/biopsy:

Gross:

  • Grey pus in the subarachnoid space, usually basal. Tuberculoma= round/oval mass with necrotic creamy centre.

Microscopic:

  • Granuloma. Caseating necrosis, Langhan multinucleated giant cells, histiocytes, lymphocytes, plasmacytes. Surrounding gliosis in tuberculoma.
  • Obliterative endarteritis= thickened intima by collagen. Fibrinoid necrosis & thrombosis of meningeal vessels.
  • Ziehl-Neelsen stain: Acid fast (red) bacilli.

Treatment options:

Treat early, on clinical suspicion before confirmation by diagnostic tests
TB chemotherapy:

  • Look up the updated regimen. Here are examples
  • WHO regimen:
    • 2 months P.O.: isoniazid +rifampin +pyrazinamide +ethambutol
    • +4 months P.O. continuation: isoniazid +rifampin
  • Infectious Diseases Society of America (IDSA) regimen:
    • 2 months P.O.: isoniazid +rifampin +pyrazinamide +ethambutol
    • 9-12 months continuation: isoniazid +rifampin
  • Immunomodulation i.e. corticosteroids, NB. rifampin increased the dose needed

Hydrocephalus:

  • Non-communicating:
    • Immediate ventriculoperiotoneal shunt or external ventricular drain
  • Communicating:
    • Consider medications: frusemide +acetazolamide
    • Consider ventriculoperitoneal shunt

Related articles:

Viral Meningitis

Diseases, ,

Diagnosis:

Clinical features plus confirmation by CSF analysis & isolation of the virus or PCR or antibody tests

Findings on Investigations:

CSF analysis:

  • Early LP may show:
    • Increased neutrophils,
  • Glucose normal
  • Later:
    • White cell counts: moderately high,
    • <1000/mL (usually 25-500/microL)
    • Lymphocytes or monocytes
  • RCC: raised in HSV encephalitis
  • Glucose normal
  • Protein:
    • Usually normal
    • Or slightly increased 0.2-0.8 g/L (20-80 mg/dL)
  • Normal or mildly elevated opening pressure 100-350 mmH2O
  • Notes: Recurrent viral meningitis a.k.a. Mollaret meningitis: lymphocytic tap, Mollaret cells= atypical monocytes with bilobed nuclei & amorphous cytoplasm
Confirmatory viral studies:
  • PCR: for HSV, enterovirus
  • Enterovirus (PCR), coxasckie, echovirus
  • HSV2 & 1 (PCR), VZV, EBV, CMV, HHV6
  • Arboviruses: St. Louis encephalitis virus, West Nile virus WNV (CSF IgG & IgM), California encephalitis virus, western equine encephalitis virus, eastern equine encephalitis virus, Japanese B virus, Murray Valley virus, coltivirus.
  • Zoonosis: Lymphocytic choriomeningitis virus LCMV (paired serology)
  • Mumps (paired serology)
  • HIV

Treatment:

  • Usually self limited
  • Treat seizures if they occur
  • Consider supportive treatment as needed depending on neurological and systemic status
  • If with HSV encephalitis, treat as encephalitis with aciclovir I.V.
  • Avoid Aspirin

Related articles:

Bacterial Meningitis

Diseases, , , ,

Diagnosis:

Clinical features plus confirmation by CSF analysis
Findings in Bacterial meningitis:

  • High opening pressure >180 mmH2O, turbid/purulent appearance
  • White cell count: high, 10-10,000/microL
    • Mainly neutrophils (usually >100), but monocytes are suggestive of Listeria monocytogenes
  • Protein: High, >0.45 g/L (>45 mg/dL)
  • Glucose: low, <0.4 of serum (roughly <1/2 serum), or <2.2 mmol/L (<40 mg/dL)
  • Borrelia burgdorferi, Lyme disease:
    • White cell count <100/mm3, <30% neurtrophils
    • Protein: normal or high
    • Glucose: normal
  • CSF PCR for Neisseria meningitides, Haemophilis influenzae, Listeria monocytogenes, Borrelia burgdorferi
  • Meningococcal septicemia: blood cultures, skin scrapings of the rash, +/-PCR

Pathology:

Gross:

  • Creamy yellow pus surrounding the brain

Microscopic:

  • Neutrophils in the subarachnoid space & in Virchow-Robin spaces surrounding vessels. Leptomeningeal vessels may be involved.
  • Gram stain: organisms

Monitor:

  • In children with meningitis consider get follow up hearing tests

Treament:

This is an emergency, start abx. before confirming the diagnosis by lumbar puncture
Antibiotics considerations:

  • See updated list according to current bacterial sensitivities in your community
  • Penicillin intravenous +3rd generation cephalosporin (Cefotaxime or ceftriaxone) I.V. X10 days
  • Or Vancomycin +3rd generation cephalosporin I.V.
  • Or if Listeria is suspected Ampicillin I.V. +Vancomycin +3rd generation cephalosporin I.V.
  • If neonatal:
    • Ampicillin I.V. +(Cefotaxime or ceftriaxone) X14-21 days
    • Or Ampicillin I.V. +gentamicin I.V.
  • If pregnant: consider Cefotaxime +ampicillin
  • If pneumococcus is suspected or confirmed. +Dexamethazone 0.15 mg/kg q6h X4 days starting before or with first dose of abx.
  • If Borrelia X14-28 days
  • Consider protein C administration [Debatable]
  • If mastoiditis, mastoidectomy

Prophylaxis of contacts:

  • If N. meningitides:
    • Give ciprofloxacin or rifampin to eradicate pharyngeal carriage.
    • In outbreaks use ciprofloxacin.

Related articles:

References:

  1. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov 1;39(9):1267-84. Epub 2004 Oct 6.

Meningitis

Diseases, , ,

Clinical features:

Patients present with headache and necks stiffness. They typically have a fever, unless they are immunosupressed, and may have a rash. The classic triad in bacterial meningitis is headache, fever and rash. It is a serious life-threatening medical emergency that often results in significant disability. However, the commonest cause of meningits overall is viral meningitis; which is typically a self-limited disease. Mycobacteria tuberculosis (TB) also causes a meningitis that may have serious medical consequences such as meningovascular infarcts, arachnoiditis or hydrocephalus. Fungal infections can also cause meningitis and may often have a very indolant course before causing significant complictions such as vasculitis or hydrocephalus. Some fungal infections are more important in immunocompromised hosts. Lastly cancers may spread to the meningeal space and result in carcinomatous meningitis or lymphomatous meningitis, but the clinical presentation is usually different. Carcinomatous meningitis usually presents with polyradiculopathy rather than with headache. This section gives a brief overview of menigitis. The other subtypes are discussed elsewhere.
On physical examination patients may be normal, have meningismus, encephalopathy or be comatose. Fundoscopy may reveal papilloedema. When secondary injury occurs other focal features may develop.
 

Findings on investigations:

CSF analysis:

  • May be normal if hyperacute (rare), raised WCC +/-raised protein

CT:

  • Commonly normal
  • Cerebral oedema +/-herniation may occur
  • Distended subarachnoid space +/-distended basal cisterns
  • Communicating hydrocephalus: enlarged ventricles including 4th, effacement of basal cisterns

MRI:

  • Commonly normal
  • Cerebral oedema +/-herniation
  • Distended subarachnoid space, communicating hydrocephalus
  • FLAIR: high signal in subarachnoid space, rarely parenchymal hyperintensity
  • DWI: high signal in sulci, hyperintense cortex if infarction or vasculitis occur
  • T1 +contrast: leptomeningeal enhancement that extends to the sulci may occur. Look at (basal cisterns, cerebellar folia, sulcal perivascular spaces)
Investigations to consider:
  • Blood cultures before antibiotics if feasible
  • CT head
  • CSF analysis, Lumber puncture. Note: exclude raised intracranial pressure and mass lesions before:
    • Cell count & differential, Glucose, protein, gram stain & culture

Consider:

  • HIV testing; presence of HIV broadens the list of possible causes significantly
  • Bacterial antigen panel
  • Viral studies
  • Atypical bacteria & related:
    • Acid fast bacilli staining
    • TB PCR
  • Spirochetes: VDRL (CSF & Serum), Lyme serology (CSF & serum)
  • India ink preparation & culture
  • Tests for Rickettsia rickettsii (Rocky mountain spotted fever)
  • Fungal wet mount & culture
  • Cryptococcal antigen
  • Oligoclonal bands, IgG index
  • PCR for certain organisms as appropriate
  • Cytology: Metastasis
  • Flow cytometry: lymphomatous meningitis
  • Coccidioides: blastocysts
  • If a rash is present, skin scrapings & blood cultures
  • If TB meningitis is suspected, obtain systemic confirmatory tests as well as CSF TB PCR

CT or MRI: to assess for hydrocephalus or competing diagnosis

Causes of meningism:

  • Meningtitis: (see causes)
  • Subarachnoid hemorrhage
  • Pituitary infarction a.k.a. pituitary apoplexy

 

Causes of meningitis:

  • Bacterial meningitis:
    • Neisseria meningitides, Streptococcus pneumonia
    • Mycobacterium tuberculosis
  • Viral meningitis:
    • Enterovirus, coxasckie, echovirus
    • HSV2 & 1, VZV, EBV, CMV, HHV6-
    • Arboviruses:
      • St. Louis encephalitis virus, West Nile virus WNV, California encephalitis virus, western equine encephalitis virus, eastern equine encephalitis virus, Japanese B virus, Murray Valley virus, coltivirus.
    •  Zoonosis:
      • Lymphocytic choriomeningitis virus LCM
    • Mumps
    • HIV
  • Fungal meningitis:
    • Cryptococcus neoformans
  • Parasitic meningitis
  • Neoplastic meningitis/Metastatic meningitis:
    • Acute leukemia, Large cell lymphoma,
    • Breast cancer, lung cancer, melanoma, gastrointestinal malignancies, and cancers of unknown primary (CUP)
  • Chemical meningitis:
    • Drug induced meningitis: NSAIDs, Trimethorpim-sufamethoxazole TMP-SMX, IVIG, rofecoxib, OKT3 antibodies

 

Causes of lymphocytic meningitis (i.e. lymphocytic pleocytosis, i.e. mononuclear cells on CSF):

  • Viral meningitis (see viral meningitis)
  • TB meningitis
  • Listeria meningitis
  • Spirochetes:
    • Syphilis
    • Lyme disease
    • Leptosiprosis
  • Tickborn diseases (excluding arboviruses)
    • Rocky mountain spotted fever
    • Ehrlichiosis
  • Parameningeal infection & related:
    • Prevertebral abscess
    • Vertebral osteomyelitis
    • Bacterial endocarditis with cerebrospinal fluid seeding
    • Partially treated bacterial meninigitis
    • Sinusitis/otitis
  • Fungal meningitis:
    • Cryptococcus neoformans
    • Coccidioides immitis a.k.a. Coccidioidomycosis
  • Cerebral Malaria
  • Toxoplasmosis
  • Trypanosomiasis
  • Neoplastic meningitis/metastatic meningitis: (see neoplastic meningitis)
  • Others:
    • Vasculitis
    • Post-vaccinal encephalitis
    • Subarachnoid hemorrhage
    • Behcet’s syndrome
    • Sarcoidosis
    • Seizure (diagnosis of exclusion, low level pleocytosis)

 

Causes of meningitis with neutrophilic pleocytosis:

Infectious:

  • Bacterial meningitis and ruptured brain abscess (see bacterial meningitis)
  • West nile virus (WNV) meningitis (rare presentation)
  • Amebic meningoencephalitis

Non-infectious:

  • Drug induced meningitis: Sulfonamides, isoniazid, (see drug induced meningitis)
  • Chronic neutrophilic meningitis
  • NSAID meningitis in patients with collagen vascular disease
  • Severe juvenile idiopathic arthritis (JIA) a.k.a. Still’s disease

Related articles:

Amyotrophic Lateral Sclerosis

Diseases, , ,

Synonyms:

Lou Gehrig disease

Clinical features:

  • Features of upper motor neuron (UMN) disease (including increased reflexes in wasted limb) & lower motor neuron (LMN) disease
  • +/-pseudobular palsy
  • +/-cramps
  • Weakness, fasciculations
  • No sensory disturbance, no bowel or bladder dysfunction

Diagnostic criteria:

  • El Escorial criteria, also known as, World Federation of Neurology criteria (used more for research)
  • In general:
    • Features of upper motor neuron disease, by clinical testing or electrophysiology or neuropathology
    • Plus features of lower motor neuron disease, by clinical testing or electrophysiology or neuropathology
    • Progression over time within the region or to other regions
    • Exclusion of other conditions by electrophysiology and imaging

Findings on Investigations:

Nerve Conduction Studies/Electromyography NCS/EMG:
  • Use to rule out competing diagnosis in the differential diagnosis

Nerve conduction study, NCS:

  • SNAP: normal, normal amplitude, velocity & latency
  • CMAP: normal or mildly reduced velocity & latency, reduced amplitude

Electromyography, EMG:

  • Denervation (fibrillation potentials, positive sharp waves PSW) in 3 limbs or 2 limbs +bulbar muscles. Fasciculation potentials & complex repetitive discharges CRDs may occur.
  • MUAP (reinnervation): polyphasic, large amplitude, increased duration,
  • Decreased recruitment
Other tests:

MRI:

  • T2, FLAIR: symmetric hyperintensity of the corticospinal tracts in the brain (centrum semiovale, internal capsule), brainstem (cerebral peduncles) & spinal cord (lateral columns)

Pathology, Muscle biopsy:

Denervation pattern in clinically unaffected muscle see below
Gross:

  • Atrophy of cervical & lumbosacral parts of the spinal cord. Atrophy of motor nerve roots, sparing of the sensory nerve roots. Atrophy of precentral gyrus.

Microscopically:

  • Loss of anterior horn cells in the spinal cord. Loss of Betz cells in the primary motor cortex. Degeneration (anterograde) of anterior & lateral corticospinal axons/tracts. Myelin loss, astrocytic gliosis & macrophage accumulation. Bunina bodies= small eosinophilic bodies, cytoplasmic, in anterior horn cells. Skeletal muscle; features of denervation

Immunohistochemsitry:

  • Bunina bodies are cystatin C positive & ubiquitin negative. Ubiquitin: positive spherical cytoplasmic inclusions in anterior horn cells. Neurofilament: dystrophic axons
  • TDP-43 (TAR DNA binding protein 43): positive inclusions

Genetic forms:

  • ALS1: Autosomal dominant, Protein= Cu/Zn Superoxide dismutase, SOD1 gene chr. 21,
  • ALS2: autosomal recessive, chr. 2q33, protein= is a GTPase regulator

Related conditions:

  • Frontotemporal lobar degeneration with motor neuron disease FTLD-MND: see FTD
To rule out other disease consider:
  • Hexosaminidase levels: hexosaminidase deficiency
  • MRI: to rule out cervical spondylosis
  • Anti-GM1: MMN, also positive in ALS
  • Parathyroid hormone level: hypoparathyroidism can cause fasciculations & weakness

Treatment

General measures:

Consider Respiratory evaluation:

  • PFTs, Overnight pulse oximetry, SNIP
  • Early morning ABG: hypercapnea i.e. hypoventilation
  • Respiratory support:
    • Consider NIPPV at night time

Speech & language therapy evaluation
Discuss palliation & end of life decisions early & continue
Immobility: consider braces or a walker
Physiotherapy esp. to prevent contractures
Dysphagia, consider:

  • Semiliquid diet
  • Nasogastric tube feeding
  • Percutaneous endoscopic gastroscopy PEG
Pharmacological:
  • Riluzole P.O. to slow progression in ALS

If drooling consider anticholinergics:

  • Glycopyrrolate, trihexyphenidyl, amitriptyline, transdermal hyoscine

Related articles:

References:

  1. Haggiag, S., et al., Seroconversion of anti-GM1 antibodies in patients with amyotrophic lateral sclerosis. Neurology, 2004. 63(4): p. 755-6.

Parkinson's Disease

Diseases, , ,

Synonyms:

Paralysis agitans:

Clinical features:

  • Triad of:
    • Bradykinesia
    • Rigidity.
    • Tremor: this is not essential for the diagnosis
  • Important characteristics: asymmetry, upper body is affected first, fluctuation in severity, postural instability later on
  • BP & postural BP: to exclude Shy-Dragger syndrome
  • Other clinical points:
    • Re-emergent tremor: on testing for postural tremour, initially there is no tremour then after a latency the tremour re-emerges.
    • +/-levodopa challenge
    • +/-negative CT or MRI imaging
  • Parkinson’s disease dementia:
    • Dementia that develops at least 2 years after the diagnosis of Parkinson’s disease

Pathology:

Gross:

  • Pallor of the substantia nigra & locus ceruleus

Microscopically:

  • In substatian nigra; decreased density of pigmented neurons, pigment laden macrophages, free pigment (pigment incontinence), astrocytic gliosis.
  • Lewy body formation= spherical eosinophilic intraneuronal cytoplasmic inclusions. Cortical Lewy bodies lack a halo. Lewy bodies in substatia nigra, locus ceruleus, nucleus basalis of Meynert, dorsal vagal nucleus, hypothalamus, olfactory bulb, Edinger-Westphal nucleus, raphe nuclei, intermediolateral column of the spinal cord, autonomic ganglia (sympathetic= paravertebral and celiac ganglia, parasympathetic= submandibular ganglion). Also in cortex (temporal, insular, cingulate gyrus). Pale bodies are also found in the substantia nigra. Extracellular Lewy neuritis= nerve fibres with eosinophilic material, occur.
  • Immunohistochemistry: Lewy bodies and extracellular Lewy neurites are alpha synuclein positive and also ubiquitin positive
  • Silver stain: also detects alpha synuclein.
  • Epicardial space nerve fibres: Tyrosine hydroxylase staining is decreased (cardiac denervation, sympathetic)

Braak Staging:

  • Stage 1:
    • Dorsal IX/X motor nucleus,
  • Stage 2:
    • Caudal raphe nuclei (nucleus raphes magnus, obscurus, pallidus),
    • Reticular formation (Gigantocellular reticular nucleus)
    • Coeruleus-subcerulus complex
  • Stage 3:
    • Midbrain lesions: pars compacta of substatia nigra
  • Stage 4:
    • Prosencephalic lesions.
    • Cortical involvement is confined to the temporal mesocortex (transentorhinal region) and allocortex (CA2-plexus). The neocortex is unaffected
  • Stage 5:
    • High order sensory association areas of the neocortex and prefrontal neocortex
  • Stage 6:
    • First order sensory association areas of the neocortex and premotor areas,
    • Occasionally mild changes in primary sensory areas and the primary motor field

Genetic forms:

Autosomal dominant:

  • Alpha-Synuclein= protein, SNCA gene chr. 4q21
  • Protein= Dardarin= Leucine-rich repeat kinase 2, LRRK2 gene chr. 12q12

Autosomal recessive:

  • PRKN gene a.k.a. PARK2 gene 6q25.2-q27, Parkin= protein: Autosomal recessive juvenile parkinsonism.
  • PTEN-induced putative kinase-1= PINK1 gene chr. 1p36
  • DJ1 gene chr. 1p36, protein= DJ1
  • PARK7 gene
  • ATP 13A2

Findings on Investigations:

Cardiac denervation by:

  • Cardiac SPECT 123I –labeled MIBG, reduced uptake
  • PET scan

Trancranial ultrasound:

  • Hyperechogenicity: substantia nigra & median raphe

PET:

  • Cardiac denervation
  • 18F-dopa PET: Images dopa decarboxylase activity at dopamine terminals (dopamine turnover)
  • Reduced uptake in putamen,
  • Initially increased & then decreased uptake in globus pallidus

DAT PET: images presynaptic dopamine transporters,

  • Reduced uptake in putamen
  • 11C-DTBZ PET: images vesicle monoamine transporter density in dopamine terminals,

SPECT:

  • DAT SPECT (123I-FP-CIT SPECT) “DaTscan”:
    • Images presynaptic dopamine transporters
    • Helps differentiate between PD (abnormal, reduced in putamen) and essential tremor (normal)

MRI:

  • Normal
  • Hippocampal & temporal atrophy in Parkinson’s with dementia
  • DWI MRI & ADC: normal, normal putamen, normal middle cerebellar peduncle.

MRI volumetry:

  • Reduced putamen volume

Autonomic function testing:

  • Tilt table testing, if orthostatic hypotension is present:
  • Upright tilt: BP declines progressively (not suddenly) until syncope occurs. No acute bradycardia
  • Valsalva maneuver, if orthostatic hypotension is present:
  • Beat-to-Beat BP responses: during straining after the nadir (lowest BP point) there is absence of normal BP increase. Also after straining (Valsalva) there is absence of normal BP overshoot.

Monitor & Scales:

Unified Parkinson’s Disease Rating Scale UPDRS:

Grading:

  • 0 best score
  • 199 worst score
  • Motor section: 40 is severe disability

UPDRS, Motor Section:

  • Speech
  • Facial expression
  • Tremour:
    • Tremour at rest:
      • Head, right & left upper extremities, right & left lower extremities
  • Action or postural tremour:
    • Right & left upper extremities
  • Rigidity:
    • Neck, upper extremities, lower extremities
  • Bradykinesia:
    • Finger taps
    • Hand movements
    • Rapid alternating movements (wrist)
    • Leg agility (heel tap/stomp)
    • Arising from chair
  • Posture
  • Gait
  • Postural stability
  • Mentation, Behaviour, and Mood Section:
    • Intellectual impairment
    • Thought disorder
    • Depression
    • Motivation/initiative

Activities of daily living ADL:

  • Speech
  • Salivation
  • Swallowing
  • Handwriting
  • Cutting food/Handing utensils
  • Dressing
  • Hygiene
  • Turning in bed/Adjusting bed clothes
  • Falling unrelated to freezing
  • Freezing when walking
  • Walking

Hoehen & Yahr staging:

  • Five stages
  • 0: Asymptomatic.
  • 1: Unilateral involvement only.
  • 2: Bilateral involvement without impairment of balance.
  • 3: Mile to moderate involvement; some postural instability but physically independent; needs assistance to recover from pull test.
  • 4: Severe disability; still able to walk or stand unassisted.
  • 5: Wheelchair bound or bedridden unless aided.

Schwab & England Activities of Daily Living scale (100-0 %) and others.

Treatment options:

Please see our disclaimer section. This as with all treatment sections are provided for education.
Treatment is tailored to the disease stage and current symptoms. Consider whether treatment is indicated at this point in time.
General measures:

  • Physical therapy:
    • Conventional musculoskeletal therapy.
  • Speech therapy & Aids for daily living
  • Avoid high protein diet in patients with ‘off’ periods, as it may decrease levodopa absorption
  • Drugs to avoid & other options:
  • Avoid metoclopramide. Instead, use cyclizine or diphenidol or domperidone.

Tremor, consider:

  • Antimuscarinics, start with small doses, try other antimuscarinics if the 1st one fails:
  • Trihexyphenidyl (benzhexol) P.O. Benzatropine (benztropine) p.o Procyclidine P.O. Orphenadrine P.O.
  • Amantadine P.O. BID also for hypokinesia
  • Dopamine therapy

Bradykinesia, consider:

  • MAO-B inhibitor
  • Amantadine P.O.
  • Dopamine therapy

Dopamine therapy, General points:

  • No long term difference between dopamine agonist & levodopa. [PDRG-UK, Sydney multicenter study]
  • Initial therapy with ropinirole causes less dyskinesias than levodopa in the first 5 years.
  • Initial therapy with pramipexole causes less dyskinesias than levodopa.
  • Levodopa gives better UPDRS scores than pramipexole.
  • Levodopa decreases fatigue in nondepressed patients but fatigue still remains. [ELLDOPA]

Dopamine agonist:

  • Nonergot: Pramipexole, Ropinirole
  • Ergot:  Cabergoline, bromocriptine. Pergolide has been withdrawn due to valvular heart disease
  • Rotigotine transdermal patch. Reduces off time & decreases dyskinesia. For early or advanced disease [PREFER study]
  • Levodopa +carbidopa:
    • Sinemet CR ® or Sinemet ®. The dose of levodopa needs to be increased when switching from CR to sinemet.
    • Usual levodopa maintenance dose is 200-600 per day. Keep carbidopa dose <150 mg/day
    • Consider adding a COMT inhibitor: Entacapone is better than Tolcapone due to side effects
  • Apomorphine pump:
    • Use domperidone P.O. 3 days before and during treatment to prevent vomiting

For levodopa induced dyskinesia LID:

  • Depends on type of dyskinesia:
    • Dystonia, try the drugs below
    • Chorea, reduce dose of levodopa & add dopamine agonists
    • Amantadine P.O.
    • Trihexyphenidyl P.O.
    • Baclofen P.O.
    • Clonazpam P.O.
  • MAO-B inhibitors Consider as add on, also a reasonable first choice for mild symptoms:
    • Selegiline P.O.
    • or rasagiline P.O.
    • Other Drugs: Zonisamide P.O.

Consider Deep brain stimulation DBS:

  • Thalamus ventralis intermedius VIM for tremor & dyskinesia
  • Globus pallidus for tremor, rigidity, and bradykinesia.
  • Subthalamic nucleus STN for tremor, rigidity, and bradykinesia:
  • High frequency stimulation >100Hz for tremor, rigidity, and bradykinesia & to reduce dyskinesia. [prospective]
  • Low frequency 60 Hz/high voltage for gait disturbance.
  • Contraindicated in dementia & atypical Parkinsonism

Consider surgery:

  • Subthalamotomy for tremor or bradykinesia
  • Thalamotomy for tremor
  • Pallidotomy for hypokinesia
  • Globus pallidus internal segment Gpi, contralateral benefits
  • Contraindicated in dementia & diffuse vascular disease

Parkinson dementia:

  • General measures of dementia
  • Rivastigmine

Related articles:

References:

  • Emre, M., et al., Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med, 2004. 351(24): p. 2509-18.
  • Wakabayashi, K., [Parkinson’s disease: the distribution of Lewy bodies in the peripheral autonomic nervous system]. No To Shinkei, 1989. 41(10): p. 965-71.
  • Sandmann-Keil, D., et al., Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in Parkinson’s disease are detectable by an advanced silver-staining technique. Acta Neuropathol, 1999. 98(5): p. 461-4.
  • Hely, M.A., et al., Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord, 2005. 20(2): p. 190-9.
  • Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. Jama, 2000. 284(15): p. 1931-8.
  • Schifitto, G., et al., Fatigue in levodopa-naive subjects with Parkinson disease. Neurology, 2008. 71(7): p. 481-5.
  • Rascol, O., et al., A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med, 2000. 342(20): p. 1484-91.
  • LeWitt, P.A., K.E. Lyons, and R. Pahwa, Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology, 2007. 68(16): p. 1262-7.
  • Watts, R.L., et al., Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology, 2007. 68(4): p. 272-6.
  • Weaver, F.M., et al., Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama, 2009. 301(1): p. 63-73.
  • Krack, P., et al., Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med, 2003. 349(20): p. 1925-34.
  • Katzenschlager, R., et al., Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology, 2008. 71(7): p. 474-80.
  • den, H.J.W. and J. Bethlem, The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry, 1960. 23: p. 283-90.
  • Uchihara, T., et al., Silver stainings distinguish Lewy bodies and glial cytoplasmic inclusions: comparison between Gallyas-Braak and Campbell-Switzer methods. Acta Neuropathol, 2005. 110(3): p. 255-60

Myasthenia Gravis

Diseases, ,

Clinical features:

  • Ptosis, Diplopia (extraoccular muscle weaknss), dysphagia & facial weakness, respiratory failure
  • In some patients: no ocular or facial weakness occurs
  • Fatigable weakness, worse after exertion
  • Fixed proximal myopathy in end stage disease

Findings on Investigations:

Neurotransmitter related tests:

Edraphonium test (Tensilon):

  • 10 mg I.V. (2mg initially & 8mg after 30 seconds)
  • or Neostigmine test 1.5mg I.M.
  • Keep atropine ready
  • Use saline control first
Antibodies:
  • Anti-AChR: positive in ~80 % of generalised & 50% of ocular myasthenia gravis: Subtypes: blocking, binding, modulating
  • Anti-MUSK (muscle-specific tyrosine kinase): Positive in 7%
  • Anti Lrp4 antibodies in myasthenia gravis, this inhibits binding with aggrin
Nerve Conduction Studies/Electromyography NCS/EMG:

Repetitive nerve stimulation test (RNST) of a weak muscle at 3 Hz i.e. Low frequency:

  • Decreased amplitude, decremental response.
Other tests:
  • CT thorax: thymoma or thymic hyperplasia
  • TFTs: high association with thyroid disease

Muscle biopsy:

  • Rarely needed for diagnosis
  • Lymphocytitic infiltrates rarely. Type 2 fibre atrophy (non-specific)
  • Electron microscopy: simplification of post synaptic membrane. Flattening & atrophy of post synaptic folds. Reduced density of acetylcholine receptors.

Treatment options:

  • Avoid exacerbating drugs

Supportive therapy during crisis:

  • Dysphagia: Consider NG tube for feeding
  • Monitor Foced Vital Capacity (FVC) and negative inspiratory force (NIF), intubation if necessary
  • 20/30/40 rule for imminent respiratory failure:
    • Vital capacity <20mL/Kg
    • Maximum inspiratory force MIF <30
    • Maximum expiratory pressure <40
  • If intubating: Avoid succinylcholine (risk of hyperkalemia)

Symptomatic:

  • Pyridostigmine +/-atropine for side effects

Consider thymectomy
Long-term Immunosuppression:

  • Consider prednisolone high dose (1-1.5mg Kg/day) then taper & low maintenance dose on alternate days
  • May get worse before they get better if generalised
  • Steroid sparing agents:
  • Azathioprine orally
  • Mycophenolate mofetil oral BID, controversial. [Pilot] . No effect in short term in steroid responsive patients. [RCT]

In Myasthenic crisis:

  • Consider mechanical ventilation
  • Intravenous immunoglobulin IVIg 2g per kg
  • Plasmaphoresis

Related articles:

References:

  • Deymeer, F., et al., Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis. Neurology, 2007. 68(8): p. 609-11.
  • Ciafaloni, E., et al., Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology, 2001. 56(1): p. 97-9.
  • Sanders, D.B., et al., An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology, 2008. 71(6): p. 400-6.
  • A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology, 2008. 71(6): p. 394-9.

Alzheimer Disease

Diseases, ,

Clinical features:

Clinical features in general:

  • Episodic memory loss: This is usually the first symptom  to develop. It preceeds the dysfunction in activities of daily living. In most cases Alzeimer disease develops from amnestic mild cognitive impairment.
  • Later on other cognitive domains are involved this leads to:
    • Executive dysfunction
    • Agnosia
    • Apraxia
    • Aphasia
    • Neuropsychiatric symptoms: depression, apathy, agitation, anxiety, delusions.
  • In the end stages the patient becomes akinetic and mute.
  • Other features: physical frailty
Other criteria:

DSM-IVR criteria:

  • Multiple cognitive deficits:
  • Memory impairment must be present
  • Plus one or more of:
  • Aphasia
  • Apraxia
  • Agnosia
  • Disturbance in executive functioning e.g. planning, organising, abstracting
  • Must rule out other causes of dementia, must rule out delirium, rule out substance abuse
  • Early onset if = or <65 y.o.
  • Late onset if >65 y.o.
  • With our without behaviour problems

ICD-10 criteria:

  • There are separate criteria for ICD-10

NINCD-ADRDA criteria for Alzheimer:

  • Definite: clinically typical +histology
  • Probable clinically –histology
  • Possible: clinically atypical -histology -other diagnosis

Pathology:

Gross:

  • Decreased weight, gyral atrophy, ventricular dilation especially in medial temporal structures.

Microscopic pathology:

  • Neuritic plaques: found in the cortex. extracellular Abeta-amyloid protein aggregations (made from Amyloid precursor protein APP which is cleaved by Beta & gamma secretases to Abeta peptides which polymerizes into plaques) with Tau positive neurites (axons & dendrites).
  • Neurofibrillary tangles NFTs: found in the hippocampus, entorinal cortex, amygdala & neocortex, then temporal & parietal lobes. Intracellular Tau positive accumulation of abnormally phosphorylated tau, shaped like the neuron.
  • Other features:
    • Hirano bodies: in pyramidal neurons of hippocampus. Eosinophilic rod shaped bodies. Tau positive, Abeta amyloid positive, neurofilament positive.
    • Granulovacuolar degeneration of pyramidal neurons of the hippocampus. Cytoplasmic vacuoles and granules positive for tau, neurofilament, ubiquitin, tubulin.
    • Decreased acetylcholine neurons in forebrain nucleus basalis of Myenert
    • Cerebral amyloid angiopathy: Abeta-amyloid protein accumulation in media & externa of arteries & arterioles of the Cortex & meninges, sparing the white matter vessels.

CSF analysis:

  • Tau, p-tau (posphorylate tau), and isoprostanes: elevated
  • Abeta amyloid  1-42 (fibrillogenic) Abeta42: reduced in AD
  • Phosphorylated tau: increased in AD
  • Tau/Abeta42 ratio: increased in AD

Genetic forms:

  • Amyloid precursor protein= amyloid beta a4 precusor protein, APP chr. 21q21
  • Presenilin 1 protein, PSEN1 gene chr. 14q24.3
  • Presenilin 2 protein, PSEN2 gene chr. 1q31-q42
  • Microtubule associate protein tau MAPT, MTPT1 chr. 17q21.1

Genetic factors:

  • APOE gene, chr. 19q13.2:
  • ApoE4 haplotype: predisposes
  • ApoEe2 haplotype: protective
  • ApoE3 haplotype

MRI:

  • Hippocampal atrophy may occur

SPECT:

  • Regional hypoperfusion in posterior temporal & parietal lobes

Neuropsychological testing:

Mini-Mental Status Examination (MMSE)
Other neuropsychological tests:
  • Weschler Memory Scale: impaired verbal episodic memory, impaired delayed verbal episodic memory
  • Digit span forward & backward: impaired attention
  • Trailmaking test B: Impaired executive function
  • Trailmaking test A: Impaired psychomotor speed
  • Boston naming test & Category fluency test: impaired language
Clinical Dementia Rating (CDR):

A measure of functional status used to quantify the severity of dementia. Assess six areas: memory, orientation, judgment & problem solving, community affairs, home & hobbies, and personal care. Scores in each of these are combined to obtain a composite score ranging from 0 through 3 as follows
0 : no dementia
0.5: very mild dementia
1: mild dementia
2: moderate dementia
3: severe dementia

Geriatric depression scale:
  • Used for behavioural assessment

Treatment:

Institute general measures for controlling dementia, include:

  • Exercise training for physical health & depression

Memory impairment:

  • Acetylcholine esterase inhibitor e.g. rivastigmine, BID or TID. Donepezil in moderate & severe cases.
  • Galantamine. [SERAD RCT]
  • NMDA receptor antagonist e.g. memantine

Debatable efficacy:

  • Some consider adding high dose vitamin E (alpha tocopheraol) 2000 IU daily, [evidence of harm exists].

Depression:

  • SSRI: for example Sertraline or citaloparam

Agitation & psychosis:

  • Non-pharmacological therapies first, rule out pain
  • Avoid antipsychotics: quetiapine as it accelerates cognitive decline. Other atypical antipsychotics have an unfavourable risk/benefit ratio.[CATIE-AD, DART-AD] Typical antipsychotics are likely to have the same poor profile. However, often these medications are still necessary when non-pharmacological measures fail.
  • Donepezil isn’t effective for antigation [CALM-AD] [135]

Drugs that failed to show benefit:

  • Ginkgo Biloba
  • NSAIDs
  • Statins
  • Oestrogen replacement
  • Steroids

Related Articles:

References:

  1. Buchman, A.S., et al., Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology, 2008. 71(7): p. 499-504.
  2. Burns, A., et al., Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol, 2009. 8(1): p. 39-47.
  3. Ballard, C., et al., The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol, 2009. 8(2): p. 151-7.
  4. Burns, A., et al., Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol, 2009. 8(1): p. 39-47
  5. Ballard, C., et al., The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol, 2009. 8(2): p. 151-7.
  6. Cummings, J.L., Alzheimer’s disease. N Engl J Med, 2004. 351(1): p. 56-67.
  7. Black, S.E., et al., Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology, 2007. 69(5): p. 459-69
  8. Feldman, H.H. and R. Lane, Rivastigmine: A placebo-controlled trial of BID and TID regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry, 2007.
  9. Howard, R.J., et al., Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med, 2007. 357(14): p. 1382-92
  10. Buchman, A.S., et al., Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology, 2008. 71(7): p. 499-504
  11. Auchus, A.P., et al., Galantamine treatment of vascular dementia: a randomized trial. Neurology, 2007. 69(5): p. 448-58.
  12. Miller, E.R., 3rd, et al., Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med, 2005. 142(1): p. 37-46.
  13. Pollock, B.G., et al., A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry, 2007. 15(11): p. 942-52.
  14. Kales, H.C., et al., Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry, 2007. 164(10): p. 1568-76.

Guillain-Barre Syndrome

Diseases, , ,

Guillain-Barre Syndrome (GBS) is an acute inflammatory polyradiculopathy. It is immune mediated and causes ascending weakness in the limbs, respiratory failure and autonomic instability.

Synonyms:

Landry-Guillain-Barre-Strohl syndrome

Clinical features:

  • Progressive ascending weakness in both legs & arms & areflexia
  • Relative symmetry, autonomic dysfunction, mild sensory symptoms

Findings on Investigations:

CSF analysis:

  • Albuminocytological dissociation after one week i.e. raised protein but normal cell count:
  • Protein 100-1000 mg/dL, may be normal initially
  • If WCC is increased consider HIV, Lyme, sarcoid, neoplasia
  • WCC may be increased rarely. [autopsy series] [292]
  • Oligoclonal bands also may occur
  • Myelin basic protein may increase transiently

Nerve conduction studies & EMG:

  • Initially, normal
  • Earliest signs:
  • Loss of an H-reflex, Loss of F-waves
  • CMAP:
    • Demyelination pattern: Temporal dispersion & conduction block, Prolonged distal latencies, decreased conduction velocity
  • Axonal pattern: decreased amplitude
  • EMG: Denervation may be present

 

Subtypes:

  • Acute idiopathic demyelinating polyneuropathy AIDP
  • Acute motor axonal neuropathy AMAN
  • Acute motor sensory axonal neuropathy AMSAN
  • Miller Fisher syndrome MFS: ataxia, ophthalmoplegia, areflexia
  • Pharyngo-cervical brachial PCB variant
  • Bickerstaff Brainstem Encephalitis BBE

Antiganglioside antibodies:

  • Overlap occurs
  • Anti-GQ1b IgG antibody: positive, MFS, BBE, PCB,
  • Anti-GT1a IgG antibody: positive, PCB
  • Anti-GM1, Anti-GM1b, Anti-GD1a, Anti-GalNAc-GD1a: positive, AMAN

Other tests:

  • MRI Lumbar spine with contrast: enhancement of nerve roots

 

Pathology, nerve biopsy:

  • Endoneurium:
    • Inflammation: Infiltrate of macrophages & lymphocytes
  • Immunohistochemsitry: macrophages, CLA for lymphocytes
  • Features more prominent in nerve roots (autopsy specimen)
  • Demyelination occurs
  • Axonal Wallerian degeneration

Treatment:

Monitor the following:

  • Vital signs especially for labile BP
  • Oxygen saturation
  • Bedside forced vital capacity FVC:
    • 20% decrease is a poor prognostic sign
    • <12-15ml/kg is an indication to intubate
  • Negative inspiratory force NIF

Mainly supportive treatment
Admit to ICU/ITU if severely affected
Ventilatory & cardiovascular support as required

  • If intubating, avoid succinylcholine (risk of hyperkalemia)

Supportive care:

  • Passive range of motion to prevent pneumonia & joint contractures
  • Skin care with frequent turning to prevent pressure ulcers
  • DVT prophylaxis
  • Pulmonary toilet and mouth hygiene to prevent pneumonia
  • Turn to prevent decubitus ulcers
  • Pain control

Within 2 weeks of onset of neurologic symptoms:

  • Plasmapharesis (Plasma exchange) or IVIg (within 4 weeks) but not both
  • Start therapy on clinical suspicion before confirmation

Treatment of Dysautonomia:

  • Hypotension:
    • Administer fluids I.V.
    • Pressor drug with extreme caution: Dopamine or phenylephrine
    • Note: Response may be delayed for minutes
  • Hypertension:
    • Short acting beta blockers
    • Note: Hypersensitivity occurs
  • Bradycardia:
    • Sinus tachycardia (due to vagal damage): Fluids I.V.
    • Consider Transvenous pacemaker if non-sinus
  • Adynamic ileus:
    • NG tube +aspirate
    • NPO
  • Atonic bladder:
    • Catheterization

Related articles:

References:

  1. Rauschka, H., et al., Guillain-Barre syndrome with marked pleocytosis or a significant proportion of polymorphonuclear granulocytes in the cerebrospinal fluid: neuropathological investigation of five cases and review of differential diagnoses. Eur J Neurol, 2003. 10(5): p. 479-86.

Tick Paralysis

Diseases, ,

Tick paralysis also known as Tick bite paralysis is a neuromuscular condition that causes ascending symmetric flaccid paralysis.

Clinical features:

  • Prodrome phase followed by weakness
  • Then acute generalised weakness (ascending symmetric flaccid paralysis), involves cranial nerves, usually occurs in children, usually spring or summer.
  • No sensory symptoms
  • +Tick bite or tick attached to skin
  • In Australia: Ixodes holocyclus female tick bite, usually behind the ear or on the scalp.
  • In North America: Dermacentor andersoni or D. variabilis

Findings on Investigations:

Nerve conduction studies/electromyography (NCS/EMG):

  • CMAP: Low amplitude
  • Motor Conduction velocity: normal or subtle abnormalities
  • Sensory conduction velocity & sensory action potentials: normal or subtle abnormalities
  • EMG: Repetitive stimulation: normal

Treatment:

  • Removal of the tick from the skin

Diphtheria Polyneuritis

Diseases, ,

Diphtheria polyneuritis is a neuromuscular condition that is caused by the bacteria Corynebacterium diphtheriae. It classically causes pharyngitis followed by descending weakness that starts with bulbar weakness and progresses to involve the limbs.

Clinical features:

  • Corynebacterium diphtheriae infection: this causes pseudomembrane of the pharynx/tonsils, URI, sore throat
  • Then at 1-2 weeks pharyngeal & laryngeal paralysis, then loss of accommodation (preserved light reflex), VII, IX, X paralysis
  • Then 5-8 weeks descending motor>sensory neuropathy of arms then legs. May also mimic Guillain-Barre Syndrome
  • Respiratory failure can occur
  • Myocarditis can occur
  • Culture may confirm the diagnosis

Findings on investigations:

CSF analysis:

  • Increased protein: 50-200 mg/dL
  • Pleocytosis: may be absent

Pathology:

  • Segmental demyelination of spinal nerve roots
  • No inflammation

Treatment:

  • Ventilatory support if necessary
  • Antitoxin, even before culture results are known
  • Antibiotics for 2 weeks e.g. Penicillin or erythromycin to eradicate infection

Prevention:

  • Diphtheria vaccine

Related articles:

Multifocal Motor Neuropathy

Diseases, ,

Multifocal motor neuropathy (MMN) is a neuromuscular disease that usually presents with asymmetric weakness in a limb. The clinical pattern is that of mononeuropathy multiplex. The condition is treatable.
 

Clinical features:

  • Asymmetric weakness, usually upper limbs, spares cranial nerves, reflexes may be preserved, fasciculations may occur
  • Note this is a form of mononeuropathy multiplex

Investigations:

  • Serum Anti-GM1 IgM positive, titre >1:350
  • Nerve conduction studies NCS:
    • Multifocal motor demyelination
    • Conduction block
    • Normal sensory response

Pathology/Nerve biopsy:

  • In some cases evidence of demyelination & remylination
  • In some cases: inflammatory cells

Treatment options:

  • Intravenous immunoglobulin (IVIg)
  • In refractory cases Cyclophosphamide intravenously may be considered
  • There appears to be no benefit from Mycophenolate mofetil.

Related articles:

Nerve diseases

Diseases, , ,

Please start with the section on neuromuscular disease patterns for an introduction. Once you determined that the patient likely has a nerve disease you will need to consider which type to narrow down the differential diagnosis. As described in the previous section determining which of the main patterns cranial neuropathy, mononeuropathy, radiculopathy, polyneuropathy, mononeuropathy multiplex, polyradiculopathy, or autonomic neuropathy will help shorten the differential diagnosis tremendously. In this section we’ll start with some lists for cranial neuropathies and then move on to usefull lists and tables for the rest.
 

Cranial neuropathies:

Here are some lists to help with the cranial neuropathies. Also see the section on vertigo for cranial nerve VIII diseases.

Causes of Oculomotor nerve palsy (CN III): think of anatomy

Nuclear & fasciular:

  • Tumours: Glioma
  • Part of a brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar aneurysms
  • Posterior communicating artery PCOM aneurysm
  • Temporal lobe herniation (uncal herniation)

Cavernous sinus area:

  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma
  • Internal Carotid artery aneurysms
  • Cavernous sinus thrombosis
  • Mucormycosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vascular:
    • Vasculopathy: diabetes mellitus, hypertension & atherosclerosis, giant cell arteritis
  • Wegner’s granulomatosus
  • Hodgkin’s disease, VZV, encephalitis, collagen vascular disease, Paget’s disease
  • Trauma

Causes of trochlear nerve palsy (CN IV):

Nuclear & fasciular:

  • Tumours: glioma, medulloblastoma
  • Part of a Brainstem stroke syndrome

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Trauma

Causes of abducens nerve palsy (CN VI):

Nuclear & fasciular:

  • Tumours: glioma
  • Part of a Brainstem stroke syndrome
  • Multiple sclerosis

Basilar area:

  • Meningitis:
    • Bacterial, Meningovascular syphilis
    • TB meningitis
    • Fungal meningitis
  • Basilar artery aneurysm

Petrous tip area:

  • Raised intracranial pressure ‘false localising sign’
  • Hydrocephalus
  • Mastoiditis
  • Nasophareygeal tumours, paranasal sinus tumours
  • Lateral sinus thrombosis

Cavernous sinus area:

  • Internal Carotid artery aneurysm
  • Cavernous sinus thrombosis
  • Tumours: Intrasellar & extrasellar tumours e.g. pituitary, chordoma, meningioma, Nasopharymgeal tumours, craniopharygioma

Superior orbital fissure & Orbital apex area:

  • Tumours: nasopharygeal, meningioma, hemangioma, glioma, sarcoma, Hand-Schuller-Christian disease, metastasis
  • AVMs
  • Tolosa-Hunt syndrome
  • Pseudotumour of the orbit

Others:

  • Idiopathic
  • Vasculopathy:
    • Atheroma, Hypertension, Diabetes mellitus
    • Giant cell arteritis
  • Wegner’s granulomatosus

Causes of isolated facial nerve palsy (CN VII):

Upper motor neuron lesion:

  • Stroke, most common
  • Vasculitis
  • Syphilis
  • HIV

Lower motor neuron lesion:

  • Bell’s palsy a.k.a. Idiopathic (but HSV-1 is implicated), most common
  • VZV a.k.a. Herpes zoster, Ramsay Hunt Syndrome
  • Otitis media
  • Cholesteatoma
  • Tumours:
    • Cerebellopontine angle, acoustic or facial neuroma
    • Glomus tumour
    • Parotid tumour
  • Temporal bone fracture
  • Diabetes mellitus
  • Lyme disease
  • Sarcoidosis
  • Amyloidosis
  • AIDS
  • Sjogren’s syndrome
  • Lesions of the facial nucleus (usually affects other nerves as well)

Recurrent or bilateral lower motor neuron facial palsy:

  • Base of the skull tumour e.g. Lymphoma
  • Lyme disease
  • Sarcoidosis
  • Gullian-Barre syndrome
  • If immunocompromised, VZV

DDx. of bilateral facial palsy (compare with causes of bilateral facial palsy above):

  • Myasthenia gravis

Causes of cavernous sinus syndrome:

  • Sepsis
  • Tumour
  • Carotid artery aneurysms
  • Wegener’s granulomatosis

Causes of skull base syndromes including jugular foramen syndrome:

Intracranial:

  • Neoplastic:
    • Extension of cerebellopontine angle tumour
    • Meningioma
    • Cholesteotoma
    • Neurofibroma
  • Guillain-Barre syndrome & variants
  • Chronic tuburculosis
  • Syphilis
  • Diabetes mellitus

Skull:

  • Fractured base of the skull
  • Paget’s disease

Extracranial:

  • Neoplastic:
    • Lymphoma
    • Carotid body tumour
    • Glomus jugulare turmour
    • Nasopharyngeal carcinoma
    • Metastatic Squamous cell carcionoma, others
  • Jugular vein thrombosis
  • Carotid dissection

 

 
 

Nerve diseases etiology by onset and involved modality:

Motor Sensorimotor Sensory
Acute -GBS Patients with sensory
symptoms tend not to present acutely
-Porphyria
Subacute/chronic -CIDP motor forms -CIDP -Diabetic polyneuropathy
-Multifocal motor neuropathy MMN -Lewis-Somner syndrome
LSS/MADSAM (asymmetric CIDP)		 -HIV associated distal
polyneuropathy
-Coeliac disease a.k.a. gluten neuropathy (usually sensorimotor) -Vasculitic neuropathy -Migrant sensory neuritis a.k.a. Wartenberg Syndrome
-Paraproteinemic neuropathy -Sjogren syndrome
-Amyloid neuropathy -Idiopathic sensory ganglionopathy a.k.a. chronic ataxic neuropathy
-Mulfocal diabetic
neuropathy a.k.a.		 -Drugs: antiretrovirals,
-Diabetic amyotrophy
-Lyme disease
-Coeliac disease a.k.a. gluten
neuropathy
-Sjogren syndrome (usually sensory)
-Arsenic poisoning
-HMSN a.k.a. Charcot-Marie Tooth
disease

 

Causes of peripheral neuropathy/peripheral nerve disease & some radiculopathies (the full list):

Idiopathic inflammatory neuropathy:

  • Acute idiopathic polyneuropathy
  • Chronic inflammatory demyelinating polyneuropathy CIDP

Infective & granulomatous:

  • AIDS
  • Leprosy
  • Diphtheria
  • Sepsis & multiorgan failure
  • Sarcoidosis

Vasculitic:

  • Systemic necrotizing vasculitis:
  • Polyarteritis nodosa
  • Allegic angiitis & granulomatosis a.k.a. Churg Strauss syndrome
  • Wegener’s granulomatosis
  • Giant cell arteritis
  • Collagen vascular disease:
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjogren’s syndrome
  • Progressive systemic sclerosis
  • Mixed connective tissue disease

Endocrine:

  • Diabetes mellitus
  • Hypothyroidism
  • Acromegaly

Metabolic & nutritional:

  • Uremia
  • Liver disease: Primary biliary cirrhosis & chronic liver disease
  • Vitamin B12 deficiency
  • Porphyria

Drug induced & toxic:

  • Alcohol
  • Other drugs
  • Heavy metals
  • Organophosphates & hexacarbons

Neoplastic & paraproteinemic neuropathies:

  • Compression/infiltration
  • Paraneoplastic syndromes
  • Paraproteinemias
  • Amyloidosis

Hereditary:

  • Hereditary motor & sensory neuropathies:
  • Charcot-Marie-Tooth CMT
  • Dejerine-Sottas disease
  • Hereditary sensory & autonomic neuropathies HSAN types I-IV
  • Friedreich’s ataxia
  • Familial Amyloidosis
  • Metabolic:
    • Porphyria
    • Some Leukodystrophies:
    • Metachromatic leukodystrophy a.k.a. arylsufatase A deficiency
    • Krabbe’s disease a.k.a. globoid cell leukodystrophy a.k.a. galactocerebroside b-galactosidase deficiency
    • Abetalipoproteinemia
    • Tangier disease
    • Refsum’s disease
    • Fabry’s disease

Entrapment neuropathies:

  • Carpel tunnel syndrome (see below)

 

Causes of polyneuropathy:

Axonal:

  •  Acute:
    • Porphyria
    • Toxins
    • Axonal form of Guillain Barre syndrome
  •  Subacute:
    • Metabolic & Toxic
  •  Chronic:
    • Metabolic & Toxic
    • Hereditary
    • Diabetic
    • Dysproteinamia

Demyelinating:

  • Acute:
    • Guillain Barre syndrome
  •  Subacute:
    •  CIDP
  •  Chronic:
    • Hereditary
    • Inflammatory, autoimmune
    • Dysproteinemia
    • Metabolic, toxic

Types of mononeuropathy:

  • Median nerve compression a.k.a. median neuropathy:
    • Carpal tunnel syndrome (median neuropathy at the wrist)
    • Entrapment at ligament of Struthers, very rare
    • Pronator syndromeAnterior interossesous nerve AIN syndrome (a.k.a. Kiloh-Nevin syndrome)
  • Ulnar nerve and ulnar neuropathy:
    • Ulnar nerve compression at the wrist
    • Ulnar nerve compression at the Elbow
  • Radial nerve and radial neuropathy:
    • Radial nerve compression at the axilla
    • Radial nerve compression at the spiral groove
    • Posterior interosseous nerve neuropathy (PIN)
    • Superficial radial nerve neuropathy
  • Long thoracic nerve a.k.a. Thoracic nerve of Bell
  • Obturator nerve palsy a.k.a. obturator neuropathyFemoral nerve palsy a.k.a. femoral neuropathy
  • Sciatic nerve a.k.a. sciatic neuropathy
  • Peroneal nerve a.k.a. peroneal neuropathy
  • Tibial nerve neuropathy, rare
  • Tarsal tunnel syndrome (posterior tibial nerve compression in tarsal tunnel)
  • Miscellaneous syndromes:
    • Suprascapular nerve: Spinoglenoid notch
    • Lateral fermoral cutaneous nerve (Meralgia paresthetica; at the Inguinal ligament)
    • Obturator nerve at the Obturator canal
    • Plantar branches of the posterior tibial nerve (Morton metatarsalgia, plantar fasica and heads of 3rd and 4th metatarsals)

Causes of Mononeuropathy multiplex a.k.a. mononeuritis multiplex:

Vasculitis: (axonal), common

  • Rheumatoid arthritis (axonal)
  • SLE, systemic sclerosis
  • Polyarteritis nodosa
  • Wegener’s granulomatosis
  • Cryoglobulinemia (rare)

Infections:

  • HIV(axonal)
  • Lyme disease
  • Mycobacterium leprae (Leprosy)

Demyelination:

  • Mutifocal form of CIDP (demyelinating)
  • Multifocal motor neuropathy MMN (demyelinating)

Others:

  • Diabetes mellitus, common
  • Sarcoidosis, rarely
  • Amyloidosis
  • Hypereosinophilia syndrome
  • Sickle cell disease
  • Subacute asymmetric idiopathic polyneuropathy
  • Migrant sensory neuritis a.k.a. Wartenberg’s disease (pure sensory, axonal)

 

Causes of mononeuritis multiplex with lymphocytic meningitis:

  • Lyme Neuroborreliosis
  • Neurosarcoidosis
  • Zoster sine herpete
  • Uveo-meningeal syndromes

Causes of autonomic neuropathy:

Central:

  • Parkinson disease
  • Primary selective autonomic failure ?a.k.a. Shy Dragger syndrome
  • ?Wernicke encephalopathy
  • Syringomyelia/syringobulia

Peripheral:

  • Guillain-Barre syndrome
  • Diabetes mellitus
  • Infections/related:
  • Toxic/nutritional:
    • Alcoholic neuropathy
  • Drugs: amiodarone, cisplatin, vincristine, paclitaxel
  • Paraneoplastic:
    • Lambert-Eaton myasthenic syndrome
  • Familial autonomic failure a.k.a. Riley-Day syndrome
  • Familial amyloidosis
  • Hereditary neuropathies:
    • Hereditary sensory and autonomic neuropathies HSAN
    • Fabry disease
    • Triple A syndrome a.k.a. allgrove syndrome
    • Navajo Indian neuropathy
    • Tangier disease
    • MEN type 2b

 

Causes of Motor Neuropathy (& motor neuron disease)

Acute:

  •  Poliomyelitis
  • GBS
  • Porphyria

Chronic:

  • MND
  • CIDP motor forms
  • Multifocal motor neuropathy MMN
  • Lewis Somner syndrome LSS
  • Lead toxicity

 

DDx. Of amyotrophic lateral sclerosis:

  • Myathemia gravis
  • Cervical spondylosis
  • Polyradiculopathy with myelopathy
  • Paraneoplastic motor neuropathy
  • Syringobulbia
  • Post polio syndrome
  • Hexaminidase A deficiency
  • Lead intoxication

 

Causes of Axonal Neuropathy:

Immune:

  • Guillain-Barre syndrome GBS axonal forms:
    • Acute motor axonal neuropathy AMAN
    • Acute motor sensory axonal neuropathy AMSAN
    • Chronic idiopathic axonal polyneuropathy CIAP
  • Connective tissue diseases:
    • Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis

Medications:

  • Vincristine, cisplatinum, organophosphate
  • Metronidazole, dapsone

Toxins:

  • Alcohol, pyridoxine toxicity

Infectious:

  • Leprosy
  • Borrelia burgdorferi
  • HIV, HTLV1

Nutritional:

  • B1 deficiency, folic acid deficiency, vitamin E deficiency

Endocrine:

  • Diabetes mellitus, Hypothyroidism

Paraproteinemia:

  • Waldenstorm’s disease, Benign monoclonal gammopathy
  • Multiple myeloma

Hereditary neuropathy:

  • CMT 2 and CMT X
  • Familial amyloid neuropathies

Others:

  • Chronic renal failure
  • Paraneoplastic neuropathy: lung cancer, ovarian carcinoma

Causes of sensory neuropathy (most are chronic because of the nature of sensory symptoms):

  •  CIDP
  • Sarcoidosis
  • Hereditary sensory neuropathy
  • Chronic renal failure
  • Diabetes mellitus (predominantly sensory)
  • Thiamine B1 defeciency (predominantly sensory)
  • Leprosy

 

Causes of Chronic inflammatory demyelinating polyneuropathy CIDP:

CIDP alone:

  • CIDP, idiopathic

CIDP with an associated condition:

  • CIDP with paraproteinemia, includes:
    MGUS, Waldenstrom’s macroglobulinemia, multiple myeloma, plasmacytoma, POEMS syndrome, B cell lymphoma, CLL,
  • CIDP with SLE, inflammatory bowel disease, sarcoidosis, chronic active hepatitis,
  • CIDP with HIV
  • CIDP with hepatitis B, hepatitis C
  • CIDP with Diabetes mellitus, thyrotoxicosis
  • CIDP with hereditary demyelinating neuropathies
  • CIDP with bone marrow & organ transplantation

 

Causes of small fibre neuropathy:

  • Chronic idiopathic small fibre sensory neuropathy
  • Sjogren’s syndrome
  • Amyloidosis
  • Diabetes mellitus
  • Hereditary sensory and autonomic neuropathies
  • Fabry’s disease
  • Tangier disease

 

Causes of neuromyopathy:

  • Vasculitis
  • Paraneoplastic
  • Drugs:
    • Chloroquine & Hydroxychloroquine
    • Amiodarone, Colchicine
    • Vincristine, Perhexiline

 

Causes of palpable nerves (thickened nerves/enlarged nerves/hypertrophied nerves):

  • Amyloidosis
  • Acromegaly
  • Leprosy
  • Sarcoidosis
  • Neurofibromatosis
  • Some Hereditary neuropathies
  • Refsum’s disease
  • CMT
  • CIDP

 
 

IgM gammopathy associated peripheral neuropathy:

  • Cryoglobulinemia (type 1 & 2)
  • Macroglobulinemia
  • CLL

 

IgA or IgG gammopathy associated peripheral neuropathy:

  • Multiple myeloma
  • POEMS
  • Primary amyloidosis
  • Chronic inflammation

 

Causes of head drop/neck drop:

  • Myasthenia gravis
  • Polymyositis
  • Dermatomyositis
  • Motor neuron disease

 
 

Myopathy (Muscle diseases)

Diseases,

Synonyms:

Myopathies,

Introduction:

Please start with the section on neuromuscular disease patterns for an introduction. Once you determined that the patient likely has a myopathy you will need to consider which type of myopathy to narrow down the differential diagnosis.

Clinical features of myopathy:

  • Muscle may be normal, wasted or pseudohypertrophied, depending on the disease and time of presentation
  • Weakness, usually more proximal than distal
  • Usually proximal rather than distal weakness, but there are distal myopathies. Also, some myopathies are restricted to certain muscle groups e.g. ocular and pharygeal muscles
  • Usually symmetric weakness
  • Pure motor weakness without sensory signs
  • Tendon reflexes are usually preseved until late in the disease. They may be depressed later on in the disease. Normal abdominal and plantar reflexes
  • Make an attempt to characterize which muscle groups are affected: upper limb shoulders girdle (deltoids,  rotator cuff), lower limb girdle (gluteal, quadreceps), distal muscles (finger flexors, peroneal muscles), occular muscles, pharyngeal muscles, diaphgram or heart.
  • Bowel and bladder sphincters are usually spared.

Firstly history and physical examination:

  • Onset/temporal features
  • Body part:
    • Ocular
    • Bulbar
    • Oesophageal, smooth muscle
    • Cardiac
    • Respiratory
    • Limbs:
      • Upper vs. lower
      • Proximal vs. distal
  • Associated features:
    • Cramps
    • Muscle pain at rest
    • Muscle pain on exercise
    • Exercise intolerance
  • Family history
  • Associated medical conditions: connective tissue diseases etc
  • Review medication list

 

Investigations to consider:

Blood tests:

  • Electrolytes: K+, Ca++, Mg++, PO3-
  • TFTs
  • Muscle enzymes: CK, LDH
  • Other muscle enzymes: glutamic oxaloacetic and glutamate pyruvate transaminases, aldolase

Urinalysis for myoglobin
NCS:

  • Normal SNAP
  • Normal CMAP, unless severe distal myopathy is present, then reduced amplitude may occur.
  • Normal distal latency
  • Normal conduction velocity

EMG, myopathic:

  • Spontaneously: increased activity with fibrillations, complex repetitive discharges CRD and positive sharp waves PSW
  • On activation: Short duration, low amplitude polyphasic MUAP
  • Early recruitment
  • Nerve conduction studies: to exclude radiculoneuropathy

Muscle biopsy
Myositis and myopathy antibodies:

  • Necrotizing autoimmune myopathy: Anti-HMGCR Abs (3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase)
  • Myositis specific antibodies: Anti-Jo1, anti-Mi-2, anti-SRP,
  • Myositis associated antibodies: anti-RoRNP, anti-UiRNP, anti-PM/Scl, anti-ku

 

 

Causes of myopathy:

Muscular dystrophy:

Congenital myopathies (non-dystrophic congenital myopathies):

  • Nemaline myopathy
  • Central core disease
  • Centronuclear myopathy a.k.a. myotubular myopathy

Inflammatory myopathy:

Drug induced myopathies:

  • True myositis: Penicillamine, Procainamide
  • Zidovudine (a form of mitochondrial myopathy)
  • Glucocorticoids
  • Statins
  • Fibrates: Clofibrate
  • Chloroquine neuromyopathy
  • Hypokalaemic drugs (dyskalemic myopathy)

Endorine myopathy:

  • Cushing’s syndrome
  • Hyper or hypo- thyroidism
  • Hyper- or hypo- parathyroidism

Metabolic myopathy:

Infective:

  • Parasitic polymyositis:
    • Toxoplasma, Trypanosoma, Cysticerci, Trichinae
  • Pyomyositis a.k.a. Tropical polymyositis:
    • Staphylococcus aureus, Streptococcus, Yersinia
  • Other bacteria:
    • Borrelia burgdorferi ‘Lyme disease’
    • Legionella pneumophila ‘Legionnaire’s disease’
  • Viral myositis:
    • Influenza, Coxsackie B virus
    • AIDS myopathy

Others:

Causes of Polymyositis:

Idiopathic
Secondary:

  • Zidovudine
  • Penicillinamine
  • Overlap syndrome with other connective tissue disease

DDx. of polymyositis:

Chronic weakness:

Acute weakness:

  • Alcoholism
  • Neuropathy
  • Some Glycogen storage diseases
  • Parasitic polymyositis
  • Pyomyositis a.k.a. Tropical polymyositis
  • Other bacteria:
    • Borrelia burgdorferi ‘Lyme disease’
    • Legionella pneumophila ‘Legionnaire’s disease’
  • Pain and muscle tenderness:
    • Polymyalgia rheumatica
    • Fibromyalgia
    • Chronic fatigue syndrome

Causes of dermatomyositis:

Idiopathic
Secondary:

  • Neoplasia in 15%:
  • Ovarian, breast, melanoma, colon cancer
  • Penicillinamine
  • Overlap syndrome with other connective tissue disease
  • Associates vasculitis in children

Causes of rhabdomyolysis:

  • Direct muscle injury:
    • Falls with immobility
    • Severe trauma or crush injuries
    • Prolonged surgical procedures
    • Severe physical exertion
    • Severe dehydration
    • Extremes of body temperature
  • Status epilepticus
  • Hypophostphataemia
  • Drugs:
    • Cocaine, amphetamines, statins, heroin, or PCP
  • Ischemia or infarction of muscle tissue
  • Some hereditary myopathies

Causes of raised CK (hyperCKaemia, raised creatine kinase):

Idiopathic
Secondary:

Causes of myopathy with normal CK

  • Endocrine myopathies (except hypothyroidism):
    • Hyperthyroidism
    • Hypoparathyroidism
    • Hyperparathyroidism
    • Adrenal insufficiency
    • Acromegaly
  • Corticosteroid myopathy (Steroid induce myopathy)

Muscle pain on exertion:

Exercise induced exercise intolerance, cramps and increased CK:

  • Glycogenolysis defects:
    • Myophosphorylase MPH
    • Phosphorylase kinase PHK
  • Glycolysis:
    • Phosphofructokinase PFK

Causes of endoneurial lymphocytes:

  • Vasculitic neuropathy
  • Guillain Barre syndrome GBS
  • Chronic inflammatory demyelinating polyradiculopathy CIDP
  • Diabetic neuropathy
  • Normal

Migraine

Diseases

Diagnosis:

The diagnosis is clinical: after history & physical exam. On occasion imaging and other tests should be obtained to exclude competing differential diagnoses.
Adapted from International Headache Society IHS Criteria, used mainly in research:

Migraine without aura a.k.a. Common Migraine:

A.     At least 5 attacks fulfilling criteria B through D
B.     Headache lasting from 4-72 hours
C.     Headache has at least 2 of the following characteristics:

  1. unilateral
  2. pulsating
  3. moderate-severe
  4. aggravated by walking stairs or similar activity

D.     During headache, at least 1 of the following occurs:

  1. Nausea and/or vomiting
  2. Photophobia and/or phonophobia

E.     No organic disease

Migraine with aura are a.k.a. Classic Migraine:

A.     At least 2 attacks fulfilling the following characteristics:
B.     At least 3 of the following 4 features present:

  1. Fully reversible aura symptoms indicating focal brain dysfunction
  2. At least 1 aura symptom that develops gradually over more than 4 minutes, or 2 or more symptoms that occur in succession
  3. No single aura symptom lasting more than 60 minutes
  4. Headache usually follows the aura within an hour

C.     No organic disease

Chronic migraine:

Migraine = or >15 days per month for >3 months, without medications overuse.

Status migrainosus:

Migraine attack lasting >72 hours.

Other types:

Typical aura without headache

Some patients will get the typical migraine aura without the headache

Basilar type migraine formerly basilar artery migraine, basilar migraine:
  • Fully reversible
  • Aura with brainstem features without motor weakness
  • E.g. tinnitus, vertigo, diplopia, dysarthria, dysphagia, ataxia, hyperacusis, bilateral paraesthesia, bilateral visual field defects, decreased level of consciousness.
Sporadic hemiplegic migraine:
  • Migraine with aura +motor weakness but no 1st or 2nd degree relative with this condition. Dysphagia & sensory symptoms can occur.
Other features that may occur:
  • Central sensitization: development of allodynia in the head or pain on moving the head after an attack.

Clinical pearls:

  • If woman with miscarriage, check for antiphospholipid syndrome antibodies
  • If with family history of dementia & stroke: tests for CADASIL

 

Pathophysiology of migraine:

Intracranial vasoconstriction leads to the aura. Extracrainal vasodilation leads to the headache:

  • Support for the theory:
    • Vasoconstrictors abort the headache. Amyl nitrite, a vasodilator, gets rid of the aura.
    • In the aura cerebral blood flow decreases in the occipital area & spreads. Later cerebral blood flow increases in parts of the cortex & contralateral brainstem.
  • Against the theory:
    • The decrease in cerebral blood flow doesn’t follow the distribution of the vessels. It’s in cytoarchitectural pattern
    • The effects of valproate & amitriptyline

The current understanding:

  • The phases:
    • The prodrome a.k.a. premonitory: Hypothalamic dysfunction (craving, irritability etc.)
    • Aura: Electrical depolarisation (a.k.a. cortical spreading depression CSD), followed by reduced cerebral blood flow
    • Headache:
      • Trigeminovascular system:
        • CSD activates releases neuropeptides (substance P CGRP, neurokinin A) leading to sterile inflammation of the dura.
        • Trigeminal nerve afferents are activated. 1st order, then 2nd order & 3rd
      • Areas in the brainstem are stimulated e.g. dorsal raphe nuclei
    • Postdrome: feeling wiped out, tired or hung over
  • Support for the theory:
    • Brainstem stimulation in the dorsal raphe nucleus & periaqueductal gray matter leads to migraine headaches
    • CGRP (calcitonin gene-related peptide), a vasodilator, is increased in migraine headache & cluster headache. Serotonin receptor agonist decrease CGRP release (probably via action on presynaptic 5HT1D receptor)
  • 5HT1D on trigeminal nerves causes reduction of proinflammatory neuropeptides & 5HT1B found on meningeal blood vessels

Treatment options:

There are many treatment options for migraine. Generally this includes avoiding triggers, abortive medications for acute attacks. In patients with frequent or disabling attacks prophylactic medications are useful. Lastly, frequent use of abortive medications, >2 days per week, is discouraged as it can lead to medication over-use headache.
Please see pharmacology notes to learn about some of the medications.

General approach:
  • Try to avoid triggers
  • OCP is contraindicated if the migraine condition is severe
Acute treatment, consider:
  • Avoid overuse, use <3 days per week as overuse can contribute to medication overuse headache.
  • Acute treatment s most effective when taken as early as possible
  • A stratified approach: where for mild pain the patient uses simple analgesics. If the patient has severe or refractory pain tryptans or ergot preparations are used. Not that tryptans are less effective once central sensitisation occur.
  • Combined approach: for example sumatriptan/naproxen might be more effective. [RCT]

Simple analgesics:

  • Naproxen sodium, ibuprofen
  • Aspirin +paracetamol +caffeine combinations are often used. There is evidence against Paracetamol alone
  • Ketorolac or diclofenac

Triptans, 5HT1D & 5HT1B receptor agonist:

  • Sumatriptan, Rizatriptan, zolmitriptan, naratriptan, almotriptan (strong evidence base for all of tryptans)
  • Sumatriptan 25, 50, 100 mg orally, 25 mg suppository, 10, 20 mg nasal spray, 6mg subcutaneous (strong evidence base for all formulation)
  • Zolmitriptan 2.5, 5 mg oral including disintegrating form 2.5, 5mg nasal spray (strong evidence base),
  • Naratriptan 2.5 mg oral. Less efficacy but longer efficacy than sumatriptan (strong evidence base)
  • Rizatriptan 10mg oral (strong evidence base)
  • Almotriptan 12.5 mg oral A Probably less side effects than sumatriptan. (strong evidence base)
  • Eletriptan 20, 40 mg oral (strong evidence base)
  • Frovatriptan 2.5 mg oral, Less efficacy but longer efficacy than sumatriptan (strong evidence base)

Ergot preparation:

  • Dihydroergotamine +metoclopramide
  • Inconsistant evidence: for Ergotamine/caffeine

Dexamethasone IV 10-20mg X1 dose as an adjunct in emergency room acute attacks may reduce recurrence. [Metanalysis].
Other agents that have been tried:

  • Magnesium I.V.
  • Haloperidol I.V.
Prophylactic treatment:

Is indicated If:

  • Headache frequency >2 per week or >8 per month
  • Complicated (basilar or Hemiplegic migraine), migraine-induced stroke or prolonged aura >1 hour
  • Disability from headache

prophylactic treatment trial:

  • A trial of 2 months is needed to determine efficacy. i.e. >50% reduction in frequency
  • End of treatment trial: consider discontinuing therapy after 6-12 months of good effect. Discontinue by tapering

Medications that have been used for prophylaxis:

  • In female patients of childbearing potential, make note of pregnancy category and counsel the patient.
  • Betablockers:
    • Metoprolol 50–200 mg (strong evidence base)
    • Propranolol 40–240 mg (strong evidence base)
    • Bisoprolol 5–10 mg (moderate evidence base)
  • Calcium channel blockers
    • Flunarizine 5–10 mg (strong evidence base)
    • Verapamil
  • Antiepileptic drugs
    • Valproic acid 500–1800 mg but avoid in women of childbearing potential (strong evidence base)
    • Topiramate 25–100 mg (strong evidence base)
  • Antidepressants:
    • Amitriptyline 50–150 mg (moderate evidence base)
    • Venlafaxine 75–150 mg (moderate evidence base)
  • CGRP inhibitors:
    • Erenumab subscutaneously 70mg or 140mg monthely [RCT]
    • Fremanezumab subcutaneously monthly [RCT]
  • Botulinum toxin A BTX lasts 3 months, is effective for certain subtypes
  • Naproxen 2 · 250–500 mg (moderate evidence base)
  • Petasites extracts (Butterbur) 2 · 75 mg (moderate evidence base)
  • Riboflavin (B2) 400 mg P.O. [RCT],  Magnesium 400-600 mg P.O. [RCT]

Non-pharmacological measures that have been tried:

  • Acupuncture for prophyaxis, correct needle placement does not seem to be critical [good evidence, by multiple RCTs, and 2009 Cochrane systematic review]
  • Cognitive behaviour therapy CBT
  • Biofeedback
  • Relaxation techniques

Ineffective:

  • Acebutolol, pindolol, Carbamazepine CBZ, nicardipine, nifedipine, indomethacin
  • Homeopathy, TENS, Manipulative treatment,

Related articles:

References:

  1. Silberstein, S.D., et al., Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine. Neurology, 2008. 71(2): p. 114-21.
  2. Dahlof, C. and R. Bjorkman, Diclofenac-K (50 and 100 mg) and placebo in the acute treatment of migraine. Cephalalgia, 1993. 13(2): p. 117-23.
  3. Karachalios, G.N., et al., Treatment of acute migraine attack with diclofenac sodium: a double-blind study. Headache, 1992. 32(2): p. 98-100.
  4. Del Bene, E., et al., Intramuscular treatment of migraine attacks using diclofenac sodium: a crossover clinical trial. J Int Med Res, 1987. 15(1): p. 44-8.
  5. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. Eur Neurol, 1992. 32(3): p. 177-84.
  6. Cabarrocas, X., Efficacy and tolerability of subcutaneous almotriptan for the treatment of acute migraine: a randomized, double-blind, parallel-group, dose-finding study. Clin Ther, 2001. 23(11): p. 1867-75.
  7. Honkaniemi, J., et al., Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache, 2006. 46(5): p. 781-7.
  8. Singh, A., H.J. Alter, and B. Zaia, Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patients treated in the emergency department? A meta-analysis and systematic review of the literature. Acad Emerg Med, 2008. 15(12): p. 1223-33.
  9. Colman, I., et al., Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. Bmj, 2008. 336(7657): p. 1359-61.
  10. Jensen, R., T. Brinck, and J. Olesen, Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology, 1994. 44(4): p. 647-51.
  11. Schoenen, J., J. Jacquy, and M. Lenaerts, Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology, 1998. 50(2): p. 466-70.
  12. Peikert, A., C. Wilimzig, and R. Kohne-Volland, Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia, 1996. 16(4): p. 257-63.
  13. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR. Acupuncture for migraine prophylaxis. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD001218. DOI: 10.1002/14651858.CD001218.pub2.
  14. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017 Nov 30;377(22):2113-2122. doi: 10.1056/NEJMoa1709038. PMID: 29171818.
  15. Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017 Nov 30;377(22):2123-2132. doi: 10.1056/NEJMoa1705848. PMID: 29171821.

Multiple Sclerosis

Diseases, , , ,

This is an autoimmune disease of the central nervous system white matter. There is some evidence that the grey matter may be involved in the disease, but it is best to think of it as a type of white matter disease. The disease is multifocal i.e. it affects non-adjacent parts of the white matter. The areas of inflammation in the white matter are called plaques. Symptoms occur depending on where the plaques are. As the inflammation settles down, symptoms may resolve. However, symptoms often recur when the inflammatory system attacks the white matter again. Therefore, multiple sclerosis is typically a relapsing-remitting disease with patients having multiple episodes of neurological dysfunction that get better and then recur.
Some parts of the white matter are more important than others. Disease may occur in areas without any clinical symptoms. MR imaging has allowed assessment of disease activity in asymptomatic patients in-between relapses. Symptoms of multiple sclerosis can range from subtle and mild to disabling and severe.
The central nervous system white matter includes the optic nerves. In fact, optic neuritis is a common presentation of multiple sclerosis. There are 3-4 other classical multiple sclerosis syndromes; namely myelitis, internuclear ophthalmoplegia, ataxia and sensory disturbances. The neurologist is challenged with distinguishing between multiple sclerosis and a large range of differential diagnoses. These include other white matter diseases and psychogenic syndromes. It is important not to be dismissive of patients with mild sensory symptoms. On the other hand, labeling a patient with multiple sclerosis prematurely can have significant negative consequences as well. Even with modern MRI and clinical criteria for multiple sclerosis, not uncommonly patients may need to be observed to see if the disease evolves over time.

History taking in Multiple Sclerosis:

As with every interview, start with open-ended questions and then use close ended questions to narrow down the symptoms. It is important to ask when the symptoms first developed. Also, ask about any episodes in the past that may represent an early multiple sclerosis exacerbation for which, the patient may have not sought medical attention. Look for features of the classical syndromes (outlined below), but also realize that many patients present atypically.

  • Handedness
  • Weakness (arms, legs, face, swallowing)
  • Sensory deficits (numbness, pins & needles, pain,)
  • Headache
  • Loss of consciousness (faints/syncope & fits/seizure)
  • Brainstem & related (Vision & diplopia, vertigo, tinnitus, dysarthria)
  • Cerebellar & movement (balance, falls & tremor),
  • Spinal cord & sphincter (bowel & bladder control)

Classic Presentations of multiple sclerosis:

  • Optic neuritis: acute loss of vision with painful eye movements
  • Spinal cord involvement:
    • Spastic paraparesis
    • Bladder symptoms
    • Other patterns of weakness occur
  • Cerebellar syndrome/brainstem involvement:
    • Ataxia, nystagmus
    • Diplopia
    • Vertigo
    • Internuclear opthalmoplegia
  • Sensory alteration:
    • Parasthesia in the extremities
    • Neuropathic pain

Other points:

Signs of optic nerve damage:

  • Relative afferent papillary defect RAPD
  • Decreased visual acuity
  • Decreased colour vision
  • Central or paracentral scotoma
  • Optic atrophy
  • Note, ~75% of people presenting with optic neuritis will develop other signs of multiple sclerosis

Lhermitte’s sign a.k.a. Barber’s chair sign:

  • Electric shocks down radiating down the extremities on neck flexion is a sign of…… dorsal column lesion
  • Causes of Lhermitte’s sign:
    • Multiple sclerosis
    • Cervical stenosis
    • Subacute combined degeneration of the spinal cord

Uhtoff’s syndrome:

  • Exacerbation of multiple sclerosis due to a hot bath or exercise

Clinical categories:

  • Relapsing remitting: ~85%
    • Secondary progressive
  • Primary progressive ~10%
  • Progressive relapsing ~5%

Variants:

Please note that neuromyelitis optica (Devic’s disease) was formerly considred to be a variant of multiple sclerosis, but is now established as a separate condition: Devic’s disease: , optic neuritis in both eyes & transverse myelitis.
Tumefactive multiple sclerosis: multiple sclerosis lesions that are large and may mimic brain tumors clinically and on MRI

  • MS presenting like a tumour. MRI: T2= hyperintense >2 cm, mass effect & oedema. +/-Enhancing lesion.
  • Pathology: biopsy revealing, lipid laden macrophages, reactive astrocytes. No tumour.

Marburg type, very rare:

  • Clinically: Acute onset, rapidly progressive, monophasic (strictly speaking), fatal usually within a year.
  • Pathology: multiple plaques, may have poorly defined edges, may have mass effect. Microscopically, perivascular lymphocytes, foamy macrophage infiltrate, necrosis & cavitation can occur. Scattered reactive astrocytosis. No old plaques.

Balo concentric slcerosis:

  • very rare, pathologic variant of Multiple sclerosis. The plaque has alternating rings of demyelination leading to a concentric appearance grossly.

Multiple sclerosis Diagnosis:

Two different areas of central white matter affected at two different points in time
Criteria:

  • Poser’s criteria: 2 episodes of neurological deficit, with clinical evidence of >1 lesions in the CNS white matter
  • McDonald criteria: clinical +MRI
  • Barkhof criteria, criteria for what is a Positive MRI, 3 out of 4 of the following:
    • 1 Gd-enhancing lesion,
      or 9 T2 hyperintense lesions if no Gd-enhancing lesion
    • 1 or more infratentorial lesion(s)
    • 1 or more juxtacortical lesion(s)
    • 3 or more periventricular lesions
    • Note: 1 cord lesion can substitute for 1 brain lesion.
MRI findings in multiple sclerosis:
  • FLAIR: good for periventricular and juxtacortical lesions. Hyperintense.
  • T2 weighted: increased signal intensity in active plaques, occur in CNS white matter e.g. periventricular, optic nerve. Good for spinal cord lesions. Hypointense basal ganglia lesions can occur chronically.
  • PD: increased signal intensity in plaques
  • T1 +Gadolinium enhanced (semilunar, horseshow, incomplete or mass like), for age of the lesion: increased signal activity with active lesions. Gadolinium enhancement lasts <6 weeks. No meningeal enhancement in MS, but occurs in sarcoidosis. Lesions of different age occur with MS. Nodular or ring like.
  • Fat suppressed T1 +contrast, or STIR: detects optic neuritis
  • T1: low signal intensity indicates tissue destruction and correlates histologically with myelin loss, axonal loss and axonal swelling. If persisting greater than 6 months= “persistent black holes”. Hypointense lesions and atrophy also occurs.
    DWI: hyperintense. ADC: rims normal acutely, centre increased acutely. All increased chronically.

CNS white matter lesions:

  • Supratentorial (most common); 5-10mm but can be large in tumifactive MS. Linear, round or ovoid.
  • Dawson’s fingers (ovoid, perpendicular to ventricular surface) in corpus callosum on sagittal image.
  • Periventricular (perpendicular to the ventricle), juxtacortical & optic nerve lesions.
  • Infratentorial; cerebellar peduncles, floor of forth ventricle, superficial pons lesions.
  • Spinal cord lesions (<2 vertebral segments in length, posterolateral, Cervical >thoracic >lumbar).
  • Sparing of the CNS grey matter (cortex & basal ganglia) on 1.5 T MRI: helps with differential diagnosis
  • Cerebral atrophy is associated with worsening disability.
  • Spinal cord atrophy is associated with worsening disability.

MRS Magnetic resonance spectroscopy:

  • SPMS, PPMS Reduced N-acetyl aspartate in global white matter, axonal loss

DTI diffusion tensor imaging:

  • Normal appearing white matter NAWM: decreased fractional anisotropy occurs & is associated with disability & progression.
Other tests helping the diagnosis:

CSF analysis:

  • Oligoclonal bands: positive i.e. = or >2 bands
  • IgG index > 0.7. IgG Index= (CSF IgG/CSF albumin) / (serum IgG/serum Albumin)
  • IgG synthesis rate >3
  • Myelin basic protein >4mg/ml
  • Lymphocytosis and increased protein if close to a relapse

Evoked response/potential: a.k.a. triple evoked responses

  • Visually evoked response VER: increased latency in cortical response (most useful of the evoked responses)
  • Somatosensory evoked response SSER
  • Brainstem auditory evoked response BAER a.k.a. BSER

Test to help diagnose MS exacerbation:

  • CSF Myelin basic protein
  • MRI: T1, FLAIR

Key definitions:

Relapse:

  • The appearance of a new, or reappearance of a neurologic abnormality, separated by at least 30 days from the onset of the preceding event. Lasting >24 hours, in absence of fever or known infection

Clinically isolated syndrome:

  • Acute or subacute episode suggestive of demyelination affecting the optic nerves (optic neuritis), brainstem (INO) or spinal cord (transverse myelitis)
  • If MRI shows = or >1 lesion suggestive of MS, there is a high risk to progression within 5-20 years. [longitudinal prospective]

Benign MS:

  • Patient is fully functional in all neurologic systems at 15 years after onset

Aggressive MS:

  • At least two relapses with sequelae
  • Or an increase in the Expanded Disability Status Scale EDSS score of at least 2 points in 12 months + at least one gadolinium Gd enhancing lesion on MRI
Investigations that can be considered:

Blood tests:

  • FBC, U&E
  • ESR: vasculitis
  • ANA
  • VDRL: syphilis
  • TFT
  • LFTs
  • Serum B12: to exclude subacute combine degeneration of the spinal cord
  • Consider:
    • Borrelia serology, SS-A & SS-B, antiphopholipid antibodies, ACE, HIV tests, HTLV 1 tests, very long chain fatty acids (adrenoleukodystrophy), mitochondrial disease (lactate, muscle biopsy, mitrochondrial DNA analysis)

Lumbar puncture & CSF analysis:

  • Lymphocytic pleocytosis (usually <50 WBC) and increased protein if close to a relapse
  • CSF electrophoresis: oligoclonal bands
  • IgG index (increased IgG relative to albumin)
  • Consider Myelin basic protein

MRI: Brain & spine

  • T2 weighted
  • Gadolinium enhanced T1 weighted, for age of the lesion
  • Consider FLAIR

Evoked responses/potentials
Consider:

  • Measure urine residual volume
Measure of neurologic impairment:

Expanded disability scale EDSS:

  • 0.0 to 10.0

Disease steps in multiple sclerosis Scale:
0 = Normal
1 = Mild disability, mild symptoms or signs
2 = Moderate disability, visible abnormality of gait
3 = Early cane, intermittent use of cane
4 = Late cane, cane-dependent
5 = Bilateral support
6 = Confined to wheelchair
U = Unclassifiable

Pathology:

Gross: Plaques:

rounded sharply demarcated lesions in the white matter. May extend into grey matter. Periventricular location, scattered randomly.

Microscopically:

Recent plaque: Perivascular lymphocytes. Macrophage infiltrate, myelin filled. Loss of myelin (Luxol fast blue stain or Loyenz stain). Relatively preserved axons. Axonal spheroids. Preserved neuron bodies (if extending to grey matter). Astrocytic gliosis more prominent at the periphery. Fibrillary astrocytes in the centre.
Old plaque/chronic plaque: no or few lymphocytes or macrophages. Loss of axons centrally. More prominent gliosis.  Loss of oligodendrocytes.
Creudtzfeldt astrocytes and granular macrophages may occur and be confused for pleomorphism.

Four plaque patterns, recognised by special techniques:

Pattern I: T cell-mediated autoimmune encephalomyelitis. Centred on veins.
Pattern II: T cell plus antibody-mediated autoimmune encephalomyelitis: Pattern I with additional IgG deposition at sites of myelin destruction and in the macrophages & activated terminal complement (C9neo) deposition at sites of destruction, Centred on veins.
Pattern III: Loss of oligodendrocytes (oligodendrocytes apoptosis). T-cell lymphocytes, macrophages, microglia may be present but not centred on veins. No Ig or complement deposition.
Pattern IV: similar to Pattern III but with different borders. Loss of oligodendrocytes.

Pathology by clinical subtype:

Acute MS, AMS:

  • Active focal plaque
  • Absent/rare cortical demyelination
  • Meninges: Mononuclear cell infiltrate

RRMS:

  • Active focal plaque
  • Inactive plaques or slow expansion at the edges
  • Absent/rare cortical demyelination
  • Meninges: Mononuclear cell infiltrate

SPMS:

  • Inactive plaques or slow expansion at the edges
  • Cortical demyelination: luxol fast blue, Spares subcortical U fibres
  • Meninges: Mononuclear cell infiltrate
  • Lymphoid follicle-like structures in Meninges: contain B-cells (CD20+), T-cells (CD3+), plasma cells (CD138+) and a network of follicular dendritic cells (CD21+, CD35+). [312]
  • Normal appearing white matter NAWM: inflammation; CD8 positive cells, perivascular cuffing my mononuclear cells, microglial nodules with macrophages (CD68+), Diffuse axonal injury: neurofilament, axonal swellings & end bulbs

PPMS:

  • Inactive plaques or slow expansion at the edges
  • Cortical demyelination: luxol fast blue, Immunohistochemistry PLP, Spares subcortical U fibres
  • Meninges: Mononuclear cell infiltrate
  • Normal appearing white matter NAWM: inflammation; CD8 positive cells, perivascular cuffing my mononuclear cells, microglial nodules with macrophages (CD68+), Diffuse axonal injury: neurofilament, axonal swellings & end bulbs

Factors for poor prognosis in Multiple sclerosis:

  • Males
  • Old age of onset
  • Presentation with Motor & cerebellar signs
  • Multiple lesions on MRI T2
  • Relapses & remissions:
    • Short remissions between 1st two relapses
    • Frequent relapses with in the 1st 2 years
    • Incomplete remissions
  • Primary progressive disease

Conditions that mimic multiple sclerosis:

  • CNS infection:
    • Syphilis, brucellosis, Lyme’s disease, HIV, human lymphotropic virus type 1 HTLV 1
  • CNS inflammatory disease:
    • SLE, sarcoidosis
  • CNS microvascular disease:
    • Vasculitis
    • Diabetes mellitus
    • Hypertension
    • CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts & leukoencephalopathy
  • Vitamin B12 deficiency
  • Lymphoma
  • Structural lesions:
    • Cervical spondylosis, herniated disc, Arnold-Chiari malformation, tumour
  • Genetic disorders:
    • Leukodystrophy, hereditary myelopathy, Mictochondrial disease

Complications of multiple sclerosis:

  • Fatigue
  • Depression
  • Neuropathic pain including trigeminal neuralgia
  • Spasticity
  • Erectile dysfunction
  • Neurogenic bladder:
    • Detrusor hyperreflexia
  • Constipation
  • Pressure ulcers
  • Cognitive dysfunction:
    • Memory impairments
  • SIADH

Treatment options:

Please see pharmacology notes to learn about some of the medications.

Relapsing remitting diseases:
Acute relapses:
  • Corticosteroid short course: methylprednisolone 1000mg daily intravenous or orally for X3-5 days
  • In rare cases consider plasma exchange if no response
Disease modifying therapy, to prevent disease progression and relapses:

Injectables:

  • Interferon beta:
    • Interferon beta -1a intramuscular 30mcg once a week [MSCRG]
    • Interferon beta 1a subcutaneously 44mcg three times a week
    • Interferon beta-1b subcutaneously 0.25mg (1mL) on alternate days
    • Pegylated interferon beta-1a 125mg once every 2 weeks
  • Glatiramer acetate 20mg subcutaneously daily a.k.a. copolymer-1

Oral agents:

  • Dimethyl fumarate  240mg two times a day (trade name is Tecfidera)
  • Teriflunomide 14mg po daily (trade name is Aubagio)
  • Fingolimod  (trade name is Gilenya)

IV infusions (high efficacy agents):

  • Natalizumab 300mg intravenous infusion over 1 hour every 4 weeks (trade name is Tysabri) [AFFIRM]
  • Alemtuzumab (trade name is Lemtrada)
Clinically islated syndrome (CIS) treatment:
  • Interferon beta 1a intramuscular weekly 30 mcg (avonex): Treatment delays clinically definite multiple sclerosis at 5 years. Treatment reduces disability at 5 years. [CHAMPS]
  • Interferon beta 1a subcutaneous 3 time a week 44 mcg (rebif): Treatment delays clinically definite multiple sclerosis at 2 years. [REFLEX]
  • Interferon beta 1b subcutaneous every other day 250mg (betaseron): Treatment delays clinically definite multiple sclerosis at 2, 3, 5 and 8 years follow up. Treatment reduces disability at 3 years but effect is lost by 5 year follow up. [BENEFIT]
  • Glatiramer acetate subcutaneous 3 times per week 20mg or 40mg: Treatment delays clinically definite multiple sclerosis at 2 years, unknown effect on disability in CIS patients. [PreCISe]
  • Teriflunomide (aubagio) orally daily 14mg: Treatment delays clinically definite multiple sclerosis at 2 years [TOPIC]
Secondary progressive disease:
  • No proven therapy
  • Disease modifying therapy for RRMS is usually continued as long as relapses still occur
  • Cytotoxic: Mitoxantrone hydrochloride, is not usually used because of cardiotoxicity
Primary progressive disease:
  • Nothing has been proven effective
General supportive care:

Rehabilitation therapy:

  • Physical therapy and exercise without excessive exertion
  • Occupational therapy, as appropriate

If depressed:

  • SSRI

If fatigued consider:

  • Amantadine
  • SSRI
  • Modafinil

If neuropathic pain:

  • Amitriptyline
  • Carbamazepine
  • Gabapentin

Treat sexual dysfunction, usually erectile dysfunction:

  • Sildenafil

Consider spasticity treatment:

  • Baclofen, tizandine or diazepam
  • Multidisciplinary

Consider bladder & bowel Mx.

  • Bladder hyperreflexia:
    • Tolterodine
    • If residual >100 ml intermittent self catheterisation
  • Bowel: diet changes, softeners & stimulants

Attention to skin care/pressure ulcers

Related articles:

References:

  1. Frohman EM, Goodin DS, Calabresi PA, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003 Sep 9;61(5):602-11.
  2. Poser, C.M., et al., New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol, 1983. 13(3): p. 227-31.
  3. Scott, T.F., et al., Transverse myelitis. Comparison with spinal cord presentations of multiple sclerosis. Neurology, 1998. 50(2): p. 429-33Losseff, N.A., et al., Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain, 1996. 119 ( Pt 6): p. 2009-19.
  4. Losseff, N.A., et al., Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain, 1996. 119 ( Pt 3): p. 701-8
  5. Stevenson, V.L., et al., Spinal cord atrophy and disability in MS: a longitudinal study. Neurology, 1998. 51(1): p. 234-8.
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Myelopathy

Diseases, ,

 

Approaches:

  • Localization by level of lesion:
    • Cervical
    • Thoracic
    • Lumbar (Conus medullaris and cauda equina syndrome)
  • Localization by cross-sectional origin of pathology:
    • Extradural
    • Intradural extramedullary
    • Intramedullary (within the spinal cord)
  • Anatomical syndromes
    • Anterior cord syndrome
    • Central cord syndrome
    • Transverse myelitis
    • Brown-Sequard syndrome

 

Anatomical syndrome approach:

Anterior cord syndrome:

  • Anatomy: lesion at anterior aspects of the spinal cord. Involves corticospinal tracts, spinothalamic tract and bowel and bladder dysfunction.
  • Clinical features: Severe weakness, loss of pinprick and fine sensation, bowel and bladder dysfunction. Intact proprioception and vibration.
  • Etiology: usually spinal cord infarction.

Central cord syndrome:

  • Anatomy:  lesions at the central structures in the spinal cord. Damage to crossing spinothalamic tract fibres, corticospinal tract.
  • Clinical features: weakness in the hands much more than the legs, suspended sensory level to pin-prick, and loss of sensation lower to the level,
  • Etiology: trauma is the most common cause, syringomyelia can cause similar symptoms

Transverse myelopathy:

  • Anatomy: lesions at the anterior and posterior aspects as well as right and lateral aspects of the spinal cord. Damage to corticospinal tract, spinothalamic tract, dorsal column tract, bowel and bladder fibers.
  • Clinical features: Partial or complete dysfunction. weakness, sensory loss in all modalities, bowel and bladder dysfunction.
  • Etiology: many causes including immune, infectious, trauma etc.

Brown-Sequard syndrome:

  • Anatomy: lesions at half (side) of the spinal cord. Damages the ipsilateral corticospinal tract, ipsilateral dorsal column tract, contralateral spinothalamic tract,
  • Clinical features: ipsilateral weakness, contralateral pin-prick sensation loss, ipsilateral paraesthesia,
  • Etiology: rare, Radiation myelopathy, penetrating puncture trauma (very rare),

Conus medullaris syndrome:

  • Anatomy: lesions in the lower terminal part of the spinal cord. Damage to structures controlling bowel and bladder sphincters. May interrupt motor fibers and sensory fibers
  • Clinical features: bowel and bladder sphincter dysfunction, with back pain, saddle anesthesia, erectile dysfunction, less commonly weakness in the legs (usually more symmetric than cauda equina syndrome when present)
  • Etiology: tumors, lumbar intervertebral disc central herniation,

Cauda equina syndrome:

  • Anatomy: lesion at the nerve roots in the cauda equina (lower than end of the spinal cord proximal to exiting the spinal canal and thecal sac)
  • Clinical features: asymmetric painful lumbar polyradiculopathy, Asymmetric weakness (lower motor neuron pattern), painful polyradiculopathy, bowel and bladder sphincter dysfunction
  • Etiology: lumbar intervertebral disc herniation, lumbar spinal stenosis, epidural abscess, metastatic tumors, ankylosing spondylitis, trauma, spinal bifida,

 

Causes of myelopathy:

Spinal cord compression:

  • Herniated intervertebral disc
  • Tumor
  • Vertebral fracture

Vascular myelopathy:

Inflammatory i.e. Acute  myelitis:

Infectious myelopathy:

  •  Mycoplasma pneumonia, syphilis, HSV-1, HIV-1, HTILV,

Radiation induced myelopathy and radiation induced spinal cord hemorrhage
Neoplastic:

  • Extradural neoplasms:
    • Metastatic to vertebral column: Lung, breast, prostate
    • Primary vertebral column neoplasms
  • Intradural extramedullary neoplasms:
    • Schwannoma
    • Neurofibroma
    • Carcinomatous meningitis (usually don’t present as myelopathy, more often polyradiculopathy)
  • Intramedullary (within the spinal cord):

 

Investigations to consider:

MRI spine:

  • Assesses compressive myelopathy, assesses for pattern length & enhancement, abscess, features of specific diagnosis, cord expansion in tumors & abscess, flow voids in AVMs

CSF analysis including:

  • Cell count with differential, glucose, protein
  • IgG index, oligoclonal bands,

B12, Methylmalonic acid levels
Vitamin E levels, Copper levels
Infectious Investigations to consider::
Bacteria:

  • Syphilis serology & CSF VDRL
  • Lyme serology i.e. Borrelia burdorferi serology
  • Tests for Brucella spp. (Brucellosis),
  • Mycoplasma pneumoniae  & cold agglutinins
  • Mycobacterium tuberculosis TB
  • Yersinia enterocolitica,
  • Chlamydiae psittaci, (psittacosis)
  • Rachalimaea henselae (cat scratch fever)

Viral testing:

  • HIV tests, HTLV 1 tests,
  • PCR: HSV, VZV, EBV
  • VZV antibodies
  • EBV, CMV, HHV6,
  • Enteroviruses, lymphocytic choriomeningitis virus LCM, Influenza virus
  • Echovirus, coxsackie virus, hepatitis A, hepatitis B, rubella, measles, mumps
  • Poliomyelitis, West Nile Virus WNV: +/- LMN signs

Fungal: Cryptococcus testing
Parasitic:

  • Schistosomiasis tests (serology & stool)
  • Toxaplasma gondii Toxoplasmosis
  • Cysticercosis
  • Toxocariasis, gnathostoma, angiostrongyllus

Autoimmune Investigations to consider::

  • Anti-NMO antibody: neuromyelitis optica
  • SS-A & SS-B, antiphopholipid antibodies,
  • Lip biopsy: Sjogren syndrome
  • ACE levels
  • Only if clinically indicated (not routine) consider coeliac antibodies
  • Stiff person syndrome: anti-GAD65, anti-amphiphysin, anti-gephyrin

Very Long Chain Fatty Acids: adrenoleukodystrophy
Mitochondrial disease: lactate, muscle biopsy, mitochondrial DNA analysis

Monitor:

Urodynamics: neurogenic bladder
Screening or osteoporosis
Autonomic dysreflexia: an episode of extremely high BP or increase of or >20mmHg above patients baseline. Headache & flushing may also occur. Note: this occurs in lesions above T5

Treatment:

Treat the underlying cause
Consider empiric therapy for inflammatory, viral or bacterial causes while tests are pending

General measures for myelopathy:

Monitor & support respiratory function
Monitor & treat neurogenic shock
Monitor & treat constipation
Monitor & treat for neurogenic bladder
Monitor & treat erectile dysfunction
Monitor & treat osteoporosis
Monitor & treat spasticity:

  • Baclofen, diazepam, dantrolene or tizanidine P.O.
  • 2nd line: Baclofen intrathecally

Prevent joint contractures:

  • Physical therapy & mobilisation

Treat neuropathic pain
Skin care: Monitor, prevent & treat pressure sores
If autonomic dysreflexia occurs:

  • Removal of noxious stimulus e.g.
  • Bladder drainage (insertion of or insuring function of Foley catheter),
  • Consider PR examination to rule out Fecal impaction
  • Assess skin below the level of injury
  • Sit up the patient & lower the patient’s legs
  • If BP remains high:
    • Nifedipine or nitroprusside
    • Consider clonidine for prophylaxis

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