Category Archives: Diseases

These are a diseases, syndromes and neurological conditions

Subacute Encephalopathies (Rapidly Progressive Dementias)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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)

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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)

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)

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

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

Related articles:

Mononeuropathy Multiplex

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

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

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

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

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

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

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

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

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

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

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

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

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

Related articles:

Giant Cell Arteritis

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

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

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

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

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

Related articles:

Tuberous Sclerosis

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

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

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

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

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

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

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

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

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

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Superior Orbital Fissure Syndrome

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

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

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)

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)

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)

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)

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

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)

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

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Nystagmus

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

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Ataxia

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

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Chorea, in general

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

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

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)

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.

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Klüver-Bucy syndrome

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

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

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)

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

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

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

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

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)

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

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

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"

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

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

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