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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:

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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

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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

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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

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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

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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

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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,

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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.

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