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CENTRAL NERVOUS SYSTEM INVOLVEMENT & NEUROPATHY

• Toxic
  • Cholinesterase Inhibitors (Organophospates)
  • Hexacarbons: Occasional delayed myelopathy
  • Nitrous oxide (N₂O)
• Hereditary
  • Adrenomyeloneuropathy
  • Adult-onset Leukodystrophy
  • Charlevoix-Saguenay - Spastic Ataxia
  • Familial spastic paraparesis
  • Metachromatic Leukodystrophy
  • SOX10
• Neoplastic: Lymphoma (angiotropic large-cell)
• Cuban neuropathy
• Vernant's disease

• Ataxias
  • Friedreich
  • Mitochondrial - NARP Syndrome: (Neuropathy; Ataxia; Retinitis Pigmentosa)
  • Posterior column ataxia + Retinitis pigmentosa
• Hereditary neuropathy
  • HMSN VI
  • CEDNIK
  • AAA syndrome
• Toxic
  • Alcohol
    
  • Carbon disulfide
  • Chloramphenicol
  • Disulfiram
  • Isoniazid
  • Mercury (Hg)
  • Nitrous oxide (N₂O)
• Nutrition: Cuban neuropathy
• Vernant's disease

• Hereditary Motor-Sensory Neuropathies: HMSN, CMT & Other
  • X-linked
    • Cowchock
    • HMSN X (Connexin 32)
  • Recessive
    • CMT 4D (Lom)
    • Refsum
    • Xeroderma Pigmentosum
    • HMSN & Deafness
    • HMSN, Optic neuropathy & Hearing loss
    • Hereditary ataxia with thermoanalgesia & loss of fungiform papillae
    • CEDNIK
  • Dominant
    • CMT 1A (Ala67Pro mutation in PMP-22)
    • CMT 1B (Thr124Met mutation in P0)
    • CMT 2E
    • Connexin-31 (D66del mutation)
    • HMSN & Deafness
    • HMSN 6
    • Dejerine-Sottas (Dominant)
    • HSN + Cough & GE reflux
• Motor neuron disorders
  • Brown-Vialetto-van Laere
  • Madras
• Muscular dystrophy & Myopathy
  • FSH
  • Scapuloperoneal
  • Myhre syndrome
• Other hereditary disorders
  • Neuralgic Amyotrophy, Hereditary (HNA1)
  • Hirschsprung: HSCR2; SOX 10
  • Sensory neuropathy with scoliosis & deafness (Robinson)
  • Sensory neuropathy, Deafness & Global delay
  • Anhidrotic ectoderma dysplasia
  • Mitochondrial
  • Neurofibromatosis-2
  • Neuroaxonal Dystrophy (Late infantile)
  • Coffin-Lowry
  • Duane's syndrome
  • Dilated cardiomyopathy with sensorineural hearing loss (CMD1J; CMD1K)
• Other acquired disorders
  • Cuban epidemic neuropathy
  • Hypothyroidism
  • Paraneoplastic (Anti-Hu)
  • Sarcoid
  • Superficial siderosis

• Hereditary
  • A-β-lipoproteinemia
  • Adult-onset Leukodystrophy
  • Ataxia with neuropathy
    
  • Ataxia with Oculomotor apraxia (AOA): 1; 2
  • Ataxia telangectasia
  • Ataxia, Tremor & Cognitive decline
  • Cerebrotendinous Xanthomatosis
  • Charlevoix-Saguenay - Spastic Ataxia
  • Friedreich Ataxia
  • Infantile Onset Spinocerebellar Ataxia (IOSCA)
  • Metachromatic Leukodystrophy
  • Pelizaeus Merzbacher-like
  • Refsum
  • RPIA deficiency
  • Salla disease
  • SCA 1, 2, 3, 4
• Paraneoplastic: Hu; CV2
• Alcohol
  

• Hereditary
  • ALS, Familial: Higher prevalence of dementia (~15%) than sporadic ALS
  • CEDNIK
  • Chorea-Acanthocytosis
  • CMT
    • 1X: Transient encephalopathy
    • Andermann: Agenesis of corpus callosum
  • Cowchock Syndrome
  • Fabry's
  • Hexosaminidase A (Late Onset Tay-Sachs)
  • Hypomyelination & Congenital cataract
  • α-Methyl-acyl-CoA-racemase
  • Minifascicles & 46,XY Gonadal dysgenesis
  • Multi-Infarct Dementia (CADASIL)
  • Polyglucosan body syndromes
  • Porphyria
  • Prion protein (PrP27-30) mutation: Glu200Lys
  • Salla disease
  • SOX10
• Infections
  • HIV
  • Lyme disease
  • Rabies
  • Syphilis
• Inflammatory & Immune
  • Sarcoid
  • Vasculitis
• Metabolic
  • Thyroid
  • Vitamin B₁₂ deficiency
  • Hypophosphatemia
• Mitochondrial:
  • MELAS (Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke)
    
  • MERRF (Myoclonic Epilepsy; Ragged Red Fibers
    
  • MNGIE Syndrome (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy)
• Motor neuron disorders with dementia (Sporadic)
  • Western Pacific ALS
  • Frontal Dementia followed by motor system disease
    • Upper motor neuron: Especially bulbar
    • Lower motor neuron: Fasciculations; Less prominent weakness
    • ? Atypical Creutzfeld-Jacob syndromes
• Neoplastic: Lymphoma (angiotropic large-cell); Carcinomatous meningitis
• Paraneoplastic: anti-Hu
• Toxic: Alcohol; Anticholinergic; Arsenic; Lead; Mercury; Podophyllin; Thallium; Vacor

• Metachromatic Leukodystrophy
• Krabbe
• Neuroaxonal Dystrophy
• Giant Axonal Neuropathy
  

from R Schmidt MD

CADASIL Vessels in brain

Multi-Infarct Dementia (CADASIL)

• Clinical
  • Onset: Adult
  • Recurrent subcortical ischemic events
  • Migraine
  • Cognitive dysfunction: Dementia; Psychiatric disorders
  • Neuropathy³
    • Often subclinical
    • Occasional clinical features
      • Sensory loss (40%): Distal; Symmetric
      • Weakness (30%): Distal
      • Areflexia
• Electrodiagnostic: Axon loss
  • NCV: Mildly slow motor & sensory
  • CMAP & SNAP: Reduced amplitudes
• MRI
  • Leukoencephalopathy
  • Subcortical infarcts
• Pathology
  • Angiopathy (Small arterial vessels)
    • Vessels: Granular deposition of material in smooth muscle layer
    • Staining: Congophilic, PAS positive material in vessel walls
    • Location: Brain; Skin; Muscle; Nerve
  • Peripheral nerve
    • Axon loss: Myelinated axons; Mild to moderate
    • Electron microscopy of peripheral nerve & muscle
      • Electron dense deposits associated with smooth muscle cells (vascular)

Chorea-Acanthocytosis (Neuroacanthocytosis)

• Genetics: Mutations
  • Japanese: Frameshift deletion
  • Other: Missense & Nonsense
• Protein function: ? Protein sorting
• Epidemiology: Especially common in Japan
• Onset: 3rd to 5th decade; Mean 32 years; Range 8 to 62 years
• CNS
  • Movement disorders
    • Oro-facial-lingual dyskinesia
    • Chorea: Limbs, especially legs; Frequent but not all patients
    • Parkinsonism
  • Cortical: Dementia; Personality disorders; Seizures (50%)
  • Pathology: Neuronal loss & gliosis in Caudate, Putamen, Pallidum & Substantia nigra
• PNS
  • Motor
    • Distal wasting
    • Anterior horn cell loss
  • Sensory: Small SNAPs; Normal motor potentials
  • Tendon reflexes: Reduced or Absent
  • Laboratory
    • EMG: Distal denervation
    • Nerve pathology: Distal axonopathy; Loss of large myelinated axons
    • Muscle imaging: Distal symmetric wasting
    • Serum CK: May be elevated
• Acanthocytosis
  • Differential diagnosis: A-β-lipoproteinemia; McLeod syndrome
  • Carriers: Mild acanthocytosis

Superficial Siderosis1 General Definition: Hemosiderin deposition along superficial (subpial) surfaces of CNS Pathogenesis Chronic bleeding into subarachnoid space Uptake of iron by astrocytes & microglia Most prominent involvement of nerves in regions with CNS myelin Underlying causes: Intracranial bleeding AVM Neoplasms: Ependymoma Dural disorders 2° surgery or trauma Neonatal intracranial hemorrhage Familial2 Cerebral cavernous angiomas Amyloidosis: Transthyretin No bleeding source: 50% Clinical features Onset: 4 months to 30 years after initial intracranial bleeding Sensorineural hearing loss (95%) Bilateral Sensorineural: Especially high tones Auditory nerve has long region of CNS myelin Cerebellar ataxia (88%) Onset usually after hearing loss Spinal cord Pyramidal signs (76%) Spinal myoclonus Sphincters: Bladder disturbance; Anal sphincter paresis Other Dementia (24%) Polyradiculopathy Anatomy: Motor; Axonal Weakness: Legs > Arms Anosmia Eye Nystagmus Ocular motility deficits: Smooth pursuit reduced Reduced Pupil reflexes (Preganglionic) Course: Slowly progressive Laboratory CSF Cells: Increased Ferritin: High Protein: High Xanthochromia MRI (T2-weighted and gradient-echo): Marked hypointensity of CNS surfaces

From M Al-Lozi Dark ring of hemosiderin deposition around cervical spinal cord (MRI-T2)