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A. Symptoms [2]

  1. Preferential involvement of large myelinated sensory fibers
  2. Onset of Symptoms
    1. Simultaneous onset of weakness in the arms and legs for demyelinating diseases
    2. Axonal neuropathies involve onset of problems in distal nerves, symmetrically
  3. Elevated concentration of protein in cerebrospinal fluid (CSF) in demyelinating diseases
  4. Tremor with gait ataxia common in patients with anti-MAG Ab and in CIDP
  5. Inherited and acquired demyelinating diseases exist

B. Immune [3]

  1. Peripheral Nervous System (PNS)
    1. Guillain-Barre Syndrome
    2. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
  2. Central Nervous System (CNS) [4]
    1. Multiple Sclerosis
    2. Transverse Myelopathy
    3. Acute Disseminated Encephalomyelitis (ADEM) [6]
    4. Acute hemorrhagic leukoencephalitis (probably immune)
    5. Neuromyelitis Optica
    6. Hereditary: adrenoleukodystrophies, Krabbe disease, metachromatic leukodystrophy

C. Infection

  1. PNS: Diphtheria
  2. CNS
    1. Progressive Multifocal Leukoencephalopathy (PML)
    2. Subacute Sclerosing Panencephalitis (SSPE)
    3. Diffuse encephalitis
  3. HIV is associated with both PNS and CNS demyelinating diseases
  4. HTLV I associated with tropical spastic paraparesis

D. Systemic Disease

  1. PNS
    1. Solvent, Toxins
    2. Drug: Dapsone, Thallium
    3. Paraneoplastic
    4. POEMS Syndrome, Dysglobulinemia
    5. Chemotherapy
    6. Vitamin deficiencies
  2. CNS
    1. Post-Anoxia
    2. Hypothyroidism
    3. Leukoencephalopathy (see below)
    4. Nutritional Deprivation
  3. Inherited demyelinating disease: Charcot-Marie-Tooth Neuropathies (Types 1 and 2)

E. Differential for Polyneuropathy

  1. Mnemonic "DANG THERAPIST"
  2. This differential includes both demyelinating and nondemyelinating diseases
  3. D Diabetic
  4. A Alcoholic
  5. N Nutritional
  6. G Guillain-Barre Syndrome
  7. T Toxic (lead, arsenic, vinblastine, others)
  8. He Hereditary
  9. R Recurrent
  10. A Amyloid
  11. P Porphyria (motor involvment, intermittant)
  12. I Infections (AIDS, mononucleosis, leprosy, diphtheria, syphilis)
  13. S Systemic (collagen vascular disease, uremia, dysproteinemia)
  14. T Tumor (paraneoplastic, POEMS syndrome)

F. Acute Disseminated Encephalomyelitis (ADEM) [4,6]

  1. Rapidly progressive demyelinating disease of CNS
  2. Typically follows viral infection or vaccination
    1. Complication of 1:500 cases of measles
    2. Associated with respiratory infection with EBV, CMV, or Mycoplasma pneumoniae
  3. Believed to be autoimmune etiology
  4. Related to multiple sclerosis (which is a chronic CNS demyelinating disease)
  5. Lateralizing signs are common initially
  6. Rapid (over days) progression of neurologic dysfunction, often with death
  7. Probably related to acute hemorrhagic leukoencephalitis (AHLE)
    1. Very rapid progression from confusion to stupor to coma
    2. Leukocytosis may occur
    3. CNS pleiocytosis is common
    4. RBC in the cerebrospinal fluid (not in all cases)
    5. Death more common with AHLE than with ADE
  8. Treatment with glucocorticoids ± plasmapheresis has been advocated

G. Leukoencephalopathy [5]

  1. Structural alteration of cerebral white matter
  2. Myelin suffers the most damage
  3. Includes inflammatory and non-inflammatory (mainly toxin) forms
  4. Major Classes of Etiolgic Agents
    1. Chemotherapy: carmustine, methotrexate, others
    2. Cranial Radiotherapy
    3. Toxins: toluene, carbon tetrachloride, arsenic, carbon monoxide
    4. Recreational drugs: ethanol, toluene, cocaine, MDMA ("ecstasy"), heroin
    5. Genetic: leukodystrophies, Krabbe Disease, others
  5. Symptoms
    1. Mild: chronic confusion, inattention, forgetfulness, emotional dysfunction
    2. Moderate: somnolence, apathy, memory impairment, dementia
    3. Severe: akinetic mutism, stupor, coma, death
    4. Language skills are maintained until severe symptoms occur
    5. Change in personality may be earliest signs
  6. Diagnosis
    1. High index of suspicion in any patient with neurobehavioral changes and toxin exposure
    2. Document exposure to toxin or other possible cause
    3. Assess neurobehavioral deficits
    4. Formal neuropsychiatric testing may be required and can rule diagnosis out
    5. Minimental status examination is NOT a sensitive indicator of white matter disease
    6. Brain MRI (T2 weighted or newer modality) is indicated in patient with clear abnormalities on mental status or neurobehavioral deficits
    7. White matter changes are detected best with newer MRI modalities
    8. Diagnosis cannot be made without neuroimaging
  7. Treatment
    1. Eliminate exposure to underlying toxin
    2. Treat other modality to extent possible
    3. Repairing oligodendrocyte (CNS myelin) damage is not yet possible
  8. Prevention by avoidance of toxin exposure

References

  1. Chalk CH. 1997. Neurol Clin. 15(3):501 abstract
  2. Gominak SC and Cros DP. 1998. NEJM. 338(17):1212
  3. Smith DR and Weiner HL. 1997. JAMA. 278(22):1956 abstract
  4. Vartanian TK and de la Monte SM. 1999. NEJM. 340(2):127 (Case Record)
  5. Filley CM and Kleinschmidt-DeMasters BK. 2001. NEJM. 345(6):425 abstract
  6. Ravin P and Hedley-Whyte ET. 2002. NEJM. 347(18):1433 (Case Record) abstract