J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Recurrent or chronically progressive neurologic dysfunction caused by lesions in the CNS
• Lesions are multiple areas of demyelination that develop in the brain, optic nerves, and spinal cord
• Affects women more than men (2:1)
• More common in whites than in blacks; rare in Asians
• Onset at 20–50 yr of age, peak at 30 yr of age
• Highest prevalence at higher latitudes
• Susceptibility is at least partly familial
• Optic neuritis
  • Usually unilateral
  • Central scotoma
  • Retro-orbital pain
  • Develops over several days
• Diplopia
• Sensitivity to heat; symptoms resolve when body temperature returns to normal
• Lhermitte symptom: paresthesias that radiate down the spine and into the extremities on neck flexion; indicates a lesion in the cervical spine
• Weakness of the upper motor neuron type
  • Accompanied by spasticity and increased reflexes
  • May be paraparesis, hemiparesis, or monoparesis
• Paresthesias or loss of sensation (most often loss of vibration sense)
• Lower extremities more severely affected
• Ataxia
• Bladder control problems
• Constipation
• Progressive or relapsing-remitting pattern
• Permanent neurologic deficits develop with repeated exacerbations

Differential Diagnosis

• Neuromyelitis optic
• Acute disseminated encephalomyelitis
• Structural lesions
• Inherited demyelinating or degenerative diseases
• Vasculitides
• Vascular disease
• Chronic infections (e.g., syphilis, Lyme disease, human T cell lymphotropic virus type I, and progressive multifocal leukoencephalopathy)
• Vitamin B₁₂ deficiency
• Neurosarcoidosis

Best Tests

• Optical examination
  • Fundus usually normal
  • Papillitis or pallor of the disk may be present
  • Failure of adduction on lateral gaze but preservation of adduction with convergence
• MRI
  • Sensitive but not specific findings supportive of MS include the following:
    • ≥ 3 white-matter lesions
    • Lesions abutting the body of the lateral ventricles
    • Juxtacortical lesions
    • Infratentorial lesions
    • Lesions > 5 mm
    • Lesions that show gadolinium enhancement
  • Lesions are hyperintense on T₂-weighted or proton-density imaging and are hypointense or isointense on T₁-weighted imaging
  • Typical lesions are ovoid and periventricular, with their long axis perpendicular to the ventricle, but they may appear anywhere in the white matter
  • Cerebral atrophy is often present and increases over time
• CSF analysis
  • Comparative electrophoresis of serum and concentrated CSF
  • Shows oligoclonal immunoglobulin bands
  • For optimal sensitivity, the paired samples should be analyzed with isoelectric focusing followed by immunofixation
  • Quantitative measures of immunoglobulin content, such as the IgG index and the rate of IgG synthesis
• Summated cortical evoked response
  • Measures conduction along visual, auditory, and somatosensory pathways
  • Slowing of conduction indicates demyelination
  • Confirms demyelination in a particular sensory pathway in the absence of signs or symptoms
  • Visual evoked responses are most useful

Best Therapy

Management of Acute Relapse

• High-dose corticosteroid therapy
  • Contraindications: type 1 diabetes mellitus, uncontrolled hypertension, prior steroid-induced depression or psychoses
  • Methylprednisolone
    • Dose: 0.5–1.0 g/day I.V. for 3–7 days
    • Oral corticosteroids may follow methylprednisolone; taper over 1–2 wk starting with prednisone, 60 mg/day
• Early start of rehabilitation therapy to counteract reduced physical activity during exacerbation

Prevention of Relapse

• The following agents can reduce the frequency of attacks, reduce the rate of MS lesion accumulation on MRI, and reduce the accumulation of disability:
• Interferon beta-1b: for patients with relapsing disease of mild to moderate severity
  • Dose: 0.25 mg (8 million IU) S.C. q.o.d.
  • Side effects
    • Flulike symptoms, which can be controlled with prior administration of an NSAID
    • Injection-site skin necrosis
    • Elevation of liver enzymes
    • Leukopenia
• Interferon beta-1a
  • Avonex
    • Dose: 30 µg I.M. once a week
    • Cost/mo: $1,195
  • Rebif
    • Dose: 44 µg S.C. three times a week
    • Cost/mo: $1,400
  • Side effects
    • Flulike symptoms, which can be controlled with prior administration of an NSAID
    • Injection-site skin necrosis
    • Elevation of liver enzymes
    • Leukopenia
• Glatiramer acetate
  • Dose: 20 mg S.C. q.d.
  • Side effects
    • Injection-site reactions
    • Infrequent postinjection syndrome
    • Cost/mo: $1,176

Progressive MS

• Interferons and glatiramer acetate not effective
• Mitoxantrone: effective for selected patients with very active disease; significant side effects
  • Dose: 12 mg/m² of mitoxantrone given every 3 mo for 2 yr
  • Side effects: nausea, hair loss, menstrual irregularities, infections; cardiotoxic at higher doses

Symptomatic Therapy

Depression

• Treatment as for others with depression

Fatigue

• Amantadine: effective for ~ 50% of patients with MS
  • Dose: 100 mg b.i.d. or t.i.d
  • Cost/mo: $24
  • Avoid dosing late in the day, which may induce insomnia
• Modafanil
  • Dose: 100 mg b.i.d.
  • Cost/mo: $285
• Methylphenidate
  • Dose: 10 mg b.i.d. to 20 mg t.i.d.

Spasticity

• Baclofen
  • Dose: 5 mg t.i.d. to 20 mg q.i.d
  • Cost/mo: $40
• Clonidine (adjunctive to baclofen)
  • Dose: 0.1. mg b.i.d. to 0.2 mg t.i.d
  • Cost/mo: $12
• Diazepam
  • Dose: 2 mg t.i.d. to 10 mg q.i.d
  • Cost/mo: $20
• Tizanidine
  • Dose: 4 mg q.d. to 12 mg q.i.d
  • Cost/mo: $307
• Clonazepam
  • Dose: 0.5 mg t.i.d. to 5 mg q.i.d
  • Cost/mo: $144
• Dantrolene
  • Dose: 25 mg q.d. to 100 mg q.i.d
  • Cost/mo: $187
• Intrathecal baclofen or selective botulinum toxin injections for selected patients with severe spasticity that is unresponsive to oral treatment

Ataxia

• Clonazepam
  • Dose: 0.5 mg t.i.d. to 5 mg q.i.d.
  • Cost/mo: $144
• Gabapentin
  • Dose: 100–600 mg t.i.d.
  • Cost/mo: $90

Bladder Urgency

• Oxybutynin
  • Dose: 5 mg b.i.d. to q.i.d.
  • Cost/mo: $26
• Tolterodine
  • Dose: 2 mg b.i.d.
  • Cost/mo: $96
• Imipramine
  • Dose: 25–75 mg q.h.s.
  • Cost/mo: $27
• Hyoscyamine
  • Dose: 0.125 mg b.i.d. to 0.25 mg q.i.d.
  • Cost/mo: $34
• Propantheline
  • Dose: 7.5 mg t.i.d. to 15 mg q.i.d.
  • Cost/mo: $51

Bladder Dyssynergia

• Phenoxybenzamine
  • Dose: 10 mg b.i.d. to 20 mg t.i.d.
  • Cost/mo: $1,050
• Clonidine
  • Dose: 0.1 mg b.i.d. to 0.2 mg t.i.d.
  • Cost/mo: $12
• Terazosin
  • Dose: 1–5 mg q.d.
  • Cost/mo: $14

Bladder Retention

• Bethanechol
  • Dose: 10 mg t.i.d. to 50 mg q.i.d.
  • Cost/mo: $240
• Intermittent self-catheterization ≥ q.i.d.

Paroxysmal Pain

• Analgesics
• Carbamazepine
  • Dose: 100–300 mg t.i.d.
  • Cost/mo: $47
• Phenytoin
  • Dose: 300–400 mg q.d.
  • Cost/mo: $36

Trigeminal Neuralgia

• Misoprostol
  • Dose: 100–200 µg q.i.d.
  • Cost/mo: $114

Dysesthetic Pain

• Amitriptyline
  • Dose: 50–150 mg q.h.s.
  • Cost/mo: $3
• Phenytoin
  • Dose: 300–400 mg q.d.
  • Cost/mo: $36
• Gabapentin
  • Dose: 100–600 mg t.i.d.
  • Cost/mo: $90
• Valproic acid
  • Dose: 250–1,000 mg t.i.d.
  • Cost/mo: $108

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Best References

Lublin FD, et al: Neurology 46:12, 1996 [PMID 8559358]

McDonald WI, et al: Ann Neurol 50:121, 2001 [PMID 11456302]

Milligan NM, et al: J Neurol Neurosurg Psychiatry 50:511, 1987 [PMID 3295122]

Noseworthy JN, et al: N Engl J Med 343:938, 2000 [PMID 11006371]

Wolinsky JS: Expert Opin Pharmacother 5:875, 2004 [PMID 15102570]

Optic Neuritis

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Acute inflammatory optic neuropathy
• Unilateral vision loss
• Retrobulbar pain with eye movement

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Differential Diagnosis

• Anterior ischemic optic neuropathy
• Hereditary diseases (e.g., Leber hereditary optic neuropathy)
• Toxic or nutritional optic neuropathies
• More than half of all MS patients have optic neuritis at some time

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Best Tests

• Evaluation by ophthalmologist to exclude ocular causes of unilateral vision, e.g. glaucoma, uveitis
• Brain and orbit MRI: may show swelling or inflammation of the optic nerve, shows one or more ovoid or periventricular lesions in ~ 40% of patients who have higher probability of developing MS
• CSF evaluation

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Best Therapy

• Methylprednisolone: hastens recovery of vision but has little residual benefit at 1 yr
  • Dose: 1 g/day I.V. for 3 days followed by oral prednisone starting at 60 mg/day and tapering over 11 days
• Even without treatment, almost all patients begin to recover vision within 4 wk

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Best References

Beck RW, et al: N Engl J Med 326:581, 1992 [PMID 1734247]

Newman NJ: Neurology 46:315, 1996 [PMID 8614487]

Rodriguez M, et al: Neurology 45:244, 1995 [PMID 7854520]

Soederstroem M, et al: Neurology 50:708, 1998 [PMID 9521261]

Acute Disseminated Encephalomyelitis

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Often preceded by a viral exanthem, an upper respiratory infection, or vaccination
• Most commonly associated with measles, paramyxovirus, varicella, rubella, and Epstein-Barr virus
• Rapid onset
• Meningeal signs, headache, seizures, altered mental status
• Variable neurologic deficits, including hemiplegia, paraplegia, sensory loss, vision loss, and transverse myelitis
• Can be fatal, but most patients begin to recover within 2–4 wk

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Differential Diagnosis

• Multiple sclerosis
• Viral encephalomyelitis
• Inherited leukodystrophies

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Best Tests

• MRI: shows multiple white-matter lesions

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Best Therapy

• Corticosteroids: efficacy not proven
• Plasmapheresis

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Best References

Lin CH, et al: J Clin Apheresis 19:154, 2004 [PMID 15493052]

Mader I, et al: AJNR Am J Neuroradiol 17:104, 1996 [PMID 8770258]

Tenembaum S, et al: Neurology 59:1224, 2002 [PMID 12391351]

Transverse Myelitis

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Syndrome of spinal cord dysfunction
• Thoracic cord is most often affected
• Rapid onset
• May follow infection or vaccination
• May be initial presentation of MS
• Paraparesis, initially flaccid and then spastic
• Loss of sensation with a sensory level on the trunk
• Bowel and bladder dysfunction
• Back pain sometimes precedes the neurologic symptoms, and the sensory symptoms may begin distally and ascend
• One third of patients have good outcome, one third have fair outcome, one third do not recover
• Spinal shock, back pain, and catastrophic onset are associated with poor outcome

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Differential Diagnosis

• Extradural structural lesion
• Neoplasms
• Ischemia
• Systemic lupus erythematosus

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Best Tests

• MRI
  • To exclude structural lesions
  • To confirm intramedullary lesion commensurate with symptoms
  • Lesions typically hyperintense on T₂-weighted imaging, involve most of the cross-sectional area of the cord over several segments, may be enhanced with contrast
  • Lesions may cause spinal cord swelling

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Best Therapy

• Usually treated with I.V. methylprednisolone, 1,000 mg/day for 5 days, but there are no controlled trials

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Best References

Choi KH, et al: AJNR Am J Neuroradiol 17:1151, 1996 [PMID 8791931]

Christensen PB, et al: Acta Neurol Scand 81:431, 1990 [PMID 2375246]

Tartaglino LM, et al: Radiology 201:661, 1996 [PMID 8939212]

Transverse Myelitis Consortium Working Group: Neurology 59:499, 2002 [PMID 12236201]

Inherited Demyelinating Diseases

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Associated with progressive demyelination and dysfunction of the adrenal cortex
• Accumulation of very long chain fatty acids (VLCFAs)
• Autosomal recessive or X-linked recessive
• Phenotypes vary considerably
• Childhood form
  • Presents with cognitive deficits and rapid neurologic deterioration
  • Death occurs in 2–5 yr
• Adult form (adrenomyeloneuropathy)
  • Mean age at onset is 28 yr
  • Progressive spinal cord dysfunction
  • Spastic paraparesis
  • Sensory loss
  • Bowel and bladder symptoms
  • Rapidly progressive cerebral lesions 5–10 yr after onset of spinal cord symptoms
  • Cerebral involvement may be minimal

• Demyelination of axons in the central and peripheral nervous systems
• Autosomal recessive
• Onset in infancy or childhood, rarely in adulthood
• Earlier onset associated with more rapid progression
• Mean survival in adult-onset disease is 12 yr
• Symptoms of adult-onset disease:
  • Progressive behavioral abnormalities
  • Dementia
  • Ataxia
  • Neuropathy

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Differential Diagnosis

• Adrenoleukodystrophy
• Metachromatic leukodystrophy
• Krabbe syndrome
• Pelizaeus-Merzbacher syndrome

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Best Tests

Adrenoleukodystrophy

• MRI
  • Only half of adult-onset patients have brain abnormalities, most often in the corticospinal tracts
  • Most patients have diffuse atrophy of the spinal cord
• Family history
• Serum VLCFA: elevated

• MRI or CT of the brain
  • Atrophy
  • Diffuse white-matter abnormalities, particularly in the frontal lobes
• Arylsulfatase A activity in peripheral blood leukocytes, urine, or skin fibroblasts

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Best Therapy

Adrenoleukodystrophy

• Dietary treatment with unsaturated fatty acids
  • Lowers level of VLCFAs
  • Does not significantly affect the progression of symptoms
• Bone marrow transplantation
  • May be effective if performed before severe symptoms develop

Metachromatic Leukodystrophy

• No effective therapy

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Best References

Aubourg P, et al: N Engl J Med 329:745, 1993 [PMID 8350883]

Eichler FS, et al: Neurology 58:901, 2002 [PMID 11914405]

Hageman AT, et al: Arch Neurol 52:408, 1995 [PMID 7710377]

Kumar AJ, et al: AJNR Am J Neuroradiol 16:1227, 1995 [PMID 7677014]

Moser HW: J Neuropathol Exp Neurol 54:740, 1995 [PMID 17350675]

Metabolic Demyelinating Diseases

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Neurologic deficits occurring after rapid correction of hyponatremia (faster than 10–12 mEq/L in 24 hr)
• Usually occurs in young to middle-aged adults
• Associated with alcohol abuse or malnutrition
• Signs and symptoms
  • Usually begin 3 days after the start of sodium replacement
  • Changes in mental status
  • Dysarthria and other signs of corticobulbar dysfunction
  • Spastic quadriplegia
• Improvement usually begins ~ 2 wk after onset of symptoms, but degree of recovery is variable
• May also occur after liver transplantation

• Causes demyelination of axons in the central and peripheral nervous systems
• Paresthesias
• Sensory loss beginning in the feet and progressing proximally
• Weakness beginning after sensory loss
• Sensory ataxia
• Memory difficulties, irritability, and confusion in some patients

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Differential Diagnosis

• Pontine infarct
• Brainstem encephalitis
• Multiple sclerosis

• Nitrous oxide exposure

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Best Tests

• T₂-weighted MRI: usually shows hyperintense lesions that usually do not enhance with contrast

• Physical examination
  • Decreased vibration and position sense, worse in the feet than in the hands
  • Spastic paraparesis
• Pathologic examination
  • Symmetrical loss of myelin in the posterior and lateral columns of the spinal cord
  • Patchy demyelination in the cerebral white matter
• MRI of the spinal cord
  • Often shows white-matter lesions, which resolve with treatment
• Serum cobalamin level: low
• Anemia

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Best Therapy

Central Pontine Myelinolysis

• No specific therapy

Vitamin B₁₂ Deficiency

• Cobalamin
  • Dose: 1,000 µg/wk parenterally for 6 wk, then monthly; or 2,000 µg/day p.o.

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Best References

Healton EB, et al: Medicine (Baltimore) 70:229, 1991 [PMID 1648656]

Lindenbaum J, et al: N Engl J Med 318:1720, 1988 [PMID 3374544]

Pirzada NA, et al: Mayo Clin Proc 76:559, 2001 [PMID 11357804]

Virus-Induced Demyelination

J. William Lindsey, M.D.
Jerry S. Wolinsky, M.D.
University of Texas Health Science Center at Houston

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Lethal disease caused by JC virus infection of oligodendrocytes in immunocompromised patients, e.g. HIV infected, post-transplant, systemic lupus
• Usually presents with relentlessly progressive focal neurologic deficits, such as hemiparesis or visual field deficits, or with alterations in mental status
• Survival 3–5 mo after diagnosis in AIDS patients

• Rare late complication of measles
• Initial infection usually occurs in patients < 2 yr
• Mean onset 7 yr after initial infection
• Progressive cognitive deterioration usually appears first, followed by motor dysfunction and myoclonus
• Progressive course with occasional temporary remissions

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Differential Diagnosis

• Progressive multifocal leukoencephalopathy
• Subacute sclerosing panencephalitis
• Neurosyphilis
• Acute disseminated encephalomyelitis

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Best Tests

Progressive Multifocal Encephalopathy

• Brain MRI
  • Shows one or more white-matter lesions, hyperintense on T₂-weighted images, and hypointense on T₁-weighted images
  • No mass effect
  • Contrast enhancement is rare
• Brain biopsy can confirm diagnosis
• PCR amplification of JC virus from the CSF can confirm diagnosis without biopsy

• EEG: shows distinctive abnormalities associated with myoclonus
• Pathologic examination
  • Shows active viral infection in the brain
  • Measles virus protein and RNA detectable in both oligodendrocytes and neurons
  • Vigorous inflammatory response

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Best Therapy

Progressive Multifocal Encephalopathy

• No effective therapy; correction of immunosuppression if possible

Subacute Sclerosing Panencephalitis

• No effective therapy

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Best References

Antinori A, et al: Neurology 48:687, 1997 [PMID 9065549]

Honarmand S, et al: Neurology 63:1489, 2004 [PMID 15505172]

Sener RN: AJNR Am J Neuroradiol 25:892, 2004 [PMID 15140742]

J. William Lindsey, M.D., has received speaking honoraria from Teva Pharmaceuticals and Serono. Jerry S. Wolinsky, M.D., has served as a consultant or speaker for Teva Pharmaceuticals, Serono, and Schering-Plough Corp.

September 2010