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13 Neurology

Multiple sclerosis (MS)                                SX  |  DX  |  Diff-Dx  |  RX  

Multiple sclerosis is a relapsing inflammatory demyelinating disorder of the CNS, the cause of which is unknown. Histologic examination shows areas of perivenular inflammatory demyelination in areas known as plaques with waves of immunoreactive cells infiltrating the brain.

Symptoms of MS
The classic relapsing-remitting form consists of a series of attacks and relapses with quiescent periods of the disease. The most common manifestations are motor weakness, eye symptoms (specifically decreased vision from an optic neuritis and double vision), and sensory findings such as paraesthesia, ataxia, severe fatigue, euphoria, and bladder dysfunction.

Diagnosis of MS
When the MRI shows white-matter lesions in the setting of abnormal CSF and evoked potentials, the diagnosis of MS is almost unequivocal.

The diagnosis of multiple sclerosis requires the exclusion of other diseases such as vitamin B12 deficiency, Lyme disease, arteriovenous malformations, and Sjögren's syndrome.

  • The CSF is examined for the presence of oligoclonal bands  of IgG (which are present in 90% of affected patients), an abnormal IgG index (present in 70%), and myelin basic protein (generally positive within the first week of a relapse).
  • MRI shows neuroanatomic lesions within the brain or spine in half of affected patients.
  • Electrophysiologic abnormalities can be detected using visual, brain stem, auditory, somato-sensory evoked potentials in 40% to 60% of patients.

The spinal fluid is abnormal in about 90% of patients, and about 50% of patients have a cerebrospinal fluid (CSF) pleocytosis with more than five lymphocytes.
By utilizing high-resolution electrophoresis of concentrated CSF, oligoclonal bands of IgG can be demonstrated in 85-95% of patients with definite MS. However, oligoclonal bands of IgG also occur in neurosyphilis, subacute sclerosing panencephalitis, fungal meningitis, and progressive rubella panencephalitis. Nevertheless, this test often is useful in confirming the diagnosis of MS, since it is frequently abnormal early in the course of the disease. The test is available from commercial laboratories.
An increase in CSF myelin basic protein may confirm an acute attack of MS. Elevated values (> 9 ng/ml) suggest active demyelination. However, myelin basic protein levels may also be increased in transverse myelitis, optic neuritis, or radiation-induced demyelination. This test is not generally useful in confirming the initial diagnosis of MS. It is also available from commercial clinical laboratories.

Although the brain MRI may be normal in MS, this is an uncommon finding. In patients with an initial neurologic event consistent with CNS demyelination and a normal MRI, the 5-year risk of MS is less than 5%. Conversely, patients with a first neurologic event consistent with demyelination and multiple white-matter brain lesions on MRI have a 5-year risk of MS of about 60%.
The MRI as a marker of disease severity in MS. The MRI burden (number and size of white-matter lesions on MRI) correlates weakly with clinical status in MS. The MRI also can detect attacks of demyelination that have no obvious clinical correlate. Nonetheless, MRI remains an excellent measure of disease severity and progression.

Differential diagnosis of MS
. Other diseases affecting CNS white matter may resemble MS clinically or radiologically. Care must be taken to exclude these conditions before confirming a diagnosis of MS:

  • Certain tumors (especially lymphomas and gliomas of the hemispheres, brainstem, and spinal cord).
  • Certain malformations (Arnold-Chiari and platybasia).
  • Spinal cord compression due to spondylosis, herniated invertebral disk, and epidural tumor.
  • Degenerations including spinocerebellar, motor neuron disease, and subacute combined degeneration of the spinal cord.
  • Collagen vascular disease including polyarteritis, isolated angiitis of the nervous system, and systemic lupus erythematosus.
  • Behcet's disease.
  • Human T-cell lymphotropic virus type I-associated myelopathy.
  • Neurosarcoidosis.
  • Postinfectious and postvaccinial encephalomyelitis.
  • Human immunodeficiency virus (HIV) encephalopathy.
  • Vitamin B12 deficiency.
  • Adult-onset adrenoleukodystrophy.

If the neurologic symptoms in a case of suspected MS are limited to the spinal cord, brainstem, or posterior fossae, MRI is useful in excluding cord compression, tumors, or malformations. Features that cast doubt on the diagnosis of MS include completely normal CSF, completely normal MRI of brain and spinal cord, neurologic signs and symptoms that can be explained by a focal lesion, or absences of fluctuations in the clinical course.

Treatment of MS
Corticosteroid therapy may shorten the duration of attacks. Other forms of immunosuppression including cyclophosphamide, plasma exchange, azathioprine, total lymphoid irradiation, hyperbaric oxygen, intravenous gamma globulin, and antilymphocyte globulin, have shown only marginal effects in halting the progression of disease.

Intravenous methylprednisolone for acute attacks of MS
Dosage: IV 250-500 mg q12h for 3-7 days, followed by oral prednisone at a dosage of 60-80 mg daily for 7 days. The prednisone is then tapered 10 mg every 4 days over a 1-month period.

More than 85% of patients with relapsing-remitting MS show improvement with intravenous methylprednisolone; less than 50% of patients with chronic progressive MS will improve with such treatment.

Oral corticosteroids may also be effective in shortening acute attacks of MS. Prednisone may be used in less severe exacerbations of MS when hospitalization is unnecessary. However, the decision to use oral prednisone in place of intravenous methylprednisolone must be made with some caution; in a placebo-controlled study of optic neuritis, intravenous methylprednisolone followed by oral prednisone proved superior to either oral prednisone or placebo.

Interferon beta-1B (Betaseron) -  8 million IU SC every other day x 2 years.
has been approved for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1B is a new drug so its full range of indications, its long-term efficacy, and long-term risks are not yet fully known.  Efficacy data beyond 2 years of treatment are not currently available. Safety data beyond 3 years are not currently available.    In a 2-year placebo-controlled study, interferon beta-1B reduced exacerbations by 31% compared to placebo.

Deterioration in the neurologic status of a patient with MS may be due to a new attack of demyelination or, less commonly, intercurrent infection (especially of the urinary tract), electrolyte imbalance, fever, drug intoxication, or conversion reaction. When doubt exists, demonstration of lymphocytes in the CSF may support the diagnosis of acute demyelination.

Management of the Complications of MS

1. Weakness. Physical therapy is of benefit when weakness is due to lack of use, but it does not strengthen muscles weakened by CNS demyelination. This therapy maintains range of motion, assists in gait training, and boosts patient fitness and morale.

2. Spasticity

a. Physical therapy is of little benefit in diminishing spasticity.

b. Baclofen (Lioresal) is the drug of choice in the treatment of spasticity due to MS. It is highly effective in reducing painful flexor and extensor spasms and is somewhat less effective in reducing baseline spasticity or hyperreflexia. Its major side effect is drowsiness, which generally diminishes with continued use. Confusion may occur at higher dosages, especially if cognitive impairment is present. Unlike dantrolene, use of baclofen is not associated with increased weakness. However, some very weak patients cannot tolerate the loss in spasticity that is important in permitting them to bear weight. The usual starting dosage is 5-10 mg tid, which may be gradually increased to 20 mg qid. Intrathecal baclofen is under investigation for intractable spasticity.

c. Diazepam (Valium) may reduce spasticity in some patients. Its mechanism of action is believed to be central. Side effects include drowsiness and fatigue. Usual effective dosage is 5-50 mg daily.

d. When diazepam and baclofen are ineffective, dantrolene (Dantrium) may be tried. Dantrolene always produces increased weakness, since its mechanism of action involves decoupling of excitation-contraction in muscle. The drug has proved useful in only a few patients with spasticity, but in responsive individuals the improvement can be dramatic. Dosage can be initiated at 25 mg daily and gradually increased to a maximum of 400 mg daily over several weeks. Dantrolene may produce hepatitis, and its use is contraindicated in the presence of hepatic disease. Thus, liver function must be monitored regularly. Other side effects include drowsiness, dizziness, and diarrhea. Because dantrolene is a potentially toxic drug, its use should be discontinued unless a therapeutic effect can be demonstrated.

e. Intrathecal phenol, anterior rhizotomy, and peripheral nerve block are considered only if spasticity or flexor spasms are refractory to drug treatment and make the patient uncomfortable. These procedures are reserved for patients with long-standing paraplegia, since relief of spasticity is accompanied by further paralysis.

(1) Intrathecal injection of 5-20% phenol in glycerol has been used widely to relieve spasticity. The procedure can be performed easily without general anesthesia. A radiopaque dye is added to the phenol solution, and the procedure is done under fluoroscopic control on a myelography table. Spasticity is relieved by the production of a flaccid paralysis that lasts 3-12 months. Sensory loss usually accompanies the paralysis and can lead to pressure sores. Also, bladder and bowel sphincter dysfunction commonly occurs.

(2) In patients with normal bowel and bladder function, anterior rhizotomy is probably the procedure of choice. Irreversible weakness is produced, but sensory loss and urinary retention are avoided. Alternatively, peripheral nerve block with phenol may relieve spasticity without risking bladder or bowel dysfunction.

3. Tremor and ataxia. About 70% of patients experience cerebellar intention tremor or ataxis at some time during their illness.

a. Mild degrees of tremor or ataxia are often improved by weighting the affected limbs. Tremors of the head and trunk are particularly resistant to treament.

b. Thalamotomy remains a rarely used procedure for cerebellar tremor.

c. Propranolol (40-160 mg daily), diazepam (5-15 mg daily), primidone (500-1500 mg daily), or clonazepam (0.5-2.0 mg daily) may be tried for the tremor, although results are often unsatisfactory.

4. Pain. Shooting or lancinating pains that affect the pelvic girdle, shoulders, and face are common features of MS. Facial pain that is indistinguishable from trigeminal neuralgia occurs in about 3% of patients, and most bilateral trigeminal neuralgia is caused by MS.

a. These neuritic pains, regardless of location, often respond to carbamazepine, 400-1200 mg daily.

b. In drug-refractory cases, surgical management is recommended (see Chap. 9).

c. Baclofen, 10-20 mg tid is also effective for the neuritic pains of MS and may be useful in refractory cases of trigeminal neuralgia.

d. Burning pains or uncomfortable dysesthesias may improve with tricyclic antidepressants such as imipramine, 25-100 mg daily.

5. Bladder, bowel, and sexual dysfunction are common. In patients with either urinary retention of incontinence, correctable anatomic lesions must be excluded.

a. Rational therapy of bladder dysfunction depends on urodynamic (cystometric) studies. Bladder dysfunction is often complex in MS. About 33% of patients have difficulty retaining urine, about 20% have difficulty emptying the bladder, and 50% have a mixture of retention and emptying difficulties.

b. When failure to store urine is due to uninhibited involuntary detrusor contractions, propantheline, 7.5-15.0 mg qid, may abolish incontinence. However, some of these patients may develop urinary retention that requires intermittent catheterization.

c. Failure to store urine associated with both involuntary detrusor contractions and sphincter incompetence may require either a urinary diversion procedure, an indwelling catheter, or an external drainage appliance (condom catheter).

d. In patients with a failure to empty the bladder, anatomic obstructions should be corrected. In cases of functional obstruction at the bladder neck, alpha-sympathetic blocking agents may be of value (phenoxybenzamine [Dibenzyline], 5-10 mg bid). If there are weak contractions of the detrusor muscle, bethanechol (Urecholine), 10-25 mg qid, may be of benefit. Other patients show improved voiding with either Crede's or Valsalva's maneuvers. The remaining patients will require either indwelling catheters, intermittent catheterization, or urinary diversion procedures.

e. A penile prosthesis may restore potency in men whose impotence is secondary to MS.

6. Psychiatric complications include depression, euphoria, emotional lability, and psychosis.

a. Reactive depressions that occur soon after diagnosis are often relieved by sympathetic, supportive psychotherapy.

b. Depressions related to increasing disability are best managed by providing the patient with a positive therapeutic regimen, including physical therapy.

c. Depression related to cerebral lesions may be resistant to treatment. However, antidepressant drugs are sometimes of benefit.

d. Euphoria tends to occur late in the course of MS, and it is associated with signs of generalized intellectual deterioration and extensive cerebral demyelination. Psychosis is a relatively rare complication, usually related to high-dose corticosteroid therapy. Treatment with an appropriate major tranquilizer (haloperidol, 10-40 mg, or chlorpromazine, 100-1000 mg daily) is generally effective.

7. Fatigue is a common complaint in MS, affecting up to 90% of patients. Amantadine (Symmetrel), 100 mg PO bid, may relieve fatigue in some patients. Patients unresponsive to amantadine may respond to pemoline (Cylert), 37.5 mg PO every morning.

8. Heat sensitivity is common in MS. Neurologic deterioration may occur in hot weather or during febrile illnesses. Management consists of aggressive treatment of intercurrent illnesses and liberal use of air conditioning during hot weather.

9. Seizures occur in about 5% of patients with MS. They are generally easily controlled with either phenytoin, 200-400 mg daily, or carbamazepine, 600-1800 mg daily.

Manual of Neurological Therapeutics - Martin A. Samuels
ACP Library on Disk 2- (c) 1997 - American College of Physicians