187 MULTIPLE SCLEROSIS (MS)
Harrison’s Manual of Medicine
MULTIPLE SCLEROSIS (MS)
Characterized by chronic inflammation and selective destruction of CNS myelin; peripheral nervous system is spared. Pathologically, the multifocal scarred lesions of MS are termed plaques. Etiology is thought to be autoimmune, with susceptibility determined by genetic and environmental factors. MS affects 350,000 Americans; onset is most often in early to middle adulthood, and women are affected approximately twice as often as men.
Onset may be dramatic or insidious. Most common are recurrent attacks of focal neurologic dysfunction, typically lasting weeks or months, and followed by variable recovery; some pts initially present with slowly progressive neurologic deterioration. Symptoms often transiently worsen with fatigue, stress, exercise, or heat. The manifestations of MS are protean (Table 187-1) but commonly include weakness and/or sensory symptoms involving a limb, visual difficulties, abnormalities of gait and coordination, urinary urgency or frequency, and abnormal fatigue. Motor involvement can present as a heavy, stiff, weak, or clumsy limb. Localized tingling, “pins and needles,” and “dead” sensations are common. Optic neuritis can result in blurring or misting of vision, especially in the central visual field, often with associated retroorbital pain accentuated by eye movement. Involvement of the brainstem may result in diplopia, nystagmus, vertigo, or facial symptoms of pain, numbness, weakness, hemispasm, or myokymia (rippling muscular contractions). Ataxia, tremor, and dysarthria may reflect disease of cerebellar pathways. Lhermitte’s symptom, a momentary electric shock-like sensation evoked by neck flexion, indicates disease in the cervical spinal cord. Diagnostic criteria are listed in Table 187-2.
Table 187-1 Initial Symptoms of MS
Table 187-2 Diagnostic Criteria for MS
Abnormal signs usually more widespread than expected from the history. Check for abnormalities in visual fields, loss of visual acuity, disturbed color perception, optic pallor or papillitis, abnormalities in pupillary reflexes, nystagmus, internuclear ophthalmoplegia (slowness or loss of adduction in one eye with nystagmus in the abducting eye on lateral gaze), facial numbness or weakness, dysarthria, incoordination, ataxia, weakness and spasticity, hyperreflexia, loss of abdominal reflexes, ankle clonus, upgoing toes, sensory abnormalities.
Four general categories:
Relapsing-remitting MS is characterized by recurrent attacks of neurologic dysfunction with or without recovery; between attacks, no progression of neurologic impairment is noted.
Secondary progressive MS initially presents with a relapsing-remitting pattern but evolves to be gradually progressive.
Primary progressive MS is characterized by gradual progression of disability from onset.
Progressive-relapsing MS is a rare form that begins with a primary progressive course, but superimposed relapses occur.
MS is a chronic illness; 15 years after diagnosis, 20% of pts have no functional limitation, 70% are limited or unable to perform major activities of daily living, and 75% are not employed.
MRI reveals multifocal bright areas on T2-weighted sequences in > 90% of pts; gadolinium DPTA results in enhancement of active lesions due to disruption of blood-brain barrier. MRI also useful to exclude disorders that mimic MS. CSF findings include mild lymphocytic pleocytosis (5–75 cells in 25%), oligoclonal bands (75–90%), elevated IgG (80%), and normal total protein level. Visual, auditory, and somatosensory evoked response tests can identify lesions that are clinically silent; one or more evoked response tests abnormal in > 80% of patients. Urodynamic studies aid in management of bladder symptoms.
TREATMENT (Fig. 187-1 and Table 187-3)
FIGURE 187-1. Therapeutic decision-making for MS. (From SL Hauser, DE Goodkin: HPIM- 15, p. 2459.)
Table 187-3 Disease-Modifying Therapy for Relapsing Forms of MS
Prophylaxis Against Relapses Three treatments are available: Interferon (IFN) b1b (Betaseron), IFN-b1a (Avonex), and copolymer 1 (Copaxone). Each of these therapies reduces annual exacerbation rates by approximately one-third; IFN-b1a most convincingly delays the time to onset of sustained progression. Injection site reactions are common in IFN-b1b and copolymer 1 recipients. Approximately 15% of copolymer 1 recipients experience transient flushing, chest tightness, dyspnea, and palpitations. Approximately 40% of IFN-b1b and 5–25% of IFN-b1a recipients develop neutralizing antibodies within 12 months of initiating therapy, and these pts appear to lose the benefit of therapy.
Acute Relapses Acute relapses that produce functional impairment may be treated with a short course of IV methylprednisolone (MePDN) followed by oral prednisone (PDN). This regimen speeds recovery and may modestly improve the degree of recovery that occurs. Initial attacks of demyelinating disease—such as optic neuritis or myelitis—are treated in a similar fashion. In one small controlled trial, plasma exchange was effective in some pts with unusually fulminant attacks unresponsive to glucocorticoids.
Chronic Progression For pts with secondary progressive MS who continue to experience relapses, treatment with one of the interferons is reasonable (see above). The immunosuppressant/immunomodulator drug mitoxantrone (12 mg/m2 by intravenous infusion every 3 months) has recently been approved in the U.S. for treatment of secondary progressive MS; however, dose-related cardiac toxicity is an important concern. Methotrexate (7.5–20 mg po once each week) or azathioprine [2–3 (mg/kg)/d PO] is sometimes tried, but efficacy is modest. Pulse therapy with cyclophosphamide is employed in some centers for young adults with aggressive forms of MS. For patients with primary progressive MS, symptomatic therapy only is recommended.
Symptomatic Therapy Spasticity may respond to baclofen (15–80 mg/ d in divided doses), diazepam (2 mg bid-tid), or tizanidine (2–8 mg tid). Dysesthesia may respond to carbamazepine (100–1200 mg/d in divided doses), phenytoin (300 mg/d), or amitriptyline (50–200 mg/d). Treatment of bladder symptoms is based on the underlying pathophysiology: hyperreflexia is treated with anticholinergics such as oxybutinin (5 mg bid-tid), hyporeflexia with the cholinergic drug bethanecol (10–50 mg tid-qid), and dyssynergia with anticholinergics and intermittent catheterization.
For a more detailed discussion, see Hauser SL, Goodkin DE: Multiple Sclerosis and Other Demyelinating Diseases, Chap. 371, p. 2452, in HPIM-15.