Multiple Sclerosis

In MS, the initial attack occurs abruptly (minutes to hours) from a single lesion. These attacks last between 6 and 8 weeks. Recovery between bouts of demyelination can be incomplete or complete, depending on the amount of remyelination. Any part of the central nervous system can be affected. In decreasing order of frequency, the patient may exhibit optic neuritis, paresthesias in a limb, diplopia, trigeminal neuralgia, urinary retention, vertigo, or transverse myelitis. Depending on the spinal cord level, transverse myelitis can also cause loss of bladder or bowel function.

Ocular findings are the most common initial symptom. Optic neuritis is manifested as subacute monocular vision loss, although it can affect both eyes, and pain exacerbated with eye movement. It is the initial symptom in 25% and ultimately affects 50% of patients.¹ The course usually progresses over a period of 2 weeks and may be include headache, retroorbital or periocular pain, and alterations in color vision and visual fields. Slit-lamp examination may demonstrate cell and flare in the anterior chamber. The optic disk is frequently swollen on initial evaluation. In addition to optic neuritis, the patient may have an afferent pupillary defect (Marcus Gunn pupil, or decreased pupillary constriction on direct light confrontation but a normal consensual response) or intranuclear ophthalmoplegia, which is characterized by dysconjugate gaze with limited adduction of one eye and nystagmus in the abducting eye on lateral gaze as a result of a lesion involving the medial longitudinal fasciculus.

Sensory symptoms in patients with MS usually include numbness, tingling, pins and needles sensation, and tightness and coldness of the limbs and trunk. Radicular pain and itching may also occur. Symptoms result from involvement of the spinothalamic, posterior column, and dorsal nerve roots. The loss of vibration sense is often most prominent. Ataxia is uncommon at the onset of MS, but it occurs to some degree in most patients. Exacerbation of sensory symptoms can occur frequently and in different patterns with a patchy distribution. Patients may note either paresthesias or loss of sensation.

Sensitivity to heat is a characteristic complaint. Exercise, fever, a hot bath, or other activities that raise body temperature may result in the appearance of new symptoms or the recurrence of old symptoms. These events occur as a result of a temperature-induced conduction block across partially demyelinated fibers. Symptoms resolve when body temperature returns to normal.

In addition to loss of sensation, patients may also report “positive” symptoms. In addition to causing a slowing of conduction, demyelination may result in ectopic impulses with resultant abnormal signal transmission and abnormal mechanical sensitivity. These aberrant signals can produce the Lhermitte sign—an electric-like tingling or vibrating sensation in the torso or extremities with neck flexion. The patient may also report flashes of light (phosphenes) and paroxysmal symptom, including trigeminal neuralgia, ataxia, and dysarthria or painful tetanic posturing of the limbs triggered by touch or movement.

Motor weakness may occur in any pattern, including paraparesis, hemiparesis, and monoparesis; the lower extremities are usually affected more than the upper ones. Upper motor neuron dysfunction accompanied by spasticity and increased reflexes may also be present. Transverse myelitis with ascending weakness and numbness below the level of the lesion can occur as an initial symptom.

Autonomic symptoms are a frequent finding. Patients have difficulty with bladder function, including frequency and urgency, and may experience urge incontinence from bladder spasticity or hesitancy, retention, and overflow incontinence from poor signal conduction. Constipation is the most common bowel complaint. This autonomic dysfunction is frequently very embarrassing and distressful.

Normal disease progression is variable: MS may remain indolent or occur in a progressive manner, with steady accumulation of neurologic deficits in the absence of clearly defined exacerbations. Typically, acute exacerbations are followed by partial or complete resolution. New neurologic deficits develop over the course of several hours or days, remain stable for a few days to a few weeks, and then gradually improve.

With repeated exacerbations, permanent neurologic deficits tend to develop. Patients usually have symptom-free intervals of months or years between attacks. Patients who initially have relapsing-remitting disease (two or more episodes lasting more than 24 hours separated by more than 1 month) and who then enter a progressive phase are said to have secondary progressive disease (initial exacerbations and remissions followed by slow progression over at least a period of 6 months), whereas those whose symptoms are progressive from the onset are said to have primary progressive disease (slow or stepwise progression over a period of at least 6 months). About 15% of patients have primary progressive disease; of those who initially have relapsing-remitting disease, 30% to 50% will experience progressive symptoms during the first 10 years.

Optic Neuritis

Optic neuritis may occur by itself or be the initial symptom of MS. The relationship of optic neuritis to MS is controversial. Some regard optic neuritis as a distinct entity, but others consider it part of the clinical continuum of MS. More than half of all patients with MS have optic neuritis at some time during the disease. Patients with completely normal results on magnetic resonance imaging (MRI) and comprehensive cerebrospinal fluid (CSF) evaluation seldom progress to MS. Optic neurits is usually manifested initially as unilateral vision loss and retrobulbar pain with eye movement.

Transverse Myelitis

Like optic neuritis, transverse myelitis may occur in isolation or be part of the symptomatology of MS. It is usually manifested as paraparesis, which is initially flaccid and then spastic; as loss of sensation at a sensory level on the trunk; and as bowel and bladder dysfunction. Back pain precedes the neurologic symptoms, and the sensory symptoms may begin distally and ascend. The thoracic cord is most often affected.

Guillain-Barré Syndrome

Patients with GBS have weakness, paresthesias, and decreased or absent deep tendon reflexes. The distribution typically includes distal involvement with symmetric paresthesias (pins and needles). It spreads proximally, with weakness occurring a few days later; weakness also progresses to involve the upper extremities. Weakness is most prominent in the lower extremities and tends to involve the proximal muscles. It is usually first manifested as difficulty rising from a chair. The disease progresses from a few days to 3 to 4 weeks (progressive phase), followed by a plateau phase (days to weeks) and then by a recovery phase lasting from weeks to months. Weakness is varied but can be profound and involve the face and respiratory muscles. A loss or decrease in deep tendon reflexes is frequently the initial finding, and these reflexes should be tested if GBS is suspected. Variants include the acute axonal form, which has a poor prognosis, and the Miller-Fisher syndrome, which is characterized by ataxia, ophthalmoplegia, and areflexia.

Cerebrospinal Fluid Analysis

With MS, CSF analysis (with electrophoresis) frequently demonstrates albuminocytologic dissociation with increased protein (usually less than 100 mg/dL) and a normal cell count. However, 10% of patients have a normal CSF protein level. Mild mononuclear cell pleocytosis can be found during acute MS relapses, but total cell counts greater than 50/mm³ are uncommon. During acute attacks of MS, especially those involving the spinal cord and brainstem, CSF may contain measurable amounts of myelin basic protein. Oligoclonal bands or abnormal immunoglobulin synthesis is found in about 90% of patients with a diagnosis of MS. Though not specific to MS, these findings support the diagnosis of MS in equivocal cases.

CSF studies may demonstrate elevated protein levels and leukocytes in patients with transverse myelitis; such studies are not generally required for optic neuritis but are usually obtained to help in the diagnosis of MS.

Nerve Conduction Studies

Electrodiagnostic testing may demonstrate conduction blocks, differential slowing, or focal slowing. Slowing of conduction over demyelinated segments of axons or over incompletely remyelinated pathways provides a useful marker for identifying additional subclinical lesions in the sensory pathways. Conduction can be measured along the visual, auditory, and somatosensory pathways with the use of summated cortical evoked responses. In these tests, a time-locked recording of the electroencephalogram over the afferent cortex of interest is obtained after repeated visual, auditory, or sensory stimulation. If the demyelination is significant, conduction is delayed.

Electrodiagnostic testing may demonstrate abnormal motor and sensory conduction, but these signs can take a few weeks to develop.

Magnetic Resonance Imaging

MRI permits the exclusion of many diseases that mimic MS and identifies certain lesions that are hyperintense on T2-weighted or proton density imaging and hypointense or isointense on T1-weighted imaging. Typical lesions are ovoid and periventricular, with the long axis perpendicular to the ventricle, but lesions may appear anywhere in the white matter. Although MRI is extremely sensitive in detecting white matter lesions in patients with MS, it is not very specific because many other diseases produce multiple white matter lesions. Useful features for increasing the predictive value of MRI for the diagnosis of MS include the presence of three or more white matter lesions, lesions that abut the body of the lateral ventricles, infratentorial lesions, lesions larger than 5 mm in diameter, and lesions that demonstrate gadolinium enhancement.

MRI is extremely useful for confirming the presence of an intramedullary lesion at the level in the spinal cord commensurate with the symptoms of transverse myelitis. The lesions are typically hyperintense on T2-weighted imaging; they involve the majority of the cross-sectional area of the cord over several segments and may be enhanced with contrast agents. The lesions may cause swelling of the spinal cord. Gadolinium-enhanced MRI may show abnormal enhancement of the nerve roots in the region of the conus medullaris and cauda equina.³

MRI is also useful for diagnosing optic neuritis and evaluating for concomitant MS. Gadolinium enhancement may demonstrate optic nerve involvement. In questionable cases, visually evoked potentials may demonstrate prolonged latency.

Multiple Sclerosis

Treatment of MS can be discussed in terms of the management of acute relapses, prevention of relapses as a modification of the disease process, and management of symptoms and fixed neurologic deficits. High-dose pulsed corticosteroid therapy is indicated for exacerbations of acute relapses that adversely affect the patient’s function. Intravenous (IV) methylprednisolone at doses of 0.5 to 1 g daily for 5 days reduces the maximal neurologic signs and hastens the resolution of associated fatigue. A controversial study by Sellebjerg et al. supports the use of oral methylprednisolone (500 mg daily for 5 days with a 10-day tapering period).⁴

In patients with relapsing-remitting MS, disease-modulating drugs reduce the frequency of attacks, the rate of increase in lesions seen on MRI, and the accumulation of disability. In patients with relapsing disease of mild to moderate severity, interferon beta-1b, given subcutaneously every other day, reduced the year-on-year relapse rate by one third and severe attacks by one half. The effect was maintained for up to 5 years.^5,6 In another study, interferon β1b reduced MRI contrast-enhanced lesions by 1.6%, as opposed to a 15% increase in those receiving placebo. The number of enlarging or new lesions was also significantly reduced.⁷ Antibodies developed in 35% of patients taking interferon β1b, but there is a lack of consistent effect of antibodies on clinical outcome. Additionally, these antibody levels were found to have disappeared in the majority of patients after 8 years of treatment.^8,9

Interferon β1a produced similar benefits when given intramuscularly three times per week, with a 17% reduction in the relapse rate. When compared with weekly, low-dose interferon β1a, high-dose interferon β1a given three times per week demonstrated a 32% relative reduction in steroid use to treat relapses.¹⁰

Glatiramer, a synthetic random compound composed of four amino acids, is found in myelin. Its exact mechanism is unknown, but it is believed that glatiramer acetate binds to the major histocompatibility complex class II antigen and induces organ-specific T helper type 2 cell responses, thus converting proinflammatory T cells to antiinflammatory agents.¹¹ Treatment with glatiramer reduces the relapse rate by 30% and may delay disease progression.¹²

Natalizumab, a monoclonal antibody against α₄ integrins, is effective for relapsing-remitting MS. The reduction in annualized relapse rates with natalizumab is similar to that with glatiramer or interferon β.¹³ However, it is not a first-line agent because it can cause progressive multifocal leukoencephalopathy in 0.1% of cases.¹⁴

Mitoxantrone is an anthracenedione, antineoplastic agent approved for the relapsing-remitting and progressive forms of MS. Cardiotoxicity, acute leukemia, and questionable efficacy limit it to treatment failures or cases of rapidly progressive MS.

Fingolimod, the first oral treatment option for MS approved by the Food and Drug Administration, is a sphingosine analogue that blocks lymphocyte release from lymph nodes through interaction with the sphingosine 1-phosphate receptor. Fingolimod can significantly reduce relapse rates when compared with interferon β1a. However, fingolimod is associated with life-threatening infections, bradycardia, atrioventricular block, tumor development, and macular edema.¹⁵

Specific therapies for relief of symptoms are provided in Table 98.3.

Table 98.3 Symptomatic Treatment of Multiple Sclerosis

Transverse Myelitis

Corticosteroids and plasma exchange may be beneficial in the treatment of transverse myelitis.¹⁶ In a small case series, patients treated with steroids were able to walk after a median time of 23 days versus 97 days for historical controls.¹⁷ Plasma exchange is often used for those with more severe disease (e.g., unable to walk) who fail to improve with IV steroid therapy.¹⁸ The prognosis for transverse myelitis is variable.

Optic Neuritis

IV methylprednisolone (1 g/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days with a 4-day taper) and interferon β1a (30 mcg intramuscularly once a week) for patients at high risk for MS based on MRI has been shown to hasten recovery of vision in patients with optic neuritis.¹⁹ However, this therapy shows little residual benefit at 1 year. Additionally, oral prednisone therapy alone was found to actually increase the recurrence rate.²⁰ Regardless of therapy, most patients recover their vision within a month.

Guillain-Barré Syndrome

Therapy is largely supportive. Most patients recover function if they survive the acute phase. The key therapeutic measure is ventilatory support. FVC should be measured in all patients in whom GBS is suspected. Patients with an FVC of less than 20 mL/kg should be admitted to the intensive care unit because of their high risk for ventilatory insufficiency. For those with FVC lower than 15 mL/kg, intubation is indicated. If intubation is necessary, succinylcholine should be avoided because it can cause hyperkalemia with resultant arrhythmia and hypotension. Dysautonomia can result in severe paroxysmal hypertension, orthostatic hypotension, and arrhythmias. Cardiovascular function should be monitored carefully. Plasmapheresis and IV gamma globulin therapy have both been shown to reduce recovery time by 50%. IV gamma globulin is less expensive and easier to administer, but the risk for viral transmission is greater. IV steroids are frequently administered, but their actual benefit is questionable.