Multiple Sclerosis
Megan R. Weigel
Joanne V. Hickey
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS), which predominantly affects white matter, though gray matter involvement also occurs. It is a progressive neurodegenerative condition; early axonal loss has been identified.1 MS causes demyelination and scarring of myelin, resulting in plaques visible on MRI and in histopathologic specimens. The manifestations of the disease vary from an insidious progressive to a rapidly progressive and disabling illness that has a profound effect on physical function and quality of life.2 See Figure 32-1.
The classification of MS is based on its variable clinical courses (see Table 32-1). These courses are defined by periods of relapse, remission, and chronic progression.4 The etiology of MS is unknown, although it is hypothesized that a virus may precipitate an autoimmune response in a genetically susceptible individual with certain environmental exposures. MS has been called the disease of young adults because the highest rate of incidence is between the ages of 20 and 50 years. In fact, it is the most common nontraumatic cause of neurologic disability in young adults.5 Recent research suggests that low vitamin D levels, smoking, and Epstein-Barr virus infections are associated with increased risk of MS.6
There are more than 4,00,000 cases of MS in the United States,1 with women being affected at least three times as frequently as men. Whites are affected more frequently than any other racial group. The lifetime risk of MS in the general population is approximately 0.1%, but children of a parent with MS have a 3% risk, thus supporting genetic susceptibility theories. There have been many susceptibility loci identified through genetic studies in recent years.6 Epidemiologic studies report that MS is more prevalent in the colder northern latitudes, though there may be an attenuation in latitude gradient that suggests other environmental associative factors. In general, MS is more common in Europe, the United States, Canada, New Zealand, and Southern Australia than in more tropical regions. Moving to a warmer climate before the age of 15 years confers a lower risk of climate influence.
The course of MS is unpredictable even within each subtype. Cohort studies have provided broad prognostic factors. Younger age at onset, female gender, monosymptomatic presentation, complete relapse recovery, long interval between first and second relapses, few relapses, and a relapsing rather than a progressive course are factors associated with a better prognosis. In addition to
male gender, poorer prognosis is associated with age of onset over 40 years; initial presentation of motor, cerebellar, or sphincter symptoms or polysymptomatic presentation; frequent attacks in the first 5 years; and a short interval between attacks.6
male gender, poorer prognosis is associated with age of onset over 40 years; initial presentation of motor, cerebellar, or sphincter symptoms or polysymptomatic presentation; frequent attacks in the first 5 years; and a short interval between attacks.6
 Figure 32-1 ▪ Myelin destruction in multiple sclerosis. Asset provided by Anatomical Chart Co. |
TABLE 32-1 FOUR CATEGORIES OF MULTIPLE SCLEROSIS (MS) BASED ON CLINICAL COURSE | ||||||||||
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PATHOGENESIS AND PATHOPHYSIOLOGY
The inflammation in the brain and spinal cord in MS begins because of a complex interplay of genetic, environmental, and immunologic factors. The traditionally accepted model of inflammation is based on the animal model of experimental autoimmune encephalitis (EAE). It begins with peripheral activation and proliferation of T cells by an antigen-presenting complex (APC) in the periphery, causing the expression of inflammatory cytokines and matrix metalloproteinases (MMPs). MMPs disrupt the blood-brain barrier, allowing proinflammatory cells (T cells, B cells, and macrophages) to enter the CNS. Once inside the CNS, T cells are reactivated by myelin antigens. Inflammation continues with recruitment of other cytokines, causing demyelination and axonal loss. B cells are also involved, secreting antibodies directed against myelin. These antibodies are found in the CSF and are called oligoclonal bands. The suspected mechanism of action (MOA) of current disease-modifying therapies is a shift from proinflammatory T cells, interleukins, and other cytokines, to an anti-inflammatory milieu.4
The pathologic hallmark of MS is demyelinated lesions or plaques, which are sharply demarcated areas easily distinguishable from surrounding white matter.2 They appear as bright spots on T2-weighted MRI images (see Fig. 32-2). Newer MRI techniques have exposed MS lesions in gray matter. The composition of a lesion varies depending on its age. In an acute lesion, there is partial or complete damage to the myelin, called vesicular demyelination. The damage consists of a breakdown of the myelin sheath that surrounds axon cylinders. As the lesion evolves, there is a proliferation of astrocytes and oligodendrocytes (myelin-producing cells), although many oligodendrocytes are destroyed by the cellular infiltrates of T cells and macrophages. Acute MS plaques will be seen as bright white lesions on T1-weighted gadolinium (contrast)-enhanced MRI images (see Fig. 32-2). The surviving oligodendrocytes may partially remyelinate the affected areas. Long-standing lesions are composed of thick, matted, relatively acellular fibroglial tissue. Long-standing lesions may appear as dark areas, sometimes termed “black holes,” on T1-weighted MRI images (Fig. 32-2). Wallerian degeneration does occur in MS as axonal transection is present even early in the disease. Axonal loss is visible in normalappearing white matter of histopathological specimens.4 Lesions have an affinity for the optic nerves, periventricular white matter, brainstem, cerebellum, and spinal cord white matter. The plaques vary in diameter from 1 to 2 mm to several centimeters.7
MS affects primarily the white matter of the brain and spinal cord by causing scattered, demyelinated lesions, preventing or impeding conduction of normal nerve impulse through the demyelinated zone. Conduction blocks occur when the nerve impulse is unable to move across a demyelinated segment. This is caused by a resting axon membrane that becomes hyperpolarized due to the exposure of voltage-dependent potassium channels (normally located under the myelin sheath). A temporary conduction block often follows a demyelinating event before the sodium channels (originally concentrated at the nodes) have undergone a redistribution that allows the continuous propagation of nerve action potentials through the demyelinated segment. However, the leakage currents are too large for the nerve impulse to jump the internode distance and conduction fails.1 These variations in conduction help
to explain the variations in symptoms that occur with MS throughout a day or a week and in relationship to activity or illness.
to explain the variations in symptoms that occur with MS throughout a day or a week and in relationship to activity or illness.
 Figure 32-2 ▪ Axial T2-weighted image shows ovoid hyperintense lesions in both hemispheres. |
Remission or improvement of symptoms may occur with MS as the result of healing or in response to the conclusion of an acute inflammatory event. Eventually, the axonal cylinder of the neuron may become affected, so that disabilities increase and become permanent, or symptoms worsen. At autopsy, MS plaques are scattered throughout the white matter of the brain and cord. Plaque distribution differs from patient to patient, accounting for the variety of symptoms experienced by patients. Some cases of MS are clinically silent, and the presence of the disease process is identified incidentally at autopsy, or when MRI imaging of the brain or spinal cord is performed for another reason.
Signs and Symptoms
The signs and symptoms of MS vary greatly from patient to patient and can vary over time in the same patient. The most common initial symptoms are sensory loss (37%), optic neuritis (36%), weakness (35%), paresthesias (24%), diplopia (15%), ataxia (11%), and vertigo (6%).8 Other symptoms mentioned below may occur paroxysmally throughout the course of disease or with a relapse. The multiple signs and symptoms of MS may include the following.
Sensory symptoms: numbness or sensory loss; paresthesia (burning, prickling, tingling); pain; decreased proprioception and perception of temperature, depth, and vibration.
Motor symptoms: paresis, paralysis, dragging of foot; spasticity; diplopia; bladder and bowel dysfunction (incontinence or retention).
Cerebellar symptoms: ataxia; loss of balance and coordination; nystagmus; speech disturbances (dysarthria, dystonia, scanning speech, slurred speech); tremors (intentional tremors, described as tremors that increase when a purposeful act is initiated); vertigo.
Other symptoms: fatigue; optic neuritis; eye movement disorders; tremor; respiratory disturbance; dysphagia; sleep disorders; neurogenic bowel or bladder; impotence or decreased genital sensation and sexual dysfunction; cognitive dysfunction; neurobehavioral disorders such as depression, anxiety, or euphoria. Less common symptoms include tonic spasms, visual loss, trigeminal neuralgia, facial palsy, and impotence.
Sensory Symptoms
Sensory loss and tingling on the face or involved extremities are common and may be painful. Loss of proprioception and joint sensation may be accompanied by edema of the limb or feelings of constriction. Fifty percent of patients develop objective sensory loss (position, vibration, shape, texture). Pain is not uncommon; it can be complex and either acute or chronic. Lhermitte’s sign is described as an electric or shock-like sensation that extends down the arms, back, or lower trunk bilaterally upon flexion of the neck. The sensation probably results from the buckling effect on the dorsal roots of the posterior columns from sclerotic plaques, and is an example of acute pain. Chronic pain can be related to dysesthesias, band-like pain around the torso or limbs, musculoskeletal conditions or radiculopathies, or headache. Sensory symptoms can contribute to disorders of gait and balance.
Motor Symptoms
Motor symptoms often begin with weakness in an extremity and complaint of a feeling of heaviness or uselessness of the involved limb. Hemibody weakness or paraparesis may occur. Spasticity, with its usual concurrent hyperreflexia, is common. The presence of spasticity often interferes with ambulation, ADLs, and sleep. The decline in motor function may last from minutes to hours and is therefore not always observed by the physician. Motor function can worsen spontaneously after strenuous exercise, fever, or a hot shower or hot tub bath. This response is called Uhtoff’s phenomenon, and is thought to be due to heat-related nerve conduction block.
Incoordination is another frequent symptom and may be manifested on examination as ataxia of the limbs or tremor. Various types of tremors may occur in MS with the upper extremities usually affected. An action tremor (previously called intentional tremor), produced by voluntary muscle contraction, is the most commonly reported type. The finer the required movement, the greater the tremor will be… Spastic weakness or ataxia of the muscles of speech is responsible for the dysarthria common in MS. Speech may be slurred (dysarthric). In later stages, speech may be explosive or staccato and unintelligible. Scanning speech—slow and measured with pauses between syllables—is seen sometimes with bulbar involvement, if cerebellar ataxia is prominent.
Ocular, Vestibular, and Auditory Symptoms
Optic neuritis, a common presenting event, is evidenced by visual clouding, visual field (often central) deficits, and pain with eye movement; pallor of the optic discs is usually noted. Optic neuritis may cause optic neuropathy, or permanent visual loss to varying degrees, but good visual acuity is usually regained after the first attack. Measurement of decreased retinal nerve fiber layer thickness by optical coherence tomography and abnormal visual evoked potentials may occur even in individuals without a history of optic neuritis. On examination, a patient may have an afferent pupillary defect, also known as a Marcus Gunn pupil.
Diplopia and nystagmus are common as a result of brainstem lesions. Internuclear ophthalmoplegia of lateral gaze, when noted, strongly suggests MS. Vertigo is a common symptom usually noted as instability of gait or sensations of movement. Vomiting and nystagmus can accompany the vertigo. Deafness is a rare finding.
Paroxysmal Symptoms
Paroxysmal symptoms, which are less common but can occur in MS, include focal or generalized epilepsy, tonic seizures, trigeminal neuralgia, and occasionally, paroxysmal (tonic) spasms. The spasms are described as contractions of the hands or feet into a dystonic, sustained, abnormal position and can be very painful.
Neurobehavioral Disorders
Neurobehavioral disorders associated with MS include emotional lability (pseudobulbar affect), irritability, apathy, inattentiveness, poor judgment, euphoria, dementia, and cognitive impairment. Depression is very common occurring in 30% to 50% of patients. Less common are extreme anxiety, bipolar disease, and psychosis.
Other Symptoms
Fatigue is a very common symptom in MS, can range from mild to severe disabling, and is often the reason people with MS leave the workforce. The basis for fatigue is unknown. Bladder, bowel, and sexual dysfunction are common. Bladder dysfunction is caused by detrusor hyperreflexia (failure to store), detrusor sphincter
dyssynergia (failure to empty), or a combination of the two. Constipation is the most common bowel complaint, with fecal incontinence occurring less frequently. Sexual dysfunction is caused by loss of sensation; fatigue, weakness, pain, or spasticity in the legs; erectile dysfunction and/or ejaculatory dysfunction in men; loss of lubrication and/or orgasm in women; medication side effects; psychologic effect; or loss of libido.
dyssynergia (failure to empty), or a combination of the two. Constipation is the most common bowel complaint, with fecal incontinence occurring less frequently. Sexual dysfunction is caused by loss of sensation; fatigue, weakness, pain, or spasticity in the legs; erectile dysfunction and/or ejaculatory dysfunction in men; loss of lubrication and/or orgasm in women; medication side effects; psychologic effect; or loss of libido.
Course of the Illness
The course of MS (see Table 32-1) is varied and unpredictable. Symptom clusters have been noted when a particular area of the brain is involved. For example, Charcot’s triad, which includes nystagmus, intentional tremors, and staccato speech, occurs with brainstem involvement. Typically, MS is a disease manifested by periods of relapse and remission early, with gradual accumulation of disability later. Conversion from RRMS to SPMS occurs in about 25 years for 79% of people. Periods of remission are interspersed with paroxysmal increases in symptom severity or neurologic symptoms that are present daily. Events that may precipitate increased symptomatic complaints include menstruation, emotional stress, humid, hot weather; hot baths, heat exposure or overheating due to activity, fever, and fatigue.
A relapse, also called an attack or an exacerbation, is defined as a new neurologic symptom, or worsening of an existing previously stable symptom, lasting for more than 24 hours and not having an alternative explanation for its cause. A pseudorelapse is a worsening of an existing symptom that is referable to infection, fatigue, fever, heat exposure, or over exertion. Relapses last a few days to a few weeks, after which there is complete or incomplete reversal of symptoms. Deficits present after 3 months are usually permanent. Pseudorelapses resolve with treatment of the underlying condition. Prediction of when the next relapse will occur is impossible. Some patients may experience another attack in a few weeks, whereas others may be spared for many years. The average number of relapses per year has been estimated between 0.1 and more than 1.
MS does not affect a woman’s fertility or pregnancy outcome. In fact, women with MS typically do not have relapses during pregnancy because of changes in hormone levels and circulating proteins. There is an approximate 20% to 40% risk of relapse in the first trimester postpartum. In general, risk of relapse following pregnancy is related to the degree of disease activity before becoming pregnant.9 Relapse postpartum have not been associated with an increased risk of long-term disability. The effect of pregnancy on MS has led to modern studies of the effects of hormones on the course of the disease. Pregnancy should be discussed carefully with a woman who has either severe disease related to frequent exacerbations or significant disability. Women of childbearing age should be counseled that the majority of the medications used to modify the disease and to treat its symptoms are not safe for use during pregnancy. Family planning discussions are important for these reasons.
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