Stephen L. Hauser Douglas S. Goodin
Demyelinating disorders are immune-mediated conditions characterized by preferential destruction of central nervous system (CNS) myelin. The peripheral nervous system (PNS) is spared, and most patients have no evidence of an associated systemic illness. Multiple sclerosis (MS), the most common disease in this category, is second only to trauma as a cause of neurologic disability beginning in early to middle adulthood.
Multiple sclerosis (MS) is a chronic disease characterized by inflammation, demyelination, gliosis (scarring), and neuronal loss; the course can be relapsing-remitting or progressive. Lesions of MS typically occur at different times and in different CNS locations (i.e., disseminated in time and space). MS affects ~350,000 individuals in the United States and 2.5 million individuals worldwide. Manifestations of MS vary from a benign illness to a rapidly evolving and incapacitating disease requiring profound lifestyle adjustments.
New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells, predominantly T cells and macrophages, which also infiltrate the surrounding white matter. At sites of inflammation, the blood-brain barrier (BBB) is disrupted, but unlike vasculitis, the vessel wall is preserved. Involvement of the humoral immune system is also evident; small numbers of B lymphocytes also infiltrate the nervous system, and myelinspecific autoantibodies are present on degenerating myelin sheaths. As lesions evolve, there is prominent astrocytic proliferation (gliosis). Surviving oligodendrocytes or those that differentiate from precursor cells can partially remyelinate the surviving naked axons, producing so-called shadow plaques. In many lesions, oligodendrocyte precursor cells are present in large numbers but fail to differentiate and remyelinate. Over time, ectopic lymphocyte follicles appear in perivascular and perimeningeal regions, consisting of aggregates of T and B cells and resembling secondary lymphoid structures. Although relative sparing of axons is typical of MS, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. Thus, MS is not solely a disease of myelin, and neuronal pathology is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation and plaque formation are present in the cerebral cortex, and significant axon loss indicating death of neurons is widespread, specially in advanced cases (see “Neurodegeneration,” later in this chapter).
Nerve conduction in myelinated axons occurs in a saltatory manner, with the nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes (Fig. 39-1). This produces considerably faster conduction velocities (~70 m/s) than the slow velocities (~1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment. This can happen when the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath. A temporary conduction block often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked axon (Fig. 39-1). This redistribution ultimately allows continuous propagation of nerve action potentials through the demyelinated segment. Conduction block may be incomplete, affecting high- but not low-frequency volleys of impulses. Variable conduction block can occur with raised body temperature or metabolic alterations and may explain clinical fluctuations that vary from hour to hour or appear with fever or exercise. Conduction slowing occurs when the demyelinated segments of the axonal membrane is reorganized to support continuous (slow) nerve impulse propagation.
Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin.
MS is approximately threefold more common in women than men. The age of onset is typically between 20 and 40 years (slightly later in men than in women), but the disease can present across the life span. In ~10% of cases it begins before age 18 years, and in a small percentage, it begins before the age of 10 years.
Geographic gradients have been repeatedly observed in MS, with the highest known prevalence for MS (250 per 100,000) in the Orkney Islands, located north of Scotland. In other temperate zone areas (e.g., northern North America, northern Europe, southern Australia, and south New Zealand), the prevalence of MS is 0.1–0.2%. By contrast, in the tropics (e.g., Asia, equatorial Africa, and the Middle East), the prevalence is often ten- to twentyfold less.
One proposed explanation for the latitude effect on MS is that there is a protective effect of sun exposure. Exposure of the skin to ultraviolet-B (UVB) radiation from the sun is essential for the biosynthesis of vitamin D, and this endogenous production is the most important source of vitamin D in most individuals. At high latitudes, the amount of UVB radiation reaching the earth’s surface is often insufficient, particularly during winter months, and, consequently, low serum levels of vitamin D are common in temperate zones. Prospective studies have confirmed that vitamin D deficiency is associated with an increase in MS risk and preliminary data also suggest that ongoing deficiency may increase the relapse rate in established MS. Immunoregulatory effects of vitamin D could explain this apparent relationship.
At least three sequential (population-wide) environmental events are implicated in the causal pathway leading to MS. The first factor seems to occur either in utero or in the early postnatal period and is supported, in part, by the almost twofold increase in MS risk for dizygotic twins of MS probands (5.4%) compared to siblings (2.9%). It is also supported by the month-of-birth effect (in the northern hemisphere), in which May babies are significantly more likely, and November babies less likely, to develop MS compared to babies born in other months. Importantly, a recently published population-based study in the southern hemisphere (Australia) found a similar (but inverted) month-of-birth effect with the zenith in risk occurring for November/December babies and the nadir occurring for May/June babies. This month-of-birth effect provides evidence for an early environmental event, involved in MS pathogenesis, that is both coupled to the solar cycle and time-locked to birth.
A second factor seems to occur during adolescence. Thus, several studies suggest that when individuals move (prior to their adolescent years) from an area of high MS prevalence to an area of low prevalence (or vice versa), their MS risk becomes similar to that of the region to which they moved. By contrast, when they make the same move after adolescence, their MS risk remains similar to that of the region from which they moved.
Because both of these first two factors occur well before the onset of clinically evident MS, presumably other factors are also necessary. In addition, the identification of possible point epidemics suggests a possible role for infectious agents, although the only (partially) convincing example of this occurred in the Faeroe Islands north of Denmark after the British occupation during World War II.
The prevalence of MS has increased steadily (and dramatically) in several regions around the world over the past half-century, presumably reflecting the impact of some environmental shift. Moreover, the fact that this increase has occurred primarily (or exclusively) in women indicates that women are more responsive to whatever this environmental change has been. Interestingly, recent epidemiologic data suggest that the latitude effect on MS currently may be decreasing. The reason for these changes are not known but, potentially, could be related to the increased use of sun block, which (at SPF-15) blocks 94% of the incoming UVB radiation, and which would be expected to exacerbate any population-wide vitamin D deficiency and might also mitigate the impact of differences in UVB exposure.
MS risk also correlates with high socioeconomic status, which may reflect improved sanitation and delayed initial exposures to infectious agents. By analogy, some viral infections (e.g., poliomyelitis and measles viruses) produce neurologic sequelae more frequently when the age of initial infection is delayed. Evidence of a remote Epstein-Barr virus (EBV) infection playing some role in MS is supported by a number of epidemiologic and laboratory studies. A higher risk of infectious mononucleosis (associated with relatively late EBV infection) and higher antibody titers to latency-associated EBV nuclear antigen are associated with MS. At this time, however, a causal role for EBV is not definitively established.
Whites are inherently at higher risk for MS than Africans or Asians, even when residing in a similar environment. MS also aggregates within some families, and adoption, half-sibling, twin, and spousal studies indicate that familial aggregation is due to genetic, and not environmental, factors (Table 39-1).
RISK OF DEVELOPING MS
Whites to MS is polygenic, with each gene contributing a relatively small amount to the overall risk. Despite this, the influence of genetics on MS pathogenesis is substantial. The major histocompatibility complex (MHC) on chromosome 6 is by far the strongest MS susceptibility region in the genome. Fine mapping studies implicate primarily the class II region (encoding HLA molecules involved in presenting peptide antigens to T cells) and specifically the highly polymorphic DRB1 locus, which contributes to MS risk in a allele-dependent hierarchical fashion, with the strongest association consistently found with the DRB1*15:01 allele; a secondary signal that appears to be protective against MS is located in the class 1 region near HLA-C. Whole-genome association studies have now identified more than 50 MS susceptibility genes, each of which has only a very small effect on MS risk. DRB1*15:01increases MS risk by approximately threefold in the heterozygous state, and ninefold in the homozygous state; by contrast, other MS-associated variants increase risk only by 15–30%. Most MS-associated genetic variants have known roles in the immune system (i.e., genes for the interleukin [IL]-7 receptor [CD127], the IL-2 receptor [CD25], and the T cell co-stimulatory molecule LFA-3 [CD58]); some variants also influence susceptibility to other autoimmune diseases in addition to MS. The variants identified thus far all lack specificity and sensitivity for MS; thus they are not useful for diagnosis or to predict the future course of the disease.
Autoreactive T lymphocytes
Myelin basic protein (MBP) is an important T cell antigen in experimental allergic encephalomyelitis (EAE), a laboratory model, and probably also in human MS. Activated MBP-reactive T cells have been identified in the blood, in cerebrospinal fluid (CSF), and within MS lesions. Moreover, DRB1*15:01 may influence the autoimmune response because it binds with high affinity to a fragment of MBP (spanning amino acids 89–96), stimulating T cell responses to this self-protein. Two different populations of proinflammatory T cells are likely to mediate autoimmunity in MS. T-helper type 1 (TH1) cells producing interferon γ (IFN-γ) are one key effector population, and more recently a role for highly proinflammatory TH17 T cells has been established. TH17 cells are induced by transforming growth factor β (TGF-β) and IL-6, and are amplified by IL-21 and IL-23. TH17 cells, and levels of their corresponding cytokine IL-17, are increased in MS lesions and also in the circulation of people with active MS. High circulating levels of IL-17 may also be a marker of a more severe course of MS. TH1 cytokines including interleukin (IL) 2, tumor necrosis factor (TNF) α, and interferon (IFN) γ also play key roles in activating and maintaining autoimmune responses, and TNF-α and IFN-γ may directly injure oligodendrocytes or the myelin membrane.
B cell activation and antibody responses also appear to be necessary for the full development of demyelinating lesions to occur, both in experimental models and in human MS. Increased numbers of clonally expanded B cells with properties of postgerminal center memory or antibody-producing lymphocytes are present in MS lesions and in CSF. Myelin-specific autoantibodies, some directed against myelin oligodendrocyte glyco-protein (MOG), have been detected bound to vesiculated myelin debris in MS plaques. In the CSF, elevated levels of locally synthesized immunoglobulins and oligoclonal antibodies derived from expansion of clonally restricted plasma cells are also characteristic of MS. The pattern of oligoclonal banding is unique to each individual, and attempts to identify the targets of these antibodies have been largely unsuccessful.
Serial MRI studies in early relapsing-remitting MS reveal that bursts of focal inflammatory disease activity occur far more frequently than would have been predicted by the frequency of relapses. Thus, early in MS most disease activity is clinically silent. The triggers causing these bursts are unknown, although the fact that patients may experience relapses after nonspecific upper respiratory infections suggests that either molecular mimicry between viruses and myelin antigens or viral super-antigens activating pathogenic T cells may be responsible.
Axonal damage occurs in every newly formed MS lesion, and cumulative axonal loss is considered to be the major cause of progressive and irreversible neurologic disability in MS. As many as 70% of axons are lost from the lateral corticospinal (e.g., motor) tracts in patients with advanced paraparesis from MS, and longitudinal MRI studies suggest there is progressive axonal loss over time within established, inactive lesions. Knowledge of the mechanisms responsible for axonal injury is incomplete and, despite the fact that axonal transactions are most conspicuous in acute inflammatory lesions, it is still unclear whether demyelination is a prerequisite for axonal injury in MS. Demyelination can result in reduced trophic support for axons, redistribution of ion channels, and destabilization of action potential membrane potentials. Axons can adapt initially to these injuries; with time distal and retrograde degeneration often occurs. Therefore, promotion of remy-elination and preservation of oligodendrocytes early in the disease course remain important therapeutic goals in MS. Some evidence suggests that axonal damage is mediated directly by resident and invading inflammatory cells and their toxic products, in particular by microglia, macrophages, and CD8 T lymphocytes. Activated microglia are particularly likely to cause axonal injury through the release of NO and oxygen radicals and via glutamate, which is toxic to oligodendrocytes and neurons. Interestingly, NMDA (glutamate) receptors are expressed on naked axon membranes that have undergone demyelination, perhaps providing a mechanism for glutamate-mediated calcium entry and cell death.
The onset of MS may be abrupt or insidious. Symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Indeed, at autopsy, approximately 0.1% of individuals who were asymptomatic during life will be found, unexpectedly, to have pathologic evidence of MS. Similarly, in the modern era, an MRI scan obtained for an unrelated reason may show evidence of asymptomatic MS. Symptoms of MS are extremely varied and depend on the location and severity of lesions within the CNS (Table 39-2). Examination often reveals evidence of neurologic dysfunction, often in asymptomatic locations. For example, a patient may present with symptoms in one leg but signs in both.
INITIAL SYMPTOMS OF MS
Weakness of the limbs may manifest as loss of strength, speed, or dexterity, as fatigue, or a disturbance of gait. Exercise-induced weakness is a characteristic symptom of MS. The weakness is of the upper motor neuron type (Chap. 12) and is usually accompanied by other pyramidal signs such as spasticity, hyperreflexia, and Babinski’s signs. Occasionally a tendon reflex may be lost (simulating a lower motor neuron lesion) if an MS lesion disrupts the afferent reflex fibers in the spinal cord (Fig. 12-2).
Spasticity (Chap. 12) is commonly associated with spontaneous and movement-induced muscle spasms. More than 30% of MS patients have moderate to severe spasticity, especially in the legs. This is often accompanied by painful spasms interfering with ambulation, work, or self-care. Occasionally spasticity provides support for the body weight during ambulation, and in these cases treatment of spasticity may actually do more harm than good.
Optic neuritis (ON) presents as diminished visual acuity, dimness, or decreased color perception (desaturation) in the central field of vision. These symptoms can be mild or may progress to severe visual loss. Rarely, there is complete loss of light perception. Visual symptoms are generally monocular but may be bilateral. Periorbital pain (aggravated by eye movement) often precedes or accompanies the visual loss. An afferent pupillary defect (Chap. 21) is usually present. Funduscopic examination may be normal or reveal optic disc swelling (papillitis). Pallor of the optic disc (optic atrophy) commonly follows ON. Uveitis is uncommon and should raise the possibility of alternative diagnoses such as sarcoid or lymphoma.
Visual blurring in MS may result from ON or diplopia (double vision); if the symptom resolves when either eye is covered, the cause is diplopia.
Diplopia may result from internuclear ophthalmoplegia (INO) or from palsy of the sixth cranial nerve (rarely the third or fourth). An INO consists of impaired adduction of one eye due to a lesion in the ipsilateral medial longitudinal fasciculus (Chap. 21). Prominent nystagmus is often observed in the abducting eye, along with a small skew deviation. A bilateral INO is particularly suggestive of MS. Other common gaze disturbances in MS include (1) a horizontal gaze palsy, (2) a “one and a half” syndrome (horizontal gaze palsy plus an INO), and (3) acquired pendular nystagmus.
Sensory symptoms are varied and include both pares-thesias (e.g., tingling, prickling sensations, formications, “pins and needles,” or painful burning) and hypesthesia (e.g., reduced sensation, numbness, or a “dead” feeling). Unpleasant sensations (e.g., feelings that body parts are swollen, wet, raw, or tightly wrapped) are also common. Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) indicates that the spinal cord is the origin of the sensory disturbance. It is often accompanied by a bandlike sensation of tightness around the torso. Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur anywhere on the body and can change locations over time.
Ataxia usually manifests as cerebellar tremors (Chap. 31). Ataxia may also involve the head and trunk or the voice, producing a characteristic cerebellar dysarthria (scanning speech).
Bladder dysfunction is present in >90% of MS patients, and in a third of patients, dysfunction results in weekly or more frequent episodes of incontinence. During normal reflex voiding, relaxation of the bladder sphincter (α-adrenergic innervation) is coordinated with contraction of the detrusor muscle in the bladder wall (muscarinic cholinergic innervation). Detrusor hyperreflexia, due to impairment of suprasegmental inhibition, causes urinary frequency, urgency, nocturia, and uncontrolled bladder emptying. Detrusor sphincter dyssynergia, due to loss of synchronization between detrusor and sphincter muscles, causes difficulty in initiating and/or stopping the urinary stream, producing hesitancy, urinary retention, overflow incontinence, and recurrent infection.
Constipation occurs in >30% of patients. Fecal urgency or bowel incontinence is less common (15%) but can be socially debilitating.
Cognitive dysfunction can include memory loss, impaired attention, difficulties in executive functioning, memory, problem solving, slowed information processing, and problems shifting between cognitive tasks. Euphoria (elevated mood) was once thought to be characteristic of MS but is actually uncommon, occurring in <20% of patients. Cognitive dysfunction sufficient to impair activities of daily living is rare.
Depression, experienced by approximately half of patients, can be reactive, endogenous, or part of the illness itself, and can contribute to fatigue. Fatigue is experienced by 90% of patients; this symptom is the most common reason for work-related disability in MS. Fatigue can be exacerbated by elevated temperatures, by depression, by expending exceptional effort to accomplish basic activities of daily living, or by sleep disturbances (e.g., from frequent nocturnal awakenings to urinate).
Sexual dysfunction may manifest as decreased libido, impaired genital sensation, impotence in men, and diminished vaginal lubrication or adductor spasms in women.
Facial weakness due to a lesion in the pons may resemble idiopathic Bell’s palsy (Chap. 34). Unlike Bell’s palsy, facial weakness in MS is usually not associated with ipsilateral loss of taste sensation or retroauricular pain.
Vertigo may appear suddenly from a brainstem lesion, superficially resembling acute labyrinthitis (Chap. 11). Hearing loss may also occur in MS but is uncommon.
Heat sensitivity refers to neurologic symptoms produced by an elevation of the body’s core temperature. For example, unilateral visual blurring may occur during a hot shower or with physical exercise (Uhthoff’s symptom). It is also common for MS symptoms to worsen transiently, sometimes dramatically, during febrile illnesses (see “Acute Attacks or Initial Demyelinating Episodes,” later). Such heat-related symptoms probably result from transient conduction block (discussed earlier).
Lhermitte’s symptom is an electric shock–like sensation (typically induced by flexion or other movements of the neck) that radiates down the back into the legs. Rarely, it radiates into the arms. It is generally self-limited but may persist for years. Lhermitte’s symptom can also occur with other disorders of the cervical spinal cord (e.g., cervical spondylosis).
Paroxysmal symptoms are distinguished by their brief duration (10 s to 2 min), high frequency (5–40 episodes per day), lack of any alteration of consciousness or change in background electroencephalogram during episodes, and a self-limited course (generally lasting weeks to months). They may be precipitated by hyperventilation or movement. These syndromes may include Lhermitte’s symptom; tonic contractions of a limb, face, or trunk (tonic seizures); paroxysmal dysarthria and ataxia; paroxysmal sensory disturbances; and several other less well characterized syndromes. Paroxysmal symptoms probably result from spontaneous discharges, arising at the edges of demyelinated plaques and spreading to adjacent white matter tracts.
Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia (Chap. 34) can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, seventh, and ninth cranial nerve, respectively. Trigeminal neuralgia (tic douloureux) is a very brief lancinating facial pain often triggered by an afferent input from the face or teeth. Most cases of trigeminal neuralgia are not MS related; however, atypical features such as onset before age 50 years, bilateral symptoms, objective sensory loss, or nonparoxysmal pain should raise concerns that MS could be responsible.
Facial myokymia consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the orbicularis oculi) or a contraction that slowly spreads across the face. It results from lesions of the corticobulbar tracts or brainstem course of the facial nerve.
Four clinical types of MS have been described (Fig. 39-2):
1. Relapsing/remitting MS (RRMS) accounts for 85% of MS cases at onset and is characterized by discrete attacks that generally evolve over days to weeks (rarely over hours). There is often complete recovery over the ensuing weeks to months (Fig. 39-2A). However, when ambulation is severely impaired during an attack, approximately half will fail to improve. Between attacks, patients are neurologically stable.
1. Secondary progressive MS (SPMS) always begins as RRMS (Fig. 39-2B). At some point, however, the clinical course changes so that the patient experiences a steady deterioration in function unassociated with acute attacks (which may continue or cease during the progressive phase). SPMS produces a greater amount of fixed neurologic disability than RRMS. For a patient with RRMS, the risk of developing SPMS is ~2% each year, meaning that the great majority of RRMS ultimately evolves into SPMS. SPMS appears to represent a late stage of the same underlying illness as RRMS.
1. Primary progressive MS (PPMS) accounts for ~15% of cases. These patients do not experience attacks but only a steady functional decline from disease onset (Fig. 39-2C). Compared to RRMS, the sex distribution is more even, the disease begins later in life (mean age ~40 years), and disability develops faster (at least relative to the onset of the first clinical symptom). Despite these differences, PPMS appears to represent the same underlying illness as RRMS.
2. Progressive/relapsing MS (PRMS) overlaps PPMS and SPMS and accounts for ~5% of MS patients. Like patients with PPMS, these patients experience a steady deterioration in their condition from disease onset. However, like SPMS patients, they experience occasional attacks superimposed upon their progressive course (Fig. 39-2D).
Clinical course of multiple sclerosis (MS). A. Relapsing/remitting MS. B. Secondary progressive MS. C. Primary progressive MS. D. Progressive/relapsing MS.
There is no definitive diagnostic test for MS. Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS (Table 39-3). Symptoms must last for >24 h and occur as distinct episodes that are separated by a month or more. At least one of the two required signs must be present on neurologic examination. The second may be documented by abnormal paraclinical tests such as MRI or evoked potentials (EPs). Similarly, in the most recent diagnostic scheme, the second clinical event (in time) may be supported solely by paraclinical information, usually the development of new focal white matter lesions on MRI. In patients who experience gradual progression of disability for ≥6 months without superimposed relapses, documentation of intrathecal IgG synthesis may be used to support the diagnosis.
DIAGNOSTIC CRITERIA FOR MS
Magnetic resonance imaging
MRI has revolutionized the diagnosis and management of MS (Fig. 39-3); characteristic abnormalities are found in >95% of patients, although more than 90% of the lesions visualized by MRI are asymptomatic. An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) into the parenchyma. Such leakage occurs early in the development of an MS lesion and serves as a useful marker of inflammation. Gd enhancement persists for approximately 1 month, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on spin-echo (T2-weighted) and proton-density images. Lesions are frequently oriented perpendicular to the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson’s fingers). Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions larger than 6 mm located in the corpus callosum, periventricular white matter, brainstem, cerebellum, or spinal cord are particularly helpful diagnostically. Different criteria for the use of MRI in the diagnosis of MS have been proposed (Table 39-3).
MRI findings in MS. A. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS. B. Sagittal T2-weighted FLAIR (fluid attenuated inversion recovery) image in which the high signal of CSF has been suppressed. CSF appears dark, while areas of brain edema or demyelination appear high in signal as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease. C. Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the midthoracic spinal cord. D. Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows).
The total volume of T2-weighted signal abnormality (the “burden of disease”) shows a significant (albeit weak) correlation with clinical disability, as do measures of brain atrophy. Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted imaging. Black holes may be a marker of irreversible demyelination and axonal loss, although even this measure depends on the timing of the image acquisition (e.g., most acute Gd-enhancing T2 lesions are T1 dark).
Newer MRI measures such as magnetization transfer ratio (MTR) imaging, and proton magnetic resonance spectroscopic imaging (MRSI) may ultimately serve as surrogate markers of clinical disability. MRSI can quantitate molecules such as N-acetyl aspartate, which is a marker of axonal integrity, and MTR may be able to distinguish demyelination from edema.
EP testing assesses function in afferent (visual, auditory, and somatosensory) or efferent (motor) CNS pathways. EPs use computer averaging to measure CNS electric potentials evoked by repetitive stimulation of selected peripheral nerves or of the brain. These tests provide the most information when the pathways studied are clinically uninvolved. For example, in a patient with a remitting and relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP following posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in this circumstance would permit a diagnosis of clinically definite MS (Table 39-3). Abnormalities on one or more EP modalities occur in 80–90% of MS patients. EP abnormalities are not specific to MS, although a marked delay in the latency of a specific EP component (as opposed to a reduced amplitude or distorted waveshape) is suggestive of demyelination.
CSF abnormalities found in MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG. The total CSF protein is usually normal or slightly elevated. Various formulas distinguish intrathecally synthesized IgG from IgG that may have entered the CNS passively from the serum. One formula, the CSF IgG index, expresses the ratio of IgG to albumin in the CSF divided by the same ratio in the serum. The IgG synthesis rate uses serum and CSF IgG and albumin measurements to calculate the rate of CNS IgG synthesis. The measurement of oligoclonal banding (OCB) in the CSF also assesses intrathecal production of IgG. OCBs are detected by agarose gel electrophoresis. Two or more OCBs are found in 75–90% of patients with MS. OCBs may be absent at the onset of MS, and in individual patients the number of bands may increase with time. It is important that paired serum samples be studied to exclude a peripheral (i.e., non-CNS) origin of any OCBs detected in the CSF.
A mild CSF pleocytosis (>5 cells/μL) is present in ~25% of cases, usually in young patients with RRMS. A pleocytosis of >75 cells/μL, the presence of polymorphonuclear leukocytes, or a protein concentration >1 g/L (>100 mg/dL) in CSF should raise concern that the patient may not have MS.
No single clinical sign or test is diagnostic of MS. The diagnosis is readily made in a young adult with relapsing and remitting symptoms involving different areas of CNS white matter. The possibility of an alternative diagnosis should always be considered (Table 39-4), particularly when (1) symptoms are localized exclusively to the posterior fossa, craniocervical junction, or spinal cord; (2) the patient is aged <15 or >60 years; (3) the clinical course is progressive from onset; (4) the patient has never experienced visual, sensory, or bladder symptoms; or (5) laboratory findings (e.g., MRI, CSF, or EPs) are atypical. Similarly, uncommon or rare symptoms in MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe muscular atrophy, peripheral neuropathy, episodic loss of consciousness, fever, headache, seizures, or coma) should increase concern about an alternative diagnosis. Diagnosis is also difficult in patients with a rapid or explosive (stroke-like) onset or with mild symptoms and a normal neurologic examination. Rarely, intense inflammation and swelling may produce a mass lesion that mimics a primary or metastatic tumor. The specific tests required to exclude alternative diagnoses will vary with each clinical situation; however, an erythrocyte sedimentation rate, serum B12 level, ANA, and treponemal antibody should probably be obtained in all patients with suspected MS.
DISORDERS THAT CAN MIMIC MS
Most patients with clinically evident MS ultimately experience progressive neurologic disability. In older studies, 15 years after onset, only 20% of patients had no functional limitation, and between one-third and one-half progressed to SPMS and required assistance with ambulation; furthermore, 25 years after onset, ~80% of MS patients reached this level of disability. For unclear reasons, the long-term prognosis for untreated MS appears to have improved in recent years. In addition, the development of disease-modifying therapies for MS also appears to have favorably improved the long-term outlook. Although the prognosis in an individual is difficult to establish, certain clinical features suggest a more favorable prognosis. These include ON or sensory symptoms at onset, fewer than two relapses in the first year of illness, and minimal impairment after 5 years. By contrast, patients with truncal ataxia, action tremor, pyramidal symptoms, or a progressive disease course are more likely to become disabled. Patients with a long-term favorable course are likely to have developed fewer MRI lesions during the early years of disease, and vice versa. Importantly, some MS patients have a benign variant of MS and never develop neurologic disability. The likelihood of having benign MS is thought to be <20%. Patients with benign MS 15 years after onset who have entirely normal neurologic examinations are likely to maintain their benign course.
In patients with their first demyelinating event (i.e., a clinically isolated syndrome), the brain MRI provides prognostic information. With three or more typical T2-weighted lesions, the risk of developing MS after 20 years is ~80%. Conversely, with a normal brain MRI, the likelihood of developing MS is <20%. Similarly, two or more Gd-enhancing lesions at baseline is highly predictive of future MS, as is the appearance of either new T2-weighted lesions or new Gd enhancement ≥3 months after the initial episode.
Mortality as a direct consequence of MS is uncommon, although it has been estimated that the 25-year survival is only 85% of expected. Death can occur during an acute MS attack, although this is distinctly rare. More commonly, death occurs as a complication of MS (e.g., pneumonia in a debilitated individual). Death can also result from suicide.
Effect of pregnancy
Pregnant MS patients experience fewer attacks than expected during gestation (especially in the last trimester), but more attacks than expected in the first 3 months postpartum. When considering the pregnancy year as a whole (i.e., 9 months pregnancy plus 3 months postpartum), the overall disease course is unaffected. Decisions about childbearing should thus be made based on (1) the mother’s physical state, (2) her ability to care for the child, and (3) the availability of social support. Disease-modifying therapy is generally discontinued during pregnancy, although the actual risk from the interferons and glatiramer acetate (discussed later) appears to be low.
TREATMENT Multiple Sclerosis
Therapy for MS can be divided into several categories: (1) treatment of acute attacks, (2) treatment with disease-modifying agents that reduce the biological activity of MS, and (3) symptomatic therapy. Treatments that promote remyelination or neural repair do not currently exist but would be highly desirable.
The Expanded Disability Status Score (EDSS) is a useful measure of neurologic impairment in MS (Table 39-5). Most patients with EDSS scores <3.5 have RRMS, walk normally, and are generally not disabled; by contrast, patients with EDSS scores >5.5 have progressive MS (SPMS or PPMS), are gait-impaired, and, typically, are occupationally disabled.
SCORING SYSTEMS FOR MS
ACUTE ATTACKS OR INITIAL DEMYELINATING EPISODES When patients experience acute deterioration, it is important to consider whether this change reflects new disease activity or a “pseudoexacerbation” resulting from an increase in ambient temperature, fever, or an infection. When the clinical change is thought to reflect a pseudoexacerbation, glucocorticoid treatment is inappropriate. Glucocorticoids are used to manage either first attacks or acute exacerbations. They provide short-term clinical benefit by reducing the severity and shortening the duration of attacks. Whether treatment provides any long-term benefit on the course of the illness is less clear. Therefore, mild attacks are often not treated. Physical and occupational therapy can help with mobility and manual dexterity.
Glucocorticoid treatment is usually administered as intravenous methylprednisolone, 500–1000 mg/d for 3–5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60–80 mg/d and gradually tapered over 2 weeks. Orally administered methylprednisolone or dexamethasone (in equivalent dosages) can be substituted for the intravenous portion of the therapy, although GI complications are more common by this route. Outpatient treatment is almost always possible.
Side effects of short-term glucocorticoid therapy include fluid retention, potassium loss, weight gain, gastric disturbances, acne, and emotional lability. Concurrent use of a low-salt, potassium-rich diet and avoidance of potassium-wasting diuretics is advisable. Lithium carbonate (300 mg orally bid) may help to manage emotional lability and insomnia associated with glucocorticoid therapy. Patients with a history of peptic ulcer disease may require cimetidine (400 mg bid) or raniti-dine (150 mg bid). Proton pump inhibitors such as pantoprazole (40 mg orally bid) may reduce the likelihood of gastritis, especially when large doses are administered orally. Plasma exchange (5–7 exchanges: 40–60 mL/kg per exchange, every other day for 14 days) may benefit patients with fulminant attacks of demyelination (from MS and other fulminant causes) that are unresponsive to glucocorticoids. However, the cost is high, and conclusive evidence of efficacy is lacking.
DISEASE-MODIFYING THERAPIES FOR RELAPSING FORMS OF MS (RRMS, SPMS WITH EXACERBATIONS) Seven such agents are approved by the U.S. Food and Drug Administration (FDA): (1) IFN-β-1a (Avonex), (2) IFN-β-1a (Rebif), (3) IFN-β-1b (Betaseron), (4) glatiramer acetate (Copaxone), (5) natalizumab (Tysabri), (6) fingolimod (Gilenya), and (7) mitoxantrone (Novantrone). An eighth, cladribine (Leustatin), is currently awaiting an FDA decision on its approval. Each of these treatments is also used in SPMS patients who continue to experience attacks, because SPMS can be difficult to distinguish from RRMS, and because the available clinical trials suggest that such patients also derive therapeutic benefit. In Phase III clinical trials, recipients of IFN-β-1b, IFN-β-1a, glatiramer acetate, natalizumab, and fingolimod experienced fewer clinical exacerbations and fewer new MRI lesions compared to placebo recipients (Table 39-6). Mitoxantrone (Novantrone), an immune suppressant, has also been approved in the United States, although because of its potential toxicity it is generally reserved for patients with progressive disability who have failed other treatments. When considering the data in Table 39-6, however, it is important to note that the relative efficacy of the different agents cannot be determined by cross-trial comparisons. Relative efficacy can only be determined from a non-biased head-to-head clinical trial.
TWO-YEAR OUTCOMES FOR FDA-APPROVED THERAPIES FOR MULTIPLE SCLEROSISa
Interferon-β IFN-β is a class I interferon originally identified by its antiviral properties. Efficacy in MS probably results from immunomodulatory properties, including (1) downregulating expression of MHC molecules on antigen-presenting cells, (2) inhibiting proinflammatory and increasing regulatory cytokine levels, (3) inhibition of T cell proliferation, and (4) limiting the trafficking of inflammatory cells in the CNS. IFN-β reduces the attack rate and improves disease severity measures such as EDSS progression and MRI-documented disease burden. IFN-β should be considered in patients with either RRMS or SPMS with superimposed relapses. In patients with SPMS but without relapses, efficacy has not been established. Head-to-head trials suggest that higher IFN-β doses have slightly greater efficacy but are also more likely to induce neutralizing antibodies, which may reduce the clinical benefit (discussed later). IFN-β-1a (Avonex), 30 μg, is administered by intramuscular injection once every week. IFN-β-1a (Rebif), 44 μg, is administered by subcutaneous injection three times per week. IFN-β-1b (Betaseron), 250 μg, is administered by subcutaneous injection every other day.
Common side effects of IFN-β therapy include flulike symptoms (e.g., fevers, chills, and myalgias) and mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia). Rarely, more severe hepatotoxicity may occur. Subcutaneous IFN-β also causes reactions at the injection site (e.g., pain, redness, induration, or, rarely, skin necrosis). Side effects can usually be managed with concomitant nonsteroidal anti-inflammatory medications and with the use of an autoinjector. Depression, increased spasticity, and cognitive changes have been reported, although these symptoms can also be due to the underlying disease. In any event, side effects to IFN-β therapy usually subside with time.
Approximately 2–10% of IFN-β-1a (Avonex) recipients, 15–25% of IFN-β-1a (Rebif) recipients, and 30–40% of IFN-β-1b (Betaseron) recipients develop neutralizing antibodies to IFN-β, which may disappear over time. Two very large randomized trials (one with more than 2000 patients) provide unequivocal evidence that neutralizing antibodies reduce efficacy as determined by several MRI outcomes. Paradoxically, however, these same trials, despite abundant statistical power, failed to demonstrate any concomitant impact on the clinical outcomes of disability and relapse rate. The reason for this clinical-radiologic dissociation is unresolved. Fortunately, however, there are few situations where measurement of antibodies is necessary. Thus, for a patient doing well on therapy, the presence of antibodies should not affect treatment. Conversely, for a patient doing poorly on therapy, alternative treatment should be considered, even if there are no detectable antibodies.
Glatiramer Acetate Glatiramer acetate is a synthetic, random polypeptide composed of four amino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine). Its mechanism of action may include (1) induction of antigen-specific suppressor T cells; (2) binding to MHC molecules, thereby displacing bound MBP; or (3) altering the balance between proinflammatory and regulatory cytokines. Glatiramer acetate reduces the attack rate (whether measured clinically or by MRI) in RRMS. Glatiramer acetate may also benefit disease severity measures, although this is less well established than for the relapse rate. Therefore, glatiramer acetate should be considered in RRMS patients. Its usefulness in progressive disease is entirely unknown. Head-to-head clinical trials suggest that glatiramer acetate has about equal efficacy to high IFN-β doses. Glatiramer acetate, 20 mg, is administered by subcutaneous injection every day. Injection-site reactions also occur with glatiramer acetate. Initially, these were thought to be less severe than with IFN-β-1b, although two recent head-to-head comparisons of high-dose IFN-β to glatiramer acetate did not bear out this impression. In addition, approximately 15% of patients experience one or more episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety after injection. This systemic reaction is unpredictable, brief (duration <1 h), and tends not to recur. Finally, some patients experience lipoatrophy, which, on occasion, can be disfiguring and require cessation of treatment.
Natalizumab Natalizumab (Tysabri) is a humanized monoclonal antibody directed against the α4 subunit of α4β1 integrin, a cellular adhesion molecule expressed on the surface of lymphocytes. It prevents lymphocytes from binding to endothelial cells, thereby preventing lymphocytes from penetrating the BBB and entering the CNS. Natalizumab greatly reduces the attack rate and significantly improves all measures of disease severity in MS. Moreover, it is well tolerated and the dosing schedule of monthly intravenous infusions make it very convenient for patients. However, because of the development of progressive multifocal leukoencephalopathy (PML) in approximately 0.2% of patients treated with natalizumab for more than 2 years, natalizumab is currently recommended only for patients who have failed other therapies or who have particularly aggressive disease presentations. Its usefulness in the treatment of progressive disease has not been studied. Head-to-head data for natalizumab against low-dose (weekly) IFN-β showed a clear superiority of natalizumab in RRMS; the trial design, however, was biased against IFN-β (i.e., patients recruited could already be considered IFN-β treatment failures). Natalizumab, 300 μg, is administered by IV infusion each month. Treatment with natalizumab is, in general, well tolerated. A small percentage (<10%) of patients experience hypersensitivity reactions (including anaphylaxis) and ~6% develop neutralizing antibodies to the molecule.
The major concern with long-term treatment is the risk of PML. Because the risk is extremely low during the first year of treatment with natalizumab, we currently recommend treatment for periods of 12–18 months only for most patients; after this time, a change to another disease-modifying therapy should be considered. Recently, a blood test to detect antibodies against the PML (JC) virus has shown promise in identifying individuals who are at risk for this complication. In preliminary studies, approximately half of the adult population are antibody-positive, indicating that they experienced an asymptomatic infection with the virus at some time in the past, and to date all cases of natalizumab-associated PML have occurred in seropositive individuals.
Fingolimod Fingolimod (Gilenya) is a sphingosine-1-phosphate (S1P) inhibitor and it prevents the egress of lymphocytes from the secondary lymphoid organs such as the lymph nodes and spleen. Its mechanism of action is probably due, in part, to the trapping of lymphocytes in the periphery and the prevention, thereby, of lymphocytes reaching the brain. However, because S1P receptors are widely expressed in the CNS tissue and because fingolimod is able to cross the BBB, it may also have central effects. Fingolimod reduces the attack rate and significantly improves all measures of disease severity in MS. It is well tolerated, and the oral dosing schedule makes it very convenient for patients. Moreover, from the clinical trial data presented thus far, it seems to be a reasonably safe therapy and it is approved for first-line use by the FDA. However, as with any new therapy, long-term safety remains to be established. A large head-to-head phase III randomized study demonstrated the clear superiority of fingolimod over low dose (weekly) IFN-β. Fingolimod, 0.5 mg, is administered orally each day. Treatment with fingolimod is also, in general, well tolerated. Mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia) are more common than in controls. Although rarely severe, sometimes discontinuation of the medication is necessary. First-degree heart block and bradycardia can also occur, the latter necessitating the prolonged (6-h) observation of patients receiving their first dose.
Teriflunomide Teriflunomide (Aubagio) is an oral inhibitor of the enzyme dihydroorotate dehydrogenase involved in pyramiding synthesis. Clinical trials using once daily dosages of 7 or 14 mg revealed modest effects on relapse rate (approximately 30% compared to placebo), and an effect on disability at the higher dose. Possible side effects include hepatic toxicity, nausea, and hair thinning. Teriflunomide can remain in the blood for many months following administration and is considered teratogenic.
Mitoxantrone Hydrochloride Mitoxantrone (Novantrone), an anthracenedione, exerts its antineoplastic action by (1) intercalating into DNA and producing both strand breaks and interstrand cross-links, (2) interfering with RNA synthesis, and (3) inhibiting topoisomerase II (involved in DNA repair). The FDA approved mitoxantrone on the basis of a single (relatively small) phase III clinical trial in Europe, in addition to an even smaller phase II study completed earlier. Mitoxantrone received (from the FDA) the broadest indication of any current treatment for MS. Thus, mitoxantrone is indicated for use in SPMS, in PRMS, and in patients with worsening RRMS (defined as patients whose neurologic status remains significantly abnormal between MS attacks). Despite this broad indication, however, the data supporting its efficacy are weaker than for other approved therapies.
Mitoxantrone can be cardiotoxic (e.g., cardiomyopathy, reduced left ventricular ejection fraction, and irreversible congestive heart failure). As a result, a cumulative dose >140 mg/m2 is not recommended. At currently approved doses (12 mg/m2 every 3 months), the maximum duration of therapy can be only 2–3 years. Furthermore, >40% of women will experience amenorrhea, which may be permanent. Finally, there is risk of acute leukemia, and this complication has already been reported in several mitoxantrone-treated MS patients.
Given these risks, mitoxantrone should not be used as a first-line agent in either RRMS or relapsing SPMS. It is reasonable to consider mitoxantrone in selected patients with a progressive course who have failed other approved therapies.
Cladribine Cladribine (Leustatin) is a purine analog that inhibits DNA synthesis and repair, and acts as a general immunosuppressant. Cladribine reduces the attack rate and significantly improves several measures of disease severity in MS. It seems to be well tolerated and the easy oral dosing schedule of only taking the drug for 2 weeks/year make it very convenient for patients. Again, however, the principal concern is long-term safety, a concern that is heightened by the long-term immunosuppression that occurs in some patients and, also, by the fact that, in the pivotal RCT, 10 neoplasms and all 20 herpes zoster cases occurred in Leustatin-treated patients.
Initiating and Changing Treatment Currently, most patients with relapsing forms of MS receive IFN-β or glatiramer acetate as first-line therapy. Although approved for first-line use, the role of fingolimod in this situation has yet to be defined. Regardless of which agent is chosen first, treatment should probably be changed in patients who continue to have frequent attacks or progressive disability (Fig. 39-4). The value of combination therapy is unknown.
Therapeutic decision-making for MS.
The long-term efficacy of these treatments remains uncertain, although several recent studies suggest that these agents can improve the long-term outcome of MS, especially when administered early in the RRMS stage of the illness. Beneficial effects seen in early MS include a reduction in the relapse rate, a reduction in CNS inflammation as measured by MRI, and a prolongation in the time to reach certain disability outcomes such as SPMS and requiring assistance to ambulate. Unfortunately, however, already established progressive symptoms do not respond well to treatment with these disease-modifying therapies. Because progressive symptoms are likely to result from delayed effects of earlier focal demyelinating episodes, many experts now believe that very early treatment with a disease-modifying drug is appropriate for most MS patients. It is reasonable to delay initiating treatment in patients with (1) normal neurologic exams, (2) a single attack or a low attack frequency, and (3) a low burden of disease as assessed by brain MRI. Untreated patients, however, should be followed closely with periodic brain MRI scans; the need for therapy is reassessed if scans reveal evidence of ongoing, subclinical disease.
DISEASE-MODIFYING THERAPIES FOR PROGRESSIVE MS
SPMS High-dose IFN-β probably has a beneficial effect in patients with SPMS who are still experiencing acute relapses. IFN-β is probably ineffective in patients with SPMS who are not having acute attacks. Glatiramer acetate and natalizumab have not been studied in this patient population. Although mitoxantrone has been approved for patients with progressive MS, this is not the population studied in the pivotal trial. Therefore, no evidence-based recommendation can be made with regard to its use in this setting.
PPMS No therapies have been convincingly shown to modify the course of PPMS. A phase III clinical trial of glatiramer acetate in PPMS was stopped because of lack of efficacy. A phase II/III trial of rituximab in PPMS was also negative, but in a preplanned secondary analysis treatment appeared to slow disability progression in patients with gadolinium-enhancing lesions at entry; a follow-up trial with the humanized anti-CD20 therapy ocrelizumab will soon begin. A trial of mitoxantrone in PPMS is ongoing.
OFF-LABEL TREATMENT OPTIONS FOR RRMS AND SPMS Azathioprine (2–3 mg/kg per day) has been used primarily in SPMS. Meta-analysis of published trials suggests that azathioprine is marginally effective at lowering relapse rates, although a benefit on disability progression has not been demonstrated.
Methotrexate (7.5–20 mg/week) was shown in one study to slow the progression of upper-extremity dysfunction in SPMS. Because of the possibility of developing irreversible liver damage, some experts recommend a blind liver biopsy after 2 years of therapy.
Cyclophosphamide (700 mg/m2, every other month) may be helpful for treatment-refractory patients who are (1) otherwise in good health, (2) ambulatory, and (3) <40 years of age. Because cyclophosphamide can be used for periods in excess of 3 years, it may be preferable to mitoxantrone in these circumstances.
Intravenous immunoglobulin (IVIg), administered in monthly pulses (up to 1 g/kg) for up to 2 years, appears to reduce annual exacerbation rates. However, its use is limited because of its high cost, questions about optimal dose, and uncertainty about its effect on long-term disability outcome.
Methylprednisolone administered in one study as monthly high-dose intravenous pulses reduced disability progression (discussed earlier).
OTHER THERAPEUTIC CLAIMS Many purported treatments for MS have never been subjected to scientific scrutiny. These include dietary therapies (e.g., the Swank diet in addition to others), megadose vitamins, calcium orotate, bee stings, cow colostrum, hyper-baric oxygen, Procarin (a combination of histamine and caffeine), chelation, acupuncture, acupressure, various Chinese herbal remedies, and removal of mercury-amalgam tooth fillings, among many others. Patients should avoid costly or potentially hazardous unproven treatments. Many such treatments lack biologic plausibility. For example, no reliable case of mercury poisoning resembling typical MS has ever been described.
Although potential roles for EBV, HHV-6, or chlamydia have been suggested for MS, these reports are unconfirmed, and treatment with antiviral agents or antibiotics is not currently appropriate.
Most recently, chronic cerebrospinal insufficiency (CCSVI) has been proposed as a cause of multiple sclerosis and vascular-surgical intervention recommended. However, the failure of independent investigators to even approximate the initial claims of 100% sensitivity and 100% specificity for the diagnostic procedure raised considerable doubt that CCSVI is a real entity. Certainly, any potentially dangerous surgery should be avoided until more rigorous science is available.
SYMPTOMATIC THERAPY For all patients, it is useful to encourage attention to a healthy lifestyle, including maintaining an optimistic outlook, a healthy diet, and regular exercise as tolerated (swimming is often well tolerated because of the cooling effect of cold water). It is reasonable also to correct vitamin D deficiency with oral vitamin D, and to recommend dietary supplementation with long-chain (omega-3) unsaturated fatty acids (present in oily fish such as salmon) because of their immunomodulatory properties. Ataxia/tremor is often intractable. Clonazepam, 1.5–20 mg/d; Mysoline, 50–250 mg/d; propranolol, 40–200 mg/d; or ondansetron, 8–16 mg/d, may help. Wrist weights occasionally reduce tremor in the arm or hand. Thalamotomy or deep-brain stimulation has been tried with mixed success.
Spasticity and spasms may improve with physical therapy, regular exercise, and stretching. Avoidance of triggers (e.g., infections, fecal impactions, bed sores) is extremely important. Effective medications include baclofen (Lioresal) (20–120 mg/d), diazepam (2–40 mg/d), tizanidine (8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenzaprine hydrochloride (10–60 mg/d). For severe spasticity, a baclofen pump (delivering medication directly into the CSF) can provide substantial relief.
Weakness can sometimes be improved with the use of potassium channel blockers such as 4-amino pyridine (10–40 mg/d) and 3,4-di-aminopyridine (40–80 mg/d), particularly in the setting where lower extremity weakness interferes with the patient’s ability to ambulate. The FDA has approved 4-amino pyridine (at 20 mg/d), and this can be obtained either as dalfampridine (Ampyra) or, more cheaply, through a compounding pharmacy. The principal concern with the use of these agents is the possibility of inducing seizures at high doses.
Pain is treated with anticonvulsants (carbamazepine, 100–1000 mg/d; phenytoin, 300–600 mg/d; gabapentin, 300–3600 mg/d; or pregabalin, 50–300 mg/d), antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or venlafaxine, 75–225 mg/d), or antiarrhythmics (mexiletine, 300–900 mg/d). If these approaches fail, patients should be referred to a comprehensive pain management program.
Bladder dysfunction management is best guided by urodynamic testing. Evening fluid restriction or frequent voluntary voiding may help detrusor hyperreflexia. If these methods fail, propantheline bromide (10–15 mg/d), oxybutynin (5–15 mg/d), hyoscyamine sulfate (0.5–0.75 mg/d), tolterodine tartrate (2–4 mg/d), or solifenacin (5–10 mg/d) may help. Coadministration of pseudoephedrine (30–60 mg) is sometimes beneficial.
Detrusor/sphincter dyssynergia may respond to phenoxybenzamine (10–20 mg/d) or terazosin hydrochloride (1–20 mg/d). Loss of reflex bladder wall contraction may respond to bethanechol (30–150 mg/d). However, both conditions often require catheterization.
Urinary tract infections should be treated promptly. Patients with large postvoid residual urine volumes are predisposed to infections. Prevention by urine acidification (with cranberry juice or vitamin C) inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to colonization by resistant organisms. Intermittent catheterization may help to prevent recurrent infections.
Treatment of constipation includes high-fiber diets and fluids. Natural or other laxatives may help. Fecal incontinence may respond to a reduction in dietary fiber.
Depression should be treated. Useful drugs include the selective serotonin reuptake inhibitors (fluoxetine, 20–80 mg/d; or sertraline, 50–200 mg/d), the tricyclic antidepressants (amitriptyline, 25–150 mg/d; nortripty-line, 25–150 mg/d; or desipramine, 100–300 mg/d), and the non-tricyclic antidepressants (venlafaxine, 75–225 mg/d).
Fatigue may improve with assistive devices, help in the home, or successful management of spasticity. Patients with frequent nocturia may benefit from anti-cholinergic medication at bedtime. Primary MS fatigue may respond to amantadine (200 mg/d), methylpheni-date (5–25 mg/d), or modafinil (100–400 mg/d).
Cognitive problems may respond to the cholinesterase inhibitor donepezil hydrochloride (10 mg/d).
Paroxysmal symptoms respond dramatically to low-dose anticonvulsants (acetazolamide, 200–600 mg/d; carbamazepine, 50–400 mg/d; phenytoin, 50–300 mg/d; or gabapentin, 600–1800 mg/d).
Heat sensitivity may respond to heat avoidance, air-conditioning, or cooling garments.
Sexual dysfunction may be helped by lubricants to aid in genital stimulation and sexual arousal. Management of pain, spasticity, fatigue, and bladder/bowel dysfunction may also help. Sildenafil (50–100 mg), tadalafil (5–20 mg), or vardenafil (5–20 mg) taken 1–2 h before sex are now the standard treatments for maintaining erections.
PROMISING EXPERIMENTAL THERAPIES Numerous clinical trials are currently underway. These include (1) dimethyl fumarate (BG-12), an oral immunomodulator that reduced relapses and disability accumulation in phase 3 trials; (2) monoclonal antibodies against CD20 to deplete B cells, against the IL-2 receptor, or against CD52 to induce global lymphocyte depletion; and (3) novel oral sphingosine-1-phosphate receptor antagonists to sequester lymphocytes in the secondary lymphoid organs.
CLINICAL VARIANTS OF MS
Neuromyelitis optica (NMO), or Devic’s syndrome, is an aggressive inflammatory disorder consisting most typically of attacks of acute ON and myelitis. Attacks of ON can be bilateral (rare in MS) or unilateral; myelitis can be severe and transverse (rare in MS) and is typically longitudinally extensive, involving three or more contiguous vertebral segments. Attacks of ON may be precede or follow an attack of myelitis by days, months, or years, or vice versa. In contrast to MS, progressive symptoms do not occur in NMO. The brain MRI was classically thought to be normal at the onset of NMO, but recent studies now indicate that asymptomatic lesions sometimes resembling typical MS are common. Lesions involving the hypothalamus, periaqueductal region of the brainstem, or “cloud-like” white matter lesions in the cerebral hemispheres are suggestive of NMO. Brainstem disease can present with nausea and vertigo, and large hemispheral lesions can present as encephalopathy or seizures. Spinal cord MRI typically reveals a focal enhancing region of swelling and cavitation, extending over three or more spinal cord segments and often located in central gray matter structures. Histopathology of these lesions may reveal thickening of blood-vessel walls, demyelination, deposition of antibody and complement, a characteristic loss of astrocytes, and aquaporin-4 staining not seen in MS.
NMO, which is uncommon in whites compared with Asians and Africans, is best understood as a syndrome with diverse causes. Up to 40% of patients have a systemic autoimmune disorder, often systemic lupus erythematosus, Sjögren’s syndrome, p-ANCA (perinuclear antineutrophil cytoplasmic antibody)–associated vasculitis, myasthenia gravis, Hashimoto’s thyroiditis, or mixed connective tissue disease. In others, onset may be associated with acute infection with varicellazoster virus, EBV, HIV, or tuberculosis. Rare cases appear to be paraneoplastic and associated with breast, lung, or other cancers. NMO is often idiopathic, however. NMO is usually disabling over time; in one series, respiratory failure from cervical myelitis was present in one-third of patients, and 8 years after onset 60% of patients were blind and more than half had permanent paralysis of one or more limbs.
A highly specific autoantibody directed against the water channel protein aquaporin-4 is present in the sera of 60–70% of patients who have a clinical diagnosis of NMO. Seropositive patients have a very high risk for future relapses. Aquaporin-4 is localized to the foot processes of astrocytes in close apposition to endothelial surfaces. It is likely that aquaporin-4 antibodies are directly pathogenic in NMO, as passive transfer of antibodies from NMO patients into laboratory animals reproduced histologic features of the disease.
When MS affects individuals of African or Asian ancestry, there is a propensity for demyelinating lesions to involve predominantly the optic nerve and spinal cord, an MS subtype termed “opticospinal MS.” Interestingly, some individuals with opticospinal MS are seropositive for aquaporin-4 antibodies, suggesting that such cases represent an NMO spectrum disorder.
Acute MS (Marburg’s variant) is a fulminant demyelinating process that in some cases progresses inexorably to death within 1–2 years. Typically, there are no remissions. When acute MS presents as a solitary, usually cavitary, lesion, a brain tumor is often suspected. In such cases, a brain biopsy is usually required to establish the diagnosis. An antibody-mediated process appears to be responsible for most cases. Marburg’s variant does not seem to follow infection or vaccination, and it is unclear whether this syndrome represents an extreme form of MS or another disease altogether. No controlled trials of therapy exist; high-dose glucocorticoids, plasma exchange, and cyclophosphamide have been tried, with uncertain benefit.
TREATMENT Neuromyelitis Optica
Disease-modifying therapies have not been rigorously studied in NMO. Acute attacks of NMO are usually treated with high-dose glucocorticoids (Solu-Medrol 1–2 g/d for 5–10 days followed by a prednisone taper). Because of the likelihood that NMO is antibody-mediated, plasma exchange (typically 7 qod exchanges of 1.5 plasma volumes) has also been used empirically for acute episodes that fail to respond to glucocorticoids. Prophylaxis against relapses can be achieved in some patients with one of the following regimens: mycophenolate mofetil (250 mg bid gradually increasing to 1000 mg bid); B cell depletion with anti-CD20 monoclonal antibody (Rituxan); or a combination of glucocorticoids (500 mg IV methylprednisolone daily for 5 days; then oral prednisone 1 mg/kg per day × 2 months, followed by slow taper) plus azathioprine (2 mg/kg per day started on week 3). By contrast, available evidence suggests that use of IFN-β is ineffective and paradoxically may increase the risk of NMO relapses.
ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)
ADEM has a monophasic course and is most frequently associated with an antecedent infection (postinfectious encephalomyelitis); approximately 5% of ADEM cases follow immunization (postvaccinal encephalomyelitis). ADEM is more common in children than adults. The hallmark of ADEM is the presence of widely scattered small foci of perivenular inflammation and demyelination in contrast to larger confluent demyelinating lesions typical of MS. In the most explosive form of ADEM, acute hemorrhagic leukoencephalitis, the lesions are vasculitic and hemorrhagic, and the clinical course is devastating.
Postinfectious encephalomyelitis is most frequently associated with the viral exanthems of childhood. Infection with measles virus is the most common antecedent (1 in 1000 cases). Worldwide, measles encephalomyelitis is still common, although use of the live measles vaccine has dramatically reduced its incidence in developed countries. An ADEM-like illness rarely follows vaccination with live measles vaccine (1–2 in 106 immunizations). ADEM is now most frequently associated with varicella (chickenpox) infections (1 in 4000–10,000 cases). It may also follow infection with rubella, mumps, influenza, parainfluenza, Epstein-Barr, HIV, and other viruses, and Mycoplasma. Some patients may have a nonspecific upper respiratory tract infection or no known antecedent illness. In addition to measles, postvaccinal encephalomyelitis may also follow the administration of smallpox (5 cases per million), the Semple rabies, and Japanese encephalitis vaccines. Modern vaccines that do not require viral culture in CNS tissue have reduced the ADEM risk.
All forms of ADEM presumably result from a cross-reactive immune response to the infectious agent or vaccine that then triggers an inflammatory demyelinating response. Autoantibodies to MBP and to other myelin antigens have been detected in the CSF from many patients with ADEM. Attempts to demonstrate direct viral invasion of the CNS have been unsuccessful.
In severe cases, onset is abrupt and progression rapid (hours to days). In postinfectious ADEM, the neurologic syndrome generally begins late in the course of the viral illness as the exanthem is fading. Fever reappears, and headache, meningismus, and lethargy progressing to coma may develop. Seizures are common. Signs of disseminated neurologic disease are consistently present (e.g., hemiparesis or quadriparesis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss, and brainstem involvement). In ADEM due to chickenpox, cerebellar involvement is often conspicuous. CSF protein is modestly elevated (0.5–1.5 g/L [50–150 mg/dL]). Lymphocytic pleocytosis, generally 200 cells/μL, occurs in 80% of patients. Occasional patients have higher counts or a mixed polymorphonuclear-lymphocytic pattern during the initial days of the illness. Transient CSF oligoclonal banding has been reported. MRI usually reveals extensive changes in the brain and spinal cord, consisting of white matter hyperintensities on T2 and FLAIR sequences with gadolinium enhancement on T1-weighted sequences.
The diagnosis is easily established when there is a history of recent vaccination or viral exanthematous illness. In severe cases with predominantly cerebral involvement, acute encephalitis due to infection with herpes simplex or other viruses including HIV may be difficult to exclude (Chap. 40); other considerations include hypercoagulable states including the antiphospholipid antibody syndrome, vasculitis, neurosarcoid, or metastatic cancer. An explosive presentation of MS can mimic ADEM, and especially in adults, it may not be possible to distinguish these conditions at onset. The simultaneous onset of disseminated symptoms and signs is common in ADEM and rare in MS. Similarly, meningismus, drowsiness, coma, or seizures suggest ADEM rather than MS. Unlike MS, in ADEM optic nerve involvement is generally bilateral and transverse myelopathy complete. MRI findings that favor ADEM include extensive and relatively symmetric white matter abnormalities, basal ganglia or cortical gray matter lesions, and Gd enhancement of all abnormal areas. By contrast, oligoclonal bands in the CSF are more common in MS. In one study of adult patients initially thought to have ADEM, 30% experienced additional relapses over a follow-up period of 3 years and they were now classified as having MS. Occasional patients with “recurrent ADEM” have also been reported especially in children; however, it is not possible to distinguish this entity from atypical MS.
TREATMENT Acute Disseminated Encephalomyelitis
Initial treatment is with high-dose glucocorticoids as for exacerbations of NMO (discussed earlier); depending on the response, treatment may need to be continued for 4–8 weeks. Patients who fail to respond within a few days may benefit from a course of plasma exchange or intravenous immunoglobulin. The prognosis reflects the severity of the underlying acute illness. Measles encephalomyelitis is associated with a mortality rate of 5–20%, and most survivors have permanent neurologic sequelae. Children who recover may have persistent seizures and behavioral and learning disorders.