Multiple sclerosis is a chronic condition characterized clinically by episodes of focal disorders of the optic nerves, spinal cord, and brain, which remit to a varying extent and recur over a period of many years and are usually progressive. The neurologic manifestations are protean, being determined by the varied location and extent of the demyelinating foci. Nevertheless, the lesions have a predilection for certain parts of the CNS, resulting in complexes of symptoms and signs and imaging appearances that can often be recognized as distinctive of MS as discussed in detail further on.
Typical features include weakness, paraparesis, paresthesias, loss of sight, diplopia, nystagmus, dysarthria, tremor, ataxia, impairment of deep sensation, and bladder dysfunction. The diagnosis may be uncertain at the onset and in the early years of the disease, when symptoms and signs point to a lesion in only one locus of the nervous system. Later, as the disease recurs and disseminates throughout the central nervous system, the diagnosis becomes quite certain. There may be a long period of latency (1 to 10 years or longer) between a minor initial symptom, which may not even come to medical attention, and the subsequent development of more characteristic symptoms. In most cases, there is initially a relapsing-remitting pattern, i.e., the signs and symptoms improve partially or completely, followed after a variable interval by the recurrence of the same abnormalities or the appearance of new ones in other parts of the nervous system. However, in fewer than half of patients, the disease takes the form a steadily progressive course, especially in patients older than 40 years of age at the time of onset (primary progressive MS). Or, as happens more often, an initially relapsing profile later becomes steadily progressive (secondary progressive MS).
A rule that had in the past guided clinicians is that the diagnosis of MS was not secure unless there was a history of remission and relapse and evidence on examination of more than one discrete lesion of the CNS. The advent of MRI and its capacity to identify clinically inevident lesions has replaced the exclusive dependence on clinical criteria for the diagnosis.
Before being sectioned, the brain and spinal cord generally show no evidence of disease, but the surface of the spinal cord may appear and feel uneven. Sectioning of the brain and cord discloses numerous scattered patches where the tissue is slightly depressed below the cut surface and stands out from the surrounding white matter by virtue of its pink-gray color (a result of loss of myelin). The lesions may vary in diameter from less than a millimeter to several centimeters; they principally affect the white matter of the brain and spinal cord, and do not extend beyond the root entry zones of the cranial and spinal nerves. It is because of their sharp delineation that they were called plaques by French pathologists.
The topography of the lesions is noteworthy. A periventricular localization is characteristic, but only where subependymal veins line the ventricles (mainly adjacent to the bodies and atria of the lateral ventricles). Other favored structures are the optic nerves and chiasm (but rarely the optic tracts) and the spinal cord, where pial veins lie next to or within the white matter. The lesions are distributed randomly throughout the brainstem, spinal cord, and cerebellar peduncles without reference to particular systems of fibers, but always confined predominantly to the white matter. In the cerebral cortex and central nuclear and spinal structures, the acute lesions destroy myelin sheaths but leave the nerve cells mostly intact. Severe and more chronic lesions, however, may destroy axons and neurons in the affected region, but the dominant lesion is still demyelinating.
The histologic appearance of the lesion depends on its age. Relatively recent lesions show a partial or complete destruction and loss of myelin throughout a zone formed by the confluence of many small, predominantly perivenous foci; the axons in the same region are relatively spared or less affected. There is a variable but usually slight degeneration of oligodendroglia, a variable astrocytic reaction, and perivascular and para-adventitial infiltration with mononuclear cells and lymphocytes as discussed in detail further on. Later, large numbers of microglial phagocytes (macrophages) infiltrate the lesions and astrocytes in and around the lesions increase in number and size. Long-standing lesions, on the other hand, are composed of thickly matted, relatively acellular glial tissue, with only occasional perivascular lymphocytes and macrophages; in such lesions, a few intact axons may still be found. In old lesions with interruption of axons, there may be descending and ascending wallerian degeneration of long fiber tracts in the spinal cord. Partial remyelination is believed to take place on undamaged axons and to account for incompletely demyelinated "shadow patches" (Prineas and Connell). A few of the most severe older lesions will have undergone cavitation, indicating that the disease process has affected not only myelin and axons but also supporting tissues and blood vessels. All gradations of histopathologic change between these two extremes may be found in lesions of diverse size, shape, and age, consistent with the extended clinical course.
The relatively ineffective remyelination of the MS plaque leaves in its wake denuded axons that are thinly myelinated, creating the just mentioned shadow plaques. Histologic evidence suggests that some of the oligodendrocytes are destroyed in areas of active demyelination but also that the remaining ones have little ability to proliferate. Instead, there is an influx of oligodendroglial precursor cells, which mature into oligodendrocytes and provide the remaining axons with new myelin. Probably the astrocytic hyperplasia in regions of damage and the persistent inflammatory response account for some of the inadequacy of the reparative process (see Prineas et al).
An insight into the complexity of the immunopathologic process can be appreciated in the analyses by Lucchinetti and colleagues (2000) of autopsy and brain biopsy specimens from patients with MS. They separated the lesions into four histologic subgroups: inflammatory lesions made up of T cells and macrophages alone (pattern I); an autoantibody lesion mediated by immunoglobulin and complement (pattern II); those characterized by apoptosis of oligodendrocytes and absence of immunoglobulin, complement, and with partial remyelination (pattern III); and those showing only oligodendrocyte dystrophy and no remyelination (pattern IV). Two features are of interest here. First, each case demonstrated only one pattern of pathology, suggesting that perhaps different pathophysiologic processes operated in each patient. Moreover, the last two histopathologic types were considered to represent a primary oligodendroglial cell degeneration. Some confirmation of a primary process in oligodendrocytes is the material from newly symptomatic lesions reported by Barnett and Prineas, in which there was loss of these cells. In addition, early lesions have been found to contain areas of demyelination within the cerebral cortex and these are often in contiguity with meningeal inflammatory infiltrates, or lymphoid follicles (Lucchinetti et al 2011, Howell et al).
The overall implication is that the pathologic characteristics of the chronic progressive type of MS may differ from those of the typical relapsing type (see further on). Most data suggest that antibody and complement-mediated myelin phagocytosis are the dominant mechanism of demyelination in MS. At the moment, we continue to conceptualize MS as mainly an inflammatory-immune process that targets central myelin along the lines of the observations of Adams and Kubik in their earlier studies, who were aware of the axonal and cortical changes in pathologic material they collected in the 1940s.
Etiology and Epidemiology
The incidence of MS is two or three times higher in women than in men but the basis of this fact is unclear, the best current explanation being that women are generally more susceptible to immune and inflammatory conditions. The incidence in children is very low; only 0.3 to 0.4 percent of all cases appear during the first decade. In an analysis of a small number of childhood-onset cases, Hauser and colleagues (1982) found no phenotypic differences between childhood and adult cases, but Renoux and colleagues analyzed a cohort of 394 patients who had MS with an onset at 16 years or younger and found that these patients took longer to reach states of irreversible disability, but did so at a younger age than patients with adult-onset MS. Beyond childhood, the risk of first developing symptoms of the disease rises steeply with age, reaching a peak at about 30 years, remaining high in the fourth decade, then falling off sharply and becoming low in the sixth decade. On this basis it has been pointed out that MS has a unimodal age-specific onset curve, similar to that of infectious and connective tissue diseases.
In a smaller number, the disease appears to develop in late adult life (late fifties and sixties). In such patients, early symptoms may have been forgotten or may never have declared themselves clinically (we have several times found the typical lesions of MS in aged autopsied individuals who had no history of neurologic illness). Gilbert and Sadler report five such cases and from their pathologic findings suggest that the true incidence of MS may be three times higher than the stated figures.
Although the cause of MS remains undetermined, a number of epidemiologic facts have been established and will eventually have to be incorporated in any hypothesis. The disease has a prevalence of less than 1 per 100,000 in equatorial areas; 6 to 14 per 100,000 in the southern United States and southern Europe; and 30 to 80 per 100,000 in Canada, northern Europe, and the northern United States. Mayr and colleagues reported an incidence of 8 and a prevalence of 177 cases per 100,000 in Olmstead County, Minnesota; this prevalence has been stable for approximately 30 years. A less-well-defined gradient exists in the southern hemisphere. Kurland's studies indicated that there is a threefold increase in prevalence and a fivefold gradient in mortality rate between New Orleans (30 degrees north latitude) and Boston (42 degrees north) and Winnipeg (50 degrees north). In Japan, there is a similar although less distinct latitudinal gradient (the prevalence of MS there is much lower than in corresponding latitudes of North America and northern Europe).
The increasing risk of developing MS with higher and lower latitude has been confirmed by many epidemiologists following the work of Kurtzke (1975). In the United States, African Americans are at lower risk than whites at all latitudes, but both races show the same south-to-north gradient in risk, findings that invoked an environmental factor regardless of genetic predisposition. Supporting this view are the descriptions, by Kurtzke and Hyllested, of an "epidemic" of MS in the Faroe Islands of the North Atlantic. They found a much-higher-than-expected incidence of the disease, occurring as three separate outbreaks of decreasing extent between the years 1943 and 1973. (It should be pointed out that the largest outbreak consisted of only 21 cases.) It was their contention, confirmed by Poskanzer and colleagues, that the disease was the result of an unidentified infection introduced by British troops who occupied the islands in large numbers in the years immediately preceding the outbreak. Kurtzke and colleagues (1982) described a similar postwar epidemic in Iceland. The cause of these geographic distributions has been reinterpreted in terms of migration and population genetics rather than a number of other imputed causes, but they remain interesting (see Compston and Confavreaux for a complete discussion).
The role of Vitamin D and of sun exposure has become an area of related epidemiologic research. Some data suggest that the risk of MS is in part a result of a lack of exposure to these two related environmental features (Munger et al and van der Mei et al). Whether this partly explains the latitudinally graded risk is unclear. An observed seasonal fluctuation in the activity of established MS lesions may have a similar basis.
Several studies indicate that persons who migrate from a high-risk to a low-risk zone carry with them at least part of the risk of their country of origin and genetic makeup, even though the disease may not become apparent until 20 years after migration. Such a pattern has been demonstrated in both South Africa and Israel. Dean determined that the prevalence of MS in native-born white South Africans was 3 to 11 per 100,000, whereas the rate in immigrants from northern Europe was approximately 50 per 100,000, only slightly less than among the nonimmigrating natives of those countries. The data of Dean and Kurtzke indicate further that in persons who had immigrated before the age of 15, the risk was similar to that of native-born South Africans; whereas in persons who had immigrated after that age, the risk was similar to that of their birthplace. Alter and colleagues found that in the descendants of European immigrants born in Israel, the risk of MS was low, similar to that of other native-born Israelis, whereas among recent immigrants the incidence in each national group approached that of the land of birth. Again, the critical age of immigration appeared to be about 15 years. These older epidemiologic studies and others have suggested that MS is associated with particular localities rather than with a particular ethnic group in those localities, and implicate environmental factors but not to the exclusion of genetic susceptibility. However, more current studies suggest the opposite; that genetic factors in a population predominate.
A familial aggregation of MS is now well established. Approximately 15 percent of MS patients have an affected relative, with the highest risk of concurrence being observed in the patient's siblings (Ebers, 1983). In a large population-based study carried out in British Columbia by Sadovnick and colleagues (1988), it was found that almost 20 percent of index cases had an affected relative, again with the highest risk in siblings. In a subsequent study, Sadovnick and colleagues (1996) sought to determine the degree of heritability of MS by comparing the risk of disease in the half-sibs (one biologic parent in common) of affected individuals with the risk in full sibs; the risk for full sibs was two to three times greater than for half-sibs and they interpreted these results as clearly genetic in basis.
The case for heritability is further supported by studies of twins in whom one of each pair is known to have MS. In the most extensive of these studies (Ebers et al), the diagnosis was verified in 12 of 35 pairs of monozygotic twins (34 percent) and in only 2 of 49 pairs of dizygotic twins (4 percent). Furthermore, in two additional sets of monozygotic twins who were clinically normal, lesions were detected by MRI. The concordance rate in dizygotic pairs is similar to that in nontwin siblings. Despite these provocative findings, no consistent pattern of mendelian inheritance has emerged. Of course, one must not assume that all diseases with an increased familial incidence are hereditary in that instances of the same condition in several members of a family may simply reflect an exposure to a common environmental agent. Paralytic poliomyelitis, for example, was about eight times more common in immediate family members than in the population at large.
Further evidence of a genetic factor in the causation of MS is the finding that certain histocompatibility locus antigens (HLAs) are more frequent in patients with MS than in control subjects. The strongest association is with the DR locus on chromosome 6. Other HLA haplotypes that are overrepresented in MS (HLA-DR2 and, to a lesser extent, -DR3, -B7, and -A3) are thought to be markers for an MS "susceptibility gene"—possibly an immune response gene. The presence of one of these markers increases the risk that an individual will develop MS by a factor of 3 to 5. These antigens may indeed prove to be related to the frequency of the disease, but their presence is not invariable and their exact role is far from clear. A genome-wide association study identified several alleles, interleukin (IL)-2Rα, and IL7Rα in addition to the previously established HLA loci, as heritable risk factors for MS (International Multiple Sclerosis Genetics Consortium). These findings, although they apply to a small number of individuals, support the concept that dysregulation of the immune response is a factor in the risk for developing MS.
The low conjugal incidence of MS, on the other hand, indicates that any common exposure to an inciting infection or environmental agent must occur early in life. To test this hypothesis, Schapira and coworkers determined the periods of common exposure (common habitation periods) in members of families with two or more cases. From this they calculated the mean common exposure to have happened before 14 years of age, with a latency of about 21 years—figures that are in general agreement with those derived from the migration studies quoted above.
Several studies from northern Europe and Canada suggest that the likelihood of developing MS is somewhat greater among rural than among urban dwellers; studies of American army personnel indicate the opposite (Beebe et al). A number of surveys in Great Britain intimate that the disease is more frequent in the higher socioeconomic groups than in the lower ones. Yet in the United States, no clear relationship has been established to the poverty or social deprivations that are part of a low socioeconomic status. Numerous other environmental factors (surgical operations, trauma, anesthesia, exposure to household pets [small dogs], cobalamin deficiency or resistance, mercury in silver amalgam fillings in teeth), and Lyme disease have been proposed but are unsupported by firm evidence and probably are mostly spurious associations.
These epidemiologic data point to both a genetic susceptibility and some environmental factor that is encountered in childhood that, after years of latency, evokes the disease. Over the years, data favoring an infection, most often viral as the triggering factor, have had periods of support (see above). A body of indirect evidence has been marshaled in support of this idea, based largely on alterations in humoral and cell-mediated immunity to viral agents. To this day, however, no virus (including all known members of the human retrovirus family) has been seen in, or isolated from, the tissues of patients with MS despite innumerable attempts to do so. Moreover, no satisfactory viral model of MS has been produced experimentally. The bacterial agents Chlamydia pneumoniae and Borrelia burgdorferi (the agent of Lyme disease) and herpesvirus type 6 have been similarly implicated by the finding of their genomic material in MS plaques, but the evidence for their direct participation in the disease is, at the moment, not compelling.
If, indeed, some obscure infection is the initial event in the genesis of MS, then a secondary factor must be operative in later life to reactivate the disease and cause exacerbations. One view is that this secondary mechanism is an autoimmune reaction attacking some component of myelin and, in its most intense form, destroying all tissue elements, including axons. Several lines of argument have been advanced in support of this view. One is inclined to draw an analogy between the lesions of MS and those of acute disseminated encephalomyelitis, which is almost certainly an autoimmune disease of delayed hypersensitivity type (see further on). Also in support of this possibility is the finding of antibodies to specific myelin proteins—for example, myelin basic protein (MBP)—in both the serum and cerebrospinal fluid (CSF) of MS patients, and these antibodies, along with T cells that are reactive to MBP and to other myelin proteolipids, increase with disease activity; moreover, MBP cross-reacts to some extent with measles virus antibodies. The arguments that a chronic viral infection reactivates and perpetuates the disease are, however, less convincing than those proposing a role for viruses in the initiation of the process in susceptible individuals.
The relative roles of humoral and cellular factors in the production of MS plaques are not fully understood. The deposition of immunoglobulin in the plaques of patients with acute and relapsing–remitting disease, but not in the plaques of those with progressive MS, was alluded to earlier. That the humoral immune system is involved is evident from the presence in the CSF of most patients of oligoclonal immune protein antibodies, which are produced by B lymphocytes within the CNS. Sera from patients with MS (and some normal controls), when added to cultures of nervous system tissue from newborn mice in the presence of complement, can damage myelin, inhibit remyelination, and block axonal conduction. Antibodies to oligodendrocytes are present in the serum of up to 90 percent of patients in some studies, but far less frequently in others.
Autoantibodies have been found inconsistently that are directed against myelin oligodendrocyte glycoprotein (MOG) and MBP. It has also been demonstrated that subsets of T cells (CD41 Th2 cells) are activated by MBP and MOG to activate B cells, the production of oligoclonal bands and membrane attack complexes, and the release of cytokines (tumor necrosis factor-alpha [TNF-α], interleukins, interferon-gamma [IFN-γ ]). The inflammatory process erodes the blood–brain barrier and ultimately destroys both oligodendroglia and axons. The eventual functional outcome reflects both the activity of this inflammatory cascade and the degree of axonal damage. In other cases, there may be a compromise of oligodendroglial function and axonal degeneration in the absence of prominent inflammation. Many times, one or another putative antigenic target has been found by immunologic techniques in one laboratory, only to fail to be replicated by another group. None of these provide a unifying etiology for the disease but the humoral aspects may provide insights particularly into the pauci-inflammatory type of oligodendrocyte degeneration that characterizes some lesions, as discussed in the section on pathology.
Nevertheless, most immunologists currently subscribe to the notion that MS is mediated by a T-cell sensitization to some component of myelin. This idea is supported by numerous lines of evidence, including the observation that T cells initiate the lesions of experimental allergic encephalomyelitis (EAE), which is assumed to be an approximate animal model of MS, as suggested originally by Waksman and Adams. It has been difficult, however, to produce a relapsing experimental form of the illness that would simulate MS. Although the entry of autoreactive T cells into the CNS results in a perivascular inflammatory reaction, its relationship to MS is unclear. Conceivably, intense T-cell stimulation is in itself sufficient to induce demyelination but it is also possible that the primary target of the immune reaction is the myelin sheath or some component thereof and that the T-cell infiltration is a reaction to demyelination. Most investigators believe that an additional insult is required, as illustrated by the EAE animal model, in which myelin alone is not a sufficient factor but always requires an adjuvant immune stimulus. EAE is clearly an imperfect model; it is not a naturally occurring disease but one in which a demyelination of the CNS is induced in susceptible animals in a single episode by autologous myelin antigens. The inducing antigen in EAE is known, whereas the putative antigens in MS are not.
Also incorporated into most theories of the immune pathogenesis is an alteration of the blood–brain barrier, represented by adhesion of lymphocytes to endothelial cells in the nervous system. Whether this is an active interaction or a passive event triggered by antigenic attraction is not clear; nonetheless, these cell–vascular interactions have been incorporated into pathogenic theories and are the basis of newer treatments for MS. Always in the background is the element of genetic susceptibility, presumably making certain individuals prone to these immunologic events as noted in the earlier sections.
The foregoing data notwithstanding, the immune mechanisms in MS are not fully specified and the autoimmune hypothesis is not beyond challenge. It is noteworthy that the prevalence of other diseases of presumed autoimmune origin in some series is no higher in MS patients than in the general population (De Keyser). However, various epidemiologic studies differ on this point and some have found an increase in autoimmune diseases in affected patients and in their families.
Weakness or numbness, sometimes both, in one or more limbs is the initial symptom in about half the patients. Symptoms of tingling of the extremities and tight band-like sensations around the trunk or limbs are commonly associated and are probably the result of involvement of the posterior columns of the spinal cord. The symptoms generally appear over hours or days, at times being so trifling that they are ignored, and less often, coming on so acutely and prominently as to bring the patient urgently to the doctor. The resulting clinical syndromes vary from a mere dragging or poor control of one or both legs to a spastic or ataxic paraparesis. The tendon reflexes are retained and later become hyperactive with extensor plantar reflexes; varying degrees of deep and superficial sensory loss may be associated. It is a useful adage that the patient with MS presents with symptoms in one leg but with signs in both; the patient will complain of weakness, incoordination, or numbness and tingling in one lower limb and prove to have bilateral Babinski signs and other evidence of bilateral corticospinal and posterior column disease.
There are, in addition, several syndromes that are typical of multiple sclerosis and may be the initial manifestations. These common modes of onset are: (1) optic neuritis, (2) transverse myelitis, (3) cerebellar ataxia, and (4) brainstem syndromes (vertigo, facial pain or numbness, dysarthria, diplopia). When these are unaccompanied by other features of MS, they are termed "clinically isolated syndrome" (CIS) but they are often aspects of the established disease as well. In the initial phases of the illness, they may pose diagnostic questions, as they also certainly occur with numerous diseases other than MS.
Flexion of the neck may induce a tingling, electric-like feeling down the shoulders and back and, less commonly, down the anterior thighs. This phenomenon is known as the Lhermitte sign, although it is more a symptom than a sign and was originally described by Babinski in a case of cervical cord trauma. Lhermitte's contribution was to draw attention to the frequent occurrence of this phenomenon in MS. It is probably attributable to an increased sensitivity of demyelinated axons to the stretch or pressure on the spinal cord induced by neck flexion, but it occurs in other conditions such as cervical spondylosis.
McAlpine and coworkers (1972) analyzed the mode of onset in 219 patients and found that in 20 percent the neurologic symptoms were fully developed in a matter of minutes, and, in a similar number, in a matter of hours. In approximately 30 percent the symptoms evolved more slowly, over a period of a day or several days, and in another 20 percent more slowly still, over several weeks to months. In the remaining 10 percent the symptoms had an insidious onset and slow, steady, or intermittent progression over months and years. The typical relapsing–remitting pattern of disease is more likely to appear in patients who are younger than 40 years of age. Certain paroxysmal symptoms and signs may occur in the established phase of the disease and discussed further on. The inflammatory process of MS affects no organ system other than the CNS.
Optic Neuritis (Retrobulbar Neuritis; Papillitis) (See "Optic Neuritis" in Chap. 13)
In approximately 25 percent of all MS patients (and possibly in a larger proportion of children), the initial manifestation is an episode of optic neuritis. It will be recalled that the optic nerve is in fact a tract of the brain, and involvement of the optic nerves is therefore consistent with the rule that lesions of MS are confined to the CNS. Characteristically, over a period of several days, there is partial or total loss of vision in one eye. Many patients, for a day or two before the visual loss, experience pain within the orbit, worsened by eye movement or palpation of the globe. Rarely, the visual loss is steadily progressive for several weeks, mimicking a compressive lesion or intrinsic tumor of the optic nerve (Ormerod and McDonald). Usually a scotoma involving the macular area and blind spot (cecocentral) can be demonstrated, but a wide variety of other field defects may occur, rarely even hemianopic involvement (sometimes homonymous). In some patients, both optic nerves are involved, either simultaneously or, more commonly, within a few days or weeks of one another, and at least one in eight patients will have repeated attacks.
Serial examinations may disclose evidence of swelling or edema of the optic nerve head (papillitis) in about a tenth of the patients. The occurrence of papillitis depends on the proximity of the demyelinating lesion to the nerve head. As emphasized in Chap. 13, papillitis can be distinguished from the papilledema of increased intracranial pressure by the severe and acute visual loss that accompanies only the former. More often, the optic nerve head appears normal or nearly so; this represents retrobulbar neuritis. Subtle manifestations of optic nerve affection, such as an afferent pupillary defect, atrophy of retinal nerve fibers, or sheathing of retinal veins and abnormalities of the visual evoked response (Chap. 2), should be sought in patients who have no visual complaints but are suspected of having MS. In cases of substantial visual loss, there is a diminished pupillary response to light (afferent pupillary paralysis) and instability of the direct pupillary response but the pupil is not dilated in ambient light. If the optic neuritis is unilateral, the consensual light reflex from the normal eye is retained. (Demyelination of the third nerve in its brainstem course, however, may be associated with a fixed enlargement of the pupil.) Visual evoked potentials and optical coherence tomography (OCT) may be useful in detecting optic neuritis, as discussed in a later section and in Chap. 2.
As noted in Chap. 13, about half of patients with optic neuritis recover completely, and most of the remaining ones improve significantly, even those who present initially with profound visual loss and, later, pallor of the optic disc (Slamovitis et al). Any pain in the globe is short-lived and persistent pain should prompt an evaluation for local disease. In a cohort of 397 patients enrolled in the Optic Neuritis Treatment Trial and examined 5 years after the initial attack of optic neuritis, visual acuity had returned to 20/25 or better in 87 percent of patients and to 20/40 or better in 94 percent—even if there had been a recurrence of optic neuritis during the 5-year period. Moreover, the mode of treatment did not appear to influence the outcome. Dyschromatopsia, generally taking the form of a perceived desaturation of colors, frequently persists as does the Pulfrich effect, wherein an object such as a pendulum that is swinging perpendicular to the patient's line of sight, appears to moving in a three-dimensional, circular motion.
When improvement occurs, it usually begins within 2 weeks of onset, as is true of most acute manifestations of MS, perhaps sooner with corticosteroid treatment. Once improvement in neurologic function begins, it may continue for several months.
More than one-half of adult patients who present with optic neuritis will eventually develop other signs of MS. The prospective investigation of Rizzo and Lessell showed that MS developed in 74 percent of women and 34 percent of men by the fifteenth year after onset of visual loss; similar results were reported by the Optic Neuritis Study Group (Beck et al, 2003). The risk is much lower if the initial attack of optic neuritis occurs in childhood (26 percent developed after 40 years of followup [Lucchinetti et al 1997]); this suggests that some instances of the childhood disease may be of a different type, perhaps viral or postinfectious. The longer the period of observation and the greater the care given to detection of mild cases, the greater the proportion of patients who are found to develop signs of MS; however, most do so within 5 years of the original attack (Ebers, 1985; Hely et al). In fact, in many patients with clinically isolated optic neuritis, MRI has disclosed lesions of the cerebral white matter—suggesting that dissemination, albeit asymptomatic, had already occurred and thereby establishing the diagnosis of MS (Jacobs et al, 1986; Ormerod et al). The Optic Neuritis Study Group has made the point, well known to neurologists, that the recurrence of optic neuritis greatly increases the chances of developing MS. Of practical value is the observation, in the study by Beck and colleagues (2003), that the risk of relapsing-remitting MS is also considerably lower (22 percent at 10 years) if the cranial MRI fails to reveal demyelinating lesions.
It is unclear whether optic neuritis that occurs alone and is not followed by other evidence of demyelinating disease is simply a restricted form of MS or a manifestation of some other disease process, such as postinfectious encephalomyelitis. By far the most common pathologic basis for optic neuropathy is demyelinating disease, although it is known that a vascular lesion or compression of an optic nerve by a tumor or mucocele may cause a central or cecocentral scotoma that is indistinguishable from the defect of optic neuritis. Also, there may be a special form of chronic relapsing optic neuritis that is the result of an undefined granulomatous process such as sarcoid, as suggested by Kidd and colleagues. Uveitis and sheathing of the retinal veins are other ophthalmic disorders that occur with higher than expected incidence in patients with MS. The retinal vascular sheathing is caused by T-cell infiltration, identical to that in typical plaques, but this is an unusual finding, because the retina usually contains no myelinated fibers (Lightman et al). Optic neuritis is, of course, a common feature in neuromyelitis optica (Devic disease), discussed in a later section.
The treatment of optic neuritis is discussed further on.
Acute Myelitis (Transverse Myelitis) (See Chap. 44)
This is the common designation for an acutely evolving inflammatory–demyelinating lesion of the spinal cord, which proves in many, but not all, instances to be an expression of MS. In this sense, the myelitic lesion is analogous to that of optic neuritis. The term transverse in relation to the myelitis is somewhat imprecise, implying that all of the elements in the cord are involved in the transverse plane, usually over a short vertical extent. Instead, in MS, the spinal cord signs are asymmetrical and incomplete and involve only a part of the long ascending and descending tracts, i.e., paraplegia and complete sensory loss are unusual.
Clinically, the illness is characterized by a rapidly evolving (several hours or days) symmetrical or asymmetrical paraparesis or paraplegia, ascending paresthesia, loss of deep sensibility in the feet, a sensory level on the trunk, sphincteric dysfunction, and bilateral Babinski signs. The CSF shows a modest number of lymphocytes and increase in total protein but both may be normal early in the illness. As many as one-third of patients report an infectious illness in the weeks preceding the onset of neurologic symptoms, in which case a monophasic postinfectious demyelinating disease rather than MS is the likely cause of the myelitis. The MRI usually shows indications of focal demyelination in the spinal cord at the appropriate level and there may be enhancement with gadolinium infusion, but neither of these findings is invariable. The lesions, as shown in Fig. 36-1 (lower right panel), are almost indistinguishable from those of postinfectious myelitis. In those instances associated with existing MS, even if not previously symptomatic, MRI of the cerebral hemispheres will show lesions consistent with demyelination; the absence of such lesions, however, does not ensure that the myelitic illness is monophasic and will not evolve to MS. Some cases progress to a necrotic myelopathy, with or without optic neuropathy, that is an expression of neuromyelitis optica, as discussed in a later section.
MRI in multiple sclerosis. Upper left, axial T2-FLAIR image showing multiple discrete periventricular hyperintense plaques, as well as two subcortical plaques in the right frontal and parietal lobes. Upper right, coronal T1-post gadolinium image showing abnormal enhancement of the right optic nerve in a case of acute optic neuritis (arrow). Lower left, sagittal T2-FLAIR image showing two hyperintense plaques emanating radially from the body of the corpus callosum ("Dawson fingers"). Lower right, sagittal T2 MRI showing multiple discrete hyperintense plaques within the cervical spinal cord. The lesion at C3 is acute with accompanying expansion of the cord. The lesion at the T1 level of the cord is chronic and shows cord atrophy.
Fewer than half the patients have evidence of an asymptomatic demyelinating lesion elsewhere in the nervous system or develop clinical evidence of dissemination within 5 years of the initial attack of acute myelitis (Ropper and Poskanzer). Not entirely in accord with our experience is the analysis of subgroups in a trial of interferon therapy conducted by Beck and colleagues (2002), in which the cumulative probability of developing MS after 2 years was similar after either optic neuritis or transverse myelitis. Our sense has been that acute transverse myelitis is somewhat less often an initial expression of MS than is optic neuritis.
A special problem is presented by patients with recurrent myelitis at one level of the spinal cord but in whom no other signs of demyelinating disease can be found by careful clinical examination or MRI. Some of them may even have oligoclonal bands in the CSF, which are commonly associated with MS (see further on). Enough cases of this limited nature have come to our attention to permit the conclusion that there is a recurrent form of spinal cord MS in which cerebral dissemination is infrequent (Tippett et al). Isolated recurrent myelitis or myelopathy occurs also with lupus erythematosus, sarcoidosis, Sjögren syndrome, mixed connective tissue disease, and the antiphospholipid antibody syndrome or in the presence of other autoantibodies, as well as with dural and cord vascular fistulas and arteriovenous malformations. An analogous situation pertains in respect to some instances of optic neuritis—repeated attacks that remain confined to the optic nerve.
Other aspects of transverse myelitis are discussed in Chap. 44, and later in this chapter.
Other Clinical Features of Acute Attacks
Like the modes of onset cited above, other early manifestations of MS are unsteadiness in walking, brainstem symptoms (diplopia, vertigo, vomiting), paresthesias or numbness of an entire arm or leg, facial pain often simulating tic douloureux, and disorders of micturition. Vertigo of central type is also a frequent initial sign of MS, but it more often appears in established cases. Discrete manifestations such as hemiplegia, pain syndromes, facial paralysis, deafness, or seizures occur in an only small proportion of cases. Most often the disease presents with more than one of the aforementioned symptoms almost simultaneously or in rapid succession. Another relatively isolated syndrome, occurring mainly in older women, is a slowly progressive cervical myelopathy with weakness and ataxia. This is particularly difficult to differentiate from cervical spondylosis.
Not infrequently a prominent feature of the disease is nystagmus and ataxia, with or without weakness and spasticity of the limbs, a syndrome that reflects involvement of the cerebellar and corticospinal tracts. Ataxia of cerebellar type can be recognized by scanning speech, rhythmic instability of the head and trunk, intention tremor of the arms and legs, and incoordination of voluntary movements and gait, as described in Chap. 5. The combination of nystagmus, scanning speech, and intention tremor is known as the Charcot triad. While this group of symptoms is often seen in the advanced stages of the disease, most neurologists would agree that it is not a common mode of presentation. The most severe forms of cerebellar ataxia, in which the slightest attempt to move the trunk or limbs precipitate a violent and uncontrollable ataxic tremor, are observed among patients with long-standing MS. The responsible lesion probably lies in the tegmentum of the midbrain and involves the dentatorubrothalamic tracts and adjacent structures. Cerebellar ataxia may be combined with sensory ataxia, owing to involvement of the posterior columns of the spinal cord or medial lemnisci of the brainstem. In most cases of this type, the signs of spinal cord involvement ultimately predominate; in others, the cerebellar signs are more prominent.
Diplopia is another common presenting complaint. It is most often a result of involvement of the medial longitudinal fasciculi, producing an internuclear ophthalmoplegia (see Chap. 14). The signs are characterized by paresis of the medial rectus on attempted lateral gaze, with a coarse nystagmus in the abducting eye; in MS, this abnormality is usually bilateral (unlike small pontine infarcts, which cause a unilateral internuclear ophthalmoplegia [INO]). As a corollary, the presence of bilateral internuclear ophthalmoplegia in a young adult is virtually diagnostic of MS. Occasionally, internuclear ophthalmoplegia in one direction is combined with a horizontal gaze paresis in the other, although this "one-and-a-half syndrome" is more typical of brainstem stroke. Other palsies of gaze (a result of interruption of supranuclear connections) or palsies of individual ocular muscles (because of involvement of the ocular motor nerves in their intramedullary course) also occur, but less frequently. Additional manifestations of brainstem involvement include myokymia or paralysis of facial muscles, deafness, tinnitus, vertigo—as noted above, vomiting (vestibular connections), and, rarely, stupor and coma. The occurrence of transient facial hypesthesia or anesthesia or of trigeminal neuralgia in a young adult should always suggest the diagnosis of MS implicating the intramedullary fibers of the fifth cranial nerve.
Dull, aching, but otherwise nondescript pain in the low back is a common complaint, but its relation to the lesions of MS is uncertain. Infrequently, there is sharp, burning, poorly localized, or lancinating radicular pain, localized to a limb or discrete part of the trunk. Nevertheless, these types of pains, presumably caused by demyelinating foci involving the dorsal root entry zones, have a few times been the presenting feature of the disease or have appeared at a later time in established cases (see Ramirez-Lassepas et al for a discussion of pain in MS).
Symptoms and Signs in the Established Disease
When the diagnosis of MS has become virtually certain, a number of clinical syndromes are observed to occur with regularity. Approximately one-half of the patients will manifest a clinical picture of mixed or generalized type with signs pointing to involvement of the optic nerves, brainstem, cerebellum, and spinal cord—specifically signs relating to the posterior columns and corticospinal tracts. Another 30 to 40 percent will exhibit only varying degrees of spastic ataxia and deep sensory changes in the extremities, i.e., essentially a spinal form of the disease. In either case, an asymmetrical spastic paraparesis with some degree of impaired joint position and vibration sense in the legs is probably the most common manifestation of progressive MS. A predominantly cerebellar or brainstem–cerebellar form occurs in approximately 5 percent of cases. Thus the mixed and spinal forms together have made up at least 80 percent of our clinical material.
It has become evident that some degree of cognitive impairment, and probably a progressive decline, is present in perhaps one-half of patients with long-standing MS. The process is characterized by reduced attention, diminished processing speed and executive skills, and memory decline, while language skills and other intellectual functions are preserved, features that have been subsumed under "subcortical dementia," as discussed in Chap. 21. Other mental disturbances, such as a loss of retentive memory, a global dementia, or a confusional–psychotic state, also occur in limited cases in the advanced stages of the disease, but we have found this degree of deterioration to be exceptional. The decline in cognitive functions correlates with quantifiable MRI measurements, particularly loss of white matter volume, thinning of the corpus callosum, and brain atrophy (reviewed by Bobholz and Rao).
Traditional teaching has probably overemphasized the frequency of euphoria, a pathologic cheerfulness or elation that seems inappropriate in the face of the obvious neurologic deficit. (Charcot spoke of this phenomenon as "stupid indifference" and Vulpian as "morbid optimism." It has often been referred to as "la belle indifférence.") Some patients do show this abnormality, usually in association with other signs of cerebral impairment. In some instances, it is manifestly a part of the syndrome of pseudobulbar palsy. A much larger number of patients, however, are depressed, irritable, and short-tempered, sometimes as a reaction to the disabling features of the disease but also apparently as a primary effect of the brain disease; the incidence of depression has been estimated to be as high as 25 to 40 percent in some series. Dalos and coworkers, in comparing MS patients with a group of traumatic paraplegics, found a significantly higher incidence of emotional disturbance in the former group, especially during periods of relapse. As mentioned above, the cognitive impairment is in keeping with what has been ascribed to "subcortical dementia" (see Chap. 21) but demyelination in the cortical layers is increasingly being recognized as a possible basis for dementia in MS. Loss of the volume of gray matter, for example, appears to be predictive of dementia as much as loss of central white matter. Either can give rise to global cerebral atrophy.
Symptoms of bladder dysfunction, including hesitancy, urgency, frequency, and incontinence, occur commonly with spinal cord involvement. Urinary retention, as a result of damage to sacral segments of the cord is less frequent (see Fig. 26-4). These symptoms are often associated with erectile dysfunction, a symptom that the patient may not report unless specifically questioned in this regard.
Paroxysmal attacks of neurologic deficit, lasting a few seconds or minutes and sometimes recurring many times daily, are relatively infrequent but well-recognized features of MS (see Mathews and also Osterman and Westerbey). Usually the attacks occur during the course of relapsing and remitting phase of the illness, rarely as an initial manifestation. These clinical phenomena are referable to any part of the CNS but tend to be stereotyped in an individual patient. The most common phenomena are dysarthria and ataxia, paroxysmal pain and dysesthesia in a limb, flashing lights, paroxysmal itching, or tonic "seizures", taking the form of flexion (dystonic) spasm of the hand, wrist, and elbow with extension of the lower limb. The paroxysmal symptoms, particularly the tonic spasms, may be triggered by sensory stimuli or can be elicited by hyperventilation. On a few occasions we have seen dystonic hand and arm spasms as the first symptoms; an acute plaque was detected in the opposite internal capsule. In advanced cases, the spasms may involve all four limbs and even a degree of opisthotonos. The cause of paroxysmal phenomena is uncertain. They have been attributed by Halliday and McDonald to ephaptic transmission ("cross-talk") between adjacent demyelinated axons within a lesion.
These transitory symptoms appear suddenly, may recur frequently for several days or weeks, sometimes longer, and then remit completely, i.e., they exhibit the temporal profile of a relapse or an exacerbation. It is sometimes difficult to determine whether they represent an exacerbation or a new lesion. Years ago, Thygessen pointed out, in an analysis of 105 exacerbations in 60 patients, that there were new symptoms in only 19 percent; in the remainder there was only a recurrence of old symptoms. Another problem is that the original lesion may have been asymptomatic. This is most obviously reflected in the many patients who are found to have impaired visual evoked responses but have never had symptomatic visual changes. Thus, new symptoms and signs may be manifestations of previously formed but asymptomatic plaques. However, the observations of Prineas and Connell indicate that symptoms and signs may progress without the appearance of new plaques. These and other factors need to be taken into consideration in evaluating the clinical course of the illness and the effects of a therapeutic program (see Poser, 1980). Carbamazepine is usually effective in controlling such spontaneous attacks, and acetazolamide blocks the painful tonic spasms that are elicited by hyperventilation.
Unusually severe fatigue is another peculiar symptom of MS; it is often transient and more likely to occur when there is fever or other evidence of disease activity but it can be a persistent complaint and a source of considerable distress. Depression may play a role in these recalcitrant cases, although the response to pharmacologic agents suggests that these two aspects of the disease are dissociable. Thus, antidepressants often do not improve fatigue, whereas drugs that alleviate fatigue, such as modafinil and amantadine, do not function as antidepressants.
A number of other interesting manifestations of MS have come to attention over the years and have given rise to difficulties in diagnosis. The occurrence of typical tic douloureux in young patients has already been mentioned; only their young age and the bilaterality of the pain in some of them raised the suspicion of MS, confirmed later by sensory loss in the face and other neurologic signs. It is notable, however, that facial palsy along the lines of Bell's palsy is almost never a sign of MS. Brachial, thoracic, or lumbosacral pain consisting mainly of thermal and algesic dysesthesias was a source of puzzlement in several of our patients until additional lesions developed. Other types of pain in MS have been addressed earlier.
In two of our cases, the relatively acute occurrence of a right hemiplegia and aphasia first raised the probability of a cerebrovascular lesion; in still others, a more slowly evolving hemiplegia had led to an initial diagnosis of a cerebral glioma. The dystonic and paroxysmal symptoms are mentioned earlier; they do not typically bring the diagnosis of MS to mind.
There may be a slightly increased incidence of seizures in patients with MS but the frequency of the problem varies greatly among studies. It should be emphasized that seizures are usually in relation to an obvious cerebral lesion and advanced disease of many years duration. Seizures at an early stage of illness are almost always attributable to previous head injury, idiopathic epilepsy, or withdrawal of sleep medication, but not to MS.
Several times we have seen coma during relapse of longstanding MS, and in each instance it continued to death. In one case it occurred in a 64-year-old woman who had had two previous episodes of nondisabling spinal MS at 30 and 44 years of age. A confusional state with drowsiness was the initial syndrome in another patient whom we saw later with a relapse involving the cerebellum and spinal cord. Another unusual syndrome is one of slow intellectual decline with slight cerebellar ataxia. The chronic progressive form of MS is addressed below.
Precipitating Factors for Acute Attacks
A variety of events occurring immediately before the initial symptoms or exacerbations of MS have been invoked as precipitating factors. The most common are infection, trauma, and pregnancy. However, in our view, none of these has been convincingly related to an increased risk of new attacks of MS, but there is little question that some febrile illnesses such as urinary infections can exaggerate the existing symptoms. The issue of truly precipitating a relapse as a result of a nondescript febrile illness is not resolved. Nonetheless, we have had experience with two patients who regularly had acute exacerbations of MS following each outbreak of labial genital herpes. The incidence of respiratory, urinary, or gastrointestinal viral infections that precede the onset or exacerbations of the disease varies greatly in different series, from 5 to 50 percent. The swine influenza vaccine, which was given to 45 million persons in the United States in late 1976, caused a slight increase in the incidence of Guillain-Barré disease but not of MS (Kurland et al), and more recent surveys of immunization programs, such as the one by Confavreux and colleagues (2001), have had similar results.
The possible role of trauma in precipitating MS is more difficult to assess. McAlpine and Compston found that the incidence of trauma within a 3-month period preceding the onset of MS was slightly greater than in a control group of hospital patients. Furthermore, there appeared to be a relationship between the site of the injury and the site of initial symptoms, particularly in patients who developed symptoms within a week of injury. We do not find this evidence convincing, particularly when given as an explanation for a large number of attacks. Other forms of trauma (including lumbar puncture and general surgical procedures) that occur after the onset of the neurologic disorder have not been shown to have an adverse effect on the course of the illness. Matthews, who has extensive personal experience with survivors of penetrating head wounds, did not find a single instance of MS among them. One of the most meaningful prospective studies of the relation of physical injury to MS is that of Sibley and colleagues, who followed 170 MS patients and 134 controls for an average of 5 years, during which they recorded all (1,407) instances of trauma and measured their effects on exacerbation rate and progression of the disease. With the possible exception of a case or two of electrical injury, there was no correlation between traumatic episodes and exacerbations. The current authoritative view on this subject is that the coincidence of trauma and new or exacerbated MS is incidental.
Certain other epidemiologic data have a bearing on this subject. There are, in the United States, 250,000 to 350,000 cases of physician-diagnosed MS (Anderson et al). Also, a study from the National Center for Health Statistics has determined that trauma sufficiently severe to be recalled at a periodic health examination occurs in one-third of the population of the United States (some 83 million persons) each year. Moreover, MS patients suffer physical injuries two or three times more often than normal persons (Sibley et al). In light of these data, it is perhaps not surprising that a traumatic event and an exacerbation should sometimes coincide, quite by chance.
Issues related to MS and pregnancy are addressed in a later section.
Balo and Schilder Diseases
The concentric sclerosis of Balo has as its distinguishing feature the occurrence of alternating bands of destruction and preservation of myelin in a series of concentric rings that represent alternating areas of myelin loss, and preservation. The configuration of lesions in this pattern suggests the centrifugal diffusion of some factor that is damaging to myelin. While usually a part of an acute illness, a similar pattern of lesions, although less extensive, is seen in occasional cases of chronic relapsing MS. Some studies have found a high incidence in the Philippines.
A related but confusing entity, which had been the subject of much discussion in the earlier part of the last century, is that of diffuse sclerosis, or Schilder disease. Exceptionally, the cerebrum is the site of diffuse and massive demyelination. Such cases are more frequent in childhood and adolescence than in adult life. Despite the undoubted occurrence of such cases, to call them "Schilder disease" is to refer to a clinical entity of ambiguous standing.
The term diffuse sclerosis was first used by Strümpell (1879) to describe the hard texture of the freshly removed brain of an alcoholic; later the term was applied to widespread cerebral gliosis of whatever cause. In 1912, Schilder described an instance of what he considered to be "diffuse sclerosis." The case was that of a 14-year-old girl with progressive mental deterioration and signs of increased intracranial pressure, terminating fatally after 19 weeks. Postmortem examination disclosed large, well-demarcated areas of demyelination in the white matter of both cerebral hemispheres, as well as a number of smaller demyelinating foci, resembling the common lesions of MS. Because of the similarities of the pathologic changes to those of MS (prominence of the inflammatory reaction and relative sparing of axons), Schilder called this disease encephalitis periaxialis diffusa, bringing it in line with encephalitis periaxialis scleroticans, a term that Marburg had used to describe a case of acute MS. Unfortunately, in subsequent publications, Schilder applied the same term to two other conditions of different types. One appears to have been a familial leukodystrophy (probably adrenoleukodystrophy) in a boy, and the other, quite unlike either of the first two cases, was suggestive of an infiltrative lymphoma. The last two reports seriously confused the subject, and for many years the terms Schilder disease and diffuse sclerosis were indiscriminately attached to quite different conditions.
If one sets aside the hereditary metabolic leukodystrophies and other childhood disorders of cerebral white matter, there remains a characteristic group of cases allied with multiple sclerosis that does, indeed, correspond to Schilder's original case description. They are most frequently encountered in children or young adults. As with the case reported by Ellison and Barron, the disease may follow the course of MS, either steady and unremitting or punctuated by a series of episodes of rapid worsening. The CSF may show changes similar to those in chronic relapsing MS. Death occurs in most patients within a few months or years, but some survive for a decade or longer. In the differential diagnosis, a diffuse cerebral neoplasm (gliomatosis or lymphoma), adrenoleukodystrophy, and progressive multifocal leukoencephalopathy (Chap. 33) are the main considerations. Histologically, the large single focus, as well as the smaller disseminated ones, shows the characteristic features of MS. These features were elaborated by Poser and colleagues in a subsequent (1986) review of this subject.
Multiple Sclerosis in Conjunction with Peripheral Neuropathy
From time to time there have been patients with MS who also have a polyneuropathy or mononeuropathy multiplex. This relationship always invites speculation and controversy especially as several autopsy cases have shown a coexistent demyelinating lesions in the central white matter and scattered in peripheral nerves but there are reasons for skepticism as vitamin deficiency polyneuropathy or multiple pressure palsies may be responsible. The rarity of the combination suggests a purely coincidental occurrence, perhaps with another underlying disease as an explanation (e.g., Lyme disease, AIDS). Another view, expressed by Thomas and colleagues and by Mendell et al, is that an autoimmune demyelination has been incited in both spinal cord and peripheral nerve, the latter taking the form of a chronic inflammatory polyradiculoneuropathy. Of course, radicular and neuropathic symptoms, motor and/or sensory, can result from the involvement of myelinated fibers in the root entry zone of the cord or fibers of exit in the ventral white matter. At the moment, we consider the two components to be most often different in origin.
Laboratory Findings in Typical Multiple Sclerosis
In about one-third of all MS patients, particularly those with an acute onset or an exacerbation, there may be a slight to moderate mononuclear pleocytosis (usually in the range of 6 to 20 and in any case, less than 50 cells/mm3). In rapidly progressive cases of neuromyelitis optica (see further on) and in certain instances of severe demyelinating disease of the brainstem, the total cell count may reach or exceed 100, and rarely in the hyper-acute cases 1,000, cells/mm3 and in the last of these processes, the greater proportion of cells may be polymorphonuclear leukocytes. This pleocytosis may in fact be the only measure of activity of the disease.
It has been shown that the gamma globulin proteins in the CSF of patients with MS are synthesized in the CNS (Tourtellotte and Booe) and that they migrate in agarose electrophoresis as abnormal discrete populations, called oligoclonal bands. This is currently the most widely used CSF test for the confirmation of the diagnosis. Determination for oligoclonal IgG bands will show several bands in the CSF in more than 90 percent of cases of MS. A lower proportion of patients in Asian countries demonstrate bands. Such bands also appear in the CSF of patients with syphilis, Lyme, and subacute sclerosing panencephalitis, disorders that should not be difficult to distinguish from MS on clinical grounds. The demonstration of oligoclonal bands in the CSF and not in the blood is particularly helpful in confirming the diagnosis of MS, but they are not always found with the first attack or even in the later stages of the disease. The presence of bands in a first attack of MS is predictive of a chronic relapsing course, according to Moulin and coworkers and others. Oligoclonal bands are usually reported as being present if there is more than one band; the meaning of a single band is not clear, and we have treated this result as a negative test. As will be pointed out, the conditions of necrotic myelopathy and Devic disease generally lack oligoclonal bands.
Also, in approximately 40 percent of patients, the total protein content of the CSF is increased. The increase is slight, however, and a concentration of more than 100 mg/dL is so unusual that the possibility of another diagnosis should be entertained. Less used as a diagnostic test currently is measurement of IgG and the IgG index in the CSF. The latter refers to proportion of gamma globulin (mainly IgG) in reference to the total protein in CSF; a positive test is considered to be greater than 12 percent of the total protein. The same diseases mentioned above as being associated with oligoclonal bands can also increase the IgG index.
It has also been shown, by the use of a sensitive radio-immunoassay, that the CSF of many patients contains high concentrations of MBP during acute exacerbations of MS and that these levels are lower or normal in slowly progressive MS and normal during remissions of the disease. Other lesions that destroy myelin (e.g., infarction) can also increase the level of MBP in the spinal fluid. Thus the assay is not particularly useful as a diagnostic test and probably simply reflects the destruction of central myelin.
When cells, total protein, gamma globulin, and oligoclonal bands are all taken into account, some abnormality of the spinal fluid will be found in the great majority of patients with established MS. At present, the oligoclonal bands in the CSF is the most widely used of the CSF tests for MS, particularly when taken some interval after an acute exacerbation or during the chronic progressive phase of disease. The more complicated laboratory procedures, such as CSF measurements of globulin production or MBP provide little additional sensitivity.
It is now widely appreciated that MRI is the most helpful ancillary examination in the diagnosis of MS, by virtue of its ability to reveal symptomatic and asymptomatic plaques in the cerebrum, brainstem, optic nerves, and spinal cord (Fig. 36-1). Most experience indicates that the incidence of lesions, if the cerebra and spinal cord are imaged, is greater than 90 percent in established cases of MS. It is remarkable that even when there are a multitude of cerebral lesions, they tend to be asymptomatic; by contrast, spinal cord lesions are almost always symptomatic.
Several MRI features are characteristic of the MS lesion. In general, MS plaques are hyperintense (white) on T2-weighted images and even more obvious on T2 fluid-attenuated inversion recovery (T2-FLAIR) images. The T2 sequence is particularly sensitive in detecting lesions in the brainstem, cerebellum, and spinal cord. Acute lesions tend to demonstrate tissue expansion due to edema that is evident as T1 hypointensity and T2 hyperintensity. Chronic lesions, in distinction, are usually contracted and hyperintense on T2 sequences. The presence of T1 hypointensity depends on the extent of remyelination of the lesion. If there is no or scant remyelination, the center of the chronic lesion gives the appearance of a "black hole." As assessed histologically with both autopsy and MRI studies, T1 hypointensity was inversely proportional to the degree of remyelination (Barkhof et al).
The individual cerebral lesions on MRI do not always ensure the diagnosis of MS, but the finding of multifocal, well-demarcated, oval or linear, radially oriented lesions adjacent to the ventricular surface usually denotes the typical relapsing-remitting form of MS. When viewed in sagittal images, they extend from the corpus callosum in a filiform pattern and have been termed "Dawson fingers." The radial orientation of these lesions corresponds to the course of venules embedded within the cerebral white matter. In addition to these periventricular lesions, subcortical and infratentorial lesions are frequently seen, most often in white matter tracts such as the cerebral and cerebellar peduncles and the medial longitudinal fasciculus. Lesions in MS do not conform to cerebral vascular territories and lack the wedge shape of typical embolic cerebral infarctions. Further assisting in distinguishing an MS lesion from an infarction, diffusivity in MS is variable.
Early in the evolution of an MS lesion, there is disruption of the blood–brain barrier, presumably as a consequence of inflammation. The MRI correlate of this inflammation is abnormal T1 hyperintensity (enhancement) following the administration of gadolinium. Gadolinium enhancement, may last for many weeks. One characteristic pattern is of a C-shaped partial or open ring of abnormal enhancement; which assists in differentiation a MS lesion from other lesions such as abscess and neoplasm. The open segment of the ring is most often medially situated. Many of these imaging characteristics are listed in Table 2-3 and displayed in Fig. 36-1.
In advanced cases of MS, the periventricular lesions may become confluent, usually at the poles of the ventricles. Infrequently, a large acute lesion may have a mass effect and a ring-like contrast-enhancing border, then resembling a glioblastoma or an infarct—the previously referred to "tumefactive" lesion (see Fig. 36-2).
As discussed below, in recent criteria for diagnosis, and in keeping with the traditional notion of MS as a disease that is "disseminated in time and space," the MRI is invaluable for demonstrating asymptomatic lesions. It is the discovery of these additional lesions in a patient with a single clinical episode that can establish the diagnosis of MS. Similarly, the unsuspected diagnosis of MS may be revealed on a single MRI by detecting one or more acute (enhancing) lesions with additional non-enhancing ones. Some of these asymptomatic lesions may be found in the spinal cord as discussed by Bot and colleagues. Furthermore, serial MRIs showing accumulating T2 hyperintense lesions over time are consistent with the diagnosis. As with other laboratory procedures, MRI changes assume maximal significance when they are consistent with the clinical findings.
Less evident than the focal lesions of MS is the progressive cerebral atrophy that accompanies most cases. This change probably reflects both the loss of glial cells and, importantly, wallerian degeneration and loss of axons triggered acutely by inflammation and more chronically by other neurodegenerative stimuli (Miller et al, 2002). Several studies document that slowly progressive brain atrophy, as gauged by volumetric MRI measurements of the cortical mantle, deep nuclei, and white matter, is a feature of MS. This is demonstrable both early and late in the disease and correlates particularly with cognitive disability.
The spinal lesions of MS occupy only a portion of the transverse surface of the cord, most commonly being situated in white matter tracts in a subpial location. The lesions infrequently extend longitudinally beyond three contiguous vertebral segments (Fig. 36-1), in contrast to those of neuromyelitis optica as discussed further on. As described above, acute lesions may cause focal expansion of the cord and enhance with contrast, while chronic lesions tend to produce atrophy.
It should be stressed that foci of periventricular T2 hyperintensity are observed with a variety of pathologic processes and even in normal persons, particularly older ones. Unlike the lesions of MS, these periventricular lesions are usually oriented parallel to the ventricular surfaces, are smoother in outline than the lesions of MS, and have been attributed to microvascular changes as discussed in Chapter 34. The same lack of specificity of cerebral lesions pertains to those in the spinal cord.
CT may also demonstrate cerebral lesions, sometimes unexpectedly, but with far less sensitivity than MRI. Two points worth noting about the CT are that acute plaques can appear as contrast-enhanced ring lesions, simulating abscess or tumor, and that some contrast-enhanced periventricular lesions become radiologically inevident after steroid treatment.
Evoked Potentials and Other Tests
When the clinical data point to only one lesion in the CNS, as often happens in the early stages of the disease or in the spinal form, a number of other sensitive physiologic and radiologic tests may establish the existence of additional asymptomatic lesions. These include visual, auditory, and somatosensory-evoked responses and the less standardized and infrequently tested perceptual delay on visual stimulation; electrooculography; altered blink reflexes; and a change in flicker fusion of visual images. Abnormalities of visual evoked responses have been found in approximately 70 percent of patients with the clinical features of definite MS and 60 percent of patients with probable or possible MS. The corresponding figures for somatosensory evoked responses have been 60 percent and 40 percent, and for brainstem auditory evoked responses (usually prolonged interwave latency or decreased amplitude of wave 5), approximately 40 percent and 20 percent, respectively (see Chap. 2). These tests had been used with greater frequency in the past and have been largely supplanted by MRI to detect dispersed demyelinating lesions.
Optical coherence tomography (OCT) is a technique for creating two- and three-dimensional images of the optic nerve and retina. By using near-infrared interferometry, it displays axonal loss and thinning of the retina that assists in the evaluation of optic neuritis and subsequent optic atrophy. It is used mainly to follow the course of optic neuritis.
Whether tests for serum antibodies against oligodendrocytes and myelin have the predictive value remains to be seen. Berger and colleagues published provocative findings in which 23 percent of patients who lacked such antibodies had further attacks after their first one, whereas 95 percent of those who had both antibodies suffered a relapse. Attempts to reproduce these findings by Kuhle and colleagues did not meet with success and there is no serum test for multiple sclerosis that has proven consistent, nor is there a predictive test for relapse. The importance of anti-aquaporin (NMO) antibodies in Devic disease will be discussed further on.
Clinical Course and Prognosis
The intermittency of the clinical manifestations—the disease advancing in a series of attacks, each permitting remission—is perhaps the most important clinical attribute of most cases of MS. Some patients will have a complete clinical remission after the initial attack, or, there may be a series of exacerbations, each with complete remission; rarely, such exacerbations may be severe enough to have caused quadriplegia and pseudobulbar palsy. The average relapse rate is 0.3 to 0.4 attacks per year according to the calculations of McAlpine and Compston, but the interval between the opening symptom and the first relapse is highly variable. It occurred within 1 year in 30 percent of McAlpine's cases and within 2 years in another 20 percent. A further 20 percent relapsed in 5 to 9 years, and another 10 percent in 10 to 30 years. Not only the length of this interval is remarkable, but also the fact that the basic pathologic process can remain potentially active for such a long time.
Weinshenker and colleagues (1989), on the basis of observations in 1,099 MS patients over a 12-year period, have identified a number of features of the early clinical course that were predictive, in a general way, of the outcome of the illness. Perhaps not surprisingly, they found that a high degree of disability, as measured by the Kurtzke Disability Status Scale, was reached earlier in patients with a higher number of attacks, a shorter first interattack interval, and a shorter time to reach a state of moderate disability. Kurtzke had earlier reported that the feature most predictive of long-term disability was the degree of disability at 5 years from the first symptom. Confavreux and colleagues (2000) analyzed a cohort of 1,844 patients with multiple sclerosis and found, somewhat surprisingly, that relapses did not significantly influence the progression of irreversible disability. Furthermore, large population studies (Pittock et al 2004; Tremlett et al) have shown that many patients develop only mild disability after long follow-up (so-called benign MS). Regardless of the age of onset, approximately 20 percent of patients do not become disabled, even after many decades of illness. These data should inform the use of the long-term disease-modifying therapies discussed in a later section but, as pointed out by Sayao and colleagues, reliable criteria for identifying patients who are destined to accumulate minimal or no disability are not available but are being sought.
After a number of years there is an increasing tendency for the patient to enter a phase of slow, steady, or fluctuating deterioration of neurologic function, attributable to the cumulative effect of increasing numbers of lesions (secondary progressive MS as described in the introductory section). However, in approximately 10 percent of cases, the clinical course lacks periodic relapses and is almost evenly progressive from the beginning (primary progressive MS; see Thompson et al). In these latter cases, the disease usually takes the form of a chronic asymmetrical spastic paraparesis and probably represents the most frequent type of difficult to diagnose as MS. In Thompson's review of primary progressive MS, there was little change over time in the MRI findings, a negligible response to therapy, and a poor outcome. The frequency with which acute MS blends into the progressive variety has already been emphasized. (See earlier comments regarding the pathologic distinctions between types of MS.)
Pregnancy is typically associated with clinical stability or even with improvement (as it is in a number of autoimmune diseases). The average relapse rate in established cases declines in each trimester, reaching a level less than one-third of the expected rate by the third trimester. However, there appears to be an increased risk of exacerbations, up to twofold, in the first few months postpartum (Birk and Rudick). An extensive study of 269 pregnancies by Confavreux and colleagues (1998) established a rate of relapse of 0.7 per woman per year before pregnancy and rates of 0.5 in the first, 0.6 in the second, and 0.2 in the third trimester, the rate then increasing substantially to 1.2 in the first 3 months postpartum.
The duration of the disease is exceedingly variable. A small number of patients die within several months or years of the onset, but the average duration of the illness is in excess of 30 years. A 60-year appraisal of the resident population of Rochester, Minnesota, disclosed that 74 percent of patients with MS survived 25 years, as compared with 86 percent of the general population. At the end of 25 years, one-third of the surviving patients were still working and two-thirds were still ambulatory (Percy et al). Other statistical analyses have given a less optimistic prognosis; these were reviewed by Matthews. Patients with mild and quiescent forms of the disease are, of course, less likely to be included in such surveys. Although exceptional, one of our patients relapsed and developed massive brainstem demyelination and coma after 30 years (confirmed by postmortem examination) and cases of an aggressive myelopathy that appears after years are well known.
No environmental, dietary, or activity-related changes are known to alter the course of the illness.
In the usual forms of MS—that is, in those with a relapsing and remitting course and evidence of disseminated lesions in the CNS—the diagnosis is rarely in doubt. Vascular malformations such as cavernous angiomas of the brainstem or spinal cord with multiple episodes of bleeding, brain lymphoma, lupus erythematosus, the antiphospholipid antibody syndrome, and Behçet disease all may simulate relapsing MS, and each has its own characteristic and diagnostic features. The list can be expanded by the inclusion of corticosteroid-responsive intravascular lymphoma and the other numerous causes of multiple, well-demarcated white matter abnormalities on MRI, such as embolic infarcts, progressive multifocal leukoencephalopathy, migraine-associated white matter lesions, Lyme disease, sarcoidosis, and tumors. Difficulties are most likely to arise when the standard clinical criteria for the diagnosis of MS are lacking, as occurs in the acute initial attack of the disease and in cases with an insidious onset and slow, steady progression. Other features that call for caution in diagnosis of MS are an absence of symptoms and signs of optic neuritis, the presence of widespread amyotrophy, entirely normal eye movements, a hemianopic field defect, pain as the predominant symptom, or a progressive nonremitting illness that begins in youth. Other points against MS are fever and nonneurologic features such as joint inflammation, skin rash, sicca syndrome, or evidence of peripheral neuropathy. The differentiation from Devic disease is discussed further on.
As has been stated, the initial attack of MS may mimic acute labyrinthine vertigo or tic douloureux (trigeminal neuralgia). Careful neurologic examination of such patients usually discloses other signs of a brainstem lesion; the CSF examination may be particularly helpful in these circumstances. Extensive brainstem demyelination of subacute evolution, involving tracts and cranial nerves sequentially, may be mistaken for a pontine glioma. With brainstem symptoms of acute onset, there may be difficulty in distinguishing an MS plaque from a small infarction because of a basilar branch occlusion. In several patients who we have observed, recurrent bleeding from cavernous vascular malformations and small brainstem arteriovenous malformations simulated MS clinically. Only with MRI, visualization of blood products surrounding the small vascular lesions may the diagnosis be clarified. Sequential MRIs and the course of the illness usually settle the matter.
Acute disseminated encephalomyelitis (ADEM; see further on) is an acute illness with widely scattered small demyelinating lesions but it is self-limited and monophasic. Furthermore, fever, stupor, and coma, which are characteristic of severe cases, rarely occur in MS. The encephalomyelitis may, however, progress for several weeks, making the distinction from MS difficult.
White Matter Lesions Associated with Systemic Autoimmune and Inflammatory Diseases
In systemic lupus erythematosus and less often in other autoimmune diseases (mixed connective tissue disease, Sjögren syndrome, scleroderma) there may be multiple lesions of the CNS white matter. These may parallel the activity of the underlying immune disease or the level of autoantibodies, particularly those against native DNA or phospholipids but myelitis or lesions in the cerebral hemispheres are known to occur before other organ systems are affected. Conversely, between 5 and 10 percent of MS patients have antinuclear or anti-double stranded DNA antibodies without signs of lupus, but the significance of this finding is not at all clear. In addition, as discussed in the introductory section relatives of patients with MS in some series have a higher than expected incidence of autoantibodies of various types, suggesting an as yet unproved connection between systemic autoimmune disease and MS.
On MRI, the lesions of lupus and of antiphospholipid antibody syndrome appear similar to plaques, and both the optic nerve (rarely) and the spinal cord may be involved, even repeatedly, in a succession of attacks resembling MS. The lesions may be small and single, multiple, or confluent in large regions (Akasbi). Nevertheless some of the lesions represent small zones of infarct necrosis rather than demyelination and are traceable to small-vessel occlusion. Others may be autoimmune and demyelinating and this group of processes that affect the cerebral white matter remains difficult to understand. In a few instances, inflammatory demyelination without vascular changes may be seen. It is best for the moment to consider these as special manifestations of lupus or related diseases that mimic MS. The neurologist should be cautious in initiating some of the treatments for MS, such as β-interferon, as they may worsen the systemic autoimmune illness.
Periarteritis nodosa or vasculitis confined to the nervous system may produce multifocal lesions simulating MS. The distinction may be particularly difficult in rare instances of the vasculitic process in which the neurologic manifestations take the form of a relapsing or steroid-responsive myelitis. In these cases, the CSF may contain 100 or more white blood cells/mm3 and there may be no evidence of disease elsewhere in the nervous system. Occasionally, a young person with Lyme disease may have complaints of inordinate fatigue and vague neurologic symptoms coupled with hyperintense lesions on the T2-weighted cranial MRI. Close attention to the characteristic history (rash, arthritis, etc.) and serologic findings permit the distinction between MS and systemic diseases. The distinguishing features of Behçet disease are recurrent iridocyclitis and meningitis, mucous membrane ulcers of mouth and genitalia, and symptoms of articular, renal, lung, and multifocal cerebral disease. The chronic forms of brucellosis in the Mediterranean regions and Lyme borreliosis throughout North America and Europe may cause myelopathy or encephalopathy with multiple white matter lesions on imaging studies, but in each case the history and other features of the disease help to identify the infectious illness (see Chap. 32).
Spinal Multiple Sclerosis
The purely spinal form of MS, presenting as a progressive spastic paraparesis, hemiparesis, or, in several of our cases, spastic monoparesis of a leg with varying degrees of posterior column involvement, is a special source of diagnostic difficulty. A tendency to affect older women has already been mentioned. Such patients require careful evaluation for the presence of spinal cord compression from neoplasm or cervical spondylosis. Dural arteriovenous fistula is also a consideration as mentioned below. Radicular pain at some point in the illness is a frequent manifestation of these disorders and is much less frequent in MS. Pain in the neck, restricted mobility of the cervical spine, and severe muscle wasting as a result of spinal root involvement, as is sometimes seen in spondylosis, are almost unknown in MS. However, atrophy of the first dorsal interosseus muscles, a frequent finding in spondylosis, is also in MS. As a general rule, loss of abdominal reflexes, erectile dysfunction, and disturbances of bladder function occur early in the course of demyelinating myelopathy but late or not at all in cervical spondylosis. The CSF protein in cervical spondylosis is often elevated, but oligoclonal bands and elevated IgG are not found.
A special problem arises when imaging procedures reveal a regional swelling of the spinal cord suggestive of a tumor. In a patient with this finding and a subacute, saltatory myelopathy restricted to several adjacent levels (usually thoracic), a search for an arteriovenous malformation or fistula may be required. In several of our patients, this finding has led to an ill-advised attempt at spinal cord biopsy. Sarcoidosis affecting the cord presents similar problems; steroid-responsive granulomatous lesions of sarcoid that follow a venous pattern in the cerebrum may cause confusion with MS when viewed by MRI. A subpial pattern of enhancement with gadolinium is helpful in identifying sarcoid.
The problem of differentiating chronic spinal MS from tropical spastic paraparesis (human lymphotropic virus, myelitis of the HTLV-1 type) and progressive familial spastic paraplegia may also arise occasionally. Amyotrophic lateral sclerosis (ALS) and subacute combined degeneration (SCD) may be confused with MS, but ALS can be identified by the presence of muscle wasting, fasciculations, and the absence of sensory involvement, whereas SCD is characterized by symmetrical involvement of the posterior and then lateral columns of the spinal cord. Reports that vitamin B12 levels are marginally low in a proportion of MS patients have suggested an underlying disturbance of homocysteine metabolism but this has not been confirmed (Vrethem et al).
Platybasia and basilar impression of the skull should also be considered in the differential diagnosis, but patients with these conditions usually have a characteristic shortening of the neck; images of the base of the skull are diagnostic. Neurologic syndromes resulting from the Chiari malformation, syringomyelia, rheumatoid destruction of the upper cervical segments, and tumors of the foramen magnum, cerebellopontine angle, clivus, and other parts of the posterior fossa have been misdiagnosed clinically as MS. In each of these instances, a solitary, strategically placed lesion may give rise to a variety of neurologic symptoms and signs referable to the lower brainstem and cranial nerves, cerebellum, and upper cervical cord, giving the impression of dissemination of lesions. It is a dependable clinical dictum that a diagnosis of MS should be made with caution when all of the patient's symptoms and signs can be explained by a single lesion in one region of the neuraxis.
Occasionally, the chronic progressive form of MS may be confused with the hereditary ataxias, particularly the spinocerebellar types. The latter are generally distinguished by their familial incidence and other associated genetic traits; by their insidious onset and slow, steady progression; and by their relative symmetry and stereotyped clinical pattern. Intactness of abdominal reflexes and sphincter function and the presence of pes cavus, kyphoscoliosis, and cardiac disease are other features that favor the diagnosis of a heredodegenerative disorder (see Chap. 39).
Treatment of Multiple Sclerosis
As one might expect, numerous forms of treatment have been proposed over the years, and many were thought to be successful, no doubt because of the remitting nature of the disease. The many therapeutic trials of recent years, using mainly anti-inflammatory and immunosuppressive are summarized below. Typical relapsing-remitting MS that is associated with episodic inflammation is most responsive to immunomodulatory therapy; on the other hand, these measures may be ineffective for chronic progressive subtypes. Therefore, as discussed earlier, therapy should be guided by the nature of the disease in each individual and with consideration of the side effects and risks of each of the expanding group of available therapies. A current list of clinical trials is maintained by the National Multiple Sclerosis Society: http://www.nationalmssociety.org/research/clinical-trials/clinical-trials-in-ms/index.aspx
Although many writers on the subject indicate that virtually all patients with proven MS should be treated soon after the diagnosis is established, the long-term effects on the illness still remain to be clarified. From the numerous studies cited below, a concept has emerged that subclinical lesions may be of importance and that, over time, cognitive decline and neurologic deficits are more likely to occur if progression is not reduced by treatment. There are few circumstances where such treatment is mandated immediately, and we allow enough time for the patient to consider the alternatives and sometimes encourage serial examinations and MRI to determine the course of illness. With all of these treatments it should be acknowledged that there is no certain correlation between the number of relapses and the ultimate disability despite authoritative statements to the contrary (as expressed by Confavreux et al ).
Under the influence of corticosteroids, recovery from an acute attack, including an attack of optic neuritis, appears to be hastened. However, a substantial group of patients with acute exacerbations fails to respond; in others, benefit is not apparent for a month or longer after the course of treatment has been completed and therefore may reflect the natural course of disease. There is no evidence that steroids have a significant effect on the ultimate course of this disease or that they prevent recurrences. Accordingly, there is limited justification for steroid treatment over a period of many months or years except in those infrequent cases where withdrawal of the medication consistently leads to relapse (alternative diagnoses should be considered in this event). In a study of intravenous methylprednisolone administered at 1 g/d for 5 days per month over 5 years, there was a reduction in disability as well as in the degree of brain atrophy and total volume of hypodense lesions on T1-weighted MRI (Zivadinov et al).
As to the dosage of corticosteroids for an acute attack, it seems that initially a high dose is more effective but this has been disputed, as noted below. A randomized trial comparing oral and intravenous methylprednisolone in acute relapses of MS demonstrated no clear advantage of the intravenous regimen (Barnes et al), but many MS experts dispute this finding. The administration of adrenocorticotropic hormone (ACTH), which was popular during the 1970s, has been abandoned.
The intravenous administration of massive doses of methylprednisolone (a bolus of 500 to 1,000 mg daily for 3 to 5 days) followed by high oral doses of prednisone (beginning with 60 to 80 mg daily and tapering to a lower dosage over a 12- to 20-day period) is generally effective in aborting or shortening an acute or subacute exacerbation of MS or of optic neuritis. Whether the tapering oral course is necessary is unclear. When it is impractical to administer parenteral methylprednisolone, one may substitute oral methylprednisolone (48 mg in a single daily dose for 1 week, followed by 24 mg daily for 1 week, and finally 12 mg daily for 1 week) or the equivalent amount of prednisone (Barnes et al).
A brief period of corticosteroid administration generally produces few adverse effects but some patients complain of insomnia and a few will develop depressive or manic symptoms. Patients who, because of clinical relapse on withdrawal of the medication, require oral treatment for more than several weeks are subject to the effects of hypercortisolism, including the facial and truncal cosmetic changes of Cushing syndrome, hypertension, hyperglycemia and erratic diabetic control, osteoporosis, avascular necrosis of the head of the femur, and cataracts; less often, there may be gastrointestinal hemorrhage and activation of tuberculosis or pneumocystis. It must be acknowledged that the corticosteroid regimens and dosages in common use are derived from anecdotal experience (the Optic Neuritis Treatment Trial being an exception) and that certain patients appear, at least for a period of time, to respond better to one or another method of treatment.
As mentioned under "Acute Disseminated Encephalomyelitis (ADEM)," there may be a role for plasma exchange (see Weinshenker et al, 1999; Rodriguez et al) and perhaps immunoglobulin in fulminant cases, but these have not been tested rigorously. One limited trial has shown some benefit, in patients with relapsing–remitting disease, of monthly infusions of intravenous immunoglobulin (0.2 g/kg) for 2 years (Fazekas et al).
Treatment of Optic Neuritis (see Chap. 13)
The Optic Neuritis Treatment Trial, reported by Beck and colleagues, cautioned against the use of oral prednisone in the treatment of acute optic neuritis (see also Lessell). In this study, it was found that the use of intravenous methylprednisolone followed by oral prednisone did, indeed, speed the recovery from visual loss, although at 6 months there was little difference between patients treated in this way and those treated with placebo. They reported that treatment with oral prednisone alone slightly increased the risk of new episodes of optic neuritis. In a subsequent randomized trial conducted by Sellebjerg and colleagues, it was found that methylprednisolone 500 mg orally for 5 days had a beneficial effect on visual function at 1 and 3 weeks. However, at 8 weeks, no effect could be shown (compared with the placebo-treated group), nor was there an effect on the subsequent relapse rate.
Interferon and glatiramer modestly alter the natural history relapsing-remitting MS. IFN-β-1b, a nonglycosylated bacterial cell product with an amino acid sequence identical to that of natural IFN-β, was the first of these agents to be tested (Arnason). Several trials have shown that the subcutaneous injection of this agent every second day for up to 5 years decreases the frequency and severity of relapses by almost one-third and also the number of new or enlarging lesions ("lesion burden") in serial MRIs. A large-scale trial European Study Group, (PRISMS Study Group) has extended the observations with IFN-β-1b to patients with the secondarily progressive type of MS; progression of the disease was delayed for 9 to 12 months in a study period of 2 to 3 years. The treatment of relapsing–remitting MS with IFN-β-1a is probably equally effective but was tested in a once weekly intramuscular regimen, making direct comparisons to the -1b preparation difficult. The dose currently used is 30 mcg, or 6.6 million units.
One issue with the longer term administration of interferon is the development of antibodies to the drug. The rate of such antibody emergence increases with the frequency of use of interferon. After a period of years, 30 percent of patients demonstrate antibodies with daily administration, 18 percent with alternate-day use, and less than 5 percent with weekly use. More recent changes in the preparation of interferon have led to reported rates of only 2 percent with antibodies after 1 year of use. There is some evidence that the presence of these antidrug antibodies diminishes the effectiveness of interferon.
Overall, the side effects of these interferon agents are modest, consisting mainly of flu-like symptoms, sweating, and malaise beginning several hours after the injection and persisting for up to 14 h; they are reduced by pre- and post-treatment with nonsteroidal anti-inflammatory drugs and tend to abate with continued use of the agents. In severe cases, prednisone 10 mg taken an hour before, a few hours after, and again 6 to 8 hours after injection may be effective. Nevertheless, some patients cannot tolerate interferon. A few migraineurs complain of exacerbation of their headaches. There may also be a tendency to depression in susceptible patients treated with interferon, and in our experience, this information, when openly discussed with the patient, has sometimes influenced the decision regarding choice of treatment. A rare but notable problem is the induction of a "systemic capillary leak syndrome" in patients with a monoclonal gammopathy who receive interferon. With more than weekly use, there may be an increase in liver function enzymes.
The need to treat patients with optic neuritis alone with interferon has not been satisfactorily resolved. We have generally avoided this approach except in a few patients with repeated episodes involving both eyes at various times. Some guidance is given by the Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS), which examined the effect of interferon (weekly) in patients with a first episode of optic neuritis and at least two lesions on MRI that were compatible with MS. Over 3 years, there was a modest reduction in clinical progression or relapse from 37 percent to 28 percent; if further MRI lesions were used as evidence of clinical progression, the difference from placebo treatment was even greater. If nothing else, this points to the value of a cerebral MRI in patients who have their first optic attack.
Copolymer I (glatiramer acetate), which was synthesized to mimic the actions of myelin basic protein, a putative autoantigen in MS, is given daily in subcutaneous doses of 20 mg. Antibodies do not develop to glatiramer, and this has been emphasized as a relative advantage of the drug. The salutary effects of treatment are definite though limited. Patients receiving glatiramer acetate should be warned of a reaction consisting of flushing, chest tightness, dyspnea, palpitations, and severe anxiety. Injection site reactions occur with both classes of drugs but are rarely troublesome if the sites are rotated. Trials that combine interferon and glatiramer have not produced benefit over either agent alone (Lublin and colleagues).
Conventional Immunosuppressive Drugs
A number of agents that modify immune reactivity have been tried with, until recently, limited success. Drugs such as azathioprine and cyclophosphamide, as well as total lymphoid irradiation and bone marrow transplantation, have been given to small groups of patients and seem to have improved the clinical course of some (Aimard et al; Hauser et al, 1983; Cook et al). However, the risks of prolonged use of immunosuppressive drugs, including a chance of neoplastic change and infection, will probably preclude their widespread use. The study by the British and Dutch Multiple Sclerosis Azathioprine Trial Group attributed no significant advantage to treatment with this drug.
For the chronic, progressive phase of the disease, an MS study group has reported a modest delay in the advance of the disease after a 2-year trial of prednisolone and cyclophosphamide. The group cautions, however, that the "burdensome and potentially serious toxicity must temper consideration of its use in this disease." At least one subsequent blinded, placebo-controlled study with cyclophosphamide has failed to show any benefit but many groups continue to use it for recalcitrant and severe acute cases. In one trial involving patients with chronic progressive MS, weekly low-dose oral methotrexate resulted in slight improvement difference and produced some reduction in the volume of cerebral lesions on the MRI compared with control cases (Goodkin et al, 1996). Because this regimen is well tolerated, it may still have some use in otherwise untreatable progressive cases. Among these more aggressive agents, mitoxantrone, a drug with broad immunosuppressant and cytotoxic activity, has attracted interest because one study has shown a slight beneficial effect on the progressive form of the disease (Hartung et al). Some have disputed the interpretation of these results; additionally, there is little effect on the number of MRI lesions. Mycophenolate and similar drugs have been tried with varying success.
These drugs, as a class, are being used less frequently, particularly as new oral agents become available.
One novel approach to treatment has been the use of monoclonal antibodies to various components of the inflammatory response. Natalizumab is directed against alpha-integrin in order to block lymphocyte and monocyte adhesion to endothelial cells and their migration through the vessel wall. It has been used in rheumatoid arthritis and fistulizing Crohn disease. In a study that ran for 6 months, Miller and colleagues (2003) were able to demonstrate a reduction in the number of relapses and a slowing of the accumulation of MRI lesions. A double-blind, placebo-controlled study of 942 patients with relapsing–remitting MS (Polman et al; the AFFIRM study) showed a 68 percent reduction in relapses, an 80 percent reduction in new or enlarging T2 cerebral lesions and a 96 percent reduction in gadolinium-enhancing lesions on MRI after a year. This represents a twofold improvement in efficacy compared to what has been reported with interferon and glatiramer acetate. There was a 2 percent rate of anaphylactic reactions. Another study suggested that the use of interferon and natalizumab may give better results (Rudick et al, 2006; the SENTINEL study) but these two are no longer combined in practice.
The advantages of this drug are once monthly intravenous treatment and a virtual lack of acute side effects. However, the appearance of cases of progressive multifocal leukoencephalopathy (PML as discussed in Chap. 33) has led to a restriction on its use. As of the time just prior to this writing, there were over 300 cases of PML recorded in relation to the use natalizumab for MS. Programs are in place to facilitate the early detection of PML since recovery may be possible if the drug is stopped promptly and removed by plasma exchange. However, the methods to detect the infection and to predict which patients will become symptomatic are imperfect. It can be stated that the absence of both JC virus in the urine and of serum antibodies to JC virus makes it very unlikely that PML will occur but there still may be rare cases. In those who have anti-JC virus antibodies, the risk is dependent on the duration of use of natalizumab (particularly if over 24 months) and the prior or concurrent use of other immunosuppressive medications. With both of these factors present, the risk of PML is approximately 11 per 1000 patients (Bloomgren et al).
One remarkable observation has been that the use of plasma exchange to rapidly clear natalizumab has reversed PML and led to disappearance of JC virus from the cerebrospinal fluid. There may be an immune reconstitution inflammatory syndrome (IRIS) soon after the exchanges, which may be ameliorated by corticosteroids (Wenning et al; Lindå et al). Some patients have survived PML using this approach, 71 percent in one series reported by Vermersch and colleagues, in distinction to the almost uniform fatality in other circumstances.
Alemtuzumab is a monoclonal antibody that targets CD-52 antigen expressed on T and B lymphocytes, reduces the number of circulating B cells and, for a longer period, T cells. It is used in an annual cycle of intravenous administration for 5 consecutive days. A randomized trial conducted over 36 months comparing the drug to interferon-β-1a found it to be superior in preventing relapses and in the accumulation of disability (CAMMS223 Trial Investigators). A series of subsequent trials have confirmed its effectiveness in comparison to interferon (Cohen et al). The drug can produce idiopathic thrombocytopenic purpura and autoimmune thyroiditis that results in either hyper- or hypothyroidism. At the time of this writing, it is being used in Europe but has not yet been approved in the United States.
Rituximab, a B-cell-depleting monoclonal antibody that targets CD20 lymphocytes, has been tested in several trials and found to be effective in reducing relapses and the accumulation of MRI lesions in a trial of relapsing–remitting cases over 4 years, but long-term safety is still being established (Hauser et al, 2008). Numerous other drugs in this class have been explored for MS with varying but generally positive results. The limiting factors have been infection, later development of lymphoma, and a number of effects that are particular to each drug. A similar anti-CD20 drug, ocrelizumab, is effective in reducing new MRI lesions (Kappos 2011).
Several novel oral agents have become available for the treatment of MS. Similar to the drugs described above, they each have particular idiosyncratic side effects, but it is patient preference in avoiding injections and infusions that is driving the development of this class.
One immunosuppressive drug that interferes with egress of lymphocytes from lymph nodes, fingolimod, has had a short-term effect on MRI lesion burden and relapse rate that is comparable or slightly superior to inject able agents in a randomized trial reported by Kappos and colleagues. The drug stands out because it is administered orally, once daily, and ostensibly has tolerable side effects. It causes a lymphopenia by restricting lymphocytes to the lymph nodes and causes adenopathy. Discontinuation of the drug is sometimes required because of extremes of bradycardia or atrioventricular block, macular edema, herpes infections and elevations in liver function tests, the last of these, in approximately 10 percent of patients.
Other oral drugs under study and in clinical use include: teriflunomide, laquinimod, cladribine, and dimethyl fumarate, not all of which have been accepted by various national drug approval agencies. The last of these has an interesting history and is perhaps notable because its mechanism of action in MS and psoriasis, the other main disease in which it is used, is not clear (Ropper 2012). Which of these orally administered drugs will be widely used remains to be determined.
Fatigue, a common complaint of MS patients, particularly in relation to acute attacks, responds to some extent to amantadine (100 mg morning and noon), modafinil (200 to 400 mg/d), or pemoline (20 to 75 mg each morning), methylphenidate, or dextroamphetamine. Confirmation of their benefit will be required before they come into general use. A number of agents exist that improve conduction through demyelinated central fibers and have been suggested as improving fatigue and gait (e.g., 4-aminopyridine).
Disorders of bladder function may raise serious problems in management. Where the major disorder is one of urinary retention, bethanechol chloride is helpful. In this situation, monitoring and reducing the residual urinary volume are important means of preventing infection; volumes up to 100 mL are generally well tolerated. Some patients with severe bladder dysfunction, particularly those with urinary retention, benefit from intermittent catheterization, which they can learn to do themselves and which lessens the constant risk of infection from an indwelling catheter. More often the problem is one of urinary urgency and frequency (spastic bladder), in which case the use of propantheline (Pro-Banthine) or oxybutynin (Ditropan) may serve to relax the detrusor muscle (Chap. 26). These drugs are best used intermittently. Severe constipation is best managed with properly spaced enemas. Often a program of bowel training can be successfully undertaken. Sexual dysfunction has been treated with sildenafil and similar drugs. When pain is a prominent symptom, its management follows the general principles of pain management outlined in Chap. 8. Carbamazepine or gabapentin are often helpful to reduce paroxysmal symptoms in MS.
In patients with severe spastic paralysis and painful flexor spasms of the legs, if local injection of botulinum toxin fails, oral and then intrathecal infusion of baclofen through an indwelling catheter and implanted pump, as in other spastic states, is sometimes of value. The selective injection of botulinum toxin into the most hypertonic muscles is an early resort. Patients with lesser degrees of spasticity have benefited from the oral administration of baclofen. An alternative to oral baclofen is tizanidine. Failing this measure, intrathecal baclofen infusion by pump may give relief for a prolonged period.
The severe and disabling tremor that is brought out by the slightest movement of the limbs, if unilateral, can be managed surgically by ventrolateral thalamotomy or implanted stimulator of the type used for the treatment of Parkinson disease. Most surgical series report that about two-thirds of patients achieve a satisfactory reduction in their intention tremor (Critchley and Richardson; Geny et al). In the experience of others, the results have not been quite this reliable. In the series of Hooper and Whittle, only 3 of 10 MS patients who underwent thalamotomy for a severe tremor had sustained improvement. Hallett and colleagues have reported that severe postural tremor of this type can be improved by the administration of isoniazid (300 mg daily, increased by weekly increments of 300 mg to a dose of 1,200 mg daily) in combination with 100 mg of pyridoxine daily. How isoniazid produces its beneficial effects is not known, and careful monitoring of liver tests is required. Variable success may also be achieved with carbamazepine or clonazepam. For the depression associated with the disease, there does not seem to be any superior antidepressant and donepezil has not been found to be helpful for cognitive problems.
There are no valid studies to substantiate claims that have been made for the value of synthetic polypeptides other than copolymer, for hyperbaric oxygen, low-fat and gluten-free diets, or linoleate supplementation of the diet. Necessary vaccinations are not prohibited in patients with MS.
The importance of an understanding and sympathetic physician in the care of patients with a chronic and potentially incapacitating neurologic disease that requires choices among many medications of this kind cannot be overemphasized. Enlisting the support of physical and occupational therapists, visiting nurses, and social workers can be equally important. From the beginning, when patients first inquire about the nature of their illness, they require advice about their daily routine, marriage, pregnancy, the use of drugs, inoculations, and so on. As indicated earlier, the term MS should not be introduced until the diagnosis is certain, and then it should be qualified by a balanced explanation of the symptoms, stressing always the optimistic aspects of the disease. Most patients desire an honest appraisal of their condition and prognosis; some consider the uncertainty of their prognosis worse than their actual disability.
Neuromyelitis Optica (Devic Disease, Necrotic Myelopathy) (See also Chap. 44)
This disease is characterized by a simultaneous or successive and usually severe involvement of optic nerves and spinal cord. The combination was remarked upon by Clifford Albutt in 1870, and Gault (1894), stimulated by his teacher Devic, devoted his thesis to the subject. Devic subsequently endeavored to crystallize medical thought about a condition that has come to be known as neuromyelitis optica. Its principal features are the acute to subacute onset of blindness in one or both eyes, preceded or followed within days or weeks by a severe transverse or ascending myelitis (Mandler et al, 1993). The singular modern insight in Devic disease has been the discovery by the group at the Mayo Clinic of a fairly specific circulating autoantibody to the aquaporin-4 water channel protein. After decades of debate, this has largely settled the controversy about Devic disease as an independent entity from MS.
In certain parts of the world, this form of aggressive and usually monophasic demyelinating disease is more common than is typical MS. The disease termed "Asian optic–spinal MS" almost certainly represents Devic disease and displays this antibody in the majority of cases. Most cases of neuromyelitis optica stand apart from MS by virtue of distinctive clinical and pathologic features, mainly, a failure to develop cerebral demyelinating lesions typical of MS even after years of illness; the absence of oligoclonal bands in the CSF; a tendency to CSF pleocytosis more so than in MS, and the necrotizing and cavitary nature of the spinal cord lesion, affecting white and gray matter alike with prominent thickening of vessels but with minimal inflammatory infiltrates. It is also quite unusual for MS to involve several contiguous longitudinal segments of the spinal cord, and this is a frequent finding in Devic disease (Fig. 36-3). It is not clear if events such as pregnancy that alter the course of MS have the same relationship to NMO (Bourre et al).
MRI of the spinal cord in neuromyelitis optica. Sagittal T2 image showing a hyperintense, longitudinally extensive, confluent cervico-thoracic lesion.
The spinal cord lesions in cases of neuromyelitis optica are often necrotizing, centrally located in the cord, and occupying several contiguous vertebral segments, leading eventually to cavitation. As would be expected, the clinical effects are more likely to be permanent than those of typical demyelination. A few affected patients have been children; in a number of instances, they have suffered only a single episode of neurologic illness. Despite the now clear distinction between Devic disease and MS, there remains a group of patients with the clinical syndrome of simultaneous or sequential optic neuritis and myelitis, who probably have the latter condition. The presence of the anti-aquaporin antibody (see below) and the MRI appearance of the cord lesion are able to differentiate most instances. In one memorable example, where hemiplegia and aphasia were followed within 2 weeks by a necrotizing myelitis from which there was no recovery, the patient later developed typical attacks of MS, including retrobulbar neuritis. Elsewhere in the brain and cord, the lesions were typically demyelinating.
Most compelling, the separation of Devic disease from MS is supported by evidence of a specific serum immunoglobulin (Ig) G antineural antibody directed against aquaporin-4, (NMO antibody) that binds complement. This has led to the conclusion that the Devic process is a humoral disease in contrast to the cellular mechanism that is proposed for MS (see Lucchinetti et al, 2002). Pittock and coworkers have explored the distribution of the antibody and found it to be located in astrocytic end feet adjacent to capillaries, pia, and Virchow-Robin spaces all in the periventricular region and surrounding the central canal of the spinal cord. This is concordant with the distribution of the lesions and many of the clinical characteristics such as the extensive myelitis but also unusual features such as vomiting and hiccoughs, which reflects damage in the area postrema.
Lennon and colleagues reported that the antibody is a marker for neuromyelitis optica in the majority of cases, and that it is virtually absent in MS. In the material of Wingerchuk and colleagues, the presence of the antibody was 76 percent sensitive and 94 percent specific. By using the additional criteria of the presence of two of the following, the sensitivity and specificity were 99 and 90 percent: longitudinally extensive myelopathy, positive antibodies and an initial MRI that is not characteristic for MS.
Occasionally, neuromyelitis optica occurs in the context of a connective tissue disease such as Sjögren syndrome or lupus, and many of these patients have this same circulating anti-aquaporin antibody. Pittock and colleagues (2008) give the frequency of these antibodies as approximately one-third in patients with systemic autoimmune disease and clinical features of Devic disease. It should also be noted that acute disseminated encephalomyelitis, discussed further on, may present as a neuromyelitis optica syndrome.
There is in addition to the myelitis described earlier a progressive and sometimes saltatory subacute necrotic myelopathy without optic neuritis that shares all the features of Devic disease but not the optic neuropathy and, in our view, they probably represent the same entity (Katz and Ropper). The differential diagnosis is broader and includes vascular malformations of the cord or dura and infarction or neoplasm of the cord. Also, a rare isolated vasculitis of the cord may cause a necrotic myelopathy; it is associated with an active CSF pleocytosis (Ropper et al). The cord in the cases we have studied was swollen on MRI in the early stages, often with edema extending many segments above and below the area of primary disease, and later became atrophic, similar to what has been reported in Devic disease. Up to 50 cells are typical in the CSF and the protein is elevated but the spinal fluid may be normal during periods of clinical stability. Several, but not all, of these cases have had positive NMO IgG antibodies (see above), further supporting the notion that most of these aggressive, purely spinal cases are allied with Devic disease.
The treatment of neuromyelitis optica and of subacute necrotic myelopathy has been largely unsuccessful, most cases progressing despite aggressive therapy, including high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, azathioprine, and cyclophosphamide. A study of several patients by Mandler and colleagues (1998) suggested that perhaps a combination of high-dose methylprednisolone and azathioprine led to clinical improvement; we cannot affirm this approach, but most other treatments have given poor results in our experience. Because a few individuals respond to them, it may be appropriate to try one or more of these therapies. A provocative approach that is being explored by Tradtrantip and colleagues is the use of blocking antibodies to the aquaporin antibody. A summary of treatment has been given by Collongues and de Seze.