MS is the most common disease caused by an inflammatory demyelinating process in the CNS. MS is a leading cause of disability in young adults (Noseworthy et al., 2000). Because MS has only a modest negative effect on longevity but potential for considerable disability over many years, the socioeconomic consequences are considerable. Pathologically, MS is characterized by multifocal areas of demyelination, axonal loss and disruption, loss of oligodendrocytes, and astroglial scarring. Certain clinical features are typical of MS, but the disease has a highly variable pace and many atypical forms. Investigative studies are often needed to confirm the diagnosis and exclude other possibilities. Understanding of the basic nature of the disease remains limited, and better control of the disease and repair of damaged CNS tissue remain goals for the future.

Pathophysiology

The symptoms and signs of MS are the manifestations of the pathological process seen in the CNS, namely demyelination and a moderate degree of axonal loss as evident from detailed pathological and advanced magnetic resonance imaging (MRI) techniques. A comparison of the physiological properties of normally myelinated axons and demyelinated axons provides insight into the basis for the symptoms and signs characteristic of MS.

Compacted myelin is the lipid-rich plasma membrane of oligodendrocytes that provides insulation for electrical impulses traveling along axons. Myelinated axons propagate nerve impulses rapidly in a saltatory fashion, with a high safety factor for transmission (five to seven times above threshold). Current is induced by the opening of voltage-gated Na⁺ channels found at the nodes of Ranvier. The resultant Na⁺ influx creates a current that then moves toward the next node of Ranvier because current cannot flow outward in myelinated internodal segments (Fig. 54.1). K⁺ channel opening terminates current flow and leads to repolarization. Several types of K⁺ channels exist in the axon. Fast K⁺ channels sensitive to 4-aminopyridine are located in internodal axonal membrane and contribute to repolarization of demyelinated axons. Slow K⁺ channels are found at the nodes of Ranvier and have a role in modulating repetitive firing. The Na⁺/K⁺-adenosine triphosphatase (ATPase) in the axon membrane restores ionic balance after high-frequency firing. Demyelination interrupts current flow by removing the insulator of internodal axon current flow. Long segments of demyelination can result in interruption of current flow because current must flow by continuous propagation. The low density of internodal Na⁺ channels, at least in the early stages of demyelination, inhibits impulse propagation. If conduction does occur, it is at a much-reduced speed (5% to 10% of normal). The refractory period of demyelinated axons is prolonged, and repetitive volleys may be blocked when encountering an axon segment in a refractory period. Persistent neurological deficits or negative symptoms of MS are caused by regions in which conduction block persists, such as in regions of large plaques, whereas transient worsening of function reflects a drop below the safety threshold for conduction because of physiological changes involving the partially demyelinated axon (Uhthoff phenomenon, worsening with increased body temperature). Symptoms or signs may also arise from slowed conduction, producing temporal dispersion at time-critical synapses. Further conduction block is absolute in transected axons.

Fig. 54.1 Schematic diagram of impulse conduction in normal (upper panel) and demyelinated (lower panel) regions of a nerve fiber. Solid arrow indicates the direction of impulse conduction; red area indicates the region occupied by the impulse. Current flow is indicated by broken arrows. In normally myelinated regions (upper), the high resistance, low capacitance directs the majority of action current to the next node of Ranvier. In contrast, in demyelinated regions (lower), action current is short-circuited through the damaged myelin sheath or denuded regions of the axon, so further propagation of the action potential is blocked.

(Reprinted with permission from Waxman, S.G., 1982. Membranes, myelin, and the pathophysiology of multiple sclerosis. N Engl Med 306, 1529-1533.)

Mechanical stimulation of demyelinated axons can generate de novo action potentials in the axon and may explain the Lhermitte phenomenon, electric shocklike sensations on flexing the neck. Spontaneous action potentials have been recorded from demyelinated axons and, if present in the CNS, could explain paroxysmal-positive symptoms of MS such as trigeminal neuralgia, myokymia, paraspinal muscle spasms, and visual phosphenes. In addition to structural changes, one must consider functional impairment of nerve transmission due to edema or soluble factors liberated by immunocompetent cells (cytokines, chemokines, adhesion molecules) in the plaque and periplaque regions that may be toxic to cells or axons. Rapid recovery of function may be caused by resolution of edema, pH changes, reduction of cellular infiltrates, and dissolution of cytokines, whereas more delayed recovery may reflect use of alternative neuronal pathways or an increase of internodal Na⁺ channels, and late recovery could reflect remyelination.

Pathology

The pathological hallmark of MS is the cerebral or spinal plaque, which consists of a discrete region of demyelination with relative preservation of axons, although spectroscopic and pathological studies suggest some axonal loss may be an integral part of the disease process.

Gross examination of the brain in MS often reveals atrophy and ventricular dilatation. Plaques may be visible on the surface of the spinal cord on inspection. The cut surface of the brain reveals the plaques, which when active, appear whitish yellow or pink with somewhat indistinct borders. Older plaques appear translucent with a blue-gray discoloration and sharply demarcated margins. Individual lesions are generally small (1-2 cm) but may become confluent, generating large plaques. Plaques develop in a perivenular distribution and are seen most frequently in the periventricular white matter, brainstem, and spinal cord (Figs. 54.2 and 54.3), a finding confirmed with MRI studies. However, large numbers of small plaques, often detected only by microscopy, are found in cortical regions affecting intracortical myelinated fibers. One of the earliest features of acute MS lesions is a disruption of the blood-brain barrier (BBB) as detected by MRI studies. Disruption of the BBB appears to be a critical early step in lesion pathogenesis. The BBB depends on tight junctions between brain endothelial cells. These junctions are not disrupted; rather, a transendothelial cell vesicular transport system will become active. It can carry water, proteins, antibodies, and cytokines (and gadolinium) into the brain.

Fig. 54.2 Coronal section of brain showing large plaques adjacent to lateral ventricles and temporal horns. A plaque is also seen in the left internal capsule (arrows) (Heidenhain myelin stain).

(Courtesy Dr. S. Carpenter.)

Fig. 54.3 Brainstem and spinal cord sections from patient with multiple sclerosis stained with Heidenhain myelin stain (A), Holzer stain for gliosis (B), and Bodian stain for axons (C). Note mirror image of myelin and Holzer stains in the pons. Also note dramatic demyelination of sacral cord with preserved myelin in nerve roots (A, bottom).

(Courtesy Dr. S. Carpenter.)

Histological examination of active plaques reveals perivascular infiltration of lymphocytes (predominantly T cells) and macrophages, with occasional plasma cells. In the plaque, myelin is disrupted, resulting in myelin debris found in clumps or within lipid-laden macrophages. Macrophages appear to have an integral role in stripping myelin lamellae from axons. Reactive astrocytes are prominent in plaques. Immunohistochemical studies have found increased levels of cytokines in active plaques, indicative of ongoing immunoreactivity.

The fate of oligodendroglia in MS lesions is disputed. Consensus is that oligodendroglia numbers are reduced proportionate to myelin loss in the plaque center, whereas at the plaque edge, oligodendroglia are preserved or even increased, suggesting an attempt at remyelination. The finding of shadow plaques (areas of thinly myelinated axons) supports the concept of central remyelination (Prineas et al., 2001), and oligodendroglial precursors have been found in the adult brain.

Remyelination may involve either oligodendrocytes that previously produced myelin or maturation of progenitor cells. Such remyelination may explain the clinical finding of slow and delayed recovery from an acute attack, whereas rapid clinical recovery presumably reflects the resolution of edema, inflammation, and removal of toxic factors associated with acute plaques in which myelin destruction is minimal. Recent pathological studies demonstrate that the extent of remyelination can be quite extensive, even in patients with progressive disease (Patrikios et al., 2006).

Evidence of recurrence of activity in old plaques may be demonstrated by gadolinium-enhanced MRI. Chronic demyelinated plaques could thus result not from a single severe episode of demyelination, but rather from recurrent bouts of demyelination at the same site (Prineas et al., 2001). This could eventually exceed the ability of oligodendroglia to remyelinate.

Data derived from biopsy as well as autopsy material (Lucchinetti et al., 2000) have emphasized the heterogeneity of the MS lesion. These investigators have described four distinct pathological patterns. Some lesions appear to be chiefly inflammatory (types I and II), with retention of active oligodendrocytes derived from identifiable precursor cells and evidence of remyelination. The most common pathological pattern seen (type II) had inflammatory infiltrates and deposition of complement and immunoglobulin (Ig)G. In other patients, extensive destruction of oligodendrocytes, little replacement, and closer resemblance to a viral or toxic cell apoptosis or necrosis was found (types III and IV) (Table 54.1). All active lesions from an individual patient were of the same type. The specific target of the immune-mediated injury in MS remains undetermined. A proportionate loss of oligodendroglia and myelin would imply a primary attack against either oligodendroglia or an antigen present on oligodendroglial cell bodies and myelin. Alternatively, myelin may be the primary target of disease, and the oligodendroglia may survive demyelination, at least in the initial stages of disease. The active lesions contain T lymphocytes and macrophages in the perivascular regions and parenchyma. Most of the T cells express the α/β T-cell receptor. Both CD4⁺ and CD8⁺ T cells are present. An apparent increase in CD8⁺ cells occurs in the CNS when compared with the prevalence of this subset in the peripheral blood. CD4⁺ cells extend from the periphery of active plaques into adjacent white matter, whereas CD8⁺ cells predominate in the perivascular regions. Some MS lesions also have an accumulation of T cells expressing the α/β T-cell receptor, which may mediate cytolysis of CNS cells expressing heat shock proteins.

Table 54.1 Pathologic Subtypes of Multiple Sclerosis

Among the lymphocytes are cells specifically sensitized to myelin antigens. Reports vary with regard to the extent of restriction and the precise profile of the T-cell receptor repertoire of CNS T cells. T-cell sensitization could occur via direct exposure to myelin antigens within the CNS or within cervical lymph nodes, a site to which CNS antigens are transported through draining, or via exposure to exogenous agents sharing antigenic determinants with myelin. The latter has been termed molecular mimicry. Microglial cells, endothelial cells, and astrocytes can be induced to express major histocompatibility complex (MHC) antigens and function as antigen-presenting cells, thus potentially promoting myelin antigen interaction with immune-mediating cells.

Activated T cells and the microglia-macrophages can contribute to tissue injury via non–antigen-restricted mechanisms. Each of these cell types releases an array of soluble factors that can contribute to tissue injury, including oligodendroglia. Cytokines characteristic of T cells include interleukin 2 (IL-2), interferon γ (IFN-γ), and tumor necrosis factor β (TNF-β; lymphotoxin). A shift toward T_H1 cells expressing IFN-γ, TNF, and IL-2 and away from T_H2 cells expressing IL-4, IL-5, IL-10, and IL-13 may be characteristic. Soluble factors released by macrophages and microglia include TNF-α, leukotrienes, thromboxanes, proteases, and complement components. Many of these immunologically active substances can result in up-regulation of adhesion molecules that can promote or facilitate nonspecific lymphocyte-macrophage migration to the site of immune injury and immune effector–target cell interactions.

B cells and Ig are also found in MS lesions. To date, no specific myelinotoxic antibody has been identified in MS, but antimyelin antibodies have been shown to enhance disease severity in the experimental allergic encephalomyelitis (EAE) model, suggesting that both cellular and humoral mechanisms may be needed for full expression of immune injury.

Chronic inactive plaques are hypocellular and show astrocytic proliferation with denuded axons and an absence of oligodendroglia (Figs. 54.4 and 54.5). Axonal loss also may be noted to a variable extent. Microglia and macrophages are scattered throughout the lesion. The edge of chronic plaques may still exhibit hypercellularity, suggesting continued disease activity.

Fig. 54.4 Punched-out appearance of old multiple sclerosis plaque surrounded by regions with varying amounts of myelin preservation (periodic acid-Schiff Luxol fast blue; bar = 100 µm).

(Courtesy Dr. S. Carpenter.)

Fig. 54.5 Plaque edge of old plaque with sharply demarcated zone of demyelination and normal myelin above (periodic acid-Schiff Luxol fast blue; bar = 50 µm).

(Courtesy Dr. S. Carpenter.)

Pathological differences are described between classical MS and disorders considered to be variants of the disease. Baló concentric sclerosis is characterized by alternating bands of myelinated and demyelinated fibers in white matter. Clinically, the illness is more fulminant in onset and course than typical MS and has a more inflammatory cerebrospinal fluid (CSF). Transitional forms exist with typical MS. The affected CNS structures in Devic neuromyelitis optica show more necrosis, cyst formation, and vascular proliferation than is seen in the usual MS case (Lucchinetti et al., 2002). Large tumor-like plaques found in the variant of MS known as Marburg variant may show extensive areas of inflammation and edema.

In secondary progressive MS (SPMS, defined later), ongoing low-grade demyelination was found at the borders of plaques, associated with C3d, an opsonin coupled with complement activation, and this profile may explain the slow expansion of plaques and occurrence of more diffuse inflammation leading to progressive loss of function (Kutzelnigg et al., 2005; Prineas et al., 2001).

Recent pathological studies have focused on the gray matter in MS and have found a lesion load within the cortex and deep gray structures. The nature of the intracortical plaques differs from those seen in white matter because there is less inflammation but considerable reactive microgliosis (Bo et al., 2003).

Etiology

Autoimmunity

Low levels of autoreactive T cells and B cells are present in normal individuals. Presumably they have escaped from clonal deletion during the process of immune development and are now tolerant of their antigens. Autoimmunity develops when these cells lose tolerance and a complex process of immune reactivity in target tissues begins. One potential way tolerance can be broken is by means of molecular mimicry between self-antigens and foreign antigens—for example, viral components. Several viral and bacterial peptides share structural similarities with important proteins of myelin, and a few of them are able to activate specific T-cell clones derived from patients with MS. Another way tolerance can be broken is by CNS infection that causes tissue damage and antigen release into the peripheral circulation, where corresponding autoreactive T cells may be encountered.

Myelin basic protein (MBP) has long been considered one of the primary candidates for an autoimmune attack. T cells that respond to MBP are found in the peripheral blood in both normal persons and those with MS, possibly at higher levels in MS patients with active disease. MBP, which accounts for 30% of the protein of myelin, can be an antigen for EAE, the primary animal model of MS. Recent clinical trials with altered peptide ligands of MBP support the potential pathogenic role of MBP-reactive T cells.

Several other myelin proteins are also candidates for an autoimmune attack. Proteolipid protein accounts for 50% of CNS myelin protein and is an integral membrane protein of the myelin leaflets. In the PNS, P0 protein fulfills this role. Myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein, and cyclic nucleotide phosphodiesterase are proteins that account for a few percent of myelin. Myelin oligodendrocyte glycoprotein and cyclic nucleotide phosphodiesterase are not found in peripheral nerve myelin and are therefore of interest because MS is a disease affecting only central myelin.

Although the possibility of autoimmunity as the causal mechanism for MS exists, the issue is not proven. The evidence for MS being a dysimmune condition is more compelling, with alterations in immune cell repertoire and activation state both in blood and CSF of MS patients compared to others (Conlon et al., 1999; Hafler et al., 2005).

Infection

A possible role for microbial infection in the causation of MS has been a matter of ongoing debate for decades. The epidemiology of MS (see Epidemiology in this chapter and in Chapter 39) suggests an exogenous or environmental factor. Beyond epidemiology and much speculation, little direct evidence supports the concept of a role for viral infection. Innumerable efforts to culture a virus from autopsy-derived or biopsy material have yielded no consistent result. Serological data are difficult to interpret, because titers may reflect only a nonspecific tendency toward increased immune reactivity. Specific efforts to recover a known viral genome (e.g., that of human T-cell lymphotropic virus type 1 [HTLV1]) have proven negative.

Human herpesvirus 6 (HHV6), Epstein-Barr virus (EBV), and Chlamydia pneumoniae have been the focus of interest as potential triggers for MS. Several studies of serum and CSF samples have yielded varying results. For example, one early study showed 47% of MS brains were positive for HHV6, and 80% showed elevation of antibodies in the serum. A more recent study found no HHV6 DNA in any CSF sample, and the serum antibody titers were comparable to the general population. High serum levels of EBV antibodies have also been associated with an increased risk of MS. The strongest association was found for antibodies to Epstein-Barr nuclear antigen (EBNA-2); a fourfold difference in titers was associated with increased relative risk (RR) of developing MS (Ascherio et al., 2001).

Epidemiology

The epidemiology (see Chapter 39) and genetics of MS are complex topics. The interested reader is referred to the articles by Dyment et al. (2004) and Kantarci and Wingerchuk (2006).

Age of Onset

Most studies agree that the mean and median age of onset in relapsing forms of MS is age 29 to 32. The peak age of onset is approximately 5 years earlier for women than for men. Primary progressive MS (PPMS) has a mean age of onset of 35 to 39 years. The onset of MS can occur as late as the seventh decade. Perhaps as many as 5% of cases of MS have their onset before age 18. Most of these cases occur in adolescents, but a small percentage begin in the first decade of life (Fig. 54.6).

Fig. 54.6 Age at onset of symptoms of multiple sclerosis in 940 patients followed at the multiple sclerosis clinic of the Montreal Neurological Institute. Mean age of onset is 30.6 years, median is 27 years, and peak incidence is 25 years.

Sex Distribution

Autoimmune diseases in general and MS in particular affect more women than men. In a summary of 30 incidence and prevalence studies, a cumulative ratio of female to male subjects was 1.77 : 1.00.

Mortality

Mortality due to MS is difficult to ascertain because of poor data collection and reporting. The U.S. Department of Health and Human Services report of deaths in the year 1992 indicates that 1900 U.S. citizens died of MS in that year, giving MS a U.S. mortality of 0.7 per 100,000. The mean age of death of all patients with MS was 58.1 years, compared with a national average of 70.5 years for all causes of death. The life expectancy of patients with MS was therefore calculated to be 82.5% of the normal lifespan. In Denmark, in an exceptionally complete survey of the country, median survival after diagnosis for men was 28 years and for women 33 years, compared with matched population death rates of 37 and 42 years, respectively. The life expectancy was 10 years shorter for MS patients than age-matched controls; this difference was becoming smaller when more recent data were studied (Bronnum-Hansen et al., 2004).

In another study, MS mortality figures were calculated for England and Wales for the years 1963-1990. Over this span of years, the death rate attributable to MS steadily and consistently declined compared with the overall death rate. Patients with MS tended to live longer, and other diseases were more likely to be the cause of death. Current estimates indicate that about half of the deaths in MS patients are directly due to the disease, slightly more than half if accidents and suicide are included as indirect causes.

Geographical and Racial Distribution

More than 250 prevalence surveys have been carried out, serving as the basis for the delineation of geographical risk for MS depicted in Fig. 54.7. High-frequency areas of the world, with current prevalence of 60 per 100,000 or more, include all of Europe (including Russia), southern Canada, the northern United States, New Zealand, and the southeastern portion of Australia. In many of these areas, the prevalence is more than 100 per 100,000, with the highest reported rate of 300 per 100,000 occurring in the Orkney Islands. In the United States, the prevalence when measured during the 1990s was approximately 350,000. Several studies suggest that the prevalence is increasing beyond what might occur because of enhanced recognition and better-appreciated diagnostic techniques.

Fig. 54.7 Worldwide distribution of multiple sclerosis as of 1980. High-frequency areas (>30 per 100,000 population) are orange, medium-frequency areas (5 to 25 per 100,000) are yellow, and low-frequency areas (<5 per 100,000) are green. Open areas are regions without data. South American frequencies are tentative. The low frequency in South Africa is for native South Africans, with medium frequency for persons of European stock native to South Africa.

(Reprinted with permission from Kurtzke, J.F., 1980. The geographical distribution of multiple sclerosis—an update with special reference to Europe and the Mediterranean region. Acta Neurol Scand 62, 65-80.

One possible conclusion is that MS is a location-related illness with a latitude gradient. However, notable exceptions then have to be explained. Japan, situated at the same latitude as areas of high prevalence in Europe, is a low-risk area. Second-generation Japanese in the United States retain their parents’ low risk of MS. The white population of South Africa, with medium prevalence of MS, is surrounded by a black population in whom the disease is very uncommon. Native North Americans, especially of pure Amerindian background, have a very low prevalence but are surrounded by a white population with a medium or high risk for MS.

It seems plausible that race is a determinant of MS risk, with populations of white extraction, especially from Northern Europe, being most susceptible. People of Asian, African, or Amerindian origin have the lowest risk, whereas other groups are variably intermediate.

Migration data have often been used to support the view that an environmental agent is involved in the pathogenesis of MS. The data indicate that persons migrating from an area of high risk to an area of low risk after the age of puberty carry their former high risk with them. With migration during childhood, the risk seems to be that of the new area to which the person has migrated.

Genetics

MS is a genetically complex disease. Many genetic and nongenetic factors of moderate effect interact to influence disease probability. Compared to the general population, a higher frequency of familial occurrence of MS suggests a strong but non-Mendelian inheritance of susceptibility. Twin studies established the importance of genetic factors: the concordance rate for a clinical diagnosis of MS in monozygotic twins is about 30%, whereas in dizygotic twins it is 2% to 5%. (Ebers et al., 1995; Willer et al., 2003). The risk is highest for siblings: 3% to 5%, or 30 to 50 times the background risk for this same population. Adoptive relatives, when raised from infancy with the patients with MS, are no more likely to develop MS than the general population. This indicates that the familial aggregation of MS is more likely to be related to shared genetic variations rather than to a shared family environment. In some studies, unaffected family members may have been found to have abnormalities on MRI, implying the risk may be even higher.

MS is associated with both MHC and human leukocyte antigen (HLA) class I A3 and B7 antigens. The class II polymorphisms, Dw2 and DR2, also show strong association, and specifically the HLA DRB1*1501 allele (Oksenberg et al., 2004). Additional HLA alleles that carry protective as well as detrimental effects with regard to MS susceptibility have been identified. HLA-A*02, for example, has a protective effect relative to MS susceptibility. In recent years, additional MS susceptibility loci outside of the MHC have been described. Specifically, the loci coding for IL-7 receptor and IL-2 receptor are strongly linked with MS susceptibility (Zuvich et al., 2010). IL-7 and IL-2 receptor signaling is critical for the differentiation of CD4⁻ CD8⁻ thymocytes and has a role in survival of CD4⁺ CD8⁺ cells after positive selection. This may be important not only in MS predisposition but also in disease course and outcome.

Recently an aggregate measure of MS risk that combines weighted odds ratios from 16 genetic susceptibility loci (the weighted genetic risk score [wGRS]) was created and used to predict a diagnosis of MS in three independent cohorts (De Jager et al., 2009). The results revealed that the wGRS can modestly but robustly predict MS risk. Individuals with MS have a greater “load” of susceptibility factors than healthy people, although the 16 loci assessed so far are insufficient to differentiate MS cases from healthy controls. While this tool is still in early stages of development, it is quite likely a useful application of the wGRS may be to predict individuals who are at higher risk for developing the disease, such as first-degree relatives of MS patients. Identifying individuals during the clinically silent phase of the disease could be extremely helpful in guiding the selection of those who would benefit most from early imaging screening, and eventually from early treatment.

Clinical Symptoms and Physical Findings

Multiple sclerosis is classically described as a relapsing-remitting disorder that affects multiple white matter tracts within the CNS, with usual onset in young adults. MS may display marked clinical heterogeneity. This variability includes age of onset, mode of initial manifestation, frequency, severity and sequelae of relapses, extent of progression, and cumulative deficit over time. The varied clinical features reflect the multifocal areas of CNS injury, although discrepancies occur between the extent of clinical and pathological findings. The high degree of variability and the difficulty in predicting the course and severity make MS one of the most puzzling CNS diseases.

Cognitive Impairment

Cognitive involvement in MS was documented as early as 1877 by Charcot. He observed that patients with “multilocular sclerosis” are slow to form conceptions, have “marked enfeeblement of the memory, and blunting of intellectual and emotional faculties.” However, the subsequent era of research in MS focused primarily on physical disability. There was a paucity of rigorous studies, with a focus on cognition. In 1981, Kurtzke reported that only 5% of patients with MS suffered from cognitive impairment. The Kurtzke Expanded Disability Status Scale (EDSS) focused primarily on somatic disability measures. A decade later, data from formal neuropsychological studies indicated that cognitive involvement has been underreported in MS (Rao et al., 1991). Neuropsychological test results have shown that 34% to 65% of patients with MS have cognitive impairment (Nocentini et al., 2006).

Cognitive abnormalities affect patients across the disease spectrum and involve all MS subtypes. Some 49% to 53.7% of clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS) patients show significant impairment in one or more cognitive domains that impacts their quality of life (Achiron and Barak, 2003; Glanz et al., 2007, 2010). A recent longitudinal study reported 29% of early PPMS patients (within 5 years from disease onset) as cognitively impaired (Penny et al., 2010; Ukkonen et al., 2009). The domains of verbal memory and attention/speed of information processing were the most affected, and premorbid IQ was a robust predictor of cognitive status in this cohort. A reported 19% of patients with a so-called benign MS variant have progressive cognitive disability and structural brain MRI changes similar to those with SPMS (Mesaros et al., 2009; Rovaris et al., 2009). It is increasingly recognized that low physical disability can coexist with significant cognitive disease. In a less common clinical presentation, patients may have a subacute or fulminant cognitive decline with signs of cortical dysfunction. This disability progresses rapidly and results in significant socio-occupational dysfunction, while physical disability remains minimal (Houtchens et al., [in press]).

In general, the most frequently reported abnormalities are with working memory, attention, and speed of information processing. Patients complain of memory loss, difficulties at work or with interpersonal relations, inability to multitask, and “mental fog and fatigue.” Comorbid depression, anxiety disorders, and emotional lability may further affect cognitive performance. Mild to moderate abnormalities are usually not apparent during a routine office visit, and simple screening tools for cognitive dysfunction are not yet available. A 5- to 15-minute battery of three tests assessing functions most commonly impaired in MS patients is now being validated (Portaccio et al., 2009). Longer neuropsychological testing batteries are designed to assess cognitive impairment in MS patients and are used primarily in research trials. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) (Rao et al., 1991) and Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) (Benedict et al., 2002) are the most widely used screening tools. Multiple Sclerosis Functional Composite (MSFC) also includes the Paced Auditory Serial Addition Test (PASAT) as a measure of sustained attention (Cutter et al., 1999).

Cognitive impairment in MS has been associated with a variety of MRI metrics of disease activity and progression. Early studies reported high correlations with the total T2 lesion burden and volume (Patti et al., 1998; Rao, 1989). Lesions located in frontal and parietal lobes showed stronger correlations with tasks of processing speed, attention, and verbal memory (Sperling et al., 2001). Global and regional atrophy plays a role in cognitive impairment. Thalamic atrophy appears to correlate particularly well with impairment on a variety of cognitive tests in MS patients (Houtchens et al., 2007). Contribution of cortical lesions (Bakshi et al., 2001; Zivadinov and Miagarb, 2009) and loss of cortical ribbon thickness (Calabrese et al., 2010) are important. Cognitively impaired patients have abnormalities in normal-appearing white and gray matter as measured by magnetization transfer ratio (MTR) that are not seen in cognitively intact MS patients (Amato et al., 2008).

Treatment of cognitive impairment in MS is challenging. Pharmacological therapy focuses on treatment of underlying disease as well as symptomatic manifestations of declining mental function, such as difficulties with attention, memory, and fatigue. Appropriate management of the comorbid psychiatric disease often improves cognitive performance. A recent randomized study of 469 patients showed that treatment with higher versus lower doses of subcutaneous interferon beta-1a was predictive of lower cognitive impairment at 3 years of follow-up (Patti et al., 2010). An earlier trial of intramuscular (IM) interferon beta-1a showed a 47% reduction in cognitive decline on PASAT testing over 2 years of follow-up (Fischer et al., 2000).

There is some evidence that treatment with l-amphetamine is associated with improved learning and memory in cognitively impaired MS patients (Benedict et al., 2008; Morrow et al., 2009). Modafinil may improve focused attention and dexterity and palliate fatigue. It has a favorable safety profile and can be used for symptomatic management of MS patients with severe fatigue and decreased focus. There is no convincing evidence that cholinesterase inhibitors improve memory in MS patients. A small study assessed the effects of donepezil on SPMS patients who were residents in a nursing home, documenting improvement in several cognitive domains after 8 weeks of therapy (Greene et al., 2000). There are additional anecdotal reports of efficacy in small numbers of subjects. Cognitive-behavioral therapy, family and individual counseling, strategies to improve day-to-day function, and necessary job modifications and accommodations can be of great help to MS patients suffering from cognitive decline.

Affective Disorders

Cross-sectional studies have shown some degree of affective disturbance in a significant number of patients with MS (Arnett et al., 2005). Depression is the most common manifestation and is in part secondary to the burden of having to cope with a chronic disease. However, it is more prevalent in MS than in other chronic diseases, suggesting an organic component as well. The lifetime risk of major depression in patients with MS is up to 50%, compared with 12.9% in patients with chronic medical conditions in another study. Some data indicate a comorbid association, presumably genetic, between bipolar illness and MS. Suicide rates are higher in patients with MS than in the general population or when compared to patients with other chronic illnesses (Bronnum-Hansen et al., 2005). Frontal or subcortical white-matter disease may also be a contributory causative factor. Euphoria, formerly considered to be common in MS, is actually infrequent and is usually associated with moderate or severe cognitive impairment and greater disease burden on MRI. However, emotional “dyscontrol” is quite common, and patients oscillate frequently between sad and happy states, at times without precipitant.

Cranial Nerve Dysfunction

Impairment of Visual Pathways

Optic neuritis (ON) is the most frequent type of involvement of the visual pathways, usually presenting as an acute or subacute unilateral syndrome characterized by pain in the eye accentuated by ocular movements, which is followed by a variable degree of visual loss affecting mainly central vision. Patients with ON often have a relative afferent pupillary defect (Marcus Gunn pupil; see Chapter 36). Bilateral ON may occur uncommonly. Bilateral simultaneous ON is rare in MS, and its occurrence in isolation may suggest another diagnosis such as Leber hereditary optic neuropathy or toxic optic neuropathy (see Chapter 14). In bilateral ON in MS cases, the impairment begins asymmetrically and is usually more severe in one eye. In a large ON treatment trial, 15% of placebo-treated patients developed recurrent ON within 6 to 24 months after the initial bout. Mapping of visual fields reveals a central or cecocentral scotoma (central scotoma involving the physiological blind spot). After an attack of acute ON, 90% of patients regain normal vision, typically over a period of 2 to 6 months.

The Uhthoff phenomenon refers to a recurrence of a neurological symptom (e.g., visual blurring) following an increase in body temperature. The basis for this phenomenon is an alteration in conduction efficiency when body temperature rises such that subclinical conduction defects become clinically apparent.

Impairment of Ocular Motor Pathways

Impairment of individual ocular motor nerves is infrequent in MS. When present, the involved nerves are, in decreasing order of frequency, cranial nerves VI, III, and (rarely) IV. More frequent findings are those that reflect lesions of vestibulo-ocular connections and internuclear connections. Nystagmus is a common finding in MS (see Chapter 35). One form of nystagmus particularly characteristic of MS is acquired pendular nystagmus, in which there are rapid small-amplitude pendular oscillations of the eyes in the primary position, resembling quivering jelly. Patients frequently complain of oscillopsia (subjective oscillation of objects in the field of vision). This type of nystagmus may be seen in the presence of marked loss of visual acuity.

Internuclear ophthalmoplegia (INO), defined as abnormal horizontal ocular movements with lost or impaired adduction and horizontal nystagmus of the abducting eye, is secondary to a lesion of the medial longitudinal fasciculus on the side of diminished adduction. Convergence is preserved. When present bilaterally, it is usually coupled with vertical nystagmus on upward gaze. Although most suggestive of MS, bilateral INO can be observed with other intraaxial brainstem lesions including brainstem glioma, vascular lesions, Arnold-Chiari malformations, and Wernicke encephalopathy. Ocular pursuit movements are frequently saccadic rather than smooth.

Impairment of Other Cranial Nerves

Impairment of facial sensation—subjective or objective—is a relatively common finding in MS. The occurrence of trigeminal neuralgia in a young adult is frequently an early sign of MS. Facial myokymia, a fine, undulating wavelike facial twitching, and hemifacial spasm can be caused by MS, but other causes of a focal brainstem lesion must be excluded. Unilateral facial paresis can occur, but taste sensation is almost never affected. In these syndromes, as with acute oculomotor palsy, the nerve is affected in its course within the brainstem, rather than peripherally. Vertigo is a reported symptom in 30% to 50% of patients with MS and is commonly associated with dysfunction of adjacent brainstem or cranial nerves. Resulting associated symptoms include hyperacusis or hypoacusis, facial numbness, and diplopia. Complete hearing loss, usually unilateral, is an infrequent complaint. Malfunction of the lower cranial nerves is usually of the upper motor neuron type (pseudobulbar syndrome) and a rather late finding in MS.

Impairment of Sensory Pathways

Sensory manifestations are a frequent initial feature of MS and are present in almost every patient at some time during the course of disease. The sensory features can reflect spinothalamic, posterior column, or dorsal root entry zone lesions. The sensory symptoms are commonly described as numbness, tingling, pins and needles, tightness, coldness, itching, or swelling of limbs or trunk. Radicular pains, unilateral or bilateral, can be present, particularly in the low thoracic and abdominal regions, or a bandlike abdominal sensation may be described.

The most frequent sensory abnormalities on clinical examination are varying degrees of impairment of vibration and joint position sense, decrease of pain and light touch in a distal distribution in the four extremities, and patchy areas of reduced pain and light touch perception in the limbs and trunk. A bilateral sensory level, frequently ascending in character, is a more frequent finding than a hemisensory (Brown-Séquard) syndrome. Patients commonly report that the feeling of pinprick is increased or feels like a mild electric shock or that the stimulus spreads in a ripple fashion from the point at which it is applied. The sensory useless hand (the “numb clumsy hand” syndrome) is a characteristic but uncommon feature, consisting of an impairment of function secondary to a pronounced alteration of proprioception, without loss of power. A lesion of the relevant root entry zones or posterior columns in the spinal cord may be responsible in such cases.

Impairment of Motor Pathways

Corticospinal tract dysfunction is common in MS. Paraparesis or paraplegia occurs more frequently than significant weakness in the upper extremities. With severe spasticity, extensor or flexor spasms of the legs and sometimes the trunk may be provoked by active or passive attempts to rise from a bed or wheelchair. The physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes are exaggerated, sustained clonus may be elicited, and extensor plantar responses are observed. All of these manifestations are commonly asymmetrical. The Achilles reflex can be absent in lesions of the sacral segments of the spinal cord, with or without concomitant sphincter and sexual problems. Occasionally, reduced reflexes reflect hypotonia due to cerebellar pathway lesions. Amyotrophy, when observed, most frequently affects the small muscles of the hand; lesions of the motor root exit zones may produce muscle denervation secondary to axon loss.

A common pattern of disease evolution seen in the spinal form of MS is an ascending pattern of weakness that begins with involvement of the lower extremities and spreads to involve first one upper extremity and then the other, beginning in the intrinsic hand muscles. Often there is an associated weakness of the trunk muscles, with abnormal posture and, much less often, involvement of respiratory muscles.

Impairment of Cerebellar Pathways

Cerebellar pathway impairment results in gait imbalance, difficulty performing coordinated actions with the arms, and slurred speech. Examination reveals the usual features of cerebellar dysfunction: dysmetria, decomposition of complex movements, and hypotonia, most often observed in the upper extremities. An intention tremor in the limbs and titubation of the head may be seen. Walking is impaired by ataxia. Ocular findings of nystagmus, ocular dysmetria, and frequent refixation saccades suggest cerebellar or cerebellovestibular connection dysfunction. Speech can be scanning or explosive in character. In severe cases, complete astasia (inability to stand), inability to use the arms because of a violent intention tremor, and virtually incomprehensible speech may occur.

Impairment of Bladder, Bowel, and Sexual Functions

The extent of sphincter and sexual dysfunction often parallels the degree of motor impairment in the lower extremities. The most common complaint related to urinary bladder dysfunction is urgency, usually the result of uninhibited detrusor contraction, reflecting a suprasegmental lesion. As the disease progresses, urinary incontinence due to urgency becomes more frequent. With involvement of sacral segments of the spinal cord, symptoms of bladder hypoactivity may evolve (e.g., decreased urinary flow, interrupted micturition, incomplete bladder emptying). An atonic dilated bladder that empties by overflow results from loss of perception of bladder fullness and is usually associated with urethral as well as anal and genital hypoesthesia, and sensory deficits in the sacral dermatomes. A dyssynergic voluntary sphincter that interrupts bladder emptying will lead to frequent, small-volume urinations combined with a large postvoid residual. Urinary tract infections are common in MS, especially in women, and may present in atypical patterns.

Constipation is more common than fecal incontinence and is mainly due to decreased general mobility and the tendency of MS patients to restrict their fluid intake in a misguided attempt to decrease urinary urgency and incontinence. Almost all patients with paraplegia require special measures to maintain regular bowel movements.

Sexual dysfunction, although frequently overlooked, occurs commonly in MS. Approximately 50% of patients become completely sexually inactive because of their disease, and an additional 20% become less sexually active. Men experience various degrees of erectile dysfunction, often with rapid loss of erection at attempted intercourse, whereas loss of ejaculation is less common. Sexual dysfunction can be the result of multiple problems, including the direct effects of lesions on the motor, sensory, and autonomic pathways within the spinal cord as well as psychological factors that affect libido: self-image, self-esteem, and fear of rejection by the sexual partner. Mechanical difficulties created by spasticity, paraparesis, and incontinence may further aggravate the problem.

Clinical features uniquely characteristic of MS (Table 54.2) include bilateral INO, the Lhermitte phenomenon, and paroxysmal attacks of motor or sensory phenomena such as paroxysmal diplopia, facial paresthesia, trigeminal neuralgia, ataxia, dysarthria, and tonic spasms. These paroxysmal attacks usually respond to low doses of anticonvulsants and frequently remit after several weeks to months, usually without recurrence. Heat sensitivity (e.g., the Uhthoff phenomenon) is a well-known occurrence in MS. Fatigue is also common and is usually described as physical exhaustion unrelated to the amount of activity performed. The degree of fatigue correlates poorly with the overall severity of disease or the presence of any particular symptom or sign. In contrast to the situation with cognitive deficits, no MRI findings correlate with fatigue or depression. Fatigue is often seen in association with an acute attack, may precede the focal neurological features of the attack, and may persist long after the attack has subsided.

Table 54.2 Common Clinical Features of Multiple Sclerosis

Clinical Features Suggestive of Multiple Sclerosis	Clinical Features Not Suggestive of Multiple Sclerosis
Onset between ages 15 and 50	Onset before age 10 or after age 60
Involvement of multiple areas of the CNS	Involvement of the PNS
Optic neuritis	Hemianopsias
Lhermitte sign	Rigidity, sustained dystonia
Internuclear ophthalmoplegia	Cortical deficits such as aphasia, apraxia, alexia, neglect
Fatigue	Deficit developing within minutes
Worsening with elevated body temperature	Early dementia

CNS, Central nervous system. PNS, peripheral nervous system.

Diagnostic Criteria

Over the years and with the advent of MRI, diagnostic criteria for MS have improved in their sensitivity and specificity. However, the cornerstone of the diagnosis of MS remains the neurological history and physical examination. In 1983, Poser and colleagues modified the diagnostic criteria previously in use. These criteria maintained the two clinical events as necessary components of the diagnosis, but they also made use of laboratory diagnostic studies including CSF analysis, evoked potentials (EP), and neuroimaging. The criteria were developed to ensure that only patients with MS were included in research studies and to improve the accuracy of MS diagnosis in clinical practice. In 2001, McDonald and colleagues proposed new criteria using MRI guidelines and timing intervals to diagnose MS. The outcome of a diagnostic evaluation was either MS, possible MS, or not MS. These latest criteria were designed for use in both practice and clinical trial settings and have most recently been expanded by a committee of the National Multiple Sclerosis Society in 2005 (Polman et al., 2005) (Table 54.3). The common thread among all MS diagnostic criteria has been the requirement for symptoms and signs that are disseminated in time and space (more than one episode involving more than one area of the CNS) (Box 54.2). In the setting of a monophasic neurological illness that is clinically consistent with MS and accompanied by typical multifocal white-matter lesions on MRI, the diagnosis of MS is almost certain. This situation is referred to as the clinically isolated syndrome. In the long-term study by Brex and colleagues (2002) that followed patients with initial demyelinating episodes for up to 14 years, in practical terms, no diagnoses were encountered other than MS or suspected MS. In addition, follow-up studies have shown that a significant percentage of patients with MRI lesions detected at onset do not progress to clinically symptomatic MS, even after many years of follow-up. The issue of the monophasic demyelinating disease is discussed later under Differential Diagnosis in this chapter. Such patients would be classified as possible MS by the latest diagnostic criteria.

Table 54.3 Revised McDonald et al. (2005) Diagnostic Criteria for Multiple Sclerosis

Clinical (Attacks)	Objective Lesions	Additional Requirements to Make Diagnosis
2 or more	2 or more	None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS
2 or more	1	Dissemination in space by MRI or 2 or more MRI lesions consistent with MS plus positive CSF or await further clinical attack implicating other site
1	2 or more	Dissemination in time by MRI or second clinical attack
1	1	Dissemination in space by MRI or 2 or more MRI lesions consistent with MS plus positive CSF AND dissemination in time by MRI or second clinical attack
0 (progression from onset)	1 or more	Disease progression for 1 year (retrospective or prospective) AND 2 out of 3 of the following:
		Positive brain MRI (9 T2 lesions or 4 or more T2 lesions with positive VEP)
		Positive spinal cord MRI (2 or more focal T2 lesions)
		Positive CSF

CSF, Cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis; VEP, visual evoked potential.

Adapted from Polman, C.H., Reingold, S.C., Edan, G., et al., 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald” criteria, Ann Neurol 58, 840-846. Courtesy of the National Multiple Sclerosis Society.

Box 54.2

Paraclinical Evidence in Multiple Sclerosis Diagnosis