Neurology_Adams

Neurology_Adams. 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. These oligoclonal bands in the CSF (after comparing to monoclonal proteins that may be present in the serum) are detected in more than 90 percent of cases of MS in some populations, but in a lower proportion of patients in Asian countries. Furthermore, oligoclonal bands are not specific for MS; such bands also appear in the CSF of patients with disorders such as syphilis, Lyme, and subacute sclerosing panencephalitis. 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 1 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


Neurology_Adams

Neurology_Adams. reported as being present if there is more than 1 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.


Neurology_Adams

Neurology_Adams. 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. Another diagnostic test sometimes used 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 (see Fig. 35-1). Most experience indicates that the incidence of MRI lesions in the cerebra and spinal cord is greater than 90 percent in established cases of MS. While the majority of cerebral lesions tend to be asymptomatic, spinal cord lesions are almost always symptomatic.


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. While the finding of individual cerebral lesions on MRI do not always ensure the diagnosis of MS, the finding of multifocal, well-demarcated, oval or linear, radially oriented lesions adjacent to the ventricular surface are fairly specific for typical relapsing-remitting form of MS (Fig. 35-1, left panel). 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. Diffusivity in MS lesions is variable, but can be a feature of larger, acute lesions.


Neurology_Adams

Neurology_Adams. 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 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 differentiating a MS plaque 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. 35-1. 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. 35-2).


Neurology_Adams

Neurology_Adams. 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 1 or more acute, enhancing lesions with additional nonenhancing 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.


Neurology_Adams

Neurology_Adams. 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 processes (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.


Neurology_Adams

Neurology_Adams. 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 (see Fig. 35-1), in contrast to those of NMO as discussed in the following text. 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 Chap. 33). The same lack of specificity of cerebral lesions pertains to those in the spinal cord.


Neurology_Adams

Neurology_Adams. Chap. 33). 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.


Neurology_Adams

Neurology_Adams. When the clinical and radiographic data point to only one definite 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 tests may establish the existence of additional asymptomatic lesions. These include visual, auditory, and somatosensory-evoked responses; electromyographic evaluation of the blink reflex; and measurement of subjective visual flicker fusion. 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 and 40 percent, and for brainstem auditory evoked responses (usually prolonged interwave latency or decreased amplitude of wave 5), approximately 40 and 20 percent, respectively (see


Neurology_Adams

Neurology_Adams. 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 that measures the back-scattering of near-infrared light to create extremely high resolution cross-sectional images of the optic nerve and retina. Automatic segmentation of the retinal nerve fiber layer thickness allows accurate, reliable quantification of axonal loss and thinning over time that follows optic neuritis. The association of anti-aquaporin 4 (anti-AQP4) antibodies and myelin oligodendrocyte glycoprotein antibodies (anti-MOG) in Devic disease acute disseminated encephalomyelitis will be discussed further on.


Neurology_Adams

Neurology_Adams. The clinician is well advised to make the diagnosis of MS on the firmest grounds possible and to withhold judgment unless the combination of clinical and laboratory features allows this degree of certainty. In the past, the passage of time was necessary to clarify the situation but presently, it is considered preferable to use MRI and other tests to attempt to establish the diagnosis at the time of the first symptoms. Certainly, the disease is likely when one of the usual syndromes, such as optic neuritis, bilateral brainstem symptoms, or transverse myelitis, occurs in a younger person. However, the time-honored—and still valid— criteria for diagnosis proposed by McAlpine and colleagues (1972), requiring several lesions that were “separated in time and space,” have been broadened greatly by the ability to detect demyelinating lesions by nonclinical means. This approach, in essence, predicts the likelihood that a clinically isolated syndrome (“CIS”) will disseminate over time and space


Neurology_Adams

Neurology_Adams. the ability to detect demyelinating lesions by nonclinical means. This approach, in essence, predicts the likelihood that a clinically isolated syndrome (“CIS”) will disseminate over time and space and conform to the diagnosis of MS.


Neurology_Adams

Neurology_Adams. Polman and colleagues in 2011 have provided one of several published diagnostic schemes based on previous consensus (2001, 2005, and 2010; also McDonald et al 2001) that incorporates MRI changes into the criteria and further revisions have increased sensitivity (Table 35-2). These criteria are provided for the reader because they are often cited but they may prove unwieldy for routine clinical work and will undoubtedly be frequently updated. Our colleague Kurtzke apocryphally is said to have quipped “MS is what the experienced neurologist says it is.” All such criteria are also relevant to predicting the course of illness, which is discussed in the following text.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.)


Neurology_Adams

Neurology_Adams. Pregnancy in MS 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.


Neurology_Adams

Neurology_Adams. The duration of the disease before death 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.


Neurology_Adams

Neurology_Adams. No environmental, dietary, or activity-related changes are known to alter the course of the illness.


Neurology_Adams

Neurology_Adams. 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, PML, migraine-associated white matter lesions, Lyme disease, sarcoidosis, Susac syndrome, 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,


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. As has been stated, the initial attack of MS (clinically isolated syndrome) 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. Other lesions may be inflammatory and demyelinating and these rheumatologic processes that affect the cerebral white matter remain difficult to understand and it is these conditions that most closely simulate native MS. 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.


Neurology_Adams

Neurology_Adams. 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 Lyme or other 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


Neurology_Adams

Neurology_Adams. 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. 31). Finally, a rare inflammatory variant of cerebral amyloid deposition can produce a few or a plethora of white matter lesions that superficially simulate MS but present with rapid dementia and TIA or stroke-like symptoms.


Neurology_Adams

Neurology_Adams. 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, also is seen in MS. As a general rule, loss of abdominal reflexes, erectile


Neurology_Adams

Neurology_Adams. are almost unknown in MS. However, atrophy of the first dorsal interosseus muscles, a frequent finding in spondylosis, also is seen 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.


Neurology_Adams

Neurology_Adams. 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 dural 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.


Neurology_Adams

Neurology_Adams. The problem of differentiating chronic spinal MS from TSP (human lymphotropic virus, myelitis of the HTLV-1 type) and progressive familial spastic paraplegia may also arise occasionally (Chap. 32). Amyotrophic lateral sclerosis (ALS) and 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).


Neurology_Adams

Neurology_Adams. Platybasia and basilar impression of the skull should also be considered in the differential diagnosis of spinal MS, 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 but clarified by imaging. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 38). Treatment of Multiple Sclerosis


Neurology_Adams

Neurology_Adams. For over a century following the early clinic-pathologic descriptions of MS by Charcot and others, the major treatments for MS purely addressed the various symptoms caused by the disease. ACTH therapy in MS was first studied in 1969 and showed faster recovery from acute clinical relapses. This treatment was ultimately abandoned as its benefit was in proportion to elevation of endogenous glucocorticoids, an effect that is more easily obtained by oral or intravenous administration of these drugs. In the 1990s and early 2000s, the major medications became subcutaneous or intramuscular injectable forms of interferon or a compound called glatiramer acetate, a synthetic mixture of polypeptides that has immunomodulatory effects. In 2006, the intravenous monoclonal antibody natalizumab became available and was shown to be quite efficacious, but its use was limited by risk of opportunistic infection with JC virus causing PML. Beginning in 2010, a number of oral disease modifying oral


Neurology_Adams

Neurology_Adams. available and was shown to be quite efficacious, but its use was limited by risk of opportunistic infection with JC virus causing PML. Beginning in 2010, a number of oral disease modifying oral medications became available. In addition, additional monoclonal antibody therapies have been developed in recent years.


Neurology_Adams

Neurology_Adams. The availability of a broad range of therapeutic options has transformed the clinical course of MS for most patients, with fewer relapses and an uncertain but apparent reduction of chronic disability. Key to the successful long-term treatment of MS is appropriate balancing of the risks, benefits, adherence, convenience, and cost of available therapies for the individual patient. In general, there are few circumstances where disease- modifying 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. In addition, it should be acknowledged that the correlation between the number of relapses and the ultimate disability is not perfect across patients.


Neurology_Adams

Neurology_Adams. In addition to the available treatments discussed below, 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


Neurology_Adams

Neurology_Adams. Glucocorticoids 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 is difficult to distinguish from the natural course of disease. Apart from a transient effect on the duration of a relapse, chronic administration of steroids generally does not have a significant effect on the ultimate course of this disease or that they prevent recurrences. Although this strategy should only apply to a minority of patients, it is of interest that a study of intravenous methylprednisolone administered at 1 g/d for 5 days per month over 5 years showed 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).


Neurology_Adams

Neurology_Adams. 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 largely been abandoned, although a newer formulation has become available again recently.


Neurology_Adams

Neurology_Adams. 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 12to 20-day period) is generally effective in shortening an acute or subacute exacerbation of MS or 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).


Neurology_Adams

Neurology_Adams. 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 require oral treatment for more than several weeks because of clinical relapse on withdrawal of the medication are subject to the effects of hypercortisolism, including the facial and truncal 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.


Neurology_Adams

Neurology_Adams. As mentioned under “Acute Multiple Sclerosis,” there may be a role for plasma exchange (see Weinshenker et al, 1999; Rodriguez et al) and perhaps immunoglobulin in fulminant cases. One limited trial has shown possible but mild benefit in patients with relapsing–remitting disease of monthly infusions of intravenous immunoglobulin (0.2 g/kg) for 2 years (Fazekas et al).


Neurology_Adams

Neurology_Adams. Treatment of optic neuritis (see Chap. 12) 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 in visual outcome 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. The putative deleterious effects


Neurology_Adams

Neurology_Adams. 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. The putative deleterious effects of oral glucocorticoids on relapse of optic neuritis have been disputed and most clinicians consider them equivalent to intravenous administration for this disorder.


Neurology_Adams

Neurology_Adams. Interferon-beta Interferon and glatiramer were the first main disease-modifying therapies introduced for MS following ACTH and corticosteroids. These injectable drugs, which are still used in some cases, 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 showed 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) 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 in a


Neurology_Adams

Neurology_Adams. 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 in a once weekly intramuscular regimen is similarly effective.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Overall, the side effects of the interferon therapies for MS 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 preand posttreatment 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, and then again after the 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, often 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The question of whether to institute disease modifying therapy with an interferon was addressed in the Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) study, which examined the effect of interferon (weekly) in patients with a first episode of optic neuritis and at least 2 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.


Neurology_Adams

Neurology_Adams. Glatiramer Copolymer I (glatiramer acetate), which was synthesized to mimic the actions of MBP, 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. 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).


Neurology_Adams

Neurology_Adams. Monoclonal antibodies One 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, 2006; 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


Neurology_Adams

Neurology_Adams. 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 this study was terminated early because 2 patients receiving the combination therapy developed PML.


Neurology_Adams

Neurology_Adams. 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. 32) has led to a restriction on its use. 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 1,000


Neurology_Adams

Neurology_Adams. 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 1,000 patients (Bloomgren et al). Serum JC virus antibody ELISA testing is performed for all patients in whom treatment with natalizumab is being considered; periodic retesting is important to reduce false-negative results or detect seroconversion, but the optimal frequency of retesting is unknown.


Neurology_Adams

Neurology_Adams. One remarkable observation has been that in cases of PML associated with the use of natalizumab, plasma exchange to rapidly clear the has reversed the clinical syndrome and led to disappearance of JC virus from the CSF. 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. The potential treatments for PML, in addition to ceasing natalizumab or other disease modifying drug for MS, are reviewed in Chap. 32.


Neurology_Adams

Neurology_Adams. Rituximab, a murine 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 of relapsing–remitting cases over 4 years, but long-term safety is still being established (Hauser et al, 2008). A similar, fully humanized anti-CD20 drug, ocrelizumab, has been introduced and has similar effects to rituximab (Kappos et al, 2011). In addition to its indication for relapsing remitting MS, it has tentatively been shown to have some effect on primary progressive MS. Appropriate use in patients should be balanced by consideration of its risks, which include opportunistic infection as well as malignancy.


Neurology_Adams

Neurology_Adams. Another monoclonal antibody that has been introduced for the treatment of MS is alemtuzumab, which targets CD-52 antigen expressed on T and B lymphocytes, thereby reducing 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 reducing 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 hyperor hypothyroidism. At the time of this writing, it is being used in Europe but has not yet been approved in the United States for patients with MS. It is associated with increased risk of infections and autoimmune conditions, including thyroid


Neurology_Adams

Neurology_Adams. it is being used in Europe but has not yet been approved in the United States for patients with MS. It is associated with increased risk of infections and autoimmune conditions, including thyroid dysregulation and immune thrombocytopenic purpura (ITP).


Neurology_Adams

Neurology_Adams. Oral therapies Since 2010, several novel oral agents have become available for the treatment of MS. Many patients with a new diagnosis of MS are now treated with one of these oral medications. While these drugs have idiosyncratic side effects, for the most part, tolerability and ease of adherence have been main reasons they have been preferred by patients to injectable medications. Dimethyl fumarate, an oral drug of uncertain mode of action, reduces annualized relapse rates by approximately one-third to one-half and has gastrointestinal side effects as well as causing flushing (Gold et al). Its effect on MS was discovered coincidentally during use to treat psoriasis.


Neurology_Adams

Neurology_Adams. Fingolimod is a sphingosine-1 phosphate 1 (S1P1) receptor analogue that interferes with egress of mature lymphocytes from lymph nodes. Two large phase 3 clinical trials (FREEDOMS and TRANSFORMS) showed a significant effect on MRI lesion burden and relapse rate that is comparable or superior to injectable agents (Cohen and colleagues, 2010; Kappos and colleagues, 2006 and 2010). The approved 0.5 mg daily dose showed 54 percent reduction in relapse rate and 17 percent reduction in risk of disability progression in these 2 year trials. The systemic side effects of fingolimod likely relate to consequences of S1P1 inactivation in several nonneural tissues. Discontinuation of the drug is sometimes required because of extremes of bradycardia or atrioventricular block, macular edema, herpes infections, occurrence of melanoma, or elevations in liver function tests, the last of these, in approximately 10 percent of patients. Patients are monitored for bradyarrhythmias for 6 hours following the


Neurology_Adams

Neurology_Adams. occurrence of melanoma, or elevations in liver function tests, the last of these, in approximately 10 percent of patients. Patients are monitored for bradyarrhythmias for 6 hours following the first dose, including an electrocardiogram before and after the observation period. Eye examinations to screen for macular edema should occur before and 3 months after initiation of the drug.


Neurology_Adams

Neurology_Adams. Teriflunomide is an oral drug that suppresses the immune system by inhibiting dihydro-orotate dehydrogenase and suppressing synthesis of DNA pyrimidine bases. In the TEMSO trial, the drug demonstrated a 31 percent reduction in annualized risk of relapse and 30 percent reduction in risk of disability progression (O’Connor and colleagues, 2011). Reported serious adverse effects included nasopharyngitis, diarrhea, transaminitis, and hair thinning. It is considered teratogenic (pregnancy category 4) and cannot be used in individuals considering pregnancy.


Neurology_Adams

Neurology_Adams. Other immunosuppressive drugs for MS 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, typically 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.


Neurology_Adams

Neurology_Adams. For the chronic, progressive phase of the disease, an MS study group reported a modest delay in the advance of the disease after a 2-year trial of prednisolone and cyclophosphamide, but also noted the potentially serious toxicity associated with this approach. 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 occasional use. Among these more aggressive agents, mitoxantrone, a drug with broad immunosuppressant and cytotoxic activity, at one time attracted interest but was limited by cardiotoxicity (Hartung et al). Mycophenolate and


Neurology_Adams

Neurology_Adams. more aggressive agents, mitoxantrone, a drug with broad immunosuppressant and cytotoxic activity, at one time attracted interest but was limited by cardiotoxicity (Hartung et al). Mycophenolate and similar drugs have been tried with varying success.


Neurology_Adams

Neurology_Adams. General Measures in the Treatment of MS 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), pemoline (20 to 75 mg each morning), methylphenidate, or dextroamphetamine. For 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. Agents such as 4-aminopyridine improve conduction through demyelinated central nerve fibers by blocking potassium channels. In some patients these drugs have shown measureable improvements in gait. They are pro-convulsant and should be avoided in individuals at risk of seizures.


Neurology_Adams

Neurology_Adams. 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. 25). These drugs are best used intermittently. Severe constipation is best managed with stool softeners and properly spaced enemas. Sexual dysfunction has been treated with sildenafil and similar drugs. When pain is a


Neurology_Adams

Neurology_Adams. best used intermittently. Severe constipation is best managed with stool softeners and properly spaced enemas. 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. 7. Carbamazepine or gabapentin are often helpful to reduce paroxysmal symptoms in MS, particularly truncal extensor spasms.


Neurology_Adams

Neurology_Adams. Oral baclofen or tizanidine are often used to reduce spasticity in patients with MS but the dose must be limited to avoid excessive sedation. In patients with severe spastic paralysis and painful flexor spasms of the legs, local injection of botulinum toxin can be very effective. In these cases, intrathecal infusion of baclofen through an indwelling catheter and implanted pump can also be considered. An alternative to oral baclofen is tizanidine.


Neurology_Adams

Neurology_Adams. 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 reported by 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 usually 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. The advances in available therapeutic options have transformed the prognosis for most patients with this disease. By carefully following a patient’s course clinically and with serial imaging, the clinician can balance the benefits and associated risk of available treatments in an individualized way. In this fashion, the clinician can have an impact upon a patient’s quality of life.


Neurology_Adams

Neurology_Adams. In addition, 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) (See Also Chap. 42)


Neurology_Adams

Neurology_Adams. Neuromyelitis Optica (Devic Disease) (See Also Chap. 42) 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, 1998).


Neurology_Adams

Neurology_Adams. While NMO was previously considered a variant of multiple sclerosis (MS), it is now recognized to have distinct clinical, pathological, and immunological features. The singular insight in Devic disease has been the discovery by the group at the Mayo Clinic of a specific circulating autoantibody to the aquaporin-4 water channel protein. Lennon and colleagues reported that the antibody is a marker for NMO 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 2 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.


Neurology_Adams

Neurology_Adams. The site of destruction with this antibody is the astrocyte rather than the oligodendrocyte or its myelin extension as occurs in conventional MS. A proportion of patients with what otherwise resembles NMO do not have the characteristic antibody and have more recently been explained by antibodies to myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. After decades of debate, these finds have largely settled the controversy about Devic disease as an independent entity from MS.


Neurology_Adams

Neurology_Adams. The place of disorders with anti-MOG antibodies as a unique clinical entity is being elucidated. The antibodies appear to be referable mainly to children and to be associated with a predominantly monophasic course or several serial monophasic episodes, linking them clinically with ADEM, discussed further on. One interesting feature of these antibodies is that they identify the native form of the MOG glycoprotein and probably eluded understanding for many years because the denatured form was used in antibody assays.


Neurology_Adams

Neurology_Adams. These immunologic findings have led to the conclusion that the Devic process is humoral, in contrast to the primarily cellular-immune mechanism that is proposed for MS (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 in the periventricular regions surrounding the central canal of the spinal cord. Binding of NMO-IgG to AQP4 causes astrocytic injury through antibody-dependent cell-mediated cytotoxicity and activation of the complement pathway. These signaling pathways attract inflammatory cells including T and B lymphocytes, macrophages, neutrophils, and eosinophils.


Neurology_Adams

Neurology_Adams. The prevalence of NMO ranges from 0.5 to 4.4 cases per 100,000 in different populations (Pandit and colleagues). It is relatively rare in the United States and European countries, with a prevalence that is 50 to 100 times lower than that of MS (Mealy et al). In persons of Asian or African descent, however, the prevalence of NMO is only 2 to 4 times lower than the prevalence of MS, primarily because MS is less common in these populations. The disease is 3 to 7 times more common in women than men, and the typical age of onset is about 1 decade later than MS (median age 33 to 46 versus 28 to 31 in MS).


Neurology_Adams

Neurology_Adams. The disease formerly termed “Asian optic–spinal MS” almost certainly represents Devic disease and displays this antibody in the majority of cases. Most cases of NMO stand apart from MS by virtue of distinctive clinical and pathologic features, mainly, a predilection for involvement of the optic nerves, spinal cord, and particular areas of the brain including the area postrema and hypothalamus; 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 lesions, affecting white and gray matter alike with prominent thickening of vessels but with minimal inflammatory infiltrates. It is quite unusual for MS to involve several contiguous longitudinal segments of the spinal cord, and this is a frequent finding in Devic disease (Fig. 35-3).


Neurology_Adams

Neurology_Adams. As would be expected, the clinical effects associated with the severe, destructive lesions of NMO are more likely to be permanent than those of typical demyelination. The optic neuritis associated with NMO is often characterized by severe vision loss, poor visual recovery, simultaneous or rapidly sequential bilateral involvement of both eyes, chiasmal lesions, and severe retinal nerve fiber layer loss demonstrated by optical coherence tomography.


Neurology_Adams

Neurology_Adams. Until the diagnostic criteria were revised in 2015, the definitive diagnosis of NMO had required the presence of optic neuritis and transverse myelitis. These syndromes may occur either simultaneously or sequentially, separated by days to several years. Because of growing recognition of the specificity of the NMO-IgG assay, the concept of NMO spectrum disorders (NMOSD) was introduced by Wingerchuk and colleagues in 2007 to describe clinically limited forms of the disease with NMO-IgG seropositivity. These diagnostic criteria were updated to reflect the importance of NMO-IgG serostatus in other clinical situations, beyond the limited forms of isolated transverse myelitis or optic neuritis (Wingerchuk and colleagues, 2015).


Neurology_Adams

Neurology_Adams. In patients with NMO-IgG positivity, NMO can be diagnosed in the setting of any of the 6 clinical criteria of optic neuritis, transverse myelitis, area postrema syndrome (characterized by hiccoughs or vomiting), or another brainstem, diencephalic, or other large cerebral lesion. On the other hand, for patients that are not known to be seropositive, the diagnosis still requires 2 of the 3 typical features of optic neuritis, extensive transverse myelitis, or area postrema syndrome with vomiting. Occasionally, NMO occurs in the context of a rheumatologic 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. Case reports of NMOSD coexisting with cancer suggest that the disease may also occasionally be a paraneoplastic immune phenomenon.


Neurology_Adams

Neurology_Adams. Differential diagnosis There is in addition to the myelitis described earlier a progressive and sometimes saltatory subacute necrotic myelopathy without optic neuritis that shares 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. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Treatment Although no adequate randomized treatment trials have been conducted, retrospective and open-label uncontrolled data permit several tentative conclusions about the use of immunomodulating therapies for acute attacks and prevention of future relapses. Acute exacerbation of confirmed or suspected NMOSD have been treated promptly with high-dose intravenous corticosteroids. A subsequent corticosteroid taper for several months may be considered. Plasma exchange (PLEX) is often recommended for severe attacks, either concomitantly or immediately following a course of glucocorticoids. Its use is supported by results of a randomized, sham-controlled double-masked clinical trial by Weinshenker and colleagues (1999) in 22 patients with demyelinating disease, of whom 2 had NMO. Retrospective studies have also shown that acute treatment PLEX yields better visual outcomes than corticosteroids alone (Merle). Treatment with intravenous immunoglobulin also appears to have benefit, although


Neurology_Adams

Neurology_Adams. studies have also shown that acute treatment PLEX yields better visual outcomes than corticosteroids alone (Merle). Treatment with intravenous immunoglobulin also appears to have benefit, although possibly less so than PLEX.


Neurology_Adams

Neurology_Adams. Chronic immunosuppressive treatment is considered possibly valuable to reduce the occurrence of relapses in NMO. The main agents that have been evaluated in retrospective studies and prospective open label series include azathioprine, mycophenolate mofetil, and rituximab (Mealy et al). Medications that have also been used, less commonly, include methotrexate, mitoxantrone, and cyclophosphamide. Accurate diagnosis of NMO is important to guide optimal treatment decisions, since several disease-modifying agents that are used for treatment of MS, including interferon-beta (IFN-β), natalizumab, and fingolimod, may have a deleterious effect on the relapse rate in NMO patients. The course of NMO across individual patients can be unpredictable, and recommendations regarding the optimal duration of preventative treatment have not been established.


Neurology_Adams

Neurology_Adams. Some of these terms, used originally to refer to the neurologic sequelae of infectious fevers, were introduced into medicine in the late 19th century but it was not until the late 1920s that Perdrau, Pette, Greenfield, and others identified a type of pathologic reaction common to a number of monophasic inflammatory syndromes following exanthems and vaccines. The current view of the entity known as ADEM is that it is distinguished pathologically by numerous foci of demyelination scattered throughout the brain and spinal cord. These lesions vary in diameter from miniscule to several millimeters (when confluent) and invariably surround small and medium-sized veins. The axons and nerve cells remain more or less intact. The perivenular inflammatory reaction consists primarily of lymphocytes and mononuclear cells. The adjacent regions of white matter are invaded by monocytes and microglia corresponding to the zones of demyelination. Multifocal meningeal infiltration is another invariable


Neurology_Adams

Neurology_Adams. and mononuclear cells. The adjacent regions of white matter are invaded by monocytes and microglia corresponding to the zones of demyelination. Multifocal meningeal infiltration is another invariable feature but is rarely severe. With the exception of this last feature, ADEM is indistinguishable on histopathologic grounds from acute MS. It is the postinfectious setting and temporal course that are the main features that set them apart. On the other hand, even the monophasic nature of ADEM has been questioned by Schwarz and colleagues, who found that 14 of 40 adults initially diagnosed with ADEM later developed clear signs of MS, usually within a year. A larger and more recent retrospective study of 228 patients with ADEM by Koelman and colleagues likewise showed that 25 percent had a multiphasic course, and that a relapsing course in adults (and women, in particular) was more likely to correspond to a transition to MS than in children with ADEM. The transition to MS in children with


Neurology_Adams

Neurology_Adams. course, and that a relapsing course in adults (and women, in particular) was more likely to correspond to a transition to MS than in children with ADEM. The transition to MS in children with typical ADEM is less common.


Neurology_Adams

Neurology_Adams. An acute encephalitic, myelitic, or encephalomyelitic process of this type is observed in a number of clinical settings and is more common in children. In our experience, the disease in children follows a febrile illness by days or infrequently up to 2 weeks; this is less often the case in adults. In the originally described form, it occurred within a few days of onset of the exanthem of measles, rubella, smallpox, or chickenpox. Prior to widespread immunization against measles, an epidemic in a large city might have resulted in 100,000 cases of measles and clinically evident neurologic complications in 1 in 800 to 1 in 2,000 cases.


Neurology_Adams

Neurology_Adams. The mortality among patients with such complications ranged from 10 to 20 percent; about an equal number were left with persistent neurologic damage. The neurologic complications of measles alone provide sufficient justification for immunization against the disease. The incidence of encephalomyelitis was less following chickenpox and rubella, and much less following mumps. In the past, a similar illness was observed to follow vaccination against rabies and smallpox and, reportedly, after administration of tetanus antitoxin (rare), as discussed further on. Now, however, most cases, clinically and pathologically indistinguishable from these 2 categories of ADEM, appear to develop after seemingly banal respiratory infections and after documented infections with Epstein-Barr, cytomegalovirus, Mycoplasma pneumoniae, and even HIV (Narisco et al); occasionally there is no clearly defined preceding illness or inoculation. Many, if not most, instances of acute transverse myelitis may represent


Neurology_Adams

Neurology_Adams. Mycoplasma pneumoniae, and even HIV (Narisco et al); occasionally there is no clearly defined preceding illness or inoculation. Many, if not most, instances of acute transverse myelitis may represent the same postinfectious process. The neurologic illness may coincide with the later stages of the manifestations of the infection, in which case the term parainfectious may be appropriate.


Neurology_Adams

Neurology_Adams. Irrespective of the clinical setting in which it occurs, disseminated encephalomyelitis in its severe form is of grave import because of the significant rate of neurologic defects in patients who survive. In children, recovery from the acute stage is sometimes followed by a permanent disorder of behavior, developmental delay, or epilepsy but there are many exceptions in milder disease; paradoxically, most adults make good recoveries. The cerebellitis and acute ataxia that follow chickenpox and other infections are more benign, normally clearing over several months, and may represent a different process, as discussed further on.


Neurology_Adams

Neurology_Adams. The pathogenesis of disseminated encephalomyelitis is still unclear despite its obvious association with preceding viral infections. In the postexanthem cases, a definite interval usually separates the onset of disseminated encephalomyelitis from the onset of the rash; also, the pathologic changes are quite different from those of viral infections and virus is rarely if ever recovered from the CSF or brains of patients with disseminated encephalomyelitis. For these reasons, it is believed that the disorder represents an immune-mediated complication of infection rather than a direct infection of the CNS, a process comparable to the Guillain-Barré syndrome. However, as discussed in Chap. 32, new molecular techniques have been used to detect fragments of DNA from varicella zoster virus, Mycoplasma, and other organisms in the CSF, so that the question of pathogenesis cannot be answered with finality. Nevertheless, Waksman and Adams found the pathologic changes in these 2


Neurology_Adams

Neurology_Adams. virus, Mycoplasma, and other organisms in the CSF, so that the question of pathogenesis cannot be answered with finality. Nevertheless, Waksman and Adams found the pathologic changes in these 2 circumstances—postinfectious demyelination and direct viral infection of the CNS—to be quite different.


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Neurology_Adams. A laboratory model of the disease, EAE, has been produced by inoculating animals with a combination of sterile brain tissue and adjuvants. The experimental disease appears most commonly between the 8th and 15th days after sensitization (see in the following text) and is characterized by the same perivenular demyelinating and inflammatory lesions that one observes in the human disease. Presumably the lesions are the result of a T-cell–mediated immune reaction to components of myelin or oligodendrocytes. Evidence of antibody binding, complement activation, and eosinophilic infiltration has led to the notion that ADEM is a humoral disorder, in contrast to the cellular mechanism that has been proposed for MS, but confirmation of this notion is required (see


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Neurology_Adams. Lucchinetti et al, 2000 and 2002). Furthermore, a proportion of cases display the earlier mentioned anti-MOG antibody; however, the titer of these antibodies drops rapidly after the onset of the acute attack, making their role in pathogenesis uncertain.


Neurology_Adams

Neurology_Adams. The notion that EAE and disseminated encephalomyelitis have a similar pathogenesis received support from the observations of R.T. Johnson and colleagues. They studied 19 patients with postinfectious encephalomyelitis complicating natural measles virus infections. Early myelin destruction was demonstrated by the presence of MBP in the CSF, and lymphocyte proliferative responses to MBP were found in 8 of 17 patients tested. Similar responses were observed in patients with encephalomyelitis after rabies vaccine and after varicella and rubella virus infections, suggesting a common immune-mediated pathogenesis. Moreover, the patients with postmeasles encephalomyelitis showed a lack of intrathecal synthesis of antibody against measles virus, indicating that the neurologic disease was not dependent on viral replication within the CNS.


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Neurology_Adams. The encephalitic form is expressed more fully in children than in adults. As an acute infectious illness is resolving or after a latency of several days or longer, there is the abrupt onset, over hours or a day or two, of confusion, somnolence, and sometimes convulsions with headache, fever, and varying degrees of neck stiffness. Ataxia is common, but myoclonic movements and choreoathetosis are observed less frequently. In severe cases, stupor, coma, and at times decerebrate rigidity may occur in rapid succession. In many cases, the disease is less severe and the patient suffers a transient encephalitic illness with headaches, confusion, and slight signs of meningeal irritation.


Neurology_Adams

Neurology_Adams. The latency between infection and the first neurologic symptoms that it is acceptable for this diagnosis is a matter of debate, but there are convincing cases (postexanthematous) in which the 2 phases of illness are separated by 3 or 4 weeks; several days is more typical, as noted below. Curiously, in the encephalitic form, new signs may continue to appear for up to 2 or 3 weeks from the onset. This is emphasized in the series of affected children collected by Hynson and colleagues. The imaging changes may also display delayed or continued evolution. These authors note that ataxia was the most common initial feature in their cases, which is not entirely in accordance with our experience.


Neurology_Adams

Neurology_Adams. In the myelitic form (postinfectious myelitis, acute transverse myelitis), there is partial or complete paraplegia or quadriplegia, diminution or loss of tendon reflexes, sensory impairment, and varying degrees of paralysis of bladder and bowel. A syndrome that simulates anterior spinal artery occlusion (spastic paraplegia and loss of pain sensation below a level on the trunk but tending to spare large-fiber sensibility) is not uncommon in our experience. Also, we have cared for a few patients with a limited sacral form of postinfectious myelitis. Midline back pain may be a prominent symptom at the onset.


Neurology_Adams

Neurology_Adams. In both the encephalitic and myelitic types, there may be slight fever, particularly in the more aggressive cases and in younger individuals, where we have seen temperatures reaching 39.4°C (103°F), but the peripheral white blood cell count is normal if the initiating infection has resolved. A few of our patients have had elevated sedimentation rates, but it is not possible to know whether this reflects the precipitating infection. Nonetheless, separating these 2 entities may be difficult, especially in children who have a greater tendency to develop fever and convulsions with ADEM. Either process may be associated with aseptic meningitis.


Neurology_Adams

Neurology_Adams. The CSF shows a slight increase in lymphocytes and protein content, but these are variable, with a few of our patients having only an increase in protein and no cells and others having up to several hundred cells. The MRI shows several bilateral confluent white matter lesions in both cerebral hemispheres early in the course of ADEM (Fig. 35-4); when these are large and numerous, the diagnosis is more certain. The lesions all appear to be of similar age, but we cannot account for several cases we have seen in which serial MRIs show new lesions accumulating over 2 or 3 weeks, as already noted. Moreover, as pointed out by Honkaniemi and colleagues, there may be a delay of several days between the clinical manifestations and the first appearance of changes in the MRI, a situation to which we can attest. Whether a single lesion on MRI can be considered compatible with ADEM is unclear.


Neurology_Adams

Neurology_Adams. In the case of postexanthem encephalomyelitis, the syndrome generally begins 2 to 4 days after the appearance of the rash. Usually the rash is fading and other symptoms are improving when the patient, typically a child, suddenly develops a recrudescence of fever, convulsions, stupor, and sometimes coma. Less commonly, the patient may develop hemiplegia or a virtually pure cerebellar syndrome, as noted below (particularly after chickenpox), and occasionally a transverse myelitis, sphincteric disturbance, or other signs of spinal cord involvement. Choreoathetotic movements are seen infrequently. Likewise, optic neuritis is uncommon, but it does occur.


Neurology_Adams

Neurology_Adams. A possibly related variant of postinfectious encephalomyelitis that involves solely or predominantly the cerebellum deserves special comment. Typically, a mild ataxia with variable corticospinal or other signs appears within days of one of the childhood exanthems as well as after Epstein-Barr virus, Mycoplasma, Legionella, and cytomegalovirus infections, and after a number of vaccinations and nondescript respiratory infections. It is described in detail in Chap. 32 because it has a close relationship to certain viruses, particularly varicella, suggesting that some, if not most, cases are caused by an infectious meningoencephalitis. Others—for example, following mycoplasmal infection—occur after a long latency and show pathologic changes that are consistent with a postinfectious demyelination. Thus it is possible that there may be 2 types of acute cerebellitis, one paraor postinfectious and the other caused by a direct infection of the brain and meninges. The benign nature of the


Neurology_Adams

Neurology_Adams. Thus it is possible that there may be 2 types of acute cerebellitis, one paraor postinfectious and the other caused by a direct infection of the brain and meninges. The benign nature of the illness has precluded adequate pathologic examination; hence some of these statements are speculative.


Neurology_Adams

Neurology_Adams. Not all the neurologic complications of measles and other exanthems and acute viral infections are examples of postinfectious encephalomyelitis. As already noted, the illness is at times difficult to distinguish from viral meningoencephalitis. Infectious mononucleosis, herpes simplex, mycoplasmal infection, and other forms of encephalitis may all mimic the postinfectious variety. The Reye syndrome is usually not difficult to separate from postinfectious encephalomyelitis, even when it follows chickenpox or viral influenza, because of the normal CSF and high serum concentrations of liver enzymes and ammonia (see Chap. 32). The MRI finding of large or multifocal areas of white matter damage can also be produced by intravascular lymphoma and progressive multifocal leukoencephalopathy (Chap. 31) and a rare leukoencephalopathy that follows inhaling heroin vapor (Chap. 41).


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Neurology_Adams. Postvaccinal ADEM Since late in the nineteenth century, it has been known that a severe form of encephalomyelitis may complicate the injection of rabies vaccine (“neuroparalytic accident”). Until quite recently, the rabies vaccine in common use consisted of killed virus that had been grown in rabbit brain tissue. Encephalomyelitis occurred in about 1 in 750 patients inoculated with this vaccine, and approximately 25 percent of cases with this complication proved fatal. Alternative vaccines, made from embryonated duck eggs (and later from human diploid cells) infected with fixed viruses, contain very little or no nerve tissue and are almost free of neurologic complications. In developing countries, where less-expensive brain-based vaccines are still in use, neuroparalytic accidents continue to occur. The observations of Hemachudha and colleagues indicate that the altered immune mechanism that is operative in the neuroparalytic accident is the same as that in postmeasles


Neurology_Adams

Neurology_Adams. continue to occur. The observations of Hemachudha and colleagues indicate that the altered immune mechanism that is operative in the neuroparalytic accident is the same as that in postmeasles encephalomyelitis and experimental allergic encephalomyelitis.


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Neurology_Adams. There are numerous recorded instances in which the old rabies vaccine (with neural tissue) induced an attack of what subsequently appeared to be MS. Shiraki and Otani reported such examples from Japan. The evolution of symptoms was subacute, over a period of 2 to 4 weeks, and the demyelinating lesions were macroscopic—up to 1 to 2.0 cm in diameter—but composed of confluent perivenous lesions. The disease could be reproduced in dogs—persuasive evidence that one form of acute MS is a variant of ADEM. Encephalomyelitis following vaccination against smallpox has been known since 1860, having occurred about once in 4,000 vaccinations. That disease is now of historical interest only, insofar as smallpox has disappeared as a human illness.


Neurology_Adams

Neurology_Adams. The temporal association of the neurologic disorder with vaccination supports the diagnosis and the characteristic combination of encephalitic and myelitic features will help to distinguish the condition from meningitis, viral encephalitis, and poliomyelitis. Rarely, an atypical case may mimic any one of these disorders. On occasion, the disease may suggest involvement of nerve roots and peripheral nerves and resemble acute inflammatory polyneuritis (Guillain-Barré syndrome). In fact, the rabies vaccine produced in South America from suckling mouse brain causes this type of peripheral nerve disease more often than encephalomyelitis. Mundane inoculations such as those for influenza or hepatitis must have a very small rate of ADEM, judging from surveillance studies; Ascherio and colleagues were unable to find any increase in cases among 2 large studies of nurses who received hepatitis B vaccine. The absence of a clear connection of MS to vaccination has already been mentioned.


Neurology_Adams

Neurology_Adams. The mortality rate of postvaccinal encephalomyelitis had in the past been high, between 30 and 50 percent. If recovery occurs, it may be surprisingly complete. However, a significant proportion of patients show residual neurologic signs, mainly in the form of seizures, intellectual impairment, or behavioral abnormalities. Corticosteroids given soon after the appearance of neurologic signs may modify the severity of experimental allergic encephalomyelitis; this provides the logic for their use in the human counterpart of this disease but controlled trials have not been carried out. We usually administer methylprednisolone in high doses intravenously for 3 to 5 days. Plasma exchange and intravenous immune globulin have also been apparently successful in some fulminant cases (Kanter et al; Stricker et al) but it is difficult to affirm this. Acute Necrotizing Hemorrhagic Encephalomyelitis (Acute Hemorrhagic Leukoencephalitis of Weston Hurst)


Neurology_Adams

Neurology_Adams. This entity, the most fulminant form of demyelinating disease, almost certainly represents the severe end of the spectrum of ADEM. It affects mainly young adults and children. It is usually preceded by a respiratory infection of variable duration (1 to 14 days), sometimes caused by M. pneumoniae, but more often it follows a mundane infection or is of indeterminate cause. The neurologic symptoms appear abruptly, beginning with headache, fever, stiff neck, and confusion. These are followed in short order by signs of disease of one or both cerebral hemispheres and brainstem—focal seizures, hemiplegia or quadriplegia, pseudobulbar paralysis, and progressively deepening coma. Peripheral leukocytosis is usually present, sometimes reaching 30,000 cells/mm3, and the sedimentation rate is elevated. The CSF is often under increased pressure; cells vary in number from a few lymphocytes to a polymorphonuclear pleocytosis of up to 3,000 cells/mm3; red cells may be present in variable numbers;


Neurology_Adams

Neurology_Adams. The CSF is often under increased pressure; cells vary in number from a few lymphocytes to a polymorphonuclear pleocytosis of up to 3,000 cells/mm3; red cells may be present in variable numbers; protein content is increased, but glucose values are normal. Diagnosis is greatly facilitated by CT scanning and MRI, which reveal bilateral but asymmetrical large, confluent, edematous lesions in the cerebral white matter with a myriad of punctate hemorrhages in gray and white matter (Fig. 35-5). The size of the lesions, their hemorrhagic character, and the extent of the surrounding edema distinguish them from the typical postinfectious ADEM. In many other ways they are similar, except for their severity. Many cases terminate fatally in 2 to 4 days, but in others, survival is longer. Patients with a similar clinical picture who are thought to have the same disease on the basis of brain biopsy examinations have recovered with almost no residual symptoms. In one of the fatal cases reported by


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Neurology_Adams. a similar clinical picture who are thought to have the same disease on the basis of brain biopsy examinations have recovered with almost no residual symptoms. In one of the fatal cases reported by Adams and colleagues, the illness evolved more slowly—over a period of 2 to 3 weeks—while another patient died with temporal lobe herniation within 12 h. A single recurrence of the disease after an interval of 2 years was observed in one of our patients.


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Neurology_Adams. Brain abscess, subdural empyema, focal embolic encephalomalacia, and acute encephalitis, especially as a result of type 1 herpes simplex virus, are the important considerations in the differential diagnosis.


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Neurology_Adams. The pathologic findings are distinctive. On sectioning of the brain, the white matter of one or both hemispheres is destroyed almost to the point of liquefaction. The involved tissue is pink or yellow-gray and flecked with multiple petechial hemorrhages. Similar changes are often found in the brainstem and cerebellar peduncles and probably in the spinal cord (one form of acute necrotizing myelitis and Devic disease). On histologic examination, one finds widespread necrosis of small blood vessels and brain tissue around the vessels, with intense cellular infiltration, multiple small hemorrhages, and an inflammatory reaction in the meninges of variable intensity. The pathologic picture resembles that of disseminated encephalomyelitis in its perivascular distribution, with the added features of a more widespread necrosis and a tendency of lesions to form large foci in the cerebral hemispheres. The vascular lesions result in a characteristic exudation of fibrin into the vessel wall and


Neurology_Adams

Neurology_Adams. of a more widespread necrosis and a tendency of lesions to form large foci in the cerebral hemispheres. The vascular lesions result in a characteristic exudation of fibrin into the vessel wall and surrounding tissue. It is possible that certain patients presenting with a severe myelitis are suffering from a necrotizing lesion of similar type, but pathologic evidence in support of this view has been difficult to obtain. Fibrin exudation in an acute fatal hemorrhagic myelitis was present in a case examined by Adams and colleagues. We also have experience with a case of this nature that evolved in steps over several months, resulting in death, with a cellular reaction in the spinal fluid on each of several lumbar punctures. There was partial steroid responsiveness.


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Neurology_Adams. The etiology of this condition remains obscure, but its resemblance to other inflammatory-demyelinating diseases should be emphasized. The similarities of the histologic changes to those of disseminated encephalomyelitis, noted above, suggest that the two diseases are related forms of the same fundamental process. In fact, cases combining both types of pathologic changes have been described (Fisher et al). It is noteworthy that, among the small number of patients who have recovered from what appeared to be a typical necrotizing hemorrhagic encephalitis, a few have gone on to develop typical MS. Treatment of Hurst Disease High-dose intravenous corticosteroids are generally used in the treatment of acute necrotizing hemorrhagic encephalopathy and can produce a favorable result. The use of plasma exchange and intravenous immunoglobulin, as for ADEM, can apparently be successful when instituted early.


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Neurology_Adams. This form of brain inflammation, pertinent to the special circumstance of bone marrow transplantation, is included here for lack of a better category with which to align it. Months or years after transplantation, subacute hemiparesis, seizures, behavioral changes, or ataxia arise and may be attributed to PML, a viral infection of the white matter (Chap. 33), or another viral process that is known to occur with circumstances of immunosuppression. The MRI shows white matter lesions that conform to an MS-like periventricular orientation or a more confluent leukoencephalopathy. A patient under our care demonstrated lesions in the splenium of the corpus callosum that extended into the adjacent centrum semiovale (Fig. 35-6). Several reports emphasize a mild vasculitis in the territory of the white matter lesions (Padovan et al). Almost all affected patients have concurrently displayed a tender erythematous, macular rash that is typical of acute graft-versus-host disease. There are also


Neurology_Adams

Neurology_Adams. white matter lesions (Padovan et al). Almost all affected patients have concurrently displayed a tender erythematous, macular rash that is typical of acute graft-versus-host disease. There are also rare, but well-characterized, neuromuscular complications of graft-versus-host disease (Chap. 43).


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Neurology_Adams. Adams RD, Cammermeyer J, Denny-Brown D: Acute hemorrhagic encephalopathy. J Neuropathol Exp Neurol 8:1, 1949. Adams RD, Kubik CS: The morbid anatomy of the demyelinating diseases. Am J Med 12:510, 1952. Aimard G, Confavreux C, Ventre JJ, et al: Etude de 213 cas de sclerose en plaques traites par l’azathiaprine de 1967–1982. Rev Neurol 139:509, 1983. Akasbi M, Berenguer A, Saiz A, et al: White matter abnormalities in primary Sjögren syndrome. QJM 105:433, 2012. Alter M, Halpern L, Kurland LT, et al: Multiple sclerosis in Israel. Arch Neurol 7:253, 1962. Anderson DW, Ellenberg JH, Leventhal CM, et al: Revised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol 31:333, 1992. Arnason BGW: Interferon beta in multiple sclerosis. Neurology 43:641, 1993. Ascherio A, Zhang SM, Hernan MA, et al: Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 344:327, 2001.


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Neurology_Adams. Ascherio A, Zhang SM, Hernan MA, et al: Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 344:327, 2001. Barkhof F, Bruck W, De Groot CJ, et al: Remyelinated lesions in multiple sclerosis: Magnetic resonance image appearance. Arch Neurol 60:1073, 2003. Barnes D, Hughes RAC, Morris RW, et al: Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 349:902, 1997. Barnett MH, Prineas JW: Relapsing and remitting multiple sclerosis. Pathology of the newly forming plaque. Ann Neurol 55:458, 2004. Beck RW, Chandler DL, Cole SR, et al: Interferon β-1a for early multiple sclerosis: CHAMPS trial subgroup analysis. Ann Neurol 51:481, 2002. Beck RW, Cleary PA, Anderson MM Jr, et al: A randomized controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326:581, 1992.


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Neurology_Adams. Beck RW, Cleary PA, Anderson MM Jr, et al: A randomized controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326:581, 1992. Beck RW, Trobe JD, Moke PS, et al: Highand low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: Experience of the optic neuritis treatment trial. Arch Ophthalmol 121:944, 2003. Beebe GW, Kurtzke JF, Kurland LT, et al: Studies on the natural history of multiple sclerosis: 3. Epidemiologic analyses of the Army experience in World War II. Neurology 17:1, 1967. Birk K, Rudick R: Pregnancy and multiple sclerosis. Arch Neurol 43:719, 1986. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366:1870, 2012. Bobholz JA, Rao SM: Cognitive dysfunction in multiple sclerosis: A review of recent developments. Curr Opin Neurol 16:283, 2003.