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InternalMed_Harrison. Chronic Subdural Hematoma (Fig. 457e-5) A subacutely evolving syndrome due to subdural hematoma occurs days or weeks after injury with drowsiness, headache, confusion, or mild hemiparesis, usually in alcoholics and in the elderly and often after only minor or unnoticed trauma. On imaging studies, chronic subdural hematomas appear as crescentic clots over the convexity of one or both hemispheres, most commonly in the frontotemporal region (Fig. 457e-3). A history of FIGURE 457e-5 Computed tomography scan of chronic bilateral subdural hematomas of different ages. The collections began as acute hematomas and have become hypodense in comparison to the adjacent brain after a period during which they were isodense and difficult to appreciate. Some areas of resolving blood are contained on the more recently formed collection on the left (arrows).


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InternalMed_Harrison. trauma may or may not be elicited in relation to chronic subdural hematoma; the injury may have been trivial and forgotten, particularly in the elderly and those with clotting disorders. Headache is common but not invariable. Additional features that may appear weeks later include slowed thinking, vague change in personality, seizure, or a mild hemiparesis. Headache fluctuates in severity, sometimes with changes in head position.


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InternalMed_Harrison. Bilateral chronic subdural hematomas produce perplexing clinical syndromes, and the initial clinical impression may be of a stroke, brain tumor, drug intoxication, depression, or a dementing illness. Drowsiness, inattentiveness, and incoherence of thought are generally more prominent than focal signs such as hemiparesis. Rarely, chronic hematomas cause brief episodes of hemiparesis or aphasia that are indistinguishable from transient ischemic attacks. Patients with undetected bilateral subdural hematomas have a low tolerance for surgery, anesthesia, and drugs that depress the nervous system; drowsiness or confusion persists for long periods postoperatively.


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InternalMed_Harrison. CT without contrast initially shows a low-density mass over the convexity of the hemisphere (Fig. 457e-5). Between 2 and 6 weeks after the initial bleeding, the clot becomes isodense compared to adjacent brain and may be inapparent. Many subdural hematomas that are several weeks in age contain areas of blood and intermixed serous fluid. Bilateral chronic hematomas may fail to be detected because of the absence of lateral tissue shifts; this circumstance in an older patient is suggested by a “hypernormal” CT scan with fullness of the cortical sulci and small ventricles. Infusion of contrast material demonstrates enhancement of the vascular fibrous capsule surrounding the collection. MRI reliably identifies subacute and chronic hematomas.


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InternalMed_Harrison. Clinical observation coupled with serial imaging is a reasonable approach to patients with few symptoms, such as headache alone, and in those with small chronic subdural collections. Treatment of minimally symptomatic chronic subdural hematoma with glucocorticoids is favored by some clinicians, but surgical evacuation is more often successful. The fibrous membranes that grow from the dura and encapsulate the collection require removal to prevent recurrent fluid accumulation. Small hematomas are resorbed, leaving only the organizing membranes. On imaging studies, very chronic subdural hematomas are difficult to distinguish from hygromas, which are collections of CSF from a rent in the arachnoid membrane.


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InternalMed_Harrison. The patient who has briefly lost consciousness or been stunned after a minor head injury usually becomes fully alert and attentive within minutes but may complain of headache, dizziness, faintness, nausea, a single episode of emesis, difficulty with concentration, a brief amnestic period, or slight blurring of vision. This typical concussion syndrome has a good prognosis with little risk of subsequent deterioration. Children are particularly prone to drowsiness, vomiting, and irritability, symptoms that are sometimes delayed for several hours after apparently minor injuries. Vasovagal syncope that follows injury may cause undue concern. Generalized or frontal headache is common in the following days. It may be migrainous (throbbing and hemicranial) in nature or aching and bilateral. After several hours of observation, patients with minor injury may be accompanied home and observed for a day by a family member or friend, with written instructions to return if symptoms worsen.


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InternalMed_Harrison. Persistent severe headache and repeated vomiting in the context of normal alertness and no focal neurologic signs is usually benign, but CT should be obtained and a longer period of observation is appropriate. The decision to perform imaging tests also depends on clinical signs that indicate that the impact was severe (e.g., persistent confusion, periorbital or mastoid hematoma, repeated vomiting, palpable skull fracture), on the seriousness of other bodily injuries, and on the degree of surveillance that can be anticipated after discharge. Two studies have indicated that older age, two or more episodes of vomiting, >30 min of retrograde or persistent anterograde amnesia, seizure, and concurrent drug or alcohol intoxication are sensitive (but not specific) indicators of intracranial hemorrhage that justify CT scanning. It may be appropriate to be more liberal in obtaining CT scans in children because a small number, even without loss of consciousness, will have intracranial traumatic


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InternalMed_Harrison. that justify CT scanning. It may be appropriate to be more liberal in obtaining CT scans in children because a small number, even without loss of consciousness, will have intracranial traumatic lesions but this exposes the child to radiation.


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InternalMed_Harrison. Concussion in Sports In the current absence of adequate data, a common sense approach to athletic concussion has been to remove the individual from play immediately and avoid contact sports for at least several days after a mild injury and for a longer period if there are more severe injuries or if there are protracted neurologic symptoms such as headache and difficulty concentrating. No individual should return to play unless all symptoms have resolved and an assessment has been made by a health care professional who has experience with treatment of concussion. Once cleared, the individual can then begin a graduated program of increasing activity. Younger athletes are particularly likely to experience protracted concussive symptoms, and a slower return to play in this age group may be reasonable. These guidelines are designed in part to avoid a perpetuation of symptoms but also to prevent the rare second impact syndrome, in which diffuse and fatal cerebral swelling follows a second


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InternalMed_Harrison. These guidelines are designed in part to avoid a perpetuation of symptoms but also to prevent the rare second impact syndrome, in which diffuse and fatal cerebral swelling follows a second minor head injury.


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InternalMed_Harrison. In the past, mental decline in boxers late in their careers had been called dementia pugilistica. There is some evidence that repeated concussions from other sports are associated with a similar delayed and progressive cognitive disorder that is due mainly to the deposition of tau protein in cortical neurons. The brains of these patients display deposition of tau protein in the superficial cortical layers, and particularly in the depths of sulci within the frontal cortices, a pattern named chronic traumatic encephalopathy (CTE) that is quite unlike other degenerative conditions. CTE is an intensively studied and provocative entity. Its contribution, if any, to late-life dementia and parkinsonism in former athletes, soldiers, or others who have sustained repeated concussive injuries is unknown. CTE is also discussed in Chap. 444e.


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InternalMed_Harrison. Patients who are not fully alert or have persistent confusion, behavioral changes, extreme dizziness, or focal neurologic signs such as hemiparesis should be admitted to the hospital and have cerebral imaging. A cerebral contusion or hematoma will usually be found. Common syndromes include: (1) delirium with a disinclination to be examined or moved, expletive speech, and resistance if disturbed (anterior temporal lobe contusions); (2) a quiet, disinterested, slowed mental state (abulia) alternating with irascibility (inferior frontal and frontopolar contusions); (3) a focal deficit such as aphasia or mild hemiparesis (due to subdural hematoma or convexity contusion or, less often, carotid artery dissection); (4) confusion and inattention, poor performance on simple mental tasks, and fluctuating orientation (associated with several types of injuries, including those described above, and with medial frontal contusions and interhemispheric subdural hematoma); (5) repetitive vomiting,


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InternalMed_Harrison. orientation (associated with several types of injuries, including those described above, and with medial frontal contusions and interhemispheric subdural hematoma); (5) repetitive vomiting, nystagmus, drowsiness, and unsteadiness (labyrinthine concussion, but occasionally due to a posterior fossa subdural hematoma or vertebral artery dissection); and (6) diabetes insipidus (damage to the median eminence or pituitary stalk). Injuries of this degree are often complicated by drug or alcohol intoxication, and clinically inapparent cervical spine injury may be present. Blast injuries are often accompanied by rupture of the tympanic membranes.


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InternalMed_Harrison. After surgical removal of hematomas, most patients in this category improve over weeks. During the first week, the state of alertness, memory, and other cognitive functions often fluctuate, and agitation and somnolence are common. Behavioral changes tend to be worse at night, as with many other encephalopathies, and may be treated with small doses of antipsychotic medications. Subtle abnormalities of attention, intellect, spontaneity, and memory return toward normal weeks or months after the injury, sometimes abruptly. Persistent cognitive problems are discussed below.


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InternalMed_Harrison. Patients who are comatose from the moment of injury require immediate neurologic attention and resuscitation. After intubation, with care taken to immobilize the cervical spine, the depth of coma, pupillary size and reactivity, limb movements, and Babinski responses are assessed. As soon as vital functions permit and cervical spine x-rays and a CT scan have been obtained, the patient should be transported to a critical care unit. Hypoxia should be reversed, and normal saline used as the resuscitation fluid in preference to albumin. The finding of an epidural or subdural hematoma or large intracerebral hemorrhage is usually an indication for prompt surgery and intracranial decompression in an otherwise salvageable patient. Measurement of ICP with a ventricular catheter or fiberoptic device in order to guide treatment has been favored by many units but has not improved outcome. Hyperosmolar intravenous solutions are used in various regimens to limit intracranial pressure. The inherently


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InternalMed_Harrison. in order to guide treatment has been favored by many units but has not improved outcome. Hyperosmolar intravenous solutions are used in various regimens to limit intracranial pressure. The inherently appealing approach of removing portions of the skull in order to decompress the intracranial contents, as has been successful for brain swelling after cerebral infarction, has so far not proven effective for traumatic brain injury. The use of prophylactic antiepileptic medications has been recommended, but there is little supportive data. Management of raised ICP, a frequent feature of severe head injury, is discussed in Chap. 330.


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InternalMed_Harrison. In severe head injury, the clinical features of eye opening, motor responses of the limbs, and verbal output have been found to be generally predictive of outcome. These three responses are assessed by the Glasgow Coma Scale; a score between 3 and 15 is assigned (Table 457e-1). Over 85% of patients with aggregate scores of <5 die within 24 h. However, a number of patients with slightly higher scores, including a few without pupillary light responses, survive, suggesting that an initially aggressive approach is justified in most patients. Patients <20 years old, particularly children, may make remarkable recoveries after having grave early neurologic signs. In one large study of severe head injury, 55% of children had a good outcome at 1 year, compared with 21% of adults. Older age, increased ICP, early hypoxia or hypotension, compression of the brainstem on CT or MRI, and a delay in the evacuation of large intracranial hemorrhages are indicators of a poor prognosis.


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InternalMed_Harrison. The postconcussion syndrome refers to a state following minor head injury consisting of combinations of fatigue, dizziness, headache, and difficulty in concentration. The syndrome simulates asthenia and anxious depression. Based on experimental models, it has been proposed that subtle axonal shearing lesions or as yet undefined biochemical alterations account for the cognitive symptoms. In moderate and severe trauma, neuropsychological changes such as difficulty with attention and memory and other cognitive deficits are undoubtedly present, sometimes severe, but many problems identified by formal 5 To loud voice 3 Confused, disoriented Note: Coma score = E + M + V. Patients scoring 3 or 4 have an 85% chance of dying or remaining vegetative, whereas scores >11 indicate only a 5–10% likelihood of death or vegetative state and 85% chance of moderate disability or good recovery. Intermediate scores correlate with proportional chances of recovery.


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InternalMed_Harrison. testing do not affect daily functioning. Test scores tend to improve rapidly during the first 6 months after injury and then more slowly for years.


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InternalMed_Harrison. Management of the postconcussive syndrome requires the identification and treatment of each separate element of depression, sleeplessness, anxiety, persistent headache, and dizziness. A clear explanation of the problems that may follow concussion has been shown to reduce subsequent complaints. Care is taken to avoid prolonged use of drugs that produce dependence. Headache may initially be treated with acetaminophen and small doses of amitriptyline. Vestibular exercises (Chap. 28) and small doses of vestibular suppressants such as promethazine (Phenergan) may be helpful when dizziness is the main problem. Patients who after minor or moderate injury have difficulty with memory or with complex cognitive tasks at work may be reassured that these problems usually improve over 6–12 months, and workload may be reduced in the interim. It is sometimes helpful to obtain serial and quantified neuropsychological testing in order to adjust the work environment to the patient’s abilities and to


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InternalMed_Harrison. workload may be reduced in the interim. It is sometimes helpful to obtain serial and quantified neuropsychological testing in order to adjust the work environment to the patient’s abilities and to document improvement over time. Whether cognitive exercises are useful in contrast to rest and a reduction in mental challenges is uncertain. Previously energetic and resilient individuals usually have the best recoveries. In patients with persistent symptoms, the possibility exists of malingering or prolongation as a result of litigation.


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InternalMed_Harrison. multiple sclerosis and other Demyelinating Diseases Stephen L. Hauser, Douglas S. Goodin Demyelinating disorders are immune-mediated conditions charac-terized by preferential destruction of central nervous system (CNS) 458 myelin. The peripheral nervous system (PNS) is spared, and most patients have no evidence of an associated systemic illness. Multiple sclerosis, the most common disease in this category, is second only to trauma as a cause of neurologic disability beginning in early to middle adulthood.


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InternalMed_Harrison. Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by chronic inflammation, demyelination, gliosis (scarring), and neuronal loss; the course can be relapsing-remitting or progressive. Lesions of MS typically develop at different times and in different CNS locations (i.e., MS is said to be disseminated in time and space). Approximately 350,000 individuals in the United States and 2.5 million individuals worldwide are affected. The clinical course can be extremely variable, ranging from a benign condition to a rapidly evolving and incapacitating disease requiring profound lifestyle adjustments.


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InternalMed_Harrison. PATHOGENESIS Pathology New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells, predominantly T cells and macrophages, which also infiltrate the surrounding white matter. At sites of inflammation, the blood-brain barrier (BBB) is disrupted, but unlike vasculitis, the vessel wall is preserved. Involvement of the humoral immune system is also evident; small numbers of B lymphocytes also infiltrate the nervous system, myelin-specific autoantibodies are present on degenerating myelin sheaths, and complement is activated. Demyelination is the hallmark of the pathology, and evidence of myelin degeneration is found at the earliest time points of tissue injury. A remarkable feature of MS plaques is that oligodendrocyte precursor cells survive—and in many lesions are present in even greater numbers than in normal tissue—but these cells fail to differentiate into mature myelin-producing cells. In some lesions, surviving oligodendrocytes or those that differentiate from


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InternalMed_Harrison. in even greater numbers than in normal tissue—but these cells fail to differentiate into mature myelin-producing cells. In some lesions, surviving oligodendrocytes or those that differentiate from precursor cells partially remyelinate the surviving naked axons, producing so-called shadow plaques. As lesions evolve, there is prominent astrocytic proliferation (gliosis). Over time, ectopic lymphocyte follicle-like structures, consisting of aggregates of T and B cells resembling secondary lymphoid tissue, appear in the meninges and especially overlying deep cortical sulci and also in perivascular spaces. Although relative sparing of axons is typical of MS, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. Thus MS is not solely a disease of myelin, and neuronal pathology is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation, demyelination, and plaque formation are also present in the cerebral


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InternalMed_Harrison. and neuronal pathology is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation, demyelination, and plaque formation are also present in the cerebral cortex, and significant axon loss indicating death of neurons is widespread, especially in advanced cases (see “Neurodegeneration,” below).


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InternalMed_Harrison. Physiology Nerve conduction in myelinated axons occurs in a saltatory manner, with the nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes (Fig. 458-1). This produces considerably faster conduction velocities (∼70 m/s) than the slow velocities (∼1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment. This can happen when the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath. A temporary conduction block often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked Na+ channels Node of Ranvier


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InternalMed_Harrison. Na+ channels Node of Ranvier FIGURE 458-1 Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin.


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InternalMed_Harrison. axon (Fig. 458-1). This redistribution ultimately allows continuous propagation of nerve action potentials through the demyelinated segment. Conduction block may be incomplete, affecting highbut not low-frequency volleys of impulses. Variable conduction block can occur with raised body temperature or metabolic alterations and may explain clinical fluctuations that vary from hour to hour or appear with fever or exercise. Conduction slowing occurs when the demyelinated segments of the axonal membrane are reorganized to support continuous (slow) nerve impulse propagation. Epidemiology MS is approximately threefold more common in women than men. The age of onset is typically between 20 and 40 years (slightly later in men than in women), but the disease can present across the lifespan. Approximately 10% of cases begin before age 18 years of age, and a small percentage of cases begin before the age of 10 years.


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InternalMed_Harrison. Geographical gradients have been repeatedly observed in MS, with the highest known prevalence for MS (250 per 100,000) in the Orkney Islands, located north of Scotland. In other temperate zone areas (e.g., northern North America, northern Europe, southern Australia, and southern New Zealand), the prevalence of MS is 0.1–0.2%. By contrast, in the tropics (e.g., Asia, equatorial Africa, and the Middle East), the prevalence is often 10to 20-fold less. The prevalence of MS has increased steadily (and dramatically) in several regions around the world over the past half-century, presumably reflecting the impact of some environmental shift. Moreover, the fact that this increase has occurred primarily (or exclusively) in women indicates that women are more responsive to this environmental change. Well-established risk factors for MS include vitamin D deficiency, exposure to Epstein-Barr virus (EBV) after early childhood, and cigarette smoking.


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InternalMed_Harrison. Vitamin D deficiency is associated with an increase in MS risk, and data suggest that ongoing deficiency may also increase disease activity after MS begins. Immunoregulatory effects of vitamin D could explain these apparent relationships. Exposure of the skin to ultraviolet-B (UVB) radiation from the sun is essential for the biosynthesis of vitamin D, and this endogenous production is the most important source of vitamin D in most individuals; a diet rich in fatty fish represents another source of vitamin D. At high latitudes, the amount of UVB radiation reaching the earth’s surface is often insufficient, particularly during winter months, and consequently, low serum levels of vitamin D are common in temperate zones. The common practice to avoid direct 2662 sun exposure and the widespread use of sun block, which (at sun protection factor [SPF] 15) blocks 94% of the incoming UVB radia tion, would be expected to exacerbate any population-wide vitamin D deficiency.


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InternalMed_Harrison. Evidence of a remote EBV infection playing some role in MS is supported by numerous epidemiologic and laboratory studies. A higher risk of infectious mononucleosis (associated with relatively late EBV infection) and higher antibody titers to latency-associated EBV nuclear antigen have been repeatedly associated with MS risk, although a causal role for EBV has not been established. A history of cigarette smoking has also been associated with MS risk. Interestingly, in an animal model of MS, the lung was identified as a critical site for activation of pathogenic T lymphocytes responsible for autoimmune demyelination. Recent data in MS models have also shown that high levels of dietary sodium activate pathogenic autoreactive T lymphocytes, suggesting that consumption of a high-salt diet, now widespread in the Western world, might be part of the explanation for the observed increase in the prevalence of MS in recent years.


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InternalMed_Harrison. Whites are inherently at higher risk for MS than Africans or Asians, even when residing in a similar environment. MS also aggregates within some families, and adoption, half-sibling, twin, and spousal studies indicate that familial aggregation is due to genetic, and not environmental, factors (Table 458-1).


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InternalMed_Harrison. Susceptibility to MS is polygenic, with each gene contributing a relatively small amount to the overall risk. The strongest susceptibility signal in genome-wide studies maps to the HLA-DRB1 gene in the class II region of the major histocompatibility complex (MHC), and this association accounts for approximately 10% of the disease risk. This HLA association, which was first described several decades ago, suggests that MS, at its core, is an antigen-specific autoimmune disease. Whole-genome association studies have now identified approximately 110 other MS susceptibility variants, each of which individually has only a modest effect on MS risk. Most of these MS-associated genes have known roles in the adaptive immune system, for example the genes for the interleukin (IL) 7 receptor (CD127), IL-2 receptor (CD25), and T cell costimulatory molecule LFA-3 (CD58); some variants also influence susceptibility to other autoimmune diseases in addition to MS. The variants identified so far all


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InternalMed_Harrison. IL-2 receptor (CD25), and T cell costimulatory molecule LFA-3 (CD58); some variants also influence susceptibility to other autoimmune diseases in addition to MS. The variants identified so far all lack specificity and sensitivity for MS; thus, at present, they are not useful for diagnosis or to predict the future course of the disease.


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InternalMed_Harrison. immunology A proinflammatory autoimmune response directed against a component of CNS myelin, and perhaps other neural elements as well, remains the cornerstone of current concepts of MS pathogenesis.


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InternalMed_Harrison. AutoreActiVe t lymphocyteS Myelin basic protein (MBP), an intracellular protein involved in myelin compaction, is an important T cell antigen in experimental allergic encephalomyelitis (EAE), a laboratory model, and probably also in human MS. Activated MBP-reactive T cells have been identified in the blood, in cerebrospinal fluid (CSF), and within MS lesions. Moreover, DRB1*15:01 may influence the autoimmune response because it binds with high affinity to a fragment of MBP (spanning amino acids 89–96), stimulating T cell responses to this self-protein. Two different populations of proinflammatory T cells are likely to mediate autoimmunity in MS. T-helper type 1 (TH1) cells producing interferon γ (IFN-γ) are one key effector population, and more recently, a role for highly proinflammatory TH17 T cells has been established. TH17 cells are induced by transforming growth factor β (TGF-β) and IL-6 and are amplified by IL-21 and IL-23. TH17 cells, and levels of their corresponding cytokine


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InternalMed_Harrison. TH17 T cells has been established. TH17 cells are induced by transforming growth factor β (TGF-β) and IL-6 and are amplified by IL-21 and IL-23. TH17 cells, and levels of their corresponding cytokine IL-17, are increased in MS lesions and also in the circulation of people with active MS. High circulating levels of IL-17 may also be a marker of a more severe course of MS. TH1 cytokines, including IL-2, tumor necrosis factor (TNF)-α, and IFN-γ, also play key roles in activating and maintaining autoimmune responses, and TNF-α and IFN-γ may directly injure oligodendrocytes or the myelin membrane.


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InternalMed_Harrison. humorAl Autoimmunity B cell activation and antibody responses also appear to be necessary for the full development of demyelinating lesions to occur, both in experimental models and in human MS. Clonally restricted populations of activated, antigen-experienced, memory B cells and plasma cells are present in MS lesions, in lymphoid follicle-like structures in the meninges overlying the cerebral cortex, and in the CSF. Similar or identical clonal populations are found in each compartment, indicating that a highly focused B cell response is occurring locally within the CNS in MS. Myelin-specific autoantibodies, some directed against an extracellular myelin protein, myelin oligodendrocyte glycoprotein (MOG), have been detected bound to vesiculated myelin debris in MS plaques. In the CSF, elevated levels of locally synthesized immunoglobulins and oligoclonal antibodies, derived from clonally restricted CNS B cells and plasma cells, are also characteristic of MS. The pattern of oligoclonal


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InternalMed_Harrison. levels of locally synthesized immunoglobulins and oligoclonal antibodies, derived from clonally restricted CNS B cells and plasma cells, are also characteristic of MS. The pattern of oligoclonal banding is unique to each individual, and attempts to identify the targets of these antibodies have been largely unsuccessful.


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InternalMed_Harrison. triggerS Serial magnetic resonance imaging (MRI) studies in early relapsing-remitting MS reveal that bursts of focal inflammatory disease activity occur far more frequently than would have been predicted by the frequency of relapses. Thus, early in MS, most disease activity is clinically silent. Although the triggers causing these bursts are unknown, molecular mimicry between environmental agents, presumably pathogens, and myelin antigens activating pathogenic T cells may be responsible (Chap. 377e).


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InternalMed_Harrison. Neurodegeneration Axonal damage occurs in every newly formed MS lesion, and cumulative axonal loss is considered to be one important cause of irreversible neurologic disability in MS. As many as 70% of axons are lost from the lateral corticospinal (e.g., motor) tracts in patients with advanced paraparesis from MS, and longitudinal MRI studies suggest there is progressive axonal loss over time within established, inactive lesions. Demyelination can result in reduced trophic support for axons, redistribution of ion channels, and destabilization of action potential membrane potentials. Axons can adapt initially to these injuries, but over time, distal and retrograde degeneration often occurs. Therefore, promoting remyelination remains an important therapeutic goal.


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InternalMed_Harrison. In progressive MS, a key unresolved question is whether the primary neurodegenerative process occurs primarily in the cerebral cortex, the white matter, or in some combination of the two sites. As noted above, meningeal infiltrates of B and T cells are particularly prominent in progressive MS cases, and these “lymphoid follicles” are associated with underlying microglial activation, gray matter plaques, and loss of cortical neurons. White matter lesions may also contribute to late progressive MS; inactive plaques are often noninflammatory at the center, but at the edges, microglia and macrophages and evidence of ongoing axonal injury can be found. This suggests that a simmering, and possibly concentrically expanding, axonopathy may be present, even in the most chronic cases. In addition, a diffuse low-grade inflammation across large areas of white matter may be present, associated with reduced myelin staining and axonal injury (“dirty white matter”). Another characteristic of


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InternalMed_Harrison. a diffuse low-grade inflammation across large areas of white matter may be present, associated with reduced myelin staining and axonal injury (“dirty white matter”). Another characteristic of progressive MS is that inflammation is often present without a concomitant disruption of the BBB; possibly, this feature might explain the failure of immunotherapies not capable of crossing the BBB to benefit patients with progressive MS.


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InternalMed_Harrison. Evidence supports a role of one, or more likely several, of the following mechanisms in progressive MS. Axonal and neuronal death may result from glutamate-mediated excitotoxicity, oxidative injury, iron accumulation, and/or mitochondrial failure either occurring as a consequence of free-radical damage or due to accumulation of deletions in mitochondrial DNA.


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InternalMed_Harrison. The onset of MS may be abrupt or insidious. Symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Indeed, at autopsy, approximately 0.1% of individuals who were asymptomatic during life will be found, unexpectedly, to have pathologic evidence of MS. Similarly, in the modern era, an MRI scan obtained for an unrelated reason may show evidence of asymptomatic MS. Symptoms of MS are extremely varied and depend on the location and severity of lesions within the CNS (Table 458-2). Examination often reveals evidence of neurologic dysfunction, often in asymptomatic locations. For example, a patient may present with symptoms in one leg but signs in both.


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InternalMed_Harrison. Weakness of the limbs may manifest as loss of strength, speed, or dexterity, as fatigue, or as a disturbance of gait. Exercise-induced weakness is a characteristic symptom of MS. The weakness is of the upper motor neuron type (Chap. 30) and is usually accompanied by other pyramidal signs such as spasticity, hyperreflexia, and Babinski signs. Occasionally a tendon reflex may be lost (simulating a lower motor neuron lesion) if an MS lesion disrupts the afferent reflex fibers in the spinal cord (see Fig. 30-2). Spasticity (Chap. 30) is commonly associated with spontaneous and movement-induced muscle spasms. More than 30% of MS patients have moderate to severe spasticity, especially in the legs. This is often accompanied by painful spasms interfering with ambulation, work, or self-care. Occasionally spasticity provides support for the body weight during ambulation, and in these cases, treatment of spasticity may actually do more harm than good.


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InternalMed_Harrison. Optic neuritis (ON) presents as diminished visual acuity, dimness, or decreased color perception (desaturation) in the central field of vision. These symptoms can be mild or may progress to severe visual loss. Rarely, there is complete loss of light perception. Visual symptoms are generally monocular but may be bilateral. Periorbital pain (aggravated by eye movement) often precedes or accompanies the visual loss. An afferent pupillary defect (Chap. 39) is usually present. Funduscopic examination may be normal or reveal optic disc swelling (papillitis). Pallor of the optic disc (optic atrophy) commonly follows ON. Uveitis is uncommon and should raise the possibility of alternative diagnoses such as sarcoid or lymphoma. Visual blurring in MS may result from ON or diplopia (double vision); if the symptom resolves when either eye is covered, the cause is diplopia.


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InternalMed_Harrison. Visual blurring in MS may result from ON or diplopia (double vision); if the symptom resolves when either eye is covered, the cause is diplopia. Diplopia may result from internuclear ophthalmoplegia (INO) or from palsy of the sixth cranial nerve (rarely the third or fourth). An INO consists of impaired adduction of one eye due to a lesion in the ipsilateral medial longitudinal fasciculus (Chaps. 41e and 42). Percentage Symptom of Cases Symptom of Cases Source: After WB Matthews et al: McAlpine’s Multiple Sclerosis. New York, Churchill Livingstone, 1991. Prominent nystagmus is often observed in the abducting eye, along 2663 with a small skew deviation. A bilateral INO is particularly suggestive of MS. Other common gaze disturbances in MS include (1) a horizontal gaze palsy, (2) a “one and a half” syndrome (horizontal gaze palsy plus an INO), and (3) acquired pendular nystagmus.


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InternalMed_Harrison. Sensory symptoms are varied and include both paresthesias (e.g., tingling, prickling sensations, formications, “pins and needles,” or painful burning) and hypesthesia (e.g., reduced sensation, numbness, or a “dead” feeling). Unpleasant sensations (e.g., feelings that body parts are swollen, wet, raw, or tightly wrapped) are also common. Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) indicates that the spinal cord is the origin of the sensory disturbance. It is often accompanied by a bandlike sensation of tightness around the torso. Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur anywhere on the body and can change locations over time. Ataxia usually manifests as cerebellar tremors (Chap. 450). Ataxia may also involve the head and trunk or the voice, producing a characteristic cerebellar dysarthria (scanning speech).


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InternalMed_Harrison. Ataxia usually manifests as cerebellar tremors (Chap. 450). Ataxia may also involve the head and trunk or the voice, producing a characteristic cerebellar dysarthria (scanning speech). Bladder dysfunction is present in >90% of MS patients, and in a third of patients, dysfunction results in weekly or more frequent episodes of incontinence. During normal reflex voiding, relaxation of the bladder sphincter (α-adrenergic innervation) is coordinated with contraction of the detrusor muscle in the bladder wall (muscarinic cholinergic innervation). Detrusor hyperreflexia, due to impairment of suprasegmental inhibition, causes urinary frequency, urgency, nocturia, and uncontrolled bladder emptying. Detrusor sphincter dyssynergia, due to loss of synchronization between detrusor and sphincter muscles, causes difficulty in initiating and/or stopping the urinary stream, producing hesitancy, urinary retention, overflow incontinence, and recurrent infection.


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InternalMed_Harrison. Constipation occurs in >30% of patients. Fecal urgency or bowel incontinence is less common (<15%) but can be socially debilitating. Cognitive dysfunction can include memory loss; impaired attention; difficulties in executive functioning, memory, and problem solving; slowed information processing; and problems shifting between cognitive tasks. Euphoria (elevated mood) was once thought to be characteristic of MS but is actually uncommon, occurring in <20% of patients. Cognitive dysfunction sufficient to impair activities of daily living is rare. Depression, experienced by approximately half of patients, can be reactive, endogenous, or part of the illness itself and can contribute to fatigue.


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InternalMed_Harrison. Depression, experienced by approximately half of patients, can be reactive, endogenous, or part of the illness itself and can contribute to fatigue. Fatigue (Chap. 29) is experienced by 90% of patients; this symptom is the most common reason for work-related disability in MS. Fatigue can be exacerbated by elevated temperatures, depression, expending exceptional effort to accomplish basic activities of daily living, or sleep disturbances (e.g., from frequent nocturnal awakenings to urinate). Sexual dysfunction may manifest as decreased libido, impaired genital sensation, impotence in men, and diminished vaginal lubrication or adductor spasms in women. Facial weakness due to a lesion in the pons may resemble idiopathic Bell’s palsy (Chap. 455). Unlike Bell’s palsy, facial weakness in MS is usually not associated with ipsilateral loss of taste sensation or retro-auricular pain.


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InternalMed_Harrison. Vertigo may appear suddenly from a brainstem lesion, superficially resembling acute labyrinthitis (Chap. 28). Hearing loss (Chap. 43) may also occur in MS but is uncommon. Ancillary Symptoms Heat sensitivity refers to neurologic symptoms produced by an elevation of the body’s core temperature. For example, unilateral visual blurring may occur during a hot shower or with physical exercise (Uhthoff ’s symptom). It is also common for MS symptoms to worsen transiently, sometimes dramatically, during febrile illnesses (see “Acute Attacks or Initial Demyelinating Episodes,” below). Such heat-related symptoms probably result from transient conduction block (see above).


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InternalMed_Harrison. Lhermitte’s symptom is an electric shock–like sensation (typically induced by flexion or other movements of the neck) that radiates down 2664 the back into the legs. Rarely, it radiates into the arms. It is generally self-limited but may persist for years. Lhermitte’s symptom can also occur with other disorders of the cervical spinal cord (e.g., cervical spondylosis). Paroxysmal symptoms are distinguished by their brief duration (10 s to 2 min), high frequency (5–40 episodes per day), lack of any alteration of consciousness or change in background electroencephalogram during episodes, and a self-limited course (generally lasting weeks to months). They may be precipitated by hyperventilation or movement. These syndromes may include Lhermitte’s symptom; tonic contractions of a limb, face, or trunk (tonic seizures); paroxysmal dysarthria and ataxia; paroxysmal sensory disturbances; and several other less well-characterized syndromes. Paroxysmal symptoms probably result from spontaneous


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InternalMed_Harrison. or trunk (tonic seizures); paroxysmal dysarthria and ataxia; paroxysmal sensory disturbances; and several other less well-characterized syndromes. Paroxysmal symptoms probably result from spontaneous discharges, arising at the edges of demyelinated plaques and spreading to adjacent white matter tracts. Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia (Chap. 455) can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, seventh, and ninth cranial nerve, respectively. Trigeminal neuralgia (tic douloureux) is a very brief lancinating facial pain often triggered by an afferent input from the face or teeth. Most cases of trigeminal neuralgia are not MS related; however, atypical features such as onset before age 50 years, bilateral symptoms, objective sensory loss, or nonparoxysmal pain should raise the possibility that MS could be responsible. Facial myokymia consists of either persistent rapid flickering contractions of the facial


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InternalMed_Harrison. objective sensory loss, or nonparoxysmal pain should raise the possibility that MS could be responsible. Facial myokymia consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the orbicularis oculus) or a contraction that slowly spreads across the face. It results from lesions of the corticobulbar tracts or brainstem course of the facial nerve.


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InternalMed_Harrison. Four clinical types of MS exist (Fig. 458-2): 1. Relapsing/remitting MS (RRMS) accounts for 85% of MS cases at onset and is characterized by discrete attacks that generally evolve over days to weeks (rarely over hours). With initial attacks, there is often substantial or complete recovery over the ensuing weeks to months, but as attacks continue over time recovery may be less evident (Fig. 458-2A). Between attacks, patients are neurologically stable. 2.


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InternalMed_Harrison. 2. Secondary progressive MS (SPMS) always begins as RRMS (Fig. 458-2B). At some point, however, the clinical course changes so that the patient experiences a steady deterioration in function unassociated with acute attacks (which may continue or cease during the progressive phase). SPMS produces a greater amount of fixed neurologic disability than RRMS. For a patient with RRMS, the risk of developing SPMS is ∼2% each year, meaning that the great majority of RRMS ultimately evolves into SPMS. SPMS appears to represent a late stage of the same underlying illness as RRMS. 3.


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InternalMed_Harrison. 3. Primary progressive MS (PPMS) accounts for ∼15% of cases. These patients do not experience attacks but only a steady functional decline from disease onset (Fig. 458-2C). Compared to RRMS, the sex distribution is more even, the disease begins later in life (mean age ∼40 years), and disability develops faster (at least relative to the onset of the first clinical symptom). Despite these differences, PPMS appears to represent the same underlying illness as RRMS. 4. Progressive/relapsing MS (PRMS) overlaps PPMS and SPMS and accounts for ∼5% of MS patients. Like patients with PPMS, these patients experience a steady deterioration in their condition from disease onset. However, like SPMS patients, they experience occasional attacks superimposed upon their progressive course (Fig. 458-2D).


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InternalMed_Harrison. There is no definitive diagnostic test for MS. Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS (Table 458-3). Symptoms must last for >24 h and occur as distinct episodes that are separated by a month or more. In patients who have only one of the two required signs on neurologic examination, the second may be documented by abnormal tests such as MRI or evoked potentials (EPs). Similarly, in the most recent diagnostic scheme, the second clinical event (in time) may be supported solely by MRI findings, consisting of either the development of new focal white matter lesions on MRI or the simultaneous presence of both an enhancing lesion and a nonenhancing lesion in an asymptomatic location. In patients whose course is progressive from onset for ≥6 months without superimposed relapses, documentation of intrathecal IgG synthesis


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InternalMed_Harrison. and a nonenhancing lesion in an asymptomatic location. In patients whose course is progressive from onset for ≥6 months without superimposed relapses, documentation of intrathecal IgG synthesis may be used to support a diagnosis of PPMS.


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InternalMed_Harrison. DIAGNOSTIC TESTS Magnetic Resonance Imaging MRI has revolutionized the diagnosis and management of MS (Fig. 458-3); characteristic abnormalities are found in >95% of patients, although more than 90% of the lesions visualized by MRI are asymptomatic. An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) into the parenchyma. Such leakage occurs early in the development of an MS lesion and serves as a useful marker of inflammation. Gd enhancement typically persists for approximately 1 month, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on spin-echo (T2-weighted) and proton-density images. Lesions are frequently oriented perpendicular to the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson’s fingers). Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions larger than 6 mm located in the corpus


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InternalMed_Harrison. to the pathologic pattern of perivenous demyelination (Dawson’s fingers). Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions larger than 6 mm located in the corpus callosum, periventricular white matter, brain-stem, cerebellum, or spinal cord are particularly helpful diagnostically. Current criteria for the use of MRI in the diagnosis of MS are shown in Table 458-3.


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InternalMed_Harrison. The total volume of T2-weighted signal abnormality (the “burden of disease”) shows a significant (albeit weak) correlation with clinical disability, as do measures of brain atrophy. Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted imaging. Black holes may be a marker of irreversible demyelination and axonal loss, although even this measure depends on the timing of the image acquisition (e.g., most acute Gd-enhancing T2 lesions are T1 dark). Newer MRI methods such as magnetization transfer ratio (MTR) FIGURE 458-2 Clinical course of multiple sclerosis (MS). imaging and proton magnetic resonance spectroscopic imaging A. Relapsing/remitting MS (RRMS). B. Secondary progressive MS (SPMS). (MRSI) may ultimately serve as surrogate markers of clinical disabil-


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InternalMed_Harrison. C. Primary progressive MS (PPMS). D. Progressive/relapsing MS (PRMS). ity. MRSI can quantitate molecules such as N-acetyl aspartate, which 2 or more attacks; objective None clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack 2 or more attacks; objec-Dissemination in space, demonstrated by tive clinical evidence of • ≥1 T2 lesion on MRI in at least 2 out of 4 1 lesion MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) 1 attack; objective clini-Dissemination in time, demonstrated by cal evidence of 2 or more • Simultaneous presence of asymptomatic lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan 1 attack; objective clinical Dissemination in space and time, demonstrated evidence of 1 lesion (clini-by: cally isolated syndrome) • ≥1 T2 lesion in at least 2 out of 4 MS-typical regions of the CNS (periventricular,


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InternalMed_Harrison. clinical Dissemination in space and time, demonstrated evidence of 1 lesion (clini-by: cally isolated syndrome) • ≥1 T2 lesion in at least 2 out of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) • Simultaneous presence of asymptomatic lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan


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InternalMed_Harrison. Insidious neurologic 1 year of disease progression (retrospectively or progression suggestive of prospectively determined) MS (PPMS) 2 out of the 3 following criteria Evidence for dissemination in space in the brain based on ≥1 T2+ lesions in the MS-characteristic periventricular, juxtacortical, or infratentorial regions Evidence for dissemination in space in the spinal cord based on ≥2 T2+ lesions in the cord Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PPMS, primary progressive multiple sclerosis. Source: From CH Polman et al: Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the “McDonald Criteria.” Ann Neurol 69:292, 2011. is a marker of axonal integrity, and MTR may be able to distinguish demyelination from edema.


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InternalMed_Harrison. is a marker of axonal integrity, and MTR may be able to distinguish demyelination from edema. Evoked Potentials EP testing assesses function in afferent (visual, auditory, and somatosensory) or efferent (motor) CNS pathways. EPs use computer averaging to measure CNS electric potentials evoked by repetitive stimulation of selected peripheral nerves or of the brain. 2665


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InternalMed_Harrison. These tests provide the most information when the pathways studied are clinically uninvolved. For example, in a patient with a remitting and relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP following posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in this circumstance would permit a diagnosis of clinically definite MS (Table 458-3). Abnormalities on one or more EP modalities occur in 80–90% of MS patients. EP abnormalities are not specific to MS, although a marked delay in the latency of a specific EP component (as opposed to a reduced amplitude or distorted wave-shape) is suggestive of demyelination.


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InternalMed_Harrison. Cerebrospinal Fluid CSF abnormalities found in MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG. The total CSF protein is usually normal. Various formulas distinguish intrathecally synthesized IgG from IgG that may have entered the CNS passively from the serum. One formula, the CSF IgG index, expresses the ratio of IgG to albumin in the CSF divided by the same ratio in the serum. The IgG synthesis rate uses serum and CSF IgG and albumin measurements to calculate the rate of CNS IgG synthesis. The measurement of oligoclonal bands (OCBs) by agarose gel electrophoresis in the CSF also assesses intrathecal production of IgG. Two or more discrete OCBs, not present in a paired serum sample, are found in >75% of patients with MS. OCBs may be absent at the onset of MS, and in individual patients, the number of bands may increase with time.


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InternalMed_Harrison. A mild CSF pleocytosis (>5 cells/μL) is present in ∼25% of cases, usually in young patients with RRMS. A pleocytosis of >75 cells/μL, the presence of polymorphonuclear leukocytes, or a protein concentration >1 g/L (>100 mg/dL) in CSF should raise concern that the patient may not have MS.


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InternalMed_Harrison. No single clinical sign or test is diagnostic of MS. The diagnosis is readily made in a young adult with relapsing and remitting symptoms involving different areas of CNS white matter. The possibility of an alternative diagnosis should always be considered (Table 458-4), particularly when (1) symptoms are localized exclusively to the posterior fossa, craniocervical junction, or spinal cord; (2) the patient is <15 or >60 years of age; (3) the clinical course is progressive from onset; (4) the patient has never experienced visual, sensory, or bladder symptoms; or (5) laboratory findings (e.g., MRI, CSF, or EPs) are atypical. Similarly, uncommon or rare symptoms in MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe muscular atrophy, peripheral neuropathy, episodic loss of consciousness, fever, headache, seizures, or coma) should increase concern about an alternative diagnosis. Diagnosis is also difficult in patients with a rapid or explosive (stroke-like) onset or with


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InternalMed_Harrison. fever, headache, seizures, or coma) should increase concern about an alternative diagnosis. Diagnosis is also difficult in patients with a rapid or explosive (stroke-like) onset or with mild symptoms and a normal neurologic examination. Rarely, intense inflammation and swelling may produce a mass lesion that mimics a primary or metastatic tumor. In the current era, the disorders most likely to be mistaken for MS are neuromyelitis optica (see below), sarcoid, vascular disorders (including antiphospholipid syndrome and vasculitis), and rarely CNS lymphoma. The specific tests required to exclude alternative diagnoses will vary with each clinical situation; however, an erythrocyte sedimentation rate, serum B12 level, ANA, and treponemal antibody should probably be obtained in all patients with suspected MS.


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InternalMed_Harrison. Most patients with clinically evident MS ultimately experience progressive neurologic disability. In older studies conducted mostly before disease-modifying therapies for MS were widely available, 15 years after onset, only 20% of patients had no functional limitation, and between one-third and one-half progressed to SPMS and required assistance with ambulation; furthermore, 25 years after onset, ∼80% of MS patients reached this level of disability. The long-term prognosis for untreated MS appears to have improved in recent years, at least in part because of the development of therapies for the early relapsing form of the disease. Although the prognosis in an individual is


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InternalMed_Harrison. FIGURE 458-3 Magnetic resonance imaging findings in multiple sclerosis (MS). A. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS. B. Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image in which the high signal of cerebrospinal fluid (CSF) has been suppressed. CSF appears dark, whereas areas of brain edema or demyelination appear high in signal as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease. C. Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the midthoracic spinal cord. D. Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows).


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InternalMed_Harrison. difficult to establish, certain clinical features suggest a more favorable prognosis. These include ON or sensory symptoms at onset; fewer than two relapses in the first year of illness; and minimal impairment after 5 years. By contrast, patients with truncal ataxia, action tremor, pyramidal symptoms, or a progressive disease course are more likely to become disabled. Patients with a long-term favorable course are likely to have developed fewer MRI lesions during the early years of disease, and vice versa. Importantly, some MS patients have a benign variant of MS and never develop neurologic disability. The likelihood of having benign MS is thought to be <20%. Patients with benign MS 15 years after onset who have entirely normal neurologic examinations are likely to maintain their benign course


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InternalMed_Harrison. In patients with their first demyelinating event (i.e., a clinically isolated syndrome), the brain MRI provides prognostic information. With three or more typical T2-weighted lesions, the risk of developing MS after 20 years is ∼80%. Conversely, with a normal brain MRI, the likelihood of developing MS is <20%. Similarly, the presence of two or more Gd-enhancing lesions at baseline is highly predictive of future MS, as is the appearance of either new T2-weighted lesions or new Gd enhancement ≥3 months after the initial episode. Mortality as a direct consequence of MS is uncommon, although it has been estimated that the 25-year survival is only 85% of expected. Death can occur during an acute MS attack, although this is distinctly rare. More commonly, death occurs as a complication of MS (e.g., pneumonia in a debilitated individual). Death can also result from suicide. Early disease-modifying therapy seems to reduce this excess mortality.


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InternalMed_Harrison. Effect of Pregnancy Pregnant MS patients experience fewer attacks than expected during gestation (especially in the last trimester), but more attacks than expected in the first 3 months postpartum. When considering the pregnancy year as a whole (i.e., 9 months of pregnancy plus 3 months postpartum), the overall disease course is unaffected. Decisions about childbearing should thus be made based on (1) the mother’s physical state, (2) her ability to care for the child, and (3) the availability of social support. Disease-modifying therapy is Acute disseminated encephalomyelitis (ADEM) Antiphospholipid antibody syndrome Behçet’s disease Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoen


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InternalMed_Harrison. Acute disseminated encephalomyelitis (ADEM) Antiphospholipid antibody syndrome Behçet’s disease Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoen Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy) Human immunodeficiency virus (HIV) infection Ischemic optic neuropathy (arteritic and nonarteritic) Lyme disease Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS) Neoplasms (e.g., lymphoma, glioma, meningioma) Sarcoid Sjögren’s syndrome Stroke and ischemic cerebrovascular disease Syphilis Systemic lupus erythematosus and related collagen vascular disorders Tropical spastic paraparesis (HTLV-1/2 infection) Vascular malformations (especially spinal dural AV fistulas) Vasculitis (primary CNS or other) Vitamin B12 deficiency Abbreviations: AV, arteriovenous; CNS, central nervous system; HTLV, human T cell lymphotropic virus.


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InternalMed_Harrison. Abbreviations: AV, arteriovenous; CNS, central nervous system; HTLV, human T cell lymphotropic virus. generally discontinued during pregnancy, although the actual risk from the interferons and glatiramer acetate (see below) appears to be low. Therapy for MS can be divided into several categories: (1) treatment of acute attacks, (2) treatment with disease-modifying agents that reduce the biologic activity of MS, and (3) symptomatic therapy. Treatments that promote remyelination or neural repair do not currently exist, but several promising approaches are being actively investigated. The Expanded Disability Status Score (EDSS) is a widely used measure of neurologic impairment in MS (Table 458-5). Most patients with EDSS scores <3.5 have RRMS, walk normally, and are generally not disabled; by contrast, patients with EDSS scores >5.5 have progressive MS (SPMS or PPMS), are gait-impaired, and, typically, are occupationally disabled.


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InternalMed_Harrison. When patients experience acute deterioration, it is important to consider whether this change reflects new disease activity or a “pseudoexacerbation” resulting from an increase in ambient temperature, fever, or an infection. When the clinical change is thought to reflect a pseudoexacerbation, glucocorticoid treatment is inappropriate. Glucocorticoids are used to manage either first attacks or acute exacerbations. They provide short-term clinical benefit by reducing the severity and shortening the duration of attacks. Whether treatment provides any long-term benefit on the course of the illness is less clear. Therefore, mild attacks are often not treated. Physical and occupational therapy can help with mobility and manual dexterity.


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InternalMed_Harrison. Glucocorticoid treatment is usually administered as intravenous methylprednisolone, 500–1000 mg/d for 3–5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60–80 mg/d and gradually tapered over 2 weeks. Orally administered methylprednisolone or dexamethasone (in equivalent dosages) can be substituted for the intravenous portion of the therapy, although gastrointestinal complications are more common by this route. Outpatient treatment is almost always possible.


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InternalMed_Harrison. Side effects of short-term glucocorticoid therapy include fluid retention, potassium loss, weight gain, gastric disturbances, acne, and emotional lability. Concurrent use of a low-salt, potassium-2667 rich diet and avoidance of potassium-wasting diuretics are advisable. Lithium carbonate (300 mg orally bid) may help to manage emotional lability and insomnia associated with glucocorticoid therapy. Patients with a history of peptic ulcer disease may require cimetidine (400 mg bid) or ranitidine (150 mg bid). Proton pump inhibitors such as pantoprazole (40 mg orally bid) may reduce the likelihood of gastritis, especially when large doses are administered orally. Plasma exchange (five to seven exchanges: 40–60 mL/kg per exchange, every other day for 14 days) may benefit patients with fulminant attacks of demyelination that are unresponsive to glucocorticoids. However, the cost is high, and conclusive evidence of efficacy is lacking.


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InternalMed_Harrison. DISEASE-MODIFYING THERAPIES FOR RELAPSING FORMS OF MS (RRMS, SPMS WITH EXACERBATIONS) Ten such agents are approved by the U.S. Food and Drug Administration (FDA): (1) IFN-β-1a (Avonex), (2) IFN-β-1a (Rebif),


InternalMed_Harrison

InternalMed_Harrison. IFN-β-1b (Betaseron or Extavia), (4) glatiramer acetate (Copaxone), (5) natalizumab (Tysabri), (6) fingolimod (Gilenya), dimethyl fumarate (Tecfidera), (8) teriflunomide (Aubagio), mitoxantrone (Novantrone), and (10) alemtuzumab (Lemtrada). Several other promising agents are in varying stages of product development. Each of these treatments can also be used in SPMS patients who continue to experience attacks, both because SPMS can be difficult to distinguish from RRMS and because the available clinical trials, although not definitive, suggest that such patients may sometimes derive therapeutic benefit. Thus, in several phase 3 clinical trials, recipients of each of these agents experienced fewer clinical exacerbations and fewer new MRI lesions compared to placebo recipients (Table 458-6). Because of its potential toxicity as an immunosuppressant, mitoxantrone is generally reserved for patients with progressive disability who have failed other treatments. When considering the data in


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InternalMed_Harrison. Because of its potential toxicity as an immunosuppressant, mitoxantrone is generally reserved for patients with progressive disability who have failed other treatments. When considering the data in Table 458-6, however, it is important to note that the relative efficacy of the different agents cannot be determined by cross-trial comparisons. Relative efficacy can only be assessed from nonbiased head-to-head clinical trials.


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InternalMed_Harrison. Interferon-β IFN-β is a class I interferon originally identified by its antiviral properties. Efficacy in MS probably results from immunomodulatory properties including (1) downregulating expression of MHC molecules on antigen-presenting cells, (2) reducing proinflammatory and increasing regulatory cytokine levels, (3) inhibiting T cell proliferation, and (4) limiting the trafficking of inflammatory cells in the CNS. IFN-β reduces the attack rate and improves disease severity measures such as EDSS progression and MRI-documented disease burden. IFN-β should be considered in patients with either RRMS or SPMS with superimposed relapses. In patients with SPMS but without relapses, efficacy has not been established. Head-to-head trials suggest that dosing IFN-β more frequently and at higher doses has better efficacy but is also more likely to induce neutralizing antibodies (see below). IFN-β-1a (Avonex), 30 μg, is administered by intramuscular injection once every week. IFN-β-1a (Rebif),


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InternalMed_Harrison. has better efficacy but is also more likely to induce neutralizing antibodies (see below). IFN-β-1a (Avonex), 30 μg, is administered by intramuscular injection once every week. IFN-β-1a (Rebif), 44 μg, is administered by subcutaneous injection three times per week. IFN-β-1b (Betaseron or Extavia), 250 μg, is administered by subcutaneous injection every other day.


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InternalMed_Harrison. Common side effects of IFN-β therapy include flulike symptoms (e.g., fevers, chills, and myalgias) and mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia). Rarely, more severe hepatotoxicity may occur. Subcutaneous IFN-β also causes reactions at the injection site (e.g., pain, redness, induration, or, rarely, skin necrosis). Side effects can usually be managed with concomitant nonsteroidal anti-inflammatory medications. Depression, increased spasticity, and cognitive changes have been reported, although these symptoms can also be due to the underlying disease. In any event, side effects due to IFN-β therapy usually subside over time.


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InternalMed_Harrison. 0.0 1.0 = No disability, minimal signs in one FS (i.e., grade 1) 1.5 = No disability, minimal signs in more than one FS (more than one grade 1) 2.0 = Minimal disability in one FS (one FS grade 2, others 0 or 1) 2.5 = Minimal disability in two FS (two FS grade 2, others 0 or 1) 3.0 = Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in three or four FS (three/four FS grade 2, others 0 or 1) although fully ambulatory 3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; or two FS grade 3; or five FS grade 2 (others 0 or 1) 4.0 4.5 5.0 5.5 = Ambulatory without aid or rest for ∼100 m 6.0 = Unilateral assistance required to walk about 100 m with or without resting 6.5 = Constant bilateral assistance required to walk about 20 m without resting 7.0 = Unable to walk beyond about 5 m even with aid; essentially restricted to wheelchair; wheels self and transfers alone 7.5 = Unable to take more than a few steps;


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InternalMed_Harrison. walk about 20 m without resting 7.0 = Unable to walk beyond about 5 m even with aid; essentially restricted to wheelchair; wheels self and transfers alone 7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid to transfer 8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of day; retains many self-care functions; generally has effective use of arms 8.5 = Essentially restricted to bed much of the day; has some effective use of arm(s); retains some self-care functions 9.0 9.5 = Totally helpless bed patient; unable to communicate or eat 10.0 = Death due to MS


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InternalMed_Harrison. A. Pyramidal functions 0 = Normal 1 = Abnormal signs without disability 2 = Minimal disability 3 = Mild or moderate paraparesis or hemiparesis, or severe monoparesis 4 = Marked paraparesis or hemiparesis, moderate quadriparesis, or 5 = Paraplegia, hemiplegia, or marked quadriparesis B. Cerebellar functions 0 = Normal 1 = Abnormal signs without disability 2 = Mild ataxia 3 = Moderate truncal or limb ataxia 4 = Severe ataxia all limbs 5 = Unable to perform coordinated movements due to ataxia C. Brainstem functions 0 = Normal 1 = Signs only 2 = Moderate nystagmus or other mild disability 3 = Severe nystagmus, marked extraocular weakness, or moderate disability of other cranial nerves 5 = Inability to swallow or speak


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InternalMed_Harrison. D. Sensory functions 1 = Vibration or figure-writing decrease only, in 1 or 2 limbs 2 = Mild decrease in touch or pain or position sense, and/or moderate decrease in vibration in 1 or 2 limbs, or vibratory decrease alone in 3 or 4 limbs 3 = Moderate decrease in touch or pain or position sense, and/or essentially lost vibration in 1 or 2 limbs, or mild decrease in touch or pain, and/or moderate decrease in all proprioceptive tests in 3 or 4 limbs 4 = Marked decrease in touch or pain or loss of proprioception, alone or combined, in 1 or 2 limbs or moderate decrease in touch or pain and/or severe proprioceptive decrease in more than 2 limbs 5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate decrease in touch or pain and/or loss of proprioception for most of the body below the head 6 = Sensation essentially lost below the head


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InternalMed_Harrison. E. Bowel and bladder functions 0 = Normal 1 = Mild urinary hesitancy, urgency, or retention 2 = Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary 4 = In need of almost constant catheterization 5 = Loss of bladder function 6 = Loss of bowel and bladder function F. Visual (or optic) functions 0 = Normal 1 = Scotoma with visual acuity (corrected) better than 20/30 2 = Worse eye with scotoma with maximal visual acuity (corrected) of 20/30 to 3 = Worse eye with large scotoma, or moderate decrease in fields, but with maximal visual acuity (corrected) of 20/60 to 20/99 4 = Worse eye with marked decrease of fields and maximal acuity (corrected) of 20/100 to 20/200; grade 3 plus maximal acuity of better eye of 20/60 or less 5 = Worse eye with maximal visual acuity (corrected) less than 20/200; grade 4 plus maximal acuity of better eye of 20/60 or less 6 = Grade 5 plus maximal visual acuity of better eye of 20/60 or less G. Cerebral (or mental) functions


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InternalMed_Harrison. G. Cerebral (or mental) functions Source: Adapted from JF Kurtzke: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33:1444, 1983.


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InternalMed_Harrison. Approximately 2–10% of IFN-β-1a (Avonex) recipients, 15–25% of IFN-β-1a (Rebif) recipients, and 30–40% of IFN-β-1b (Betaseron/ Extavia) recipients develop neutralizing antibodies to IFN-β, which may disappear over time. Two very large randomized trials (one with >2000 patients) provide unequivocal evidence that neutralizing antibodies reduce efficacy as determined by several MRI outcomes. Paradoxically, however, these same trials, despite abundant statistical power, failed to demonstrate any concomitant impact on the clinical outcomes of disability and relapse rate. The reason for this clinical-radiologic dissociation is unresolved. For a patient doing well on therapy, the presence of antibodies should not affect treatment. Conversely, for a patient doing poorly on therapy, alternative treatment should be considered, even if there are no detectable antibodies.


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InternalMed_Harrison. Glatiramer Acetate Glatiramer acetate is a synthetic, random polypeptide composed of four amino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine). Its mechanism of action may include (1) induction of antigen-specific suppressor T cells; (2) binding to MHC molecules, thereby displacing bound MBP; or (3) altering


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InternalMed_Harrison. Dose, Route, and Schedule Attack Rate, Mean Change in Disease Severity New T2 Lesionsd Total Burden of Disease aPercentage reductions (or increases) have been calculated by dividing the reported rates in the treated group by the comparable rates in the placebo group, except for magnetic resonance imaging (MRI) disease burden, which was calculated as the difference in the median percent change between the treated and placebo groups. bSeverity = 1 point Expanded Disability Status Score progression, sustained for 3 months (in the IFN-β-1a 30 μg qw trial, this change was sustained for 6 months; in the IFN-β-1b trial, this was over 3 years). cDifferent studies measured these MRI measures differently, making comparisons difficult (numbers for new T2 represent the best case scenario for each trial). dNew lesions seen on T2-weighted MRI. ep = .001. fp = .01. gp = .05.


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InternalMed_Harrison. Abbreviations: DMF, dimethyl fumarate; FDA, U.S. Food and Drug Administration; FGM, fingolimod; GA, glatiramer acetate; IFN-β, interferon β; IM, intramuscular; IV, intravenous; MTX, mitoxantrone; NR, not reported; NS, not significant; NTZ, natalizumab; PO, oral; q3mo, once every 3 months; qd, daily; qmo, once per month; qod, every other day; qw, once per week; qyr, once per year; SC, subcutaneous; TF, teriflunomide; tiw, three times per week.


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InternalMed_Harrison. the balance between proinflammatory and regulatory cytokines. Glatiramer acetate reduces the attack rate (whether measured clinically or by MRI) in RRMS. Glatiramer acetate also benefits disease severity measures, although, for clinical disability, this is less well established than for IFN-β. Nevertheless, two very large head-tohead trials demonstrated that the impact of glatiramer acetate on clinical relapse rates and disability was comparable to high-dose, high-frequency IFN-β. Therefore, glatiramer acetate should be considered as an equally effective alternative to IFN-β in RRMS patients. Its usefulness in progressive disease is unknown. Glatiramer acetate is administered by subcutaneous injection of either 20 mg every day or 40 mg thrice weekly. Injection-site reactions also occur with glatiramer acetate. Initially, these were thought to be less severe than with IFN-β, although two recent head-to-head comparisons of high-dose, high-frequency IFN-β to daily glatiramer acetate did


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InternalMed_Harrison. glatiramer acetate. Initially, these were thought to be less severe than with IFN-β, although two recent head-to-head comparisons of high-dose, high-frequency IFN-β to daily glatiramer acetate did not bear out this impression. In addition, approximately 15% of patients experience one or more episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety after injection. This systemic reaction is unpredictable, brief (duration <1 h), and tends not to recur. Finally, some patients experience lipoatrophy, which, on occasion, can be disfiguring and require cessation of treatment.


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InternalMed_Harrison. Natalizumab Natalizumab is a humanized monoclonal antibody directed against the α4 subunit of α4β1 integrin, a cellular adhesion molecule expressed on the surface of lymphocytes. It prevents lymphocytes from binding to endothelial cells, thereby preventing lymphocytes from penetrating the BBB and entering the CNS. Natalizumab is highly effective in reducing the attack rate and significantly improves all measures of disease severity in MS (both clinical and MRI). Moreover, it is well-tolerated, and the dosing schedule of monthly intravenous infusions makes it very convenient for patients. However, progressive multifocal leukoencephalopathy (PML), a life-threatening condition resulting from infection by the John Cunningham (JC) virus, has occurred in approximately 0.3% of patients treated with natalizumab. The incidence of PML is very low in the first year of treatment but then rises by the second year to reach a level of about 2 cases per 1000 patients per year. Nevertheless, the


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InternalMed_Harrison. with natalizumab. The incidence of PML is very low in the first year of treatment but then rises by the second year to reach a level of about 2 cases per 1000 patients per year. Nevertheless, the measurement of antibodies against the JC virus in the serum can be used to stratify this risk. Thus, in patients who do not have these antibodies, the risk of PML is either minimal or nonexistent (as long as they remain JC antibody free). Conversely, in patients who have these antibodies (especially those who have them in high titer), the risk may be as high as 0.6% or greater. The risk is also high in patients who have previously received immunosuppressive therapy. Natalizumab is currently recommended only for JC antibody–negative patients, unless they have failed alternative therapies or if they have a particularly aggressive disease course. Head-to-head data show that natalizumab is superior to low-dose (weekly) IFN-β-1a in RRMS. However, its relative efficacy compared to other agents has


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InternalMed_Harrison. have a particularly aggressive disease course. Head-to-head data show that natalizumab is superior to low-dose (weekly) IFN-β-1a in RRMS. However, its relative efficacy compared to other agents has not been established conclusively.


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InternalMed_Harrison. Natalizumab, 300 mg, is administered by IV infusion each month. Treatment with natalizumab is, in general, well tolerated. A small percentage (<10%) of patients experience hypersensitivity reactions (including anaphylaxis), and ∼6% develop neutralizing antibodies to the molecule (only half of which persist).


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InternalMed_Harrison. The major concern with long-term treatment is the risk of PML. Approximately half of the adult population is JC antibody positive, indicating that they experienced an asymptomatic infection with the JC virus at some time in the past. Nevertheless, because the risk is extremely low during the first year of treatment with natalizumab (regardless of antibody status), natalizumab can still be used safely in JC antibody–positive patients for a period of 12 months. After this time, in antibody-positive patients, a change to another disease-modifying therapy should be strongly considered. By contrast, persistently antibody-negative patients can be continued on treatment indefinitely. Up to 2% of seronegative MS patients undergoing treatment with natalizumab seroconvert annually; thus it is recommended that JC antibody status be assessed at 6-month intervals in all patients receiving treatment with this agent.


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InternalMed_Harrison. Fingolimod Fingolimod is a sphingosine-1-phosphate (S1P) inhibitor that prevents the egress of lymphocytes from the secondary lymphoid organs such as the lymph nodes and spleen. Its mechanism of action is probably due, in part, to the trapping of lymphocytes in the periphery and inhibiting their trafficking to the CNS. Fingolimod reduces the attack rate and significantly improves all measures of disease severity in MS. It is well tolerated, and the daily oral dosing schedule makes it very convenient for patients. A large head-to-head phase 3 randomized study demonstrated the superiority of fingolimod over low-dose (weekly) IFN-β-1a. However, its relative efficacy compared to other agents has not been established conclusively.


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InternalMed_Harrison. Fingolimod, 0.5 mg, is administered orally each day. Treatment with fingolimod is also, in general, well tolerated. Mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia) are more common than in controls, sometimes requiring discontinuation of the medication. Firstand second-degree heart block and bradycardia can also occur when fingolimod therapy is initiated. A 6-h period of observation (including electrocardiogram monitoring) is recommended for all patients receiving their first dose, and individuals with preexisting cardiac disease should probably not be treated with this agent. Other side effects 2670 include macular edema and, rarely, disseminated varicella-zoster virus (VZV) infection; prior to initiating therapy with fingolimod, an ophthalmic exam and VZV vaccination for seronegative individuals are indicated.


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InternalMed_Harrison. Dimethyl Fumarate (DMF) Although the precise mechanisms of action of DMF are not fully understood, it seems to have anti-inflammatory effects through its modulation of the expression of proinflammatory and anti-inflammatory cytokines. Also, DMF inhibits the ubiquitylation and degradation of nuclear factor E2-related factor 2 (Nrf2)—a transcription factor that binds to the antioxidant response elements (AREs) located on the DNA and thereby induces the transcription of several antioxidant proteins. DMF reduces the attack rate and significantly improves all measures of disease severity in MS patients. However, its twice-daily oral dosing schedule makes it somewhat less convenient for patients than daily oral therapies. In addition, compliance is likely to be less with a twice-daily dosing regimen—a factor that could be of concern given the observation (in a small clinical trial) that once-daily DMF lacks efficacy. A head-to-head trial provided evidence that DMF was superior to glatiramer


InternalMed_Harrison

InternalMed_Harrison. factor that could be of concern given the observation (in a small clinical trial) that once-daily DMF lacks efficacy. A head-to-head trial provided evidence that DMF was superior to glatiramer acetate on some outcome measures.


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InternalMed_Harrison. DMF, 240 mg, is administered orally twice each day. Gastrointestinal side effects (abdominal discomfort, nausea, vomiting, flushing, and diarrhea) are common at the start of therapy but generally subside with continued administration. Other adverse events included mild decreases in neutrophil and lymphocyte counts and mild elevations in liver enzymes. Nevertheless, in general, treatment with DMF is well tolerated after an initial period of adjustment. Following the release of DMF, four cases of PML were reported in patients receiving other products (not Tecfidera) that contained DMF. Each of these patients was lymphocytopenic, and most had received previous immunosuppressant therapy so that the relationship of DMF to the PML (if any) in these cases is uncertain. Nevertheless, these reports underscore the fact, stated previously, that long-term safety can never be guaranteed by the results of short-term trials. In the case of DMF for MS, only time and experience will tell us whether or


InternalMed_Harrison

InternalMed_Harrison. underscore the fact, stated previously, that long-term safety can never be guaranteed by the results of short-term trials. In the case of DMF for MS, only time and experience will tell us whether or not there is any cause for concern.


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InternalMed_Harrison. Teriflunomide Teriflunomide inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, which is a key part of the pathway for de novo pyrimidine biosynthesis from carbamoyl phosphate and aspartate. It is the active metabolite of the drug leflunomide (FDA-approved for rheumatoid arthritis), and it exerts its anti-inflammatory effects by limiting the proliferation of rapidly dividing T and B cells. This enzyme is not involved in the so-called “salvage pathway,” by which existing pyrimidine pools are recycled for DNA and RNA synthesis in resting and homeostatically proliferating cells. Consequently, teriflunomide is considered to be cytostatic rather than cytotoxic. Teriflunomide reduces the attack rate and significantly improves all measures of disease severity in MS patients. It is well tolerated, and its daily oral dosing schedule makes it very convenient for patients. A head-to-head trial suggested the equivalence, but not superiority, of teriflunomide and high-dose


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InternalMed_Harrison. It is well tolerated, and its daily oral dosing schedule makes it very convenient for patients. A head-to-head trial suggested the equivalence, but not superiority, of teriflunomide and high-dose (thriceweekly) IFN-β-1a. Teriflunomide, either 7 or 14 mg, is administered orally each day. In the pivotal clinical trials, mild hair thinning and gastrointestinal symptoms (nausea and diarrhea) were more common than in controls, but in general, treatment with teriflunomide was well tolerated. As with any new agent, the long-term safety is not guaranteed by the results of short-term trials. A major limitation, especially in women of childbearing age, is its possible teratogenicity (pregnancy category X); teriflunomide can remain in the bloodstream for 2 years, and it is recommended that exposed men and women who wish to conceive receive cholestyramine or activated charcoal to eliminate residual drug.


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InternalMed_Harrison. Mitoxantrone Hydrochloride Mitoxantrone, an anthracenedione, exerts its antineoplastic action by (1) intercalating into DNA and producing both strand breaks and interstrand cross-links, (2) interfering with RNA synthesis, and (3) inhibiting topoisomerase II (involved in DNA repair). The FDA approved mitoxantrone on the basis of a single (relatively small) phase 3 clinical trial in Europe, in addition to an even smaller phase 2 study completed earlier. Mitoxantrone received (from the FDA) the broadest indication of any current treatment for MS. Thus, mitoxantrone is indicated for use in SPMS, in PRMS, and in patients with worsening RRMS (defined as patients whose neurologic status remains significantly abnormal between MS attacks). Despite this broad indication, however, the data supporting its efficacy are weaker than for other approved therapies.


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InternalMed_Harrison. Mitoxantrone can be cardiotoxic (e.g., cardiomyopathy, reduced left ventricular ejection fraction, and irreversible congestive heart failure). As a result, a cumulative dose <140 mg/m2 is not recommended. At currently approved doses (12 mg/m2 every 3 months), the maximum duration of therapy can be only 2–3 years. Furthermore, >40% of women will experience amenorrhea, which may be permanent. Finally, there is risk of acute leukemia from mitoxantrone, estimated as at least a 1% lifetime risk, and this complication has been reported in several mitoxantrone-treated MS patients. Because of these risks, and a growing list of alternative therapies, mitoxantrone is now only rarely used for MS. It should not be used as a first-line agent in either RRMS or relapsing SPMS, but might be considered in selected patients with a progressive course who have failed other therapies.


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InternalMed_Harrison. Alemtuzumab Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen, which is expressed on both monocytes and lymphocytes. It causes lymphocyte depletion (of both B and T cells) and a change in the composition of lymphocyte subsets. Both of these changes, particularly the impact on lymphocyte subsets, are long lasting. In preliminary trials, alemtuzumab markedly reduced the attack rate and significantly improved all measures of disease severity in MS patients. In two phase 3 trials, however, its impact on clinical disability was less convincing. Notably, both trials used the active comparator of thrice-weekly, high-dose IFN-β-1a. The European and Canadian drug agencies were the first to approve this agent for use in RRMS; the FDA has also approved alemtuzumab, but only after an appeal following initial disapproval. The reasons for the initial disapproval were based on a perceived lack of a convincing disability effect and concerns over potential toxicity. The


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InternalMed_Harrison. only after an appeal following initial disapproval. The reasons for the initial disapproval were based on a perceived lack of a convincing disability effect and concerns over potential toxicity. The toxicities of concern were the occurrence (during the trial or thereafter) of (1) autoimmune diseases including thyroiditis, Graves’ disease, thrombocytopenia, hemolytic anemia, pancytopenia, antiglomerular basement membrane disease, and membranous glomerulonephritis; (2) malignancies including thyroid cancer, melanoma, breast cancer, and human papillomavirus (HPV)–related cancers; (3) serious infections; and (4) infusion reactions.


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InternalMed_Harrison. Initiating and Changing Treatment Previously, most patients with relapsing forms of MS received injectable agents (IFN-β or glatiramer acetate) as first-line therapy. However, with the introduction of effective and probably safe oral agents, including DMF, fingolimod, and teriflunomide, this has begun to change. In addition, the monthly infusion therapy natalizumab, which is highly effective, well tolerated, and apparently safe in JC antibody–negative patients, provides an attractive option in many cases. As noted above, with the exception of the first-generation injectable agents, long-term safety data are not available, and for the most part, comparative data are lacking. The value of combination therapy is also largely unknown, although a recent clinical trial demonstrated no added benefit to the combination of glatiramer acetate with low-dose, once-weekly IFN-β-1a.


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InternalMed_Harrison. Despite these unknowns, clinicians need to make decisions based on the best available evidence, coupled with practical considerations. One reasonable approach stratifies initial decision-making based on two levels of disease aggressiveness (Fig. 458-4). milD initiAl courSe In the case of recent onset, normal exam or minimal impairment (EDSS ≤2.5 or less), or low disease activity, either an injectable (IFN-β or glatiramer acetate) or an oral (DMF,


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InternalMed_Harrison. milD initiAl courSe In the case of recent onset, normal exam or minimal impairment (EDSS ≤2.5 or less), or low disease activity, either an injectable (IFN-β or glatiramer acetate) or an oral (DMF, Continue therapy Good response Intolerant or poor response Continue periodic clinical/ MRI assessments No change Successive trials of alternatives* Identify and treat any underlying infection or trauma Exacerbation Pseudoexacerbation Initial course Mild Moderate or severe Acute neurologic change Stable Relapsing-Remitting MS Functional impairment No functional impairment ?Low attack frequency or single attack ?Normal neurologic exam ?Low disease burden by MRI No Yes Repeat clinical exam and MRI in 6 months Clinical or MRI change Options: 1. Injectable (GA or IFB-˜) 2. Oral (DMF, fingolimod, or (teriflunomide) 3. Natalizumab (if JCV-negative) Options: 1. Oral (DMF, fingolimod, or (teriflunomide) 2. Natalizumab (if JCV-negative) Methylprednisolone/ prednisone Symptomatic therapy


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InternalMed_Harrison. Multiple Sclerosis and Other Demyelinating DiseasesChapter 458Secondary progressive MS With relapses Without relapses Consider 1. IFN-˜1a, or2. IFN-˜1b Intolerant or poor response 1. Mitoxantrone 2. Azathioprine 3. Methotrexate 4. Pulse cyclophosphamide 5. IVIg 6. Pulse methylprednisolone No proven treatment Primary progressive MS Symptomatic therapy Progressive MS Consider Rx with one of the following: FIGURE 458-4 Therapeutic decision-making for multiple sclerosis (MS). *Can include trials of different preparations of interferon β (IFN-β, particularly advancing from once-weekly (Avonex) to a more frequent (e.g., Rebif, Betaseron/Extavia) dosing regimen. Options also include use of natalizumab in JC virus–positive patients. MRI, magnetic resonance imaging.


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InternalMed_Harrison. fingolimod, or teriflunomide) agent is reasonable. Although head-to-head comparisons are not available, natalizumab is thought to be more effective than these other agents, and therefore, this therapy can be considered even in minimally affected, JCV antibody–seronegative patients. The injectable agents (IFN-β and glatiramer acetate) have a superb track record for safety but have a high nuisance factor due to the need for frequent injections, as well as bothersome side effects that contribute to noncompliance. Some of the oral agents (DMF and fingolimod) are probably more effective than the injectables, but long-term risks are mostly unknown; DMF produces bothersome gastrointestinal symptoms in many patients at least initially (can be mitigated by beginning at one-quarter strength and gradually advancing to full dose), and fingolimod can lead to bradycardia and other cardiac disturbances of unclear clinical significance. Teriflunomide may be less effective than the other oral agents,


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InternalMed_Harrison. advancing to full dose), and fingolimod can lead to bradycardia and other cardiac disturbances of unclear clinical significance. Teriflunomide may be less effective than the other oral agents, and there are concerns about its possible long-lasting pregnancy risks. Nevertheless, its long-term safety has likely been established because of its extensive human exposure as the active metabolite of leflunomide—a drug long approved by the FDA.


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InternalMed_Harrison. moDerAte or SeVere initiAl courSe In highly active disease or moderate impairment (EDSS >2.5), either a highly effective oral agent (DMF or fingolimod) or, if the patient is JC virus antibody seronegative, infusion therapy with natalizumab is recommended. Regardless of which agent is chosen first, treatment should probably be changed in patients who continue to have relapses, progressive neurologic impairment or, arguably, ongoing evidence of subclinical MRI activity (Fig. 458-4).


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InternalMed_Harrison. The long-term impact of these treatments on the disease course remains controversial, although several recent studies have shown that these agents improve the long-term outcome of MS including a prolongation of the time to reach certain disability outcomes (e.g., SPMS and requiring assistance to ambulate) and reduction in MS-related mortality. These benefits seem most conspicuous when treatment begins early in the RRMS stage of the illness. Unfortunately, however, already established progressive symptoms do not respond well to treatment with these disease-modifying therapies. Because progressive symptoms are likely to result from accumulated axonal and neuronal loss, many experts now believe that very early treatment with a disease-modifying drug is appropriate for most MS patients. It may also be reasonable to delay initiating treatment in patients with (1) normal neurologic exams, (2) a single attack or a low attack frequency, and (3) a low burden of disease as assessed by brain


InternalMed_Harrison

InternalMed_Harrison. may also be reasonable to delay initiating treatment in patients with (1) normal neurologic exams, (2) a single attack or a low attack frequency, and (3) a low burden of disease as assessed by brain MRI. Untreated patients, however, should be followed closely with periodic brain MRI scans; the need for therapy is reassessed if scans reveal evidence of ongoing, subclinical disease. Finally, vitamin D deficiency should be corrected in all patients with MS, and generally this requires oral supplementation with vitamin D3, 4000 to 5000 IU daily.


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InternalMed_Harrison. DISEASE-MODIFYING THERAPIES FOR PROGRESSIVE MS SPMS High-dose IFN-β probably has a beneficial effect in patients with SPMS who are still experiencing acute relapses. IFN-β is probably ineffective in patients with SPMS who are not having acute attacks. All of the other agents have not yet been studied in this patient population. Although mitoxantrone has been approved for patients with progressive MS, this is not the population studied in the pivotal trial. Therefore no evidence-based recommendation can be made with regard to its use in this setting.