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Multiple sclerosis (MS) is the most common chronic neurological disorder in young Caucasian adults (1-3), but after more than a century of active research, its etiology remains unknown. It is a peculiar disease, because it is restricted to the central nervous system (CNS), is not associated with any other neurological or systemic disorder, and has no animal counterpart. In the typical form, MS evolves through relapses and remissions, although, in the majority of patients, a secondary progressive phase ensues (4-7). Its classic pathological hallmark is the plaque, which, in the acute form of the disease, shows perivascular infiltration and contains macrophages filled with myelin debris (8-16). This classic view is challenged by magnetic resonance imaging (MRI) and pathological studies, which reveal substantial early axonal damage. [ABSTRACT FROM AUTHOR]

Future immunotherapy for immune-mediated neurologic diseases is in a state of rapid development. The current therapeutic arsenal consists of a mixture of older and new agents whose uses are actively being redefined. Our current understanding of mechanisms of action of established medications and developing approaches will be discussed in relation to disease pathogenesis models. Also, we will present a framework for incorporating current and future therapies into rational treatment strategies and will be addressed together with a review of relevant clinical studies. Mechanisms of immunotherapy and clinical strategies will be discussed in the context of multiple sclerosis (MS). [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS). The destruction of the oligodendrocyte-derived myelin lamellae leads to loss of nerve insulation and results in impairment of fast saltatory conduction. Axons and neurons are also damaged and lost in the disease process (1), and cell repopulation is hampered by the inability of mature neurons to undergo cell division. An attractive approach for reestablishing electrochemical circuits in MS would be to restore the function or number of myelin-generating oligodendrocytes in early lesions, to act as bridges that guide and promote axonal regeneration. [ABSTRACT FROM AUTHOR]

Treatment directed at the progressive phase of multiple sclerosis (MS) is the most difficult (Table 1). Immunosuppressive therapies, such as total lymphoid irradiation (TLI), cyclosporine, methotrexate, 2-chlorodeoxyadenosine (2-CdA), cyclophosphamide, mitoxantrone, azathioprine, interferon (IFN), steroids, intravenous immunoglobulin (IVIg), and plasma exchange have shown some positive clinical effects in progressive disease. However, all of these nonspecific immunosuppressants suffer from the same basic defect; they may temporarily halt a rapidly progressive downhill course, but it is difficult, or dangerous, to employ them for more than a few months to 1 or 2 years. Thus, because MS is an illness of decades, not months, immunosuppressive therapy is only at best a temporary solution. [ABSTRACT FROM AUTHOR]

Cyclophosphamide has long been a widely used alkylating agent in the treatment of malignancies, notably hematologic malignancies and, despite its long history, continues to find new uses in immune-mediated nonmalignant processes. Although cyclophosphamide has been studied as a treatment for multiple sclerosis (MS) for the past 30 years, it is only after successful trials of mitoxantrone with improved designs employing magnetic resonance imaging (MRI) as a surrogate marker that clinical researchers have become highly confident of the use of this class of drugs. Trial results suggest that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on MRI or in patients in earlier stages of progression. There is no evidence of efficacy in primary-progressive (PPMS) or later secondary-progressive MS (SPMS). Although they are usually considered a general immunosuppressive agent, immunologic studies indicate that proliferating myelin-specific T-cells may be preferentially eliminated in MS. Side effects include nausea, alopecia, infertility, bladder toxicity, and risk of malignancy. Cyclophosphamide is usually given as every 4- to 8-week outpatient intravenous (IV) pulse therapy with or without corticosteroids and is usually well tolerated. Cyclophosphamide is recommended for patients with MS whose disease is not controlled by first-line agents and those with rapid worsening. [ABSTRACT FROM AUTHOR]

Numerous autoimmune diseases affect women during their reproductive years, including multiple sclerosis (MS), rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, and Sjögren's syndrome (1-3). Most autoimmune diseases become clinically silent or are pushed into so-called "remission" during pregnancy (4). Pregnancy poses a challenge for the immune system because the fetus is essentially an allograft harboring antigens from the father. In response, pregnancy induces immune deviation in the mother, protective to the fetus, and, at the same time, alters autoimmune responses to the benefit of the pregnant woman. Studies examining disease course support the protective effect of pregnancy in the context of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) afflicts approximately 250,000 to 350,000 individuals in the United States and is the most common autoimmune disease involving the nervous system. Multifocal immune-mediated destruction of the myelin sheath and secondary axonal damage in the central nervous system (CNS) results in variable neurological dysfunction, most commonly altered vision, incoordination, gait ataxia, paralysis, and sensory disturbances (1). Relapsing-remitting MS (RRMS), where patients have attacks of neurological dysfunction lasting days to weeks followed by complete to near complete recovery, accounts for approximately 85% of patients with MS. After approximately 10 years, the majority of patients with RRMS have entered secondary-progressive MS (SPMS), where there is gradual accumulation of neurological dysfunction without recovery. This may represent a neurodegenerative phase of the disease that results from axon transfection and neuronal loss (2,3). Primary-progressive MS (PPMS), accounting for approximately 15% of patients with MS, is similar to SPMS, except that these patients do not have a preceding relapsing-remitting phase. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) has emerged as a treatable disorder with several disease-modifying therapies (DMTs) now licensed in the United States for MS treatment. These are interferon (IFN)-β-1a (two formulations, Avonex and Rebif), IFN-β-1b (Betaseron), glatiramer acetate (GA) (Copaxone), and mitoxantrone (Novantrone). Although all five DMTs were tested in phase III randomized controlled trials (RCTs) and shown to be superior to placebo, no therapy has ever been shown to halt disease progression (1-5). Because MS is a chronic, unpredictable disease and clinically variable from patient to patient, treatment choices for patients with MS can pose a dilemma, despite the plethora of information. Nonetheless, the use of DMTs in definite relapsing-remitting MS (RRMS) is well established. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is one of the more common symptoms of multiple sclerosis (MS), with an estimated point prevalence of 30 to 60%. The lifetime prevalence may be closer to 50 to 75%, as cognitive symptoms tend to progress with disease progression. Unfortunately, cognitive dysfunction can also be one of the more disabling symptoms of MS (1-3). This chapter reviews the prevalence, diagnosis, possible etiologies, assessment, and treatment of cognitive disorders in MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss for which the exact immunopathogenic mechanisms underlying disease initiation and progression are unknown. In the last two decades, magnetic resonance imaging (MRI) has become the most important laboratory diagnostic and monitoring tool in MS (1). Moreover, MRI is 5 to 10 times more sensitive than clinical data in the assessment of disease activity (2). The sensitivity of T2-weighted images (T2-WI) in detection of MS lesions, together with the ability of gadolinium (Gd)-enhanced T1-WI to reflect increased blood-brain barrier (BBB) permeability associated with active inflammatory activity, allows the demonstration of spatial and temporal dissemination of MS lesions earlier than is possible from clinical assessments. Therefore, in the last decade, metrics derived from conventional MRI have been widely employed in therapeutic clinical trials (3-6). Several conventional MRI protocols, in conjunction with clinical assessment, are now routinely used to detect therapeutic effects and extend clinical observations (7). [ABSTRACT FROM AUTHOR]

The diagnosis and prognosis of multiple sclerosis (MS) has changed dramatically over the years from the first descriptions from St. Lidwina of Schiedam (1380-1433) and Augustus D'Este (grandson of George III) between 1822 and 1848 to the pathological descriptions of Cruveilhier (1829-1842) and Carswell (1838). Serious study and synthesis of clinical and pathological human MS began with the work of Jean Martin Charcot at the Salpetriere in Paris in the last three decades of the 19th century. Recently, there has been a trend to classify MS as an immune-mediated demyelinating disease of the central nervous system (CNS). This classification is useful as a diagnostic tool, as demonstrated by Schumacher (1962) and Poser (1983). The new diagnostic criteria (1), which is discussed in detail in the remainder of this chapter, has changed the diagnosis, prognosis, and treatment of MS. [ABSTRACT FROM AUTHOR]

The signs and symptoms of multiple sclerosis (MS) range from those that command the immediate attention of patient and doctor to those that escape the attention of patient and family over the course a lifetime. For nearly a century, we have discovered some examples of MS found at autopsy that were never recognized by the family. In the modern era, we find examples of MS on magnetic resonance imaging (MRI) scans done for other reasons, such as a motor vehicle accident. [ABSTRACT FROM AUTHOR]