Page 923 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Multiple Sclerosis

Benjamin M. Segal

Multiple sclerosis (MS), a chronic inflammatory demyelinating imbalance, tremor, and/or double vision. Serial MRI studies have
disorder of the central nervous system (CNS), is the most frequent demonstrated that the majority of MS lesions are actually clinically
cause of nontraumatic neurological disability among young adults silent. This is not surprising considering the abundance of
in the Western Hemisphere. Although MS is widely considered redundant nerve fiber tracts in the CNS and the commitment
a disease of North America and Europe, there is increasing of large areas of cerebral white matter to subtle personality traits
evidence that it is more common in other regions of the world, and cognitive skills. Consequently, CNS tissue damage may be
including Asia and the Middle East, than previously appreciated. inflicted surreptitiously during clinical remissions, making MRI
The median age at presentation is 28–31 years, which is, in part, a more sensitive indicator of disease activity compared with the
responsible for the disproportionately high social and economic history or the results of neurological examination (see Fig. 66.1).
tolls of the disease. Furthermore, the incidence of MS is increasing Patients with MS often recover function following a clinical
for unknown reasons. Fortunately there have been dramatic relapse, either partially or fully, particularly during the early
advances in the treatment of relapsing forms of MS over the clinical course. However, old symptoms can temporarily reemerge
past 20 years, spurred by the introduction of 14 disease-modifying when the core body temperature is elevated as a result of infection
agents (DMAs); and more are actively under development. These or strenuous exercise. This unmasking of latent deficits, referred
drugs significantly decrease the risk of relapse and lesion forma- to as the Uhthoff phenomenon, is a consequence of the physiologi-
tion. Consequently, the implications of being diagnosed with cal slowing of axon signal propagation that normally occurs at
relapsing-remitting MS have changed considerably in the span high core body temperatures. In healthy individuals, the degree
of a generation. Despite this success, significant challenges persist. of slowing has no clinical consequence, but in MS patients, it
There is a dire need for treatments that slow, or even halt, disability may precipitate the decompensation of white matter tracts already
accumulation in patients with progressive forms of MS, and for compromised by demyelination and axonal drop-out.
interventions that restore lost neurological functions across MS
subsets. Secondary Progressive MS (SPMS)
During the course of RRMS, relapses decrease in frequency
CLINICAL SUBSETS AND PHENOMENOLOGY over time and sometimes disappear completely. However, in
the vast majority of cases, they are replaced by an insidious,
Relapsing-Remitting MS (RRMS) gradual accumulation of disability, referred to as the secondary
In the majority of cases (85–90%), MS presents with a relapsing- progressive (SP) stage. The symptoms and signs that character-
remitting course, characterized by discrete episodes of neurological ize neurological decline during SPMS are diverse. Progressive
dysfunction (relapses or exacerbations) separated by clinically myelopathy, hemiparesis, and/or gait imbalance are common.
quiescent periods (remissions). The frequency of relapses can Subcortical dementia is increasingly recognized as a feature of
vary widely among patients as well as during different periods the disease. Longitudinal natural history studies conducted before
in an individual patient’s disease course. At present no clinical DMAs were widely available found that the majority of patients
features or biomarkers that are predictive of relapse rate have with RRMS transitioned to the SP stage within 10–20 years of
been identified. The signs and symptoms that occur during the initial presentation of disease. An epidemiological study of
relapses are also diverse and unpredictable, since lesions can MS patients in British Columbia, published in 2010, found that
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form at literally any site in the CNS, spanning the cerebrum, the median time to SPMS onset was 21.4 years. A number of
brainstem, cerebellum, optic nerves, and spinal cord. By definition, factors, including male gender, the presence of motor symptoms
the peripheral nervous system is spared. at clinical onset, and a history of poor recovery from relapses,
MS lesions are readily visualized in CNS white matter via are associated with both a shorter time to, and younger age
magnetic resonance imaging (MRI) (Fig. 66.1). Symptomatic at, evolution to SPMS. It has not been definitively determined
lesions generally occur in locations where nerve fibers converge whether optimal management of RRMS with the use of DMAs can
to subserve a common function. Hence, typical presentations delay, or even prevent, the onset of SPMS. Previous longitudinal
of RRMS include optic neuritis with monocular visual deficits observational and retrospective cohort studies that investigated
(secondary to lesions in the optic nerve), myelitis with weakness whether treatment with first-generation DMAs alters the time
and numbness in the extremities, sometimes accompanied by to reach SPMS yielded conflicting results. However, a recent
incontinence (caused by spinal cord lesions), and brainstem prospective study of 517 actively treated patients found that
syndromes manifesting as slurred speech, swallowing difficulties, rates of worsening and evolution to SPMS were substantially

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