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Supplements Cost-Effectiveness of Disease- Modifying Therapies in Multiple Sclerosis: A Managed Care Perspective

Overview and Diagnosis of Multiple Sclerosis

Samuel F. Hunter, MD, PhD
Multiple sclerosis (MS), a chronic inflammatory disease of unknown etiology, involves an immunemediated attack of the central nervous system (CNS) that produces demyelination and axonal/
neuronal damage, resulting in characteristic multifocal lesions apparent on magnetic resonance imaging and a variety of neurologic manifestations. The disease pathology is characterized by multifocal lesions within the CNS, in both the white matter and gray matter, with perivenular inflammatory cell infiltrates, demyelination, axonal transection, neuronal degeneration, and gliosis. MS pathogenesis is complex, as it involves both T- and B-cell mechanisms and is heterogeneous in presentation. Relatively recently, the historical 4 core clinical categories of MS were revised in an effort to improve characterization of the clinical course, better identify where a given patient is positioned in the disease spectrum, and to guide clinical studies. In young and middle-aged adults, MS is one of the most common contributors to neurologic disability, and it exerts detrimental effects on a patient’s productivity and health-related quality of life. Typically, patients with MS have a long life span, although healthcare utilization increases over time. As a consequence, the disease places a substantial burden on patients and their caregivers/families, as well as employers, the healthcare system, and society. 
Am J Manag Care. 2016;22:S141-S150
     In the United States, multiple sclerosis (MS) affects approximately 400,000 individuals; worldwide, the disease affects 2.5 million individuals, and varies greatly by geographic region.1 The disease is predominant in women, being more than 3 times more likely in women than men. Results from a systematic review by Alonso and Hernán showed that the female-to-male ratio in MS incidence has increased with time, from an estimated 1.4 in 1955 to 2.3 in 2000. These researchers reported an overall incidence rate of MS of 3.6 cases per 100,000 person-years (95% CI, 3.0-4.2) in women and 2.0 (95% CI, 1.5-2.4) in men.2 The age of onset of MS is between 20 and 40 years, and it is slightly later in men than in women; however, MS can present across the lifespan. Approximately 10% of MS cases begin before age 18.3 The incidence of MS peaks at age 30, and the prevalence peaks at age 50.4
Risk Factors
     The pathogenesis of MS is complex, as both genetic factors and environmental exposures are contributors (Table 14,5).4,5 Both ethnicity and geography influence the prevalence of MS, suggesting that heritable factors contribute to MS pathogenesis, as well.6 The relatives of patients with MS are at greater risk for the disease; however, the genetic basis of MS is complex and heterogeneous. Multiple genes contribute cumulatively to disease risk and disease behavior, and the genes and alleles involved vary from patient to patient. Genes encoded in the class II region of the major histocompatibility complex (MHC) on chromosome 6, specifically the HLA-DR2 haplotype DRB1*1501-DQB1*0602 have been implicated. It is believed that the MHC-disease association results from effects on antigen-presenting cells, which alter immune reactivity to auto-antigens, possibly myelin-related auto-antigens.7

A number of epidemiologic studies have reported unequal geographic distribution of MS; the disease is relatively rare in the tropics and increases in prevalence with increasing latitude in both the northern and southern hemispheres.2,8-10 Compared with other ethnic groups residing at the same latitudes, those with northern European ancestry are at higher risk for MS; however, more recently, an increasing incidence of MS has been reported in southern Europe.2,6,8-11

There is also evidence of tempering of the latitude gradient in MS incidence during the past 2 decades.This may be due, in part, to the increased incidence of MS in geographic regions closer to the equator and to an increase in the female-to-male ratio of MS with time. Migration data suggest that the risk of developing MS is determined at the time of puberty or before. Other putative
risk factors include infectious agents, a diet high in salt and low in long-chain fatty acids, environmental toxins, and low exposure to sunlight—although none have been definitively associated.3,7
Overall, 3 major epidemiologic shifts in MS have been observed in recent years: (1) an increased prevalence of MS, mostly because of longer survival; (2) a possible true increase in the incidence of MS in many regions, particularly in women, leading to higher female-to-male sex ratios; and (3) a lessening of the idea of a latitudinal gradient in Europe and North America. The increase in the female-to-male sex ratio suggests an environmental influence to the risk of MS; however, environmental factors may be acting at the population level rather than at the individual level.4

Clinical Manifestations

     The broad range of signs and symptoms of MS reflect multifocal lesions in the central nervous system (CNS), including the afferent visual pathways, cerebrum, brainstem, cerebellum, and spinal cord (Table 212,13).12,13
In general, the range and severity of manifestations in an individual at a particular time reflects the extent of lesions, their location, the severity of tissue damage, and the rate of accumulation. However, the correlation between lesions (as seen on standard magnetic resonance imaging [MRI]) and clinical manifestations is only approximate. This may be because repair and neural plasticity
compensate for damage, and residual function may not parallel changes in MRI. In addition, recent work has demonstrated that there are pathological features in both white and gray matter not visible on standard MRI.12 
MS symptoms result from interruption of myelinated tracts in the CNS.3 The initial symptoms often include 1 or more of the following: weakness or diminished dexterity in 1 or more limbs, a sensory disturbance, monocular visual loss (optic neuritis), double vision (diplopia), gait instability, and ataxia. As MS ensues, bladder dysfunction, fatigue, and heat sensitivity occur in many patients.
Additional symptoms, which are listed in Table 212,13, include Lhermitte’s sign, facial weakness or pain, vertigo, brief tonic spasms, and other paroxysmal symptoms, which are believed to represent discharges along demyelinated axons.12,13 Cognitive deficits are common, particularly in advanced cases, and include memory loss, impaired attention, problem-solving difficulties, slowed information processing, and difficulties in shifting between cognitive tasks.12,13

Prognostic Factors

     Several prognostic factors have been reported to predict a poor prognosis, more rapid disease progression, or conversion from clinically isolated syndrome (CIS), which is the first clinical episode typical of MS.14 These include being older than 40 years at disease onset; male sex; ethnic origin (non-Caucasian); initial presentation with motor, cerebellar, sphincter, or polyregional symptoms;
incomplete recovery from initial attacks; frequent attacks during the first years of the disease; a short interval between the first 2 attacks; rapid disability progression during the first years; progressive disease from onset; cognitive impairment at disease onset; the presence of oligoclonal immunoglobulins in the cerebrospinal fluid (CSF); and high burden of disease or gadolinium (Gd) enhancement on initial MRI.12,14

     Clinically, MS is characterized by discrete episodes (“attacks” or “exacerbations” or “relapses”) of neurologic dysfunction. The type and severity of symptoms produced by these episodes vary considerably between patients and depend upon the site of neurologic involvement. Commonly, patients may experience numbness, tingling, weakness, vision loss, gait impairment, incoordination,
imbalance, and bladder dysfunction. In between these attacks, at least during the remitting periods of the illness, patients have fairly stable neurologic function. Nevertheless, residual symptoms may persist and many patients experience fatigue or heat sensitivity in the interval between attacks. Over several years to decades, many patients who begin with relapsing-remitting MS (RRMS) evolve to the secondary progressive features of illness, in which they experience an insidious worsening of function and the accumulation of neurologic disability unrelated to any acute attacks that may or may not occur. This is especially true in untreated patients.15
     MS diagnosis is greatly influenced by clinical judgement.16 The diagnosis of MS is primarily clinical and relies on the demonstration of symptoms and signs attributable to white matter lesions on MRI that are disseminated in time (ie, the disease course) and space (ie, the affected areas in the CNS), along with the exclusion of other conditions that may resemble MS.17,18 There is no single laboratory test diagnostic for MS.19 In addition to a thorough history and physical examination, diagnostic tools required to diagnose MS and exclude other diagnoses include MRI, CSF analysis, and evoked potential testing. CSF analysis shows increased immunoglobulin concentrations and 2 or more oligoclonal bands (OCBs) in more than 90% of patients. Delayed latencies of the visual, somatosensory, and auditory evoked potentials on electrophysiological studies, as well as prolonged central motor conduction times, are characteristic of demyelination; this may indicate clinically silent lesions. Blood tests are typically used to rule out other diseases that resemble MS.17


     MRI is an indispensable test for the diagnosis and monitoring of patients with MS.17 MRI criteria and techniques have constantly evolved, and MRI remains the most sensitive method to detect and demonstrate MS lesions. MRI is used to support the diagnosis of MS, estimate lesion load and disease activity, measure brain atrophy (a correlate of axonal loss), follow disease progression,
provide prognosis, serve as a surrogate outcome, and provide outcome measures in clinical trials. MS lesions are hyperintense on T2-weighted, proton density, or fluidattenuated inversion recovery imaging, and hypointense or isointense on T1-weighted imaging. Lesions are typically ovoid in shape, small in size (although giant plaques may occur), and located mainly in the periventricular
white matter. They are also common in the posterior fossa, spinal cord, and in subcortical locations. Lesions tend to be perpendicular to the ventricles, involve the corpus callosum and U-fibers, and may enhance with Gd, particularly during active inflammation due to disruption of the blood-brain barrier. Newer MRI techniques facilitate the detection of both gray matter and white matter microstructural damage, and combined histopathologic-MRI correlation help to clarify the pathologic specificity and sensitivity of these techniques.12,20 Due to the asymptomatic nature of many cerebral lesions and relative difficulty detecting significant brainstem and spinal cord lesions, MRI burden can be very discordant with clinical disability and disease activity.
     With regard to MRI diagnostic criteria for MS, dissemination in time (DIT) means that there must have been at least 2 discrete episodes of inflammatory disease activity separated by at least 1 month.21,22 The purpose of this requirement is to ensure that monophasic illnesses do not get classified as MS, which, by definition, is a recurrent, inflammatory process. In the pre-MRI era, these
episodes needed to be identified clinically. However, the most recent international diagnostic criteria allow the use of purely imaging events to establish such time dissemination.21 Dissemination in space (DIS) requires demonstration that the disease process involves at least 2 discrete neuroanatomic areas within the CNS. In the pre-MRI era, this demonstration required the elicitation of neurologic signs, which could be unequivocally attributed to 2 or more locations within the CNS.13 In contrast, in the modern era, DIS can be established using paraclinical evidence, primarily MRI, and clinical findings.19,21,22

Paraclinical Investigations
Paraclinical investigations, which include the examination of the CSF, the recording of evoked potentials, urodynamic studies of bladder function, and ocular coherence tomography, may be helpful in establishing the diagnosis of MS for individual patients (Table 323-25).13,15,17,23-25 The detection of a CSF oligoclonal immunoglobulin G (IgG) response by isoelectric focusing (IEF) is a nonspecific, yet sensitive, aid to diagnosis. It should be used in parallel with evoked potentials and MRI to help the clinical diagnosis of MS, as each set of investigations provides different information about the pathogenesis of the condition. Importantly, the CSF oligoclonal IgG response is not only a diagnostic, it may be a predictive test, as well. It may help to assess the risk of conversion from CIS to MS. The standard CSF profile is also useful in identifying potential conditions that resemble MS. Although there are several candidate molecular, predictive, diagnostic, disease activity, and treatment-response biomarkers under investigation (eg, cytokines, chemokines and receptors, and tau proteins), none has been sufficiently validated for widespread clinical use.12,26,27
     In a systematic review (N = 71) of articles published post-1980 of OCB detected by IEF with immunofixation in MS and CIS, OCB positivity strongly predicted conversion from CIS to MS, and latitude predicted OCB status in patients with MS (P = .009).28 Of the 12,253 patients with MS, 87.7% were OCB-positive, and of the 2685 patients with CIS, 68.6% were OCB-positive. In
patients with CIS, the presence of OCBs was associated with a markedly increased risk of conversion to MS. The magnitude of this risk equated to an odds ratio of 9.9, irrespective of the anatomical location of the CIS.29 However, another study that evaluated a cohort of patients with MS (N = 407; disease duration ≥5 years) in eastern France showed that routine CSF biologic markers
at diagnosis did not predict MS progression.28 The median time from disease onset to CSF testing was 4.6 years (range, 1.0-7.0 years). Researchers did not demonstrate the value of the CSF IgG index and presence of OCB at a mean of 8.9 + 3.8 years of follow-up for prognosis of disability in MS.28
Evoked potentials are used to demonstrate subclinical involvement (slowed conduction) in CNS sensory pathways when the neurologic examination and MRI are insufficient to provide objective evidence of a multifocal disease process.12 Evoked potentials can be used to evaluate the afferent visual pathways (visual-evoked potentials), auditory pathways (brainstem auditory evoked 
potentials), and dorsal column sensory pathways (somatosensory-evoked potentials) with median nerve (upper extremity) or posterior tibial nerve (lower extremity) stimulation. Slowing of central conduction times, particularly if asymmetric, suggests MS in the appropriate clinical setting.12

Diagnostic Criteria
The current diagnostic criteria (2010 revised McDonald criteria), aimed to retain the useful features of prior criteria, but incorporated imaging more effectively into the diagnostic process, clarified definitions, simplified categories, and created a diagnostic scheme that is useful in both research studies and clinical practice.21 The conceptual requirement for objective evidence of lesion DIT and
DIS was maintained, but formal criteria were introduced to use MRI for this purpose. The diagnostic criteria incorporated recommendations on the use and interpretation of imaging criteria for DIT and DIS (Table 421).19,21 These indicate that DIT can be demonstrated by a new T2 or Gd-enhancing lesion on a follow-up MRI, with reference to a baseline scan, regardless of when the baseline MRI was obtained. Previous iterations of the diagnostic criteria specified that the reference scan be performed at least 30 days after the initial clinical event; however, this is no longer a requirement. The criteria also indicate that DIS can be demonstrated with at least 1 T2 lesion in at least 2 out of 4 areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord. These lesions do not have to be Gd-enhanced. These revised DIT and DIS criteria allow for a simplified diagnostic process for MS, with equivalent or improved specificity and/or sensitivity compared with past criteria and potentially fewer required MRI examinations in many cases.21
In addition to the assessment of DIT and DIS, the 2010 revisions emphasized that the criteria should only be applied to patients who have experienced a typical CIS suggestive of MS.21 One important area of controversy related to the original McDonald criteria was their applicability to specific populations, such as pediatric, Asian, and Latin American populations. The international
panel concluded that the 2010 revised criteria were applicable to the majority of these populations once careful evaluation for other potential explanations for the clinical presentation was made. As with the original criteria, the 2010 revisions continue to be tested with prospective and retrospective datasets to further assess their validity and to provide suggestions for further refinements.19,21

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