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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
Classification of MS

Approximately 85% of patients experience an abrupt onset of MS.3 Early symptoms may be severe in some cases, while others may seem so insignificant that a patient may not seek medical attention for months or even years. Thereafter, the clinical course may be characterized by acute episodes of worsening (exacerbations or relapses), gradual progression of disability, or a combinantion of both.3 The 4 historical MS phenotypes, and their characteristics, are30,31:

  • RRMS: clearly defined attacks of new or recurrent neurologic symptoms and signs with full or partial recovery and lack of disease progression between disease relapses. This type accounts for approximately 70% to 80% of initial diagnoses of MS.
  • Primary-progressive MS (PPMS): disease progression from onset, with occasional plateaus and temporary minor improvements allowed. Approximately 15% to 20% of patients with MS have PPMS.
  • Primary-progressive MS (PPMS): disease progression from onset, with occasional plateaus and temporary minor improvements allowed. Approximately 15% to 20% of patients with MS have PPMS.
  • Secondary-progressive MS (SPMS): initial relapsingremitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus. Approximately 90% of patients with RRMS convert to SPMS after 25 years.32
  • Progressive-relapsing MS (PRMS): progressive disease from onset, with clear acute relapses, with or without full recovery; periods between relapses are characterized by continuing progression. PRMS may present a subtype of PPMS, as they share a similar natural history. Approximately 5% of patients have PRMS. This clinical phenotype appears to be in the process of being consolidated into the other phenotypes because it is so infrequent. 12,33 
     Patients with RRMS experience relapses with or without complete recovery and are clinically stable between episodes.Approximately 50% of patients with RRMS convert to SPMS within 15 years of disease onset. The secondary progressive phase is characterized by gradual progression of disability with or without superimposed relapses. Conversely, patients with PPMS experience gradual progression of disability from onset without superimposed relapses. Approximately 15% of patients with MS experience this clinical pattern. Additionally, approximately 1% to 2% of patients experience gradual progression of disability from disease onset, which is later accompanied by 1 or more relapses; this clinical pattern is designated PRMS. Most patients with MS ultimately
experience progressive disability. Fifteen years after diagnosis, fewer than 20% of patients with MS have no functional limitation, 50% to 60% require assistance when moving, 70% are limited or unable to perform major activities of daily living, and up to 75% are not employed. 3

Evolution of MS Phenotypes
     More recently, the historical phenotypes have been re-examined and revised, and their descriptions continue to evolve. This is attributed to increased understanding of MS and its pathology, and general concern among experts that the historical phenotypes may no longer sufficiently reflect recently identified clinical aspects of the disease.30 There is a drive to eliminate uncommon classification categories, such as PRMS; however, an ongoing dilemma with redefining MS phenotypes is the lack of validation of the proposed categories. The clinical phenotypes of CIS, RRMS, and SPMS have been collapsed to “relapsing MS” for regulatory purposes in North America. Furthermore, the evolving criteria for clinically definite MS have led to the use of “early MS” or “first symptom MS” for what is formerly referred to as CIS, due to the substantial minority meeting radiological definitions of MS (ie, both DIS and DIT criteria at first symptom). Revisions to the phenotypic
classifications have several practical and clinical advantages, such as improving the characterization of the clinical course to identify where a patient is positioned in the disease spectrum, guiding study inclusion criteria for a better-defined and more homogenous population, evaluating the adequacy of treatment, and guiding design of new studies and use of biomarkers.30,34

     Although advanced MRI metrics to differentiate among the clinical phenotypes and predict disease course are lacking, the International Advisory Committee on Clinical Trials in Multiple Sclerosis re-evaluated the core MS phenotype descriptions and provided recommendations to standardize the definitions of MS. Table 534 summarizes these definitions.34 One pertinent update to the historical
phenotypes is an assessment of disease activity (active vs not active), as defined by clinical assessment of relapse occurrence or lesion activity detected by CNS imaging.34 Appropriate amounts of disease activity may be more important than the historical phenotypic classifications.

     Another important change in phenotypes is a determination of whether disability has progressed over a given interval (Figure 130 and Figure 230).30 The committee recommended that the former category of PRMS be removed because patients who would have been classified as such are now classified as having PPMS with disease activity. In addition, PPMS is now part of the spectrum
of progressive disease, and differences from other forms are considered to be relative rather than absolute. The committee recommended that CIS be included in the spectrum of MS phenotypes, and prospective follow-up of patients with CIS should help to determine their subsequent disease phenotype. According to the committee, radiologically isolated syndrome should not be considered
a separate MS phenotype. This is because such patients lack clinical signs and symptoms of the disease. Prospective follow-up is recommended in these patients.34

Updated Terminology
     With regard to terminology, the committee noted that the term “worsening” is preferable and less confusing than “progressing” when being used to describe a patient in the relapsing phase of MS whose disease is advancing because of frequent relapses and/or incomplete relapse recovery.34 With regard to clinical trial or natural history assessment of worsening disease by the Expanded Disability Status Scale or other parameters, the committee recommended the term “confirmed” instead of “sustained” over a defined interval, either within the functional system or without considering the specific functional systems in which worsening is detected. Given that the terms “benign” and “malignant” disease are often misused, the committee recommended that these terms be used with caution. Progress has been made in MS classification; however, further research is warranted to better define the value of imaging and biological markers in assessment, confirmation, and revision of the MS phenotype descriptions.34

Differential Diagnosis
     Another critical component of MS diagnosis is the exclusion of alternate explanations. The list of conditions that resemble MS clinically or radiologically is extensive; however, in clinical practice, there are few conditions that truly mimic MS on both fronts. In MS, differential diagnosis must be guided by clinical presentation and neurologic localization.16,18 Some of the disorders that are often mistaken for MS include nonspecific neurologic symptoms (eg, migraine, functional neurologic disorders, fibromyalgia, and small vessel ischemic disease alone or in combination), other demyelinating disorders (eg, neuromyelitis optica, idiopathic transverse myelitis, and acute disseminated encephalomyelitis), systemic inflammatory diseases with CNS manifestations (eg, sarcoidosis, CNS
vasculitis/vasculopathy, HIV infection, toxoplasmosis, and Lyme disease), and neoplasms (eg, primary CNS, lymphoma, glioma).16

What constitutes an adequate “rule out” panel of mimics for the patient with a typical presentation of MS will vary somewhat based on local epidemiology and practice patterns.15 The burden for excluding infection, for example, is necessarily higher in tropical settings where MS incidence is low and CNS infection is relatively high. A “rule out” screening panel for a new diagnosis of MS
typically includes a vitamin B12 level (for vitamin B12 deficiency causing the syndrome of subacute combined degeneration), treponemal antibody testing (for syphilis), Borrelia serologies (for Lyme disease, depending on geography, local epidemiology, and season), and antiphospholipid antibody syndrome screening. Aquaporin-4 antibody testing for neuromyelitis optica should be performed in any patient with a longitudinally extensive myelitis, and in all patients who experience a first episode of acute optic neuritis. Although erythrocyte sedimentation rate may provide evidence of a systemic inflammatory process, it is extremely nonspecific. Antinuclear antibody testing is an important serologic marker of a number of systemic inflammatory (rheumatologic) syndromes, but false positives occur in otherwise healthy individuals at rates of more than 30% at the 1:40 dilution and 5% at the 1:160 dilution (using human epithelial type 2 cells as the antinuclear antibody test substrate). A positive test for a putative MS “mimic” does not itself exclude the diagnosis of MS (ie, a patient with MS can be vitamin-B12 deficient and still have MS).15
     There are also important red flags that clinicians need to consider before making a diagnosis of MS. Among these are nonspecific or nonlocalizing symptoms in a patient with multifocal MRI abnormalities, historical episodes of neurologic dysfunction without objective corroborative findings, new lesions seen on interval MRI examinations using conventional imaging methods, and
normal CSF levels.15,16,18
Burden of Disease
     Individuals with MS can experience high levels of disability and impaired quality of life (QoL) for many years.10 The costs of the disease, including healthcare, social care, and productivity losses, are substantial and are associated with disease severity. MS primarily occurs among younger people, and the patients suffer for the remainder of their life.10 A diagnosis of MS has substantial
social and psychological consequences. A number of MS manifestations are frequently underappreciated, including cognitive impairment, psychiatric disorders, pain, and fatigue, but they are often significant contributors to disability.35,36
    The disease most often occurs during a patient’s most productive years. Newly diagnosed patients may be shocked by having a disease that is chronic, unpredictable in its course, progressive, incurable, and that impacts functioning. Patients may have to cope with issues regarding reduced physical function, disability, and disruptions in education, employment, sexual and family
functioning, friendships, and activities of daily living. Physically, patients may experience fatigue, pain, visual impairments, weakness, bladder and/or bowel dysfunction, and mobility impairment. Psychologically, they may have impaired cognition, depression, reduced social interaction, and increased reliance on others.12,35 In terms of employment, one study found that rates of unemployment
were as high as 75% within 10 years after a diagnosis of MS.37 The grim prognosis and unpredictability of daily health in RRMS, and the adverse effects of medication, substantially affect QoL.38
     Moreover, MS can negatively affect a patient’s identity. Physical changes and functional limitations may result in a sense of loss of identity or role strain, especially when the individual can no longer perform previously valued activities, or an occupation.36,38 Each time the individual experiences a new loss of function, this sense of loss may be renewed. One of the major sources of psychological distress related to the physical limitations of MS is sexual dysfunction. Results from a longitudinal study (N = 93) of sexual function among persons with MS showed that the
number of patients having sexual intercourse significantly decreased at the 6-year follow-up. In addition, researchers found an increasing risk for the development of sexual dysfunction in both men and women with MS during the study interval. The percentage of patients with at least 1 symptom of sexual dysfunction increased from 77.8% to 88.9% in men and from 72.7% to 87.9% in women.39
     Another burden to consider is the profound psychological impact of MS. The lifetime prevalence of depression in patients with MS is as high as 50%, and up to 15% of patients attending MS clinics die due to suicide. The pathophysiology of depression in those with MS is not well understood; however, there is some belief that depressed patients have more lesions at particular regions of the brain. This suggests that depression may be a secondary manifestation of MS, not simply a comorbid condition. Anxiety, bipolar disorder, and psychosis also occur in higher rates among patients with MS than among the general population. This is particularly important to clinicians, because corticosteroid administration may transiently cause depression, mania, or psychosis.40

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