Impact of Diagnosis and Early Treatment on the Course of Multiple Sclerosis

Published Online: November 30, 2013
Katia Noyes, PhD, MPH; and Bianca Weinstock-Guttman, MD
Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system that results in neurological dysfunction and disability. The initiation of disease-modifying therapy (DMT) early in the course of MS may improve the prognosis for patients with MS and reduce the occurrence of neurological damage. In patients with relapsing-remitting MS (RRMS), DMT reduces the rate of relapses, reduces the appearance of magnetic resonance imaging markers of disease activity, and slows the course of disability progression. DMT has been shown to be more effective when initiated early in the course of MS. In patients who have not yet developed clinically definite MS (CDMS), but have had 1 attack of neurological symptoms consistent with MS (ie, clinically isolated syndrome [CIS]), the initiation of DMT (specifically, interferon beta, glatiramer acetate, and teriflunomide) following this attack has been shown to delay the conversion to CDMS. Current guidelines have recognized the benefits of early treatment of MS with DMTs. However, there are a number of barriers to implementing early MS treatment. Early diagnosis and treatment of MS can be hindered because patients may delay consulting a physician about their neurological symptoms or may be reluctant to start DMT. Further, even after initiating DMT, continued adherence to treatment is often poor. These delays in treatment and a lack of adherence to treatment are associated with poor patient outcomes. The objectives of this review are to highlight the importance of early diagnosis and treatment of CIS or RRMS and discuss the favorable outcomes associated with early initiation of DMT.

(Am J Manag Care. 2013;19:S321-S331)
Multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system (CNS),1,2 is characterized by demyelination of axons in the brain and spinal cord, with axonal damage or destruction.3,4 Demyelination and axonal damage and loss are thought to occur early in the course of MS.5-8 Demyelination results in altered conduction of action potentials and neuronal dysfunction, which is at least partially reversible.1,8 However, the damage to and destruction of the axons that may follow or accompany demyelination is associated with irreversible neurological disability.1,8 Demyelination and axonal damage and destruction are responsible for the various neurological symptoms and signs of MS, including impaired vision, weakness, numbness, cognitive dysfunction, dizziness, spasticity, and balance or coordination impairment.3,4

There is uncertainty about the underlying pathophysiology of MS, and while research indicates that MS has an immunemediated pathogenesis, the immunologic response targets are not defined.9 One recent study identified the potassium ion channel subunit KIR4.1 as a target of the autoantibody response in a subpopulation of patients with MS,9 but further research is needed to shed more light on immunologic targets involved in MS.

Disease-modifying therapies (DMTs) for MS, which include immunomodulatory, anti-inflammatory, and immunosuppressive drugs,10 slow MS-related neurological damage and progression of disability.10-12 Early DMT may improve the long-term course of MS and reduce permanent neurological damage.5-8 Recent studies have shown the efficacy of DMTs for reducing the rate of relapses in patients with relapsing-remitting MS (RRMS) and for slowing the course of MS progression, particularly when treatment is initiated early (Table 1).13-34 In patients with clinically isolated syndrome (CIS), a single attack consisting of 1 or more neurological symptoms secondary to a demyelinating inflammatory event, DMTs have been shown to delay the conversion to clinically definite MS (CDMS).13,17,33,34 This review discusses current guidelines for the early treatment of MS, describes the risks of delaying treatment, and summarizes current literature regarding the benefits of early initiation of DMT.

Guidelines for the Diagnosis and Early Treatment of MS

A diagnosis of MS is based on both clinical signs and symptoms, which are consistent with an inflammatory demyelinating process that affects the CNS and demonstrates evidence of dispersion in time and space of the underlying pathological process.35 The McDonald criteria, developed by the International Panel on the Diagnosis of MS and most recently revised in 2010, provide guidelines for the diagnosis of MS and include clinical, laboratory, and magnetic resonance imaging (MRI) criteria.35 The McDonald criteria are both sensitive and specific for the definitive diagnosis of MS, and the use of these criteria has led to an earlier diagnosis.35 In addition to identifying the clinical, laboratory, and MRI indicators of MS, differential diagnosis remains a critical consideration in the process of diagnosing MS.35 According to the McDonald criteria, a diagnosis of MS can be made based on clinical criteria alone or a predefined combination of MRI evidence and clinical criteria.35 The fundamental clinical evidence for MS is the occurrence of an attack of symptoms that are consistent with an acute inflammatory demyelinating CNS event.35 For a definitive diagnosis of MS, the clinical evidence of this attack should be confirmed by neurological examination findings, visual evoked potential response (for patients with prior visual disturbance), or MRI evidence of demyelination in the CNS area that is suggested by the symptoms.35 The MRI evidence of demyelination is the presence of sclerotic plaques, or lesions, in the CNS which appear as areas of high signal on T2-weighted images.1,2 These plaques can be further evaluated using gadolinium (Gd)-enhanced T1-weighted MRI, which allows for differentiation between active and inactive lesions; a Gd-enhanced lesion, which appears as a brighter spot on the MRI, is indicative of an active lesion.36,37 The dissemination of these lesions in space and/or time can track the progression of MS.3,35 According to the McDonald criteria, patients with a single attack of neurological symptoms suggestive of a demyelinating event and objective clinical evidence of a lesion are considered to have CIS.35 For a diagnosis of CDMS to be made in patients with CIS, there must be a second clinical attack, or evidence of dissemination of MRI lesions in time (ie, simultaneous presence of asymptomatic Gd-enhancing and nonenhancing lesions, or new T2 or Gd-enhancing lesions on followup MRI) and space (ie, 1 or more T2 lesions in 2 or more MS-typical regions of the CNS).35 The most recent 2010 McDonald criteria advocate the ability to make a diagnosis of MS even at the time of first event with first MRI if the specific locations of lesions fulfill the requirement for dispersion in space and if an additional Gd active lesion(s) is seen in a location different from that of the lesion responsible for the presenting clinical symptom.35

The recommendations for initiating DMT from various guidelines are summarized in Table 2.38-41 In a set of guidelines that were developed in 2002 by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines, the use of interferon (IFN) beta, which is considered to be a first-line DMT for MS, was recommended for patients who were considered to be high risk for the development of CDMS and those with relapsing MS (RMS) (including RRMS and secondary-progressive MS with relapses).38 In a separate 2008 consensus statement regarding MS disease management from the National Multiple Sclerosis Society, early treatment with glatiramer acetate (GA) or IFN beta was recommended to slow the development of permanent neurological damage.40 Recently, a series of consensus statements regarding the management of treatments for MS was published that were based on feedback from a panel of pharmacy and medical directors.41 The panel agreed that the patient’s healthcare provider should be permitted to make the decision of whether to initiate DMT in patients with CIS, and that the majority of patients with CDMS should be started on DMT.41 Further, the panel concluded that health plans should not restrict access to DMTs for patients with CIS or CDMS and should provide access to GA and at least 1 IFN beta formulation.41 (GA has been shown to have an effect similar to that of IFN beta in preventing conversion to CDMS.17) The panel recommended more stringent limitations for access to the other DMTs (eg, natalizumab and fingolimod), largely due to safety issues associated with natalizumab and a lack of long-term clinical efficacy and safety data for fingolimod.41 Newer options for the management of MS, including the recently approved oral agents teriflunomide and dimethyl fumarate, have not yet been integrated into these guidelines.

Risks of Delayed MS Diagnosis and Treatment

Brain atrophy, which accompanies axonal damage and loss, can be observed early in the MS disease course, even in patients with CIS.2,42,43 Brain atrophy continues to progress in patients with CIS; however, treatment with IFN beta-1a has been shown to reduce the rate of atrophy in patients with CIS.43 Delays in the diagnosis of MS and DMT allow for the accumulation of axonal damage, progression of brain atrophy, and the development of severe and irreversible neurological disability.2,8,42 In the open-label, 5-year study of CIS with GA, patients who were treated with GA from the beginning showed significantly less brain atrophy compared with those who initiated therapy later (mean % change in brain atrophy: -1.28% vs -0.99%; P = .0209).44

Persisting clinical signs of MS are evident early, even in patients with CIS or early MS.6,7 A study in patients with CIS who were at high risk for the development of CDMS (more than 2 MRI lesions in addition to the lesion responsible for clinical presentation) showed that cognitive impairment was present in 29% of those at baseline and 54% of those at 5 years after initial screening; approximately 96% of the patients in this study developed CDMS after 5 years.7 A separate study in patients with CIS or early MS (<6 years since their first symptom) showed that these patients experienced significant deterioration in measures of cognitive functioning, including measures of working memory and speed of information processing and immediate and delayed visual spatial memory.6 The presence of cognitive impairment in patients with CIS may be particularly telling because many patients presenting with CIS have experienced prior demyelination events that went unnoticed and unreported and they may have already accumulated associated neurological damage.45

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