Evolving Landscape of Multiple Sclerosis in India: Challenges in the Management

Abstract

Multiple sclerosis (MS) is a chronic neurological disease which often leads to disability. The complex etiology and progressive nature pose challenges in the management of patients with MS, particularly in developing countries like India. Lack of data on prevalence further complicates estimation of the magnitude of MS in India. There are various other challenges associated with management of patients with MS due to which the therapy is utilized by only a small segment of population in India. This article encapsulates the gaps and challenges in the management of patients with MS and presents suggestions and recommendations of the members of advisory boards held to discuss these challenges. The advisory board members suggested that an early diagnosis of MS and an early initiation of treatment are essential to achieve better results for tackling MS-related challenges. In addition, awareness and education about MS among people, regular training to physicians, emphasis on the use of revised 2010 McDonald criteria, and utilization of advanced diagnostic modalities in magnetic resonance imaging would help to achieve desirable as well as effective therapeutic outcomes. Further, access to an easy-to-use therapy delivery system could also be beneficial in attaining an adequate treatment adherence and related health benefits.

INTRODUCTION

Multiple sclerosis (MS), a chronic autoimmune disorder, causes demyelination of neurons in the central nervous system (CNS) leading to a severe disability.[1,2] MS can occur at any age but is usually diagnosed between the ages of 20 and 40 years and reported mostly in women (approximately 3 times more often than in men).[3,4] About 2.5 million people are affected with MS worldwide. To date, no large-scale studies have been conducted to accurately determine the incidence and prevalence of MS in India.[5,6] Some scattered studies have reported the prevalence of MS in the regions of India [Table 1]. However, in the last few years, increase in the number of practicing neurologists and easy and affordable availability of magnetic resonance imaging (MRI) have led to an increase in the reported prevalence of MS.[6,16]

Table 1.

Studies showing the prevalence of multiple sclerosis in India

The epidemiology of MS is complex and involves interaction between environmental and genetic factors.[5] Environmental factors such as minimized exposure to sunlight, i.e., lack of Vitamin D, smoking, and infections (Epstein–Barr virus) increase the susceptibility to MS.[17,18,19,20,21,22] Some studies have also stated that there is a genetic susceptibility for MS; HLA-DR2 is a common haplotype in about 40% of patients with MS.[23,24,25] The proposed immune-pathogenesis for MS can be well-described as an inflammatory autoimmune disorder caused by activation of autoreactive peripheral blood T cell lymphocytes. This leads to a cascade of events which are responsible for demyelination of the nerve fibers leading to chronic neurodegeneration.[26]

MS affects a patient's mental, emotional, and socioeconomic well-being.[27] Moreover, complexity of MS, its presentation, associated burden, diagnosis, poor referral of patients to the physicians, and management pose a bigger challenge.[28,29] Major goals of management of MS comprise modification of the disease course by reducing number and severity of relapses, decreasing accumulation of lesions, and slowing down the progression of disability. To date, there is no cure for MS; however, several disease-modifying therapies (DMTs) that help in reduction of relapse rate, delaying disability, and reducing MRI lesion load are available for the treatment of patients with MS[30] [Table 2].

Table 2.

Currently used disease-modifying drugs for the treatment of multiple sclerosis

The aim of this review is to present the challenges associated with overall management of MS in India including those related to diagnosis, treatment, and adherence to the treatment. The article also presents suggestions from members gathered in a series of company-sponsored advisory board meetings.

CHALLENGES ASSOCIATED WITH MULTIPLE SCLEROSIS

The discussion is focused on insights obtained from advisory board meetings on the current challenges associated with the management of patients with MS and devising solutions to resolve them. Literature search aided in documenting the gaps in diagnosis and treatment of MS, optimizing treatment methods and issues with patient adherence to MS therapy as the key challenges in recognition and treatment of MS.

Gaps in the diagnosis of multiple sclerosis

Early diagnosis and intervention are important to potentially limit the disability and preserve patient's health status.[31,32]

Lack of early diagnosis and intervention

Suboptimal referral of patients with MS to neurologists is a crucial barrier in the early diagnosis of MS in India. Due to overlapping conditions such as optic neuritis, patients with visual symptoms are treated by ophthalmologists, and not referred to the neurologists. Different study groups have reported the probability of occurrence of MS in patients with optic neuritis to be as high as 58% (in about 15 years).[8,33] Besides optic neuritis, other symptoms in the initial stages of MS include ocular motor syndromes (internuclear ophthalmoparesis and nystagmus), ataxia, dysarthria, sensory or motor signs, partial myelitis, and bowel or bladder dysfunction.[34]

It is also difficult to diagnose MS because of its multiple subtypes, interpatient variations in the clinical presentation and pseudorelapses.[25,29] A variant of MS, neuromyelitis optica (NMO) involves demyelination of optic nerves and spinal cord and is also a cause of serious illness in various countries including India.[35,36] NMO may lead to uncertainties in the diagnosis of MS. Certain patients of MS with NMO have additional symptoms that are not due to optic nerve or spinal cord inflammation or have MS-like lesions in MRI. In addition, some patients with MS were mistakenly diagnosed with NMO inspite of having a consequent course distinct from prototypic MS.[37,38] Several other disorders are known to have a clinical presentation similar to MS such as acute disseminated encephalomyelitis, Schilder's disease, Balo's concentric sclerosis, Eale's syndrome, sarcoidosis, vasculitis, CNS lupus, Sjogren's syndrome, and Behçet's disease. Even the MRI findings of these diseases show a resemblance to T2 white matter lesions. The presence of nonspecific white matter lesions is reported in people affected with migraine, hypertension, and diabetes. Furthermore, there are no specific guidelines in India that can assist in the management of patients with MS. Nevertheless, use of established and up-to-date revised 2010 McDonald criteria is recommended to make the diagnosis after exclusion of alternative diagnoses.

Lack of an early diagnosis of MS due to these overlapping or misleading conditions is coupled with a lack of an early intervention, i.e., even if the patients with MS reach neurologists, it is not certain that treatment will be initiated.[14]

Misinterpretation of magnetic resonance imaging findings

MRI plays a vital role in the diagnosis and treatment of MS. MRI of CNS can support as well as complement the clinical presentation of MS.[39,40,41,42] However, dissonance between position of lesions and their clinical presentation is a major limitation of MRI. Furthermore, depending on number of lesions and their area, MRI shows great variation in the diagnosis of MS as far as sensitivity and specificity are concerned. Some MRI reports have also demonstrated nonspecific white matter lesions; however, these were compatible with MS. This is particularly valid for primary progressive MS, which may not demonstrate the exemplary discrete lesions of relapsing-remitting MS.[43,44,45,46]

Schumacher criteria, developed in 1965 was the first official clinical symptom-based criteria for the diagnosis of MS.[47] Poser criteria (1983) was established on the basis of outcomes of additional tests, including visual-evoked potential and cerebrospinal fluid analysis.[48] McDonald criteria (amended in 2010) is currently used and is a well-established diagnostic criteria for the diagnosis of MS. The revised McDonald criteria use MRI findings as well as clinical parameters for making an early diagnosis of the disease with high specificity and sensitivity, which support initiating an early treatment and better management of patients with MS.[49,50,51,52] McDonald diagnostic criteria emphasizes the need to demonstrate the dissemination of lesions in space (DIS) and time (DIT) and to exclude alternative diagnosis for MS. DIS can be demonstrated with at least one T2 lesion in at least two of the four locations considered characteristic for MS and as specified in the original McDonald Criteria (juxtacortical, periventricular, infratentorial, and spinal cord), with lesions within the symptomatic region excluded in patients with brainstem or spinal cord syndromes. Whereas, DIT can be demonstrated by an appearance of a new T2 lesion on a scan compared to a reference or baseline scan performed at least 30 days after the onset of initial clinical event and simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time.[53] Figure 1 represents the McDonald diagnostic criteria to detect patients with MS.

Figure 1.

McDonald Criteria (2010) for Diagnosis of Multiple Sclerosis

Challenges in the treatment of multiple sclerosis

Lack of early initiation of treatment

MS can have devastating effects on the patients and if it is left untreated, these may occur earlier or can be more severe. It has been reported that about 90% of patients that are left untreated will have disability later in their lives (20–25 years after getting affected).[54] Treatment with DMTs should be started as early as possible considering the disabling nature of disease.[55,56,57]

Initiating an early treatment limits the progression of disability, thereby moderating overall treatment cost and improving the clinical outcomes of patients with MS.[58] In general, patients are not aware of the consequences of MS and related cost if the treatment gets delayed. With the progression of disease and an increasing disability level, there is an increase in the direct and indirect costs involved. This increment in cost is generally related to relapses and productivity cost rather than the direct cost involved in using DMTs.[59,60] The issue of higher cost is a complex problem when considered at an individual level. Patients usually neglect treatment when cost-sharing exceeds beyond their limit.[61] Moreover, the treatment plans that negatively affect initiation and adherence may be responsible for increased use of health resources, relapse risks, progression of disease, and ultimately, disability in patients.[61]

Lack of continuous treatment

Chronic diseases such as MS require continuous treatment. A discerned lack of efficacy, financial constraints, distress, and curiosity of the patient to adopt other available therapies might also lead to a poor treatment adherence.[62,63,64] The major contributing factor for noncompliance among patients with MS is the delayed symptomatic presentation after initial diagnosis. It has been found that after an initial diagnosis of MS, there is no significant relapse or development of new symptoms in some patients for few months or years, which in turn increases the chances of patient's denial of accepting the disease, understanding the need for routine therapy as well as adapting it.[62,64]

Nonadherence or poor adherence to treatment regimens is the most common challenge in the treatment of patients with chronic conditions. Nonadherence might result from complex treatment regimens as well as the adverse effects associated with them (fatigue, flu-like symptoms, and reactions at injection site) or lack of awareness/negligence among the patients and some injection-related issues (fear/anxiety, pain, and discomfort).[62,63,64] A global survey conducted among 331 patients diagnosed with MS found 31% patients to deliberately break the treatment course for 1 day or longer, whereas about 19% patients had completely evaded taking their medications.[65] This discontinuation in the treatment was reported due to associated adverse effects (42%), emotional fatigue (13%), practical issues related to the treatment (9%), lack of efficacy (9%), or lack of symptoms (6%). On forwarding the same questionnaire to some other neurologists, it was found that 17% patients took treatment breaks majorly due to associated adverse effects (82%).

There may be an underestimation of the incidence of poor adherence of patients to treatment by some physicians.[65] Studies conducted for the evaluation of adherence to injectable therapies reported approximately 80% adherence in about 80% patients for initial 6 months,[66] followed by a decrease to 60%–76% in the next 2–5 years.[67]

The availability of newer and easy-to-use therapy systems have helped to overcome the issue of nonadherence to some extent. In the SMART trial, adherence was observed in 97.3% and 93.9% of patients at 3 and 12 months, respectively, who used RebiSmart^® (an electronic auto-injector for the subcutaneous administration of interferon β-1a). Common adverse events (AEs) in patients at 3 and 12 months were anxiety, flu-like syndrome, and pain at injection site, weakness, and fatigue.[63]

Expert opinion

Early diagnosis of multiple sclerosis

Making an early diagnosis is of paramount importance so that progression of the disease and disability can be minimized. The advisory board suggested the following key points to be taken into consideration while making diagnosis of patients with MS: [Table 3]

Table 3.

Challenges observed in the diagnosis and management of patients with multiple sclerosis and expert opinion

• Timely referral from other physicians to neurologists: Referral of optic neuritis patients to the neurologists should be made on time. In addition, paroxysmal symptoms are very common and patients later on get diagnosed with MS.[68] Therefore, paroxysmal symptoms should not be missed

• Follow-up of the patient with MS: Clinical assessment is of utmost importance and Expanded Disability Status Scale scoring must be done for all patients [Figure 2]. Patients may go to the doctors for medical issues and not for MS. In later, phases of the disease, one MRI a year could be an optimal solution. As per experts' practical experience, MS progression does not always involve MRI lesions (such as in case of clinical progression from relapsing–remitting MS to secondary progressive MS)[69]

• Early diagnosis and diagnostic criteria: The evolving criteria have increased sensitivity greatly which helps in early diagnosis; however, at the same time, specificity must not be neglected. Hence, while diagnosing MS, clinical features are very important. Recommended 2016 MAGNIMS modifications to the 2010 McDonald criteria for MRI in the diagnosis of MS will help to improve early diagnosis[53]

• Exclusion of diseases with similar clinical presentation: All other causes for MS-like lesions on MRI should be excluded before diagnosing a patient with MS. MS should not be confused with NMO due to similar clinical presentations or common symptoms such as fatigue, depression, or dizziness. The diagnosis of MS should be based on diagnostic criteria that are separate from established updated diagnostic criteria for NMO. Further, exclusion of alternative diagnoses should be kept in mind while referring a person with MS to the neurologist.

Figure 2.

Assessment Parameters to Evaluate Effectiveness of Various Multiple Sclerosis Associated Therapeutic Options[39,54,72]

Improving treatment adherence

Adherence to MS therapy is associated with lower risks of disease-associated hospitalizations, fewer relapses, and less associated medical costs. In the past, limited availability of MS treatment was a barrier to optimal therapy; but today, we have multiple treatment alternatives, although the cost remains a limiting factor. The advisory board suggested that:

• Focus on “3As”: Clinicians should focus on “3As”, i.e., affordability, accessibility, and availability, to manage MS. It was suggested to make the therapy more affordable and accessible to patients. An important point to consider is the need for pharmacoeconomic studies in MS

• Counseling to be given due importance: Patients are usually concerned about how long this treatment is to be taken. When treating physicians make their patients aware of the duration of treatment, it may add to patients' anxiety. Counseling plays an important role in handling and managing physical as well as an emotional aspect of the disease. It also supports a patient in initiating treatment followed by its adherence, thereby, minimizing the progression to disability

• Factors which matter in choosing the therapy: Injectable and oral therapeutic agents are now available; however, the prescription should be made considering long-term efficacy and safety, and AE profile of the DMDs. Moreover, the patient should be given a chance to contribute to the decision of treatment options. Awareness strategies for the use of injectable therapies must include schemes to manage tolerability to the treatment, such as titration and reduction of dose, injection timings, usage of sleeping aids, nonsteroidal anti-inflammatory drugs or acetaminophen coadministration (before and after injection), and injection techniques. Interferons are the first-line treatment option. In case of disease progression, second- and third-line DMTs are used. However, in relapses, patients are treated with methyl prednisolone, followed by DMT[70]

• Switch for nonresponders: Suboptimal response to a first-line DMT warrants either a lateral/transversal switch in some cases with low-to-moderate level of concern (from one first-line immunomodulatory treatment to another one) or a vertical switch (therapeutic escalation) in more aggressive cases with moderate to high level of concern (from a first-line to a second-or third-line therapy).[31] If more than two relapses have occurred in the previous 2 years, it indicates aggressive disease[71]

• Need for adaptable and cost-effective treatment options: Factors that prevent a patient from administering treatment are multifold: Cost, AEs, and injection phobia. Experts stated that insurance companies do not cover MS related costs. Patients usually seek a lot of information on MS when diagnosed and get worried on explaining that it is noncurable. They seek an opinion from different doctors which may add to the confusion. Cost of the treatment, the most important patient-related consideration also increases with relapses. An easy to use and appealing therapeutic strategy, reduction in the cost of MS therapy and support of MS treatment by the government would largely help in improving patient adherence

• Design robust patient support programs: Designing robust patient support programs might help to improve adherence. A monthly clinic that includes clinical psychologists, psychiatrists, physiotherapists, and physicians specialized in all areas of neurology, mental health, and rehabilitation to guide and treat patients could be a good option

• Promote educational activities: Educational activities, MS programs such as organizing educational camps for patients and caregivers, might help in an easy understanding of complexity associated with the disease, as well as the importance of adherence to prolonged treatment regimen. Social media can act as an effective mode to spread awareness about early diagnosis and treatment of patients with MS. Educational activities among MS affected the population, and physicians can play a critical role in patient adherence. Focused continuing medical education on an annual basis may help to increase awareness

• Use of social media and applications to help patients and doctors: Patients should be encouraged to use calendars to improve adherence to the therapy. Usage of web applications or dedicated applications for doctors and patients would be helpful.

CONCLUSION

Timely referral and early initiation of treatment of MS are critical for a reduction in the relapse rate and disability. To achieve treatment adherence, it is essential to provide proper counseling and assurance to patients regarding the benefits of therapy. This requires a legitimate evaluation of relative risks, cost, and advantages of therapy for achieving desirable therapeutic outcomes. Further, accessibility to an easy-to-use therapy delivery system could also be beneficial in attaining an adequate treatment adherence for better outcomes. Going forward, there is still a need for considerable awareness, rehabilitation facilities, well-equipped MS clinics in the institutions, registry of MS patients, insurance coverage, and accessibility to effective and economical DMTs in India.

Financial support and sponsorship

This study was financially supported by Merck Ltd., Mumbai, Maharashtra, India, an affiliate of Merck KGaA (Darmstadt, Germany).

Conflicts of interest

The authors received honoraria as consultants for Merck Ltd, Mumbai, India, for these advisory board meetings. Dr. Harshal and Dr. Priti are employees of Merck Ltd., Mumbai, India, an affiliate of Merck KGaA (Darmstadt, Germany).[72]