|MULTIPLE SCLEROSIS: NEWER CONCEPTS ON PATHOPHYSIOLOGY, DIAGNOSTIC CRITERIA AND THERAPEUTICS
|Year : 2018 | Volume
| Issue : 1 | Page : 43-54
Multiple sclerosis: Newer concepts on pathophysiology, diagnostic criteria and therapeutics
Rohit Bhatia, Nishita Singh
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||28-Jan-2019|
Department of Neurology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Multiple sclerosis (MS) is a challenging and disabling demyelinating disorder, presumed to be of autoimmune origin. Various environmental and genetic risk factors have now been implicated in the etiopathogenesis of this disorder. Early and precise diagnosis is critical and is supported by use of recent revision of diagnostic criteria, incorporating imaging and spinal fluid abnormalities. Notably, the treatment armamentarium for MS has expanded substantially over the last two decades with approval of newer drugs and many other drugs in terminal stages of development. However, some of these therapies are associated with long-term effects on immune system and/or severe adverse events which can complicate ensuing therapies. The customisation of treatment requires consideration of many factors like safety, efficacy, patient related factors and finally a comprehensive risk-benefit assessment for an individual patient. This article is intended to help make informed ecisions, keep realistic goals and raising cognizance of multiple factors involved in treating patients with MS.
Keywords: Demyelination, disease modifying therapy, multiple sclerosis
|How to cite this article:|
Bhatia R, Singh N. Multiple sclerosis: Newer concepts on pathophysiology, diagnostic criteria and therapeutics. Astrocyte 2018;5:43-54
|How to cite this URL:|
Bhatia R, Singh N. Multiple sclerosis: Newer concepts on pathophysiology, diagnostic criteria and therapeutics. Astrocyte [serial online] 2018 [cited 2019 Apr 25];5:43-54. Available from: http://www.astrocyte.in/text.asp?2018/5/1/43/250920
| Introduction|| |
Multiple sclerosis (MS) is a chronic inflammatory disorder of central nervous system (CNS) chiefly affecting the young individuals across the globe. It was first described by scientist Jean-Marie-Charcot in 1868. It commonly affects young females and is commonly characterized by attacks of partial or completely reversible neurological deficits lasting days to weeks, which after one or two decades takes a progressive course leading to impaired ambulation and cognition. The disease may be progressive in onset in about 15% of the cases. Neurological deficits can be variable in the form of vision loss, diplopia, ataxia, sensory loss, motor weakness, bladder disturbances, and so on. Current army of agents are useful in disease stabilization, but response to treatment is heterogeneous and cost is a limitation. The understanding of this condition has evolved both in diagnostic and therapeutic aspects significantly over the past three decades [Figure 1], [Figure 2], [Figure 3]. This article overviews the newer concepts in MS with reference to pathophysiology, diagnostic criteria, and therapy.
|Figure 1: Evolution of diagnostic and therapeutic aspects of MS over the decades|
Click here to view
| Epidemiology|| |
As per the World Health Organization report, the estimated number of people with MS increased from 2.1 million in 2008 to 2.3 million in 2013, whereas healthcare and support services improved when compared with 2008. It was more than 100 per 100,000 in the United States and Canada, whereas it was 5–20 per 100,000 in India and South America, respectively. As per recent studies, prevalence of MS in the United States was 572,312 with direct annual costs being $24,327 higher than non-MS population. MS population also lost on 10.4 quality-adjusted life years more when compared with the general population. There continued to be inequity in availability of health services with a broadening gap between high- and low-income countries. The increase in prevalence could be due to increased survival or improvement in diagnosing MS and formation of registries. There was also an increase in incidence of MS; however, only 52 countries provided data of the same.
Since MS commonly affects young population, it adds to a decline in employment rate, decrease in education, and sociodemographic factor restrictions. For reasons unknown, it is more common in women and the female: male ratio has increased from 1.4 to 2.3 over the past 50 years, thus corresponding to a lifetime risk of 2.5% in women when compared with 1.4% in men. Life expectancy in these patients is less by 7–14 years when compared with general population.
| Etiology|| |
The etiology of MS is yet unknown. Various genetic and environmental risk factors have been identified as triggers of disease. These include allelic genes, geographic factors such as latitude shift, sunlight exposure, vitamin D levels, tobacco, viruses such as Epstein-Barr virus (EBV), and many more with some evidence.
MS is not a hereditary disease; however, first-degree relatives have 2%–4% risk when compared with 0.1% in the general population. There is 30%50% concordance in monozygotic twins. More than 200 gene variants have been identified via genome-wide association studies (GWASs), but the most significant is HLA DRB1 * 1501. Recently, a meta-analysis done on familial MS pooled data from 17 studies, with 14,619 patients, and found that the prevalence of familial MS (FMS) was 12.6% in the world [95% confidence interval (CI): 9.6–15.9)]. As per review of GWASs, over hundred MS risk loci were found by classical and hypothesis-driven approaches and 40 of them were found in at least two GWASs.
The most common risk factors include geographic latitude, vitamin D levels, smoking, obesity, tobacco, and infections such as EBV.
Higher latitude is associated with increased prevalence of MS, although these associations have decreased over the past few years. Latitude also co-relates with sunlight exposure, consequently vitamin D levels which are proposed to be protective of MS. A recent meta-analysis  involving seven studies with 284 patients showed a statistically significant reduction in contrast to enhancing lesions in placebo control studies; however, there was no trend toward decrease in relapses and expanded disability severity score (EDSS). The meta-analysis concluded that vitamin D may have a therapeutic role in treatment of MS, but there remains uncertainty about dose and clinically relevant outcomes.
Smoking has been associated with an increase in disease severity, disease progression, and increased risk of conversion to secondary progressive MS (SPMS). Among infectious agents, various viral pathogens, mainly EBV, have been implicated to increase risk of MS in genetically susceptible individuals. Some of these viruses may interfere with mechanism of action of self-reactive B cells, while others may act as molecular mimics. It has been found that disease risk is very low in patients seronegative for EBV, while >99% of MS are seropositive compared with 95% general population. In general, the mechanisms by which environmental triggers and genetic polymorphisms increase the risk of MS is a subject of debate and further investigation.
| Pathogenesis|| |
Mechanisms of tissue destruction in MS result from a complex interaction between the neurons, glia, and immune system. Earlier concepts involved in pathogenesis of this illness included breach in blood–brain barrier followed by invasion of CD8 and CD4 cells leading to damage restricted to focal areas of involvement in white matter. Only recently, has there been awareness that there may be diffuse infiltration with T and B cells as the disease progresses with activation of astrocyte and microglia eventually leading to diffuse myelin destruction and axonal injury causing atrophy of grey and white matter., Emerging concepts propose that chronic inflammation results in production of reactive oxygen species and reactive nitrogen species that further promote mitochondrial injury leading to metabolic stress, protein misfolding, and thus neurodegeneration, which may explain brain volume loss with chronic neurodegeneration despite treating the immune response in these patients; more evidence is needed to support this hypothesis.,
| Diagnostic Criteria|| |
The diagnostic criteria for MS have evolved over time, combining clinical, imaging, and laboratory evidence. In the past six decades, there have been Allisson and Millar (1954), Schumacher (1965), followed by Poser (1983), McDonald (2001, 2005, 2010), MAGNIMS (2016), and the latest revision of the McDonald's criteria in 2017. Advances in magnetic resonance imaging (MRI) have played a key role in the last four alterations of the criteria, with clear provisions for lesion number, site of lesions, and their contrast enhancement. There has been a clear-cut reduction in the time of onset to disease diagnosis with time from 2 years (Poser criteria) to 6 months (2010 McDonald).
The 2001 McDonald criteria  were noteworthy as it was for the first time that MRI was used as a biomarker of relapse. Further revisions led to simplification of criteria, and by 2010, the criterion of dissemination in time (DIT) could be met by a single scan showing enhancing and nonenhancing lesions, whereas dissemination in space (DIS) criterion could be met by showing two lesions in characteristic location. The 2016 MAGNIMS criteria  were different as they required three versus one periventricular lesion; it allowed symptomatic brainstem or spinal cord lesions, cortical, and optic nerve lesions to be counted as DIS, and finally it included symptomatic contrast-enhancing lesions to count DIT. Filippi et al. screened 571 patients with clinically isolated syndrome (CIS), of whom 368 met the inclusion criteria and they compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria to predict clinically definite MS (CDMS). They found that specificity was higher when three rather than one periventricular lesion was used [0.41 (95% CI: 0.29–0.55) vs. 0.33 (0.21–0.46) at 60 months). The two DIS criteria had similar specificity (0.33 and 0.32, respectively) but higher sensitivity (0.91 vs. 0.93). Adjusted hazard ratios (aHRs) were greater for DIS plus DIT using the 2016 MAGNIMS [aHR 2.95 (95% CI: 2.04–4.26)] as compared with 2010 McDonald [2.52 (1.78–3.58)] criteria while using time-to-CDMS as an outcome. Other 2016 MAGNIMS changes did not change the performance to predict CDMS. There was a further modification of McDonald's criteria in 2017 where more than two attacks with at least two lesions on MRI are needed to make a diagnosis of MS; only one lesion is enough in the presence of one attack and history suggestive of previous attack with a lesion in a characteristic location. Additional data to demonstrate DIT and space with the help of MRI and cerebrospinal fluid (CSF) oligoclonal bands (OCBs) (new addition) are needed to support the diagnosis of MS when there is only one clinical attack in the absence of history of other attacks. Unlike the 2016 MAGNIMS criteria, the latest McDonald's criteria do not include optic nerve as a site of involvement in diagnosing MS. [Table 1] gives an overview of evolution of MS criteria over the past two decades.
|Table 1: Comparison of McDonald's 2010, MAGNIMS 2016 and McDonald's 2017 criteria for RRMS|
Click here to view
Evolution of diagnosis has led to better sensitivity leading to early diagnosis but a lesser specificity comparatively. This is clinically important as it may lead to misdiagnosis and unnecessary treatment burden to patients. In a study by Solomon et al., among 110 patients misdiagnosed with MS, 51 (46%) were classified as CDMS and alternate diagnosis comprised a wide spectrum including migraine, fibromyalgia, neuromyelitis optica, and psychogenic disorders. In all, 77 (70%) patients received disease-modifying therapy (DMT) and 4 (4%) took part in research therapy for MS. Thus, it is crucial to keep in mind that patients with monophasic inflammatory or infectious or vascular diseases may fit either the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, which now require only concurrent presence of gadolinium-enhancing and gadolinium-negative lesions in specified locations. Thus, a detailed history taking, and clinical examination and exclusion of mimics are prudent in these situations.
| Advancement in Diagnostic and Prognostic Tools|| |
MRI in MS is a very important tool not just for diagnosis of the disease, but also for various other important functions such as assessing disease activity, severity and extent of disease, monitoring drug efficacy, assessing radiological response to therapy, monitoring opportunistic infections, progressive multifocal leukoencephalopathy (PML) surveillance, and for achieving no evidence of disease activity (NEDA) as target of therapy. Newer and advanced MRI techniques such as magnetization transfer ratio, diffusion tensor imaging, restricted proton fraction, pulse sequences such as double inversion recovery (DIR), and phase-sensitive inversion recovery have improved the detection rate of cortical lesions. Calabrese et al. used a combination of DIR and DTI in 168 patients with relapsing-remitting MS (RRMS) and found them to have better pick up rate of cortical lesions. Quantitative susceptibility mapping detects iron in basal ganglia and MS lesions, which is in turn suggestive of microglia activity, and positive signal has been associated with chronic active MS lesions. However, it should be kept in mind that these advanced modalities require further validation in a larger group of patients over a longer time and they hold promising results for being used as a biomarker in MS.
Oligoclonal bands (OCBs)
OCBs are thought to be products of clonal expansion of B cells in CSF. Presence of OCBs is one of the most consistent and characteristic findings in MS. It is estimated that it takes 3.2 billion lymphocytes to generate such a large amount of intrathecal IgG (30 mg in 500 mL CSF) in patients with MS, thereby implying that lymphocytes in CSF could account for only <0.1% of the extra IgG in MS. Various studies have shown that presence of OCB in patients with CIS independently predicts future risk of MS. This led to inclusion of OCB as criterion to satisfy DIS in 2001 and 2005 revision of McDonald's criteria. However, in 2010 revision the status of OCB was not evaluated, and the latest 2017 revision sees reintroduction of CSF OCB as one of the additional criteria to fulfill DIS. A recent multicenter study, in 406 patients with CIS, showed that performance of 2010 with OCB as criterion was similar to DIS alone, which was later substantiated by a study by Arrambide et al., which included 398 patients with CIS not fulfilling criteria of DIS and DIT as per 2010 McDonald's criteria and tried to see utility of OCB in these patients. They found that specificity of all cases with DIS increased from 80.6 to 88.1 after selecting those with positive OCB, thus emphasizing the need of OCB as a criterion in diagnosis of MS.
Blood and CSF biomarkers
In view of variable clinical presentation of MS which can cause delay in diagnosis and hence treatment, availability of a diagnostic laboratory test or biomarker may help in confirming the diagnosis and early initiation of treatment. Also, biomarkers that correlate with myelin loss, cord disease, and grey matter involvement may be able to categorize those at high risk and those having increased risk of progression and can help in monitoring disease activity. Various chemokines like elevated CXCL3 have been found in patients with CIS who convert to CDMS, whereas CXCL12 has been found to be protective against inflammation. Cytokines such as interleukin (IL)-6, IL-10, and IL-15 were found to correlate with relapse frequency.,,
| Treatment|| |
Until today, there are 15 medications approved by the food and drug administration (FDA) for immune modulation in MS. These include the orals (fingolimod, teriflunomide, dimethyl fumarate), injectables (interferons, glatiramer acetate, mitoxantrone), and the monoclonal antibodies [natalizumab, alemtuzumab, daclizumab, and ocrelizumab (OCR)]. Dalfampridine is approved as symptomatic therapy to improve walking speed. All these medications have been approved for RRMS except for OCR which has been approved for primary progressive multiple sclerosis (PPMS). [Table 2], [Table 3], [Table 4] give the details of injectable, oral, and intravenous drugs, respectively, with their mechanism of action, dose and route of administration, adverse effects, and monitoring. There has been a general trend to treat early; however, it is still unknown whether this would prevent disease progression.
|Table 4: Intravenous Therapies used in the treatment of Multiple Sclerosis|
Click here to view
Fogarty et al. did a systematic review and network meta-analysis comparing efficacy of DMTs in RRMS which included 28 RCTs including adult patients with RRMS and reporting at least one of the primary outcome measures of interest. The range of annualised relapse rate (ARR) varied between 15% and 36% for all interferon (IFN)-beta products, glatiramer acetate, and teriflunomide, and between 50% and 69% for alemtuzumab, dimethyl fumarate, fingolimod, and natalizumab. The risk of disability progression (3-month) was reduced by 19%–28% with IFN-beta products, glatiramer acetate, fingolimod, and teriflunomide, by 38%–45% for pegylated IFN-beta, dimethyl fumarate, and natalizumab, and by 68% with alemtuzumab. Alemtuzumab and natalizumab had the highest surface under cumulative ranking curve (SUCRA) scores (97% and 95%, respectively) for ARR. IFN-beta-1b 250 mcg ranked among the most efficacious treatments for disability progression confirmed after 6 months (92%). Another network meta-analysis by Cochrane showed similar results, with alemtuzumab, natalizumab, and fingolimod being more effective in preventing relapses, based on moderate to high-quality evidence. After looking at the results of these two meta-analyses, one may feel that alemtuzumab and natalizumab are the best treatment options available. However, it is important to cautiously balance treatment efficacy against burden of therapy due to inconvenience, need for monitoring, and bothersome/serious adverse effects. The onus is on the treating neurologist whether the patient can benefit with less effective yet safe therapy or he or she needs to start with or requires an escalation of therapy with a more effective but less safe drug.
Mendes et al. conducted a systematic review to identify the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) of DMTs approved for RRMS. The lowest NNTBs were found with IFN-β-1a-SC (NNTB 3) and natalizumab (NNTB 2). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22). Among the first-line DMTs, most favorable LHH was found for GA (LHH 59.0), and the least for IFN-b-1a-IM and IFN-b-1b (LHH 4.7 for both). Among the second-line DMTs, LHHs were estimated at 53 for natalizumab and 32 for fingolimod. To conclude, IFN-b-1a-SC and natalizumab had the most favorable benefit–risk ratio among first- and second-line treatment options for RRMS, respectively.
Certain aspects to be kept in mind while interpreting these meta-analyses are that the trials included were conducted over a period of over 25 years. In newer trials, the introduction of the new McDonald diagnostic criteria led to inclusion of participants who had earlier diagnosis and had less severe disease when compared with people in older studies which may explain decrease in pretrial relapse rate and the associated decrease in on-trial relapse rate. Also, newer studies have included participants who had made prior use of immunomodulators or immunosuppressants. Evidence on 15 treatments included in these reviews was derived from 39 trials (~2.5 trials/DMT). Different scales were used, and different assessment time points do not allow comparisons to be made. These trials are subjected to bias due to unblinding of the treatment groups owing to the well-documented side effects, and cost-effectiveness has never been considered in any of these trials. Recently, Iannazzo et al. reviewed the cost-effectiveness analyses of DMTs in patients with RRMS which included 33 articles and four Health Technology Assessment reports prepared for the United Kingdom. They found discrepancy between study criteria even in the same country, thus concluding that large amount of health economic assessments was available across the globe, yielding difficult-to-compare and conflicting results.
| Recently Approved Therapies|| |
Daclizumab is an anti-CD25 antibody directed against alpha-subunit of IL-2 receptor, with a high subcutaneous bioavailability. It acts by increasing regulatory cells, especially CD56 + natural killer cells, and controlling immune response. It has been approved by FDA in 2016 as second- or third-line therapy for treatment in RRMS as once every 28-day subcutaneous injection. Its efficacy was demonstrated by two phase 3 trials, namely, DECIDE and SELECT,, which compared daclizumab with IFN-beta-1a and placebo, respectively, in around 600 and 1800 patients, respectively. Side effects included skin reactions such as erythema, eczema, and elevation of liver enzymes. The DECIDE trial concluded that daclizumab was superior to IFN-beta-1a in terms of relapse reduction, but it did not lower risk of disability progression and had higher rates of infection, rash, and elevated liver enzymes. It has been recently pulled out from the market due to increasing concerns regarding liver damage and report of eight cases of encephalitis in Europe.
OCR is a second-generation CD20 antibody with a humanized IgG1 tail and it is thought to via complement-mediated cytotoxicity, apoptosis, and antibody-dependent cytotoxicity. Two identical randomized, double-blind, multicenter phase III trials, OPERA 1 and 2,, were consecutively initiated, comparing OCR with IFN in RRMS enrolling 821 and 835 patients, respectively, receiving intravenous OCR at a dose of 600 mg every 24 weeks or subcutaneous IFN-beta-1a at a dose of 44 μg three times weekly for 96 weeks. In both these trials, ARR in IFN-beta-1a group was 0.292 and 0.290 when compared with 0.156 and 0.155 in OCR arms, which was statistically significant. At 96 weeks, 15.2% versus 9.8% of IFN-β1a-treated vs. OCR-treated patients had clinical disease progression (CDP) with a significant relative risk reduction (RRR) of 40% (P = 0.006). ORATARIO  was yet another phase 3 trial which included 732 patients with PPMS randomized in 2:1 ratio to receive intravenous OCR (600 mg) or placebo every 24 weeks for at least 120 weeks. CDP was 32.9% with OCR versus 39.3% with placebo (HR, 0.76; 95% CI: 0.59–0.98; P = 0.03. Adverse effects seen were infusion-related reactions, upper respiratory tract infections, and oral herpes infections in OCR group. Neoplasms were seen more in OCR group than in placebo (2.3 vs. 0.8%).
| Off Label Therapies|| |
There is only one placebo control trial till date, which included 104 RRMS who received either two doses of rituximab or placebo infusions. The proportion of patients with relapses was 15.4% versus 34.3%, respectively at 24 weeks and 20.3 versus 40% at 48 weeks. Infusion reactions were common (78%) in rituximab-treated patients. Another study  conducted at three Swedish MS centers compared outcomes on switching from NTZ (due to JC virus Ab +) to fingolimod versus rituximab with 256 patients (55% on fingolimod). Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse with HR (favoring rituximab) for adverse events (5.3% vs. 21.1%), and HR for treatment discontinuation (favoring rituximab) (1.8% vs. 28.2%) was 0.25 (95% CI: 0.10–0.59) and 0.07 (95% CI: 5 0.02–0.30).
Azathioprine (AZA) may be used as an alternative to IFN as it is widely available and cheaper. However, concerns about its safety, side effect profile, increased risk of malignancy, and lack of adequately large randomized trials limit its use in MS. A systematic review by Cochrane group  including five trials had 698 randomized patients. It showed that AZA reduced the number of patients who had relapses during the first year of treatment (RRR = 20%; 95% CI: 5%–33%), at 2 years' (RRR = 23%; 95% CI: 12%–33%) and 3 years' (RRR = 18%; 95% CI: 7%–27%) follow-up with no heterogeneity among the studies. Adverse effects such as bone marrow suppression, raised liver enzymes, and gastrointestinal disturbances were higher in the azathioprine group rather than in the placebo group but could be easily managed with adequate monitoring. They did not find an increase in risk of malignancy from azathioprine. The authors concluded that AZA can be used as a maintenance treatment in those who frequently relapse and require steroids and it is a fair alternative option to IFN-beta. Future randomized head-head trials between AZA and IFN may yield better results.
Autologous stem-cell transplant
Autologous hematopoietic stem-cell transplant (AHSCT) has been evaluated as a treatment option in MS for more than two decades, with the goal of immune ablation. Earlier trials used high-dose induction therapy and were conducted in patients with advanced disease and in those having a progressive course.,, Thus, many patients continued to accumulate disability due to secondary noninflammatory degeneration. It was also found that those treated with active disease had better outcome after 15 years than those without active inflammation. It was later hypothesized that early treatment may provide better neurological outcome and may even reverse neurological dysfunction.
A recent meta-analysis, which included 15 studies comprising 764 transplanted recipients, summarized the evidence of immunoablative therapy followed by AHSCT in severe and treatment refractory MS. Treatment-related mortality was 2.1% and was higher in older studies probably due to high-dose induction therapy and in studies with a lower proportion of patients with RRMS. Pooled rate of progression was 17.1% at 2 years and 23.3% at 5 years. The pooled proportion of NEDA patients at 2 years was 83% and at 5 years was 67%.
Indications for autologous stem-cell transplant in MS would be in patients with active RRMS course (at least one relapse in the last year, at least one Gd-enhancing lesions (Gd+) in MRI, new nonenhancing (Gd-) lesions in two consecutive MRIs, rapid progression of disability despite the use of drugs of first or more lines), SPMS with active inflammatory process, Marburg form of MS, duration of MS not exceeding 5 years, EDSS between 2.5 and 6.5 points, and age between 18 and 45 years.
Mesenchymal stem-cell transplant
The advantage of mesenchymal stem cells over hematopoietic stem cells is that they can be derived from multiple adult tissues in addition to bone-marrow-like umbilical cord, blood, placenta, thymus, and dental pulp. These can be gained readily even from patients with progressive disease; they can be enriched and prolonged by in vitro culturing; they are less prone to genetic defects and malignant transformation, and finally, they can be administered without the need of immune suppressive therapy. These are administered intrathecally and intravenous route of administration has not yet been established. Till date, there are seven published (five phase 1 and two phase two studies) with numbers ranging from 7 to 25, over a median follow-up of 7–25 months. One patient each developed meningitis and transient encephalopathy with seizures, probably due to meningeal irritation after intrathecal injection. These trials were done in mixed group of patients (RRMS, SPMS, and PPMS). Two studies did not show any change in EDSS, while in others change in EDSS ranged from 0.2 to 5.9.,,, However, this evidence comes from preclinical studies, and further randomized trials are needed to know consistency and efficacy of these methods.
Mouse models have shown that myelin also provides support other than increase in conduction velocity to its underlying axon. Remyelination is a common mechanism of repair in nervous system after demyelination and is an evolving field in MS; however, it has not yet transformed into clinical reality.,, Multiple studies have identified molecules that promote recruitment, differentiation, and survival of oligodendrocytes. Most of them, like benztropine, clemastine fumarate, quetiapine, and GSK239512, target either muscarinic or histaminic (H1 and H2) receptors. Domperidone promotes remyelination by elevating prolactin levels through prolactin receptor (PRLR). Molecules that act through nuclear receptors include clobetasol (glucocorticoid receptor), liothyronine (thyroid hormone receptor), and vitamin D (vitamin D receptor). Monoclonal antibodies like opicinumab target LINGO1 and rHIgM22. Miconazole acts through stimulating the mitogen-activated protein kinase pathway.
Current treatment of MS has entered an exciting phase, because remyelination can confer neuroprotection and these along with immunomodulators can control destructive aspects of inflammation. Challenges which remain to bring remyelination as a therapeutic option from bench to clinic are knowledge about complex roles of immune response, CNS penetration of these compounds, objective measures to monitor remyelination, and deciding clinical outcomes.
| Outcome Assessment|| |
The goals of disease management in MS comprise treating relapses, managing symptoms, modifying/reducing relapses, delaying progression to disability, and facilitating an acceptable quality of life. Over the past two and half decades, newer drugs have broadened out therapeutic options and the availability of more potent drugs has prompted definition of more ambitious treatment goals.
However, the main challenges remain the heterogeneity of disease, ideal treatment/goals of therapy, and use of scores to identify disease severity/response to treatment. Heterogeneity in treatment response of MS is due to diverse pathological processes involved which may not be addressed by single drug. Also, each individual's response and tolerance to a particular drug varies; in addition, each drug has its own efficacy in a particular individual.
The currently used treatment goal is NEDA which represents strict standards of therapeutic efficacy and suggests complete remission of disease. Earlier, NEDA was a composite measure of three items, namely, no relapses (clinically defined), no disability progression (as per EDSS), and no MRI activity (in terms of new or enlarging T2 or Gd-enhancing lesions) which were derived from post hoc analysis of trials on natalizumab and cladribine. Currently, NEDA-4 includes brain volume loss as an additional parameter. This was because NEDA-3 gave more importance to focal inflammatory disease activity than diffuse damage and neurodegeneration. Kappos et al. evaluated the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 on data pooled from placebo-controlled trials on fingolimod (FREEDOMS and FREEDOMS II). They found that at 2 years, 31% (217/700) of patients on fingolimod 0.5 mg achieved NEDA-3 and 19.7% (139/706) achieved NEDA-4 as against 9.9% (71/715) and 5.3% (38/721), respectively, in placebo group. They concluded that classical definition of NEDA-3 is driven by MRI activity and CDP contributed to fewer than 10% of unique events in both treatment groups. NNT for NEDA-3 was 5 and for NEDA-4 was 7. But NEDA has its own controversies and limitations. One being, it is a tough to attain this target. Second, NEDA does not mean that the patient is free of “all” disease activity; while considering relapses, it is important to consider the type (e.g., motor vs. sensory; complete vs. incomplete recovery) as it has variable clinical implications, and for progression the question remains whether there is a preceding history of relapses (e.g., primary vs. secondarily progressive). Yet another potential criticism is that progressive disability may have nothing to do with ongoing inflammation and may simply represent postinflammatory degeneration or a nonrelapsing progressive MS. Various other scores available are Rio score, modified Rio score, Canadian Working Group criteria, MS decision model, and many more. Also, it is important to know that there is a difference in applicability in practice, because in a clinical trial these measures are used for evaluating treatment effects at a population level, while in clinics these are used for decision-making of an individual and to assess disease severity, progression, and response in an individual. Other aspects which need to be considered are patients' perception of risk and his or her priorities which are equally important and critical in decision-making.
| Rehabilitation|| |
Patients with MS have various combinations of deficits including motor (weakness, spasticity), sensory (sensory loss, visual loss), cerebellar (ataxia, falls), bowel and bladder impairment (overflow or urge incontinence), cognitive (memory, attention) along with pain, fatigue, psychosocial, and behavioral issues which impair their activities of daily living and social participation. Khan et al. did a systematic review of 39 reported systematic reviews till 2017 and concluded that there was high-quality evidence for physical therapeutic modalities (exercise/physical activities) for improved functional abilities like mobility and strength and for comprehensive fatigue management programs for patient-reported fatigue. Evidence was of moderate quality for multidisciplinary rehabilitation for longer term gains, for cognitive-behavioral therapy for the treatment of depression and of information provision to increase patient's knowledge. There was low-quality evidence for exercise therapy for improved balance and cognitive symptoms and for psychological interventions, occupational therapy strategies, hyperbaric oxygen therapy, whole-body vibration, upper limb rehabilitation programs, vocational rehabilitation, and tele rehabilitation. There was inconclusive evidence for dietary (polyunsaturated fatty acids, vitamin D), hippotherapy, and electrical stimulation.
| Conclusion|| |
As historian T. Jock Murray recollects the saying of a young British man who died in early 19th century of disease believed to be MS: “It would be nice if a physician from London, one of these days, were to gallop up hotspur, tether his horse to the gait post, and dash in waving a reprieve – the discovery of a cure!” Now, almost a century later we are much closer to cure with advent of newer diagnostic tools, newer drugs, and better understanding of the disease, and researchers continue to strive to achieve this goal.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Clanet M. Jean-Martin Charcot. 1825 to 1893. Int MS J 2008;15:59-61.
Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al
. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014;83:1022-4.
Bhatia R, Bali P, Chowdhary R. Epidemiology and genetic aspects of multiple sclerosis in India. Ann Indian Acad Neurol 2015;18:6.
] [Full text]
Campbell JD, Ghushchyan V, Brett McQueen R, Cahoon-Metzger S, Livingston T, Vollmer T, et al
. Burden of multiple sclerosis on direct, indirect costs and quality of life: National US estimates. Mult Scler Relat Disord 2014;3:227-36.
Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010;9:520-32.
Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Ebers GC. Mortality in patients with multiple sclerosis. Neurology 2013;81:184-92.
Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO. A review of genome-wide association studies for multiple sclerosis: Classical and hypothesis-driven approaches. Hum Genet 2015;134:1143-62.
Harirchian MH, Fatehi F, Sarraf P, Honarvar NM, Bitarafan S. Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord 2017;20:43-7.
Evans C, Beland S-G, Kulaga S, Wolfson C, Kingwell E, Marriott J, et al
. Incidence and prevalence of multiple sclerosis in the Americas: A systematic review. Neuroepidemiology 2013;40:195-210.
Laursen JH, Søndergaard HB, Sørensen PS, Sellebjerg F, Oturai AB. Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab. Mult Scler Relat Disord 2016;10:169-73.
Ben-Nun A, Kaushansky N, Kawakami N, Krishnamoorthy G, Berer K, Liblau R, et al
. From classic to spontaneous and humanized models of multiple sclerosis: Impact on understanding pathogenesis and drug development. J Autoimmun 2014;54:33-50.
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al
. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain J Neurol 2009;132(Pt 5):1175-89.
Haider L, Fischer MT, Frischer JM, Bauer J, Höftberger R, Botond G, et al
. Oxidative damage in multiple sclerosis lesions. Brain J Neurol 2011;134(Pt 7):1914-24.
Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015;15:545-58.
McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al
. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al
. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292-302.
Filippi M, Rocca MA, Ciccarelli O, De Stefano N, Evangelou N, Kappos L, et al
. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 2016;15:292-303.
Filippi M, Preziosa P, Meani A, Ciccarelli O, Mesaros S, Rovira A, et al
. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: A retrospective study. Lancet Neurol 2018;17:133-42.
Solomon AJ, Bourdette DN, Cross AH, Applebee A, Skidd PM, Howard DB, et al
. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology 2016;87:1393-9.
Calabrese M, Rinaldi F, Seppi D, Favaretto A, Squarcina L, Mattisi I, et al
. Cortical diffusion-tensor imaging abnormalities in multiple sclerosis: A 3-year longitudinal study. Radiology 2011;261:891-8.
Wang Y, Liu T. Quantitative susceptibility mapping (QSM): Decoding MRI data for a tissue magnetic biomarker. Magn Reson Med 2015;73:82-101.
Huss AM, Halbgebauer S, Öckl P, Trebst C, Spreer A, Borisow N, et al
. Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: A German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome. J Neurol 2016;263:2499-504.
Arrambide G, Tintore M, Espejo C, Auger C, Castillo M, Río J, et al.
The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain 2018;141:1075-84.
Sellebjerg F, Börnsen L, Khademi M, Krakauer M, Olsson T, Frederiksen JL, et al
. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 2009;73:2003-10.
Miljković D, Stanojević Z, Momcilović M, Odoardi F, Flügel A, Mostarica-Stojković M. CXCL12 expression within the CNS contributes to the resistance against experimental autoimmune encephalomyelitis in Albino Oxford rats. Immunobiology 2011;216:979-87.
Karimabad MN, Arababadi MK, Hakimizadeh E, Daredori HY, Nazari M, Hassanshahi G, et al
. Is the IL-10 promoter polymorphism at position -592 associated with immune system-related diseases? Inflammation 2013;36:35-41.
Schneider R, Mohebiany AN, Ifergan I, Beauseigle D, Duquette P, Prat A, et al
. B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients. J Immunol Baltim Md 1950 2011;187:4119-28.
Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M5. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis. [Internet]. [cited 2018 Feb 12]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27645339
Tramacere I, Del Giovane C, Salanti G, D'Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis. Cochrane Database Syst Rev 2015:CD011381.
Mendes D, Alves C, Batel-Marques F. Benefit-risk of therapies for relapsing-remitting multiple sclerosis: Testing the number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and the likelihood to be helped or harmed (LHH): A systematic review and meta-analysis. CNS Drugs 2016;30:909-29.
Iannazzo S, Iliza A-C, Perrault L. Disease-modifying therapies for multiple sclerosis: A systematic literature review of cost-effectiveness studies. PharmacoEconomics 2018;36:189-204.
Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue E-W, et al
. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): A randomised, double-blind, placebo-controlled trial. Lancet 2013;381:2167-75.
Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, et al
. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015;373:1418-28.
Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al
. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-34.
Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al
. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-20.
D'Amico E, Caserta C, Patti F. Monoclonal antibody therapy in multiple sclerosis: Critical appraisal and new perspectives. Expert Rev Neurother 2015;15:251-68.
Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, et al
. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol 2016;79:950-8.
Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev 2007 :CD003982.
Fassas A, Kimiskidis VK, Sakellari I, Kapinas K, Anagnostopoulos A, Tsimourtou V, et al
. Long-term results of stem cell transplantation for MS: A single-center experience. Neurology 2011;76:1066-70.
Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, et al
. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology 2017;88:2115-22.
Szczechowski L, Śmiłowski M, Helbig G, Krawczyk-Kuliś M, Kyrcz-Krzemień S. Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis – Whom, when and how. Int J Neurosci 2016;126:867-71.
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al
. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187-94.
Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, et al
. Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch Med Res 2013;44:266-72.
Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al
. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: An open-label phase 2a proof-of-concept study. Lancet Neurol 2012;11:150-6.
Mohajeri M, Farazmand A, Mohyeddin Bonab M, Nikbin B, Minagar A. FOXP3 gene expression in multiple sclerosis patients pre- and post mesenchymal stem cell therapy. Iran J Allergy Asthma Immunol 2011;10:155-61.
Odinak MM, Bisaga GN, Novitskii AV, Tyrenko VV, Fominykh MS, Bilibina AA, et al
. Transplantation of mesenchymal stem cells in multiple sclerosis. Neurosci Behav Physiol 2012;42:516-20.
Nave K-A. Myelination and the trophic support of long axons. Nat Rev Neurosci 2010;11:275-83.
Plemel JR, Liu W-Q, Yong VW. Remyelination therapies: A new direction and challenge in multiple sclerosis. Nat Rev Drug Discov 2017;16:617-34.
Franklin RJM, Ffrench-Constant C. Remyelination in the CNS: From biology to therapy. Nat Rev Neurosci 2008;9:839-55.
Franklin RJM. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002;3:705-14.
Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sørensen PS, Vermersch P, et al
. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: A post-hoc and subgroup analysis. Lancet Neurol 2011;10:329-37.
Kappos L, De Stefano N, Freedman MS, Cree BA, Radue E-W, Sprenger T, et al
. Inclusion of brain volume loss in a revised measure of “no evidence of disease activity” (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler Houndmills Basingstoke Engl 2016;22:1297-305.
Khan F, Amatya B. Rehabilitation in multiple sclerosis: A systematic review of systematic reviews. Arch Phys Med Rehabil 2017;98:353-67.
Orrell RW. Multiple sclerosis: The history of a disease. J R Soc Med 2005;98:289.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]