MULTIPLE SCLEROSIS (MS)

• ACRONYMS

• AAN - American Academy of Neurology
• AV - Atrioventricular
• CSF - Cerebrospinal fluid
• CIS - Clinically isolated syndrome
• CNS - Central nervous system (brain and spinal cord)
• DIS - Dissemination in space
• DIT - Dissemination in time
• DMT - Disease-modifying therapy
• EAN - European Academy of Neurology
• ECTRIMS - European Committee for Treatment and Research in Multiple Sclerosis
• HSCT - Haematopoietic stem cell transplant
• JCV - John Cunningham virus
• MRI - Magnetic resonance imaging
• MS - Multiple sclerosis
• Nrf2 - Nuclear factor (erythroid-derived 2)-like 2
• PML - Progressive multifocal leukoencephalopathy
• PP - Primary progressive
• RR - Relapsing-remitting
• SP - Secondary progressive
• UC - Ulcerative colitis
• ULN - Upper limit of normal

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• DEFINITIONS

• Clinically isolated syndrome (CIS) - a single episode lasting at least 24 hours that includes MRI findings of a demyelinating event and objective clinicalsymptoms that coincide with those findings. If the patient goes on to have another event and is diagnosed with MS, then the clinically isolated event becomes the patient's first MS attack.In studies lasting up to 20 years, 65 - 80% of patients with a CIS and an abnormal baseline MRI have gone on to be diagnosed with MS.

• Dissemination in space (DIS) - the development of demyelinating lesions during a single attack in at least two of the four regions that are characteristic for MS. The four areas that are characteristic for MS include periventricular, cortical or juxtacortical, infratentorial, and the spinal cord.

• Dissemination in time (DIT) - the development of demyelinating lesions during two distinctly different time periods. DIT can be demonstrated by new lesions appearing on a follow-up MRI or by the presence of gadolinium-enhancing and nonenhancing lesions on the same MRI. New MS lesions typically enhance for 2 - 6 weeks before they become non-enhancing lesions; therefore, the presence of enhancing and nonenhancing lesions on the same MRI indicates DIT.

• Myelin - lipid-rich substance produced and maintained by oligodendrocytes in the CNS. Myelin forms an insulating sheath around neuronal axons that increases the speed of nerve conduction. In MS, the myelin sheath is destroyed by autoimmune inflammation.

• Primary progressive MS - MS that is characterized by objective neurologic disability that continues to progress over time independent of relapses and remissions. In primary progressive MS, progressive disability begins with the onset of MS compared to secondary progressive MS where progressive disability occurs after a period of relapsing-remitting MS. About 10 - 15% of patients diagnosed with MS have the primary progressive type.

• Radiologically isolated syndrome - MRI findings consistent with MS in a patient who has no neurologic symptoms. About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS over the next 5 years.

• Relapsing-remitting MS - most common type of MS (85 - 90% of patients). It is marked by MS attacks lasting at least 24 hours that are followed by periods of stable remission that can last weeks to years. Recovery from relapses is variable and residual disability may persist. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period

• Secondary progressive MS - MS that is characterized by objective neurologic disability that continues to progress over time independent of relapses and remissions. In secondary progressive MS, progressive disability develops after a period of relapsing-remitting MS which typically lasts 10 - 15 years. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period.

• T2-hyperintense lesion - MRI finding that is typical for MS lesions. T2-hyperintensities occur in areas of demyelination and axonal loss.

• White matter - areas of the brain that are primarily made up of myelinated axons. In a dissected brain, white matter appears lighter because it is full of myelin which is lipid-rich. Grey matter is primarily made of cell bodies and appears darker. [1,2,3,4,5,6]

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• EPIDEMIOLOGY

• The prevalence of MS is between 50 - 300 cases per 100,000 people. It is estimated that 2.3 million people in the world have MS with at least 400,000 people in the U.S. being affected.
• The estimated lifetime risk of MS in the general population is around 0.1%
• MS is one of the most common causes of serious physical disability in working adults [5,6,8]

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• RISK FACTORS

• Female sex - around 75% of patients diagnosed with MS are female
• Age
• Relapsing remitting MS has a mean age of onset of 30 years
• Primary progressive MS has a mean age of onset of 40 years
• Family history
• People with an affected first-degree relative have 2 - 4% lifetime risk
• Monozygotic twins have 30 - 50% concordance
• Genetics (HLA-DR15 and HLA-DR16)
• Vitamin D deficiency
• Obesity
• Cigarette smoking
• Epstein-Barr virus infection
• Temperate latitudes [5,6,8,23]

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• PATHOPHYSIOLOGY

• Overview
• The precise cause of MS is unknown. It is believed to occur from the autoimmune destruction of myelin sheaths that surround the axons of nerve cells in the CNS. Over time, demyelination leads to axonal degeneration and neuronal loss. In some cases, remyelination can occur.
• The stimulus for autoimmunity in MS has not been confirmed but it is believed to be caused by an interplay of genetic and environmental factors. Because MS pathology only occurs in the CNS, two theories have arisen that attempt to explain its origin. In the intrinsic model, an initial event is believed to occur in the CNS that leads to the release of CNS antigens into the periphery where they stimulate an autoimmune response against the CNS. In the extrinsic model, an initial event takes place outside the CNS that leads to an autoimmune attack against the CNS.
• Demyelinating lesions appear as hyperintense white areas on T2-weighted MRI images
• MS lesions are typically found in the following areas:
• Periventricular - next to the lateral ventricles
• Juxtacortical - next to the cerebral cortex
• Infratentorial - area of the brain below the tentorium cerebelli that includes the brainstem, cerebellum, pons, and medulla
• Optic nerve - nerve that connects the retina to the brain
• Spinal cord - cervical cord is most often affected [1,5,6,8]
• The first two images below show examples of periventricular and juxtacortical lesions on transverse MRI images. The third image shows examples of infratentorial, optic nerve, and spinal cord lesions.



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• SYMPTOMS

• Overview
• Patients with MS typically develop symptoms in their late twenties to early thirties. Presenting symptoms typically have an acute onset (hours to days) and are dependent on the area of the CNS that is affected. Maximum deficit typically occurs within 4 weeks of onset and is followed by spontaneous remission.


• Common neurologic symptoms seen in MS
• Unilateral optic neuritis - symptoms include visual impairment, visual abnormalities (e.g. flashing lights, rings of light), and pain on eye movement
• Double vision - caused by brainstem lesions that affect conjugate gaze
• Facial numbness or paresthesia
• Loss of motor coordination (ataxia) - indicative of cerebellar lesions
• Partial myelopathy - spinal cord symptoms (e.g. limb weakness, numbness, or paresthesia) that only affect one side of the body
• Lhermitte's sign - sudden sensation of electric shock that runs down the spine and sometimes into the extremities that is usually triggered by bending the head forward
• Urinary urge incontinence
• Erectile dysfunction [1,5,6]

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• DIAGNOSIS

• Overview
• The diagnosis of MS is based on a combination of clinical findings and MRI findings. In some cases, CSF-specific oligoclonal bands may also be a part of the diagnosis.
• A number of other conditions can mimic findings in MS (see differential below) so it is important to make the correct diagnosis in order to initiate prompt and appropriate treatment. The McDonald criteria which were last updated in 2017 are the primary tool used to establish a diagnosis of MS.

• Magnetic resonance imaging (MRI)
• Brain MRI findings are the primary tool used to diagnose MS. MS lesions are characterized as T2-hyperintensities that occur in areas of demyelination and axonal loss. MS lesions are typically seen in the following areas: periventricualr, juxtacortical, infratentorial, optic nerve, and spinal cord (see pathophysiology above).
• Lesions should be classified as those that are consistent with objective clinical findings and those that are not
• The terms below are used to characterize MRI lesions in MS
• Clinically isolated syndrome (CIS) - a single episode lasting at least 24 hours that includes MRI findings of a demyelinating event and objective clinicalsymptoms that coincide with those findings. If the patient goes on to have another event and is diagnosed with MS, then the clinically isolated event becomes the patient's first MS attack.In studies lasting up to 20 years, 65 - 80% of patients with a CIS and an abnormal baseline MRI have gone on to be diagnosed with MS.
• Dissemination in space (DIS) - the development of demyelinating lesions during a single attack in at least two of the four regions that are characteristic for MS. The four areas that are characteristic for MS include periventricular, cortical or juxtacortical, infratentorial, and the spinal cord (see pathophysiology above).
• Dissemination in time (DIT) - the development of demyelinating lesions during two distinctly different time periods. DIT can be demonstrated by new lesions appearing on a follow-up MRI or by the presence of gadolinium-enhancing and nonenhancing lesions on the same MRI. New MS lesions typically enhance for 2 - 6 weeks before they become nonenhancing lesions; therefore, the presence of enhancing and nonenhancing lesions on the same MRI indicates DIT.
• Radiologically isolated syndrome - MRI findings consistent with MS in a patient who has no neurologic symptoms. About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS over the next 5 years. [1,2,3,4,5,6]

• Oligoclonal bands
• The only laboratory used in the diagnosis of MS is CSF-specific oligoclonal bands. CSF-specific oligoclonal bands are defined as antibodies (typically IgG) that are produced specifically in the CNS. In order to detect oligoclonal bands, cerebrospinal fluid (CSF) and serum must both be obtained. Electrophoresis is then performed on both samples and proteins including immunoglobulins are separated out. The difference in antibodies between the two samples is then compared. If immunoglobulin-secreting B-cells and plasma cells are active in the CNS and not the periphery, then bands of immunoglobulins will appear on the CSF sample that are not present on the serum sample. These bands are referred to as "oligoclonal bands," and the presence of two or more bands is considered a positive test. Oligoclonal bands are present in about 90% of patients with MS, but they are not specific for the disease.

• Symptomatic and asymptomatic MRI lesions may be considered
• Reference [2]

2017 McDonald Criteria for Diagnosing Primary Progressive MS

Primary progressive MS can be diagnosed in patients with 1 year of progressive disability (retrospectively or prospectively determined) independent of clinical relapse who meet two of the following criteria: One or more T2-hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial Two or more T2-hyperintense spinal cord lesions Presence of CSF-specific oligoclonal bands

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• DIFFERENTIAL

• Overview
• The differential diagnosis for MS is broad and given the lifelong implications of an MS diagnosis, careful consideration of other conditions should be made. In some studies, misdiagnosis of MS has been as high as 10%.
• The table below lists some other conditions that can mimic MS. Most of these conditions are rare or represent uncommon sequelae of other diseases.

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• CLINICAL COURSE AND PROGNOSIS

• Overview
• The clinical course of MS is highly variable with most patients experiencing attacks followed by periods of stabilization while others have progressive disability from the onset
• New disease-modifying therapies have been effective in improving outcomes in relapsing-remitting MS, but less options are available for primary progressive MS
• The table below gives some guidance on the typical clinical course of MS and its related syndromes along with prognostic factors that may be helpful in predicting disease progression

• Reference [1,2,3,4,5,7]

Clinical Course and Prognostic Factors of MS and Related Syndromes
Radiologically isolated syndrome About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS (typically relapsing-remitting) over the next 5 years Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS Spinal cord lesions and male sex increase the risk of developing primary progressive MS
Clinically isolated syndrome In studies lasting up to 20 years, 65 - 80% of patients with a clinically isolated syndrome and an abnormal baseline MRI have gone on to be diagnosed with MS Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS The presence of ≥ 10 brain lesions on MRI is strongly associated with progression to MS
Relapsing-remitting MS Most common type of MS accounting for 85 - 90% of cases. Throughout the disease, women have higher relapse rates than men. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability Short interval between first and second attacks and higher number of lesions at clinical onset are associated with greater risk for long-term disability
Primary progressive MS Accounts for 10 - 15% of patients diagnosed with MS Typically presents at an older age (mean age of onset is 40 years) and men and women are affected equally Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and cognitive dysfunction may also be progressive
Secondary progressive MS Typically occurs after a 10 - 15 year course of relapsing-remitting MS. Occurs more frequently in women than men. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around11% over a ten-year period Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and/or cognitive dysfunction may also be progressive

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• TREATMENT

• Overview
• In 1993, interferon beta became the first drug approved for the treatment of MS. Since that time, MS treatment has evolved rapidly. There are currently 9 distinct drugs that are approved to treat MS in the U.S.
• In 2018, the AAN and the EAN/ECTRIMS issued guidelines on the treatment of MS. The guidelines offer some guidance on choosing medications, but in general, only make broad recommendations. The recommendations in the tables below are derived from a combination of the AAN and EAN/ECTRIMS recommendations along with review articles that give expert opinion.

Clinically Isolated Syndrome (CIS) Treatment Recommendations

AAN recommendations Multiple trials have confirmed that treating CIS with disease-modifying therapies (DMTs) is associated with a significant delay in second clinical relapse or new brain MRI-detectedlesions in people with a first demyelinating event who are considered to be at high risk for MS on the basis of brain MRI-detected lesions Clinicians should discuss the benefits and risks of treatment for people with CIS who have ≥ 2 brain lesions that have imaging characteristics consistent with MS After discussing the risks and benefits, clinicians should prescribe treatment to people with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy. There is insufficient evidence to recommend a specific therapy. For patients who are not being treated, annual imaging with close follow-up is recommended for at least 5 years [9] EAN/ECTRIMS recommendations Offer interferon or glatiramer acetate to patients with CIS and an abnormal MRI with lesions suggestive of MS who do not fulfil criteria for MS [10] Studies in CIS Interferon Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial, Lancet Neurol (2012) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes, Neurology (2006) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study, Lancet (2001) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis, NEJM (2000) Glatiramer acetate Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet (2009) Teriflunomide Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Neurol (2014)

Relapsing-remitting MS Treatment Recommendations

AAN recommendations Clinicians should offer disease-modifying therapies (DMTs) to people with relapsing forms of MS with recent clinical relapses or MRI activity Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab to people with highly active MS✝ Clinicians may recommend azathioprine or cladribine for people with relapsing forms of MS who do not have access to approved DMTs Annual imaging with close follow-up for at least 5 years may be recommended for patients who are not on DMTs, have not had relapses in the preceding two years, and do not have active new MRI lesion activity on recent imaging [9] EAN/ECTRIMS recommendations Offer early treatment with DMTs in patients with active relapsing-remitting MS as defined by clinical relapses and/or MRI activity (active lesions, contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually) Choice of DMT will depend on the following factors: patient characteristics and comorbidities, disease severity/activity, drug safety profile, drug accessibility Use one of the following drugs: interferon beta-1b, interferon beta-1a SQ or IM, peginterferon beta-1a, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, daclizumab, natalizumab, ocrelizumab and alemtuzumab [10] Expert opinion recommendations Initial therapy - patients with average-active MS✝ Dimethyl fumarate Teriflunomide Interferon beta Glatiramer acetate Initial therapy - patients with highly-active MS✝ Natalizumab Fingolimod Alemtuzumab Daclizumab [3] ✝Definition of highly-active MS varies by trial. In one trial, the following criteria were used: ≥ 2 relapses in the prior year with ≥ 1 gadolinium-enhancing lesion on MRI. In another trial, ≥ 2 relapses in the past year or ≥ 3 relapses in the past 2 years was used. [11,12]

Primary Progressive MS Treatment Recommendations

AAN recommendations Clinicians should offer ocrelizumab to people with primary progressive MS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits [9] EAN/ECTRIMS recommendations Consider treatment with ocrelizumab for patients with primary progressive MS [10] Studies in primary progressive MS Ocrelizumab Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis, NEJM (2017) Rituximab Rituximab in patients with primary progressive multiple sclerosis. Results of a randomized double-blind placebo-controlled multicenter trial, Ann Neurol (2009) Glatiramer acetate Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial, Ann Neurol (2007) Fingolimod Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial, Ann Neurol (2016)

Secondary Progressive MS Treatment Recommendations

AAN recommendations The AAN does not make specific recommendations for secondary progressive MS [9] EAN/ECTRIMS recommendations Consider treatment with interferon beta-1a (subcutaneously) or interferon beta-1b in patients with active secondary progressive MS taking into account, in discussion with the patient, the dubious efficacy, as well as the safety and tolerability profile of these drugs Consider treatment with mitoxantrone in patients with active secondary progressive MS taking into account, in discussion with the patient, the efficacy and specifically the safety and tolerability profile of this agent Consider treatment with ocrelizumab or cladribine for patients with active secondary progressive MS [10]

Monitoring Therapy Recommendations

AAN recommendations Patients not being treated with DMTs For patients who are not being treated with DMTs, annual imaging with close follow-up is recommended for at least 5 years [9] Patients being treated with DMTs Clinicians should recognize that relapses or new MRI-detected lesions may develop after initiation of a DMT and before the treatment becomes effective in people with MS who are using DMTs. Consequently, many clinicians obtain new baseline MRI three to six months after initiating DMTs to monitor from a treated baseline. EAN/ECTRIMS recommendations When monitoring treatment response in patients treated with DMTs, perform a standardized reference brain MRI usually within 6 months of treatment onset and compare it with a further brain MRI performed typically 12 months after starting treatment. Adjust the timing of both MRIs, taking into account the DMTs typical onset of treatment effect and disease activity. The preferred measure of treatment response to DMTs is the appearance of new or unequivocally enlarging T2 lesions supplemented by gadolinium-enhancing lesions When monitoring treatment safety, perform MRI according to the following: Low risk of PML: annually High risk of PML (JCV+, natalizumab for ≥ 18 months): every 3 - 6 months and when switching drugs [10]

Therapy Failure / Intolerance Recommendations

AAN recommendations General recommendations Clinicians should discuss switching from one DMT to another in people with MS who have been using a DMT long enough for the treatment to take full effect and are adherent to their therapy when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination, over a one-year period of using a DMT Switching to a DMT with a different mechanism or efficacy profile may be beneficial Alemtuzumab, natalizumab, fingolimod, and ocrelizumab may have higher efficacy when compared to previously approved self-injectable DMTs [9] Natalizumab recommendations Clinicians should discuss switching to a DMT with a lower PML risk in patients with MS taking natalizumab who are or become JCV antibody positive, especially with an index of above 0.9 while on therapy Clinicians should check for natalizumab antibodies in people with MS who have infusion reactions before subsequent infusions, or in people with MS who experience breakthrough disease activity with natalizumab use. Clinicians should switch DMTs in people with MS who have persistent natalizumab antibodies. Physicians must counsel people with MS considering natalizumab discontinuation that there is an increased risk of MS relapse or MRI-detected disease activity within six months of discontinuation Physicians and people with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after natalizumab discontinuation (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity [9] Cancer while receiving DMTs If a patient with MS develops a malignancy while using a DMT, clinicians should promptly discuss switching to an alternate DMT, especially for people with MS using azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate [9] Serious infections while receiving DMTs People with MS who develop serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in people with MS using DMT [9] EAN/ECTRIMS recommendations Offer a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of treatment failure When treatment with a highly efficacious drug is stopped, either due to inefficacy or safety concerns, consider starting another highly efficacious drug In treatment decisions, consider the possibility of resumed disease activity or even rebound when stopping treatment, particularly with natalizumab Expert opinion recommendations for relapsing-remitting MS Step 1 For patients who do not achieve therapeutic goals on their initial therapy, consider switching to one of the following: Natalizumab Fingolimod Alemtuzumab Mitoxantrone - due to side effects, should only be used as a last resort Step 2 For patients who fail Step 1, consider the following: Rituximab Ofatumumab Stem cell transplant [3]

Stopping Therapy Recommendations

AAN recommendations Clinically-isolated syndrome There is insufficient evidence to make a recommendation in regards to the risk/benefit of stopping therapy in patients with CIS who are being treated with DMTs [9] In CIS treatment studies (see CIS treatment above), patients were typically treated for 2 - 3 years Relapsing-remitting MS No randomized controlled trials have directly addressed the question of whether, when, or why to discontinue DMTs in an individual with relapsing-remitting MS who has no evidence of relapses or disability progression and has stable brain imaging. The natural history of untreated relapsing-remitting MS is for relapses and disability accumulation to occur. In a randomized controlled trial of 175 individuals taking natalizumab who had been relapse free for one year and had no gadolinium-enhanced lesions on MRI, participants were randomized to continue natalizumab use, switch to placebo, or switch to other therapies. Relapses occurred in 4% of those continuing natalizumab use and in 15 - 29% of those in other treatment arms over 24 weeks. An observational study comparing outcomes in individuals who did or did not stop DMT after a period of at least five years without relapses found a similar risk of relapses between the groups but an increased risk of disability progression among those who stopped DMT. Younger age and lower Expanded Disability Status Scale (EDSS) scores were significant predictors of relapse (clinical or MRI) after treatment discontinuation. Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability progression, stable imaging) on DMT should continue their current DMT unless the patient and physician decide a trial off therapy is warranted [9] Secondary progressive MS People with secondary progressive MS who have relapses or active MRI-detected new lesion formation benefit from DMT No randomized controlled trials have directly addressed the question of whether or when to discontinue DMTs in people with secondary progressive MS. Clinical trials have not evaluated the benefits of DMT in individuals with secondary progressive MS who are nonambulatory with respect to other clinically relevant domains, including vision, cognition, and upper limb function Among individuals with secondary progressive MS (those with and those without clinical relapses) for at least two years at the time of treatment withdrawal, an EDSS ≥ 6 was associated with a 50% lower risk of relapses or MRI-detected activity after treatment discontinuation Clinicians should assess the likelihood of future relapse in individuals with secondary progressive MS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion). Clinicians may advise discontinuation of DMT in people with secondary progressive MS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS ≥ 7) for at least two years [9] EAN/ECTRIMS recommendations Consider continuing a DMT if a patient is stable (clinically and on MRI) and shows no safety or tolerability issues [10]

Pregnancy Recommendations

AAN recommendations Relapse risk is reduced during pregnancy and increases in the postpartum period (3 - 6 months) Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specificDMT during pregnancy Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy [9] EAN/ECTRIMS recommendations Advise all women of childbearing potential that the only DMT that has an FDA pregnancy category rating of "B" is glatiramer acetate For women planning a pregnancy, if there is a high risk of disease reactivation, consider using interferon or glatiramer acetate until pregnancy is confirmed. In some very specific (active) cases, continuing this treatment during pregnancy could also be considered. For women with persistent high disease activity, it would generally be advised to delay pregnancy. For those who, despite this advice, still decide to become pregnant or have an unplanned pregnancy, consider the following: Treatment with natalizumab throughout pregnancy may be considered after full discussion of potential implications Treatment with alemtuzumab could be an alternative therapeutic option for planned pregnancy in very active cases, provided that a 4-month interval is strictly observed from the latest infusion until conception [10]

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• SYMPTOMATIC TREATMENT

Fatigue
Overview Fatigue, which is often severe, affects up to 80% of patients with MS. It may be precipitated by heat, overexertion, and stress. It may also be related to the time of day. [8,13] Treatment Amantadine Starting: 100 mg twice daily Max: 400 - 600 mg/day [13] Efficacy: mostly unproven [PMID 17253480] Exercise - aerobic, strength training, stretching and yoga; has shown benefit in trials [PMID 26358158] Modafinil (Provigil®) Starting: 200 mg once daily Max: 400 mg/day Efficacy: mostly unproven in larger trials [PMID 15824337, PMID 21561959] L-Carnitine Dosing: 1000 mg twice daily [13] Efficacy: mostly unproven in trials [PMID 22592719] Studies A crossover study (N=141) published in 2021 that compared amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), and methylphenidate (up to 10 mg twice daily) to placebo for MS fatigue found that none of the drugs were superior to placebo [PMID 33242419]
Spasticity
Overview Spasticity is common in MS affecting up to 80% of patients Spasticity can range from a sense of tightness, especially in the legs, to prolonged muscle contraction that can lead to contractures and an inability to walk [8] The efficacy of recommended treatments has not been well-studied [PMID 23450612, PMID 14583932] Treatment First-line Gabapentin Tizanidine Baclofen Second-line Diazepam Clonazepam Dantrolene Dosing: titrate as follows: 25 mg once daily for seven days, then 25 mg three times a day for seven days, then if necessary 50 mg three times a day for seven days, then if necessary 100 mg three times a day Use lowest effective dose Do not exceed 100 mg four times a day Other Exercise Cannabidiol or tetrahydrocannabinol Botulinum injections Phenol injections
Oscillopsia
Overview Oscillopsia is a condition where objects in the visual field appear to oscillate Patients with MS who have brainstem and/or cerebellar lesions may develop oscillopsia Only a few small trials have looked at the efficacy of gabapentin and memantine in treating oscillopsia [PMID 20437565, PMID 19756822] Treatment First-line Gabapentin - in trials, doses of 1200 mg/day have been used Second-line Memantine (Namenda®) - in trials, doses of 40 - 60 mg/day have been used
Gait disturbance
Overview Gait disturbance is a common problem in MS affecting up to 85% of patients Mobility issues are often multifactorial with lesion pathology, fatigue, spasticity, and muscle weakness/deconditioning all playing a role Treatment First-line Exercise and physical therapy Second-line Dalfampridine (Ampyra®) Dosing: 10 mg every 12 hours May increase risk of seizures. FDA-approved to improve walking in adults with MS. Efficacy: [PMID 19249634]
Tremor
Overview Tremor is a common condition in MS affecting 25 - 60% of patients MS-associated tremor can be severe and disabling. The most common types of tremor in MS are postural tremor (tremor while maintaining stationary position against gravity) and intention tremor (tremor occurring with target-directed movement that increases in amplitude as the movement gets closer to the target). Medications are mostly ineffective at treating tremor while surgery may be indicated in severe cases [14] Treatment Medications Propranolol Clonazepam Levetiracetam Isoniazid - dosed 400 - 1200 mg/day in trials Botulinum toxin injections - for focal tremors [5,14] Surgery Thalamotomy Deep brain stimulation
Bladder dysfunction
Overview As MS progresses, the prevalence of bladder dysfunction symptoms approaches 100%. Initial symptoms typically appear around 8 years after diagnosis with about 10% of patients having symptoms at the time of diagnosis. Urinary storage symptoms (e.g. urgency, frequency, incontinence) and voiding symptoms (e.g. hesitancy, weak/interrupted stream, straining, incomplete emptying sensation) may occur depending on the location of MS lesions [15] Treatment Medications Antimuscarinic agents (e.g. oxybutynin, tolterodine, solifenacin, darifenacin) - for storage symptoms Mirabegron (Myrbetriq®) - for storage symptoms Alpha-1 blockers - for voiding symptoms Desmopressin (DDAVP) - for storage symptoms Dosing (tablet): 0.1 - 0.6 mg once daily. Restrict fluid intake one hour before and up to 8 hours after taking. Use lowest effective dose. Contraindicated in hyponatremia (Na ≤ 135 mmol/L) and CrCl < 50 ml/min After initiating or changing therapy, monitor for hyponatremia at 1 week, 1 month, and every 6 months thereafter depending on risk Risk factors for hyponatremia include elderly, female sex, decreased renal function, and concomitant drugs that lower sodium [15,16,17] PDE-5 inhibitors (e.g. tadalafil) - may be beneficial for storage and voiding symptoms Cannabinoids - may help storage symptoms Other Intravesical botulinum toxin Urinary catheterization - permanent and intermittent Pelvic floor exercises Sacral neuromodulation [15]
Sexual dysfunction
Overview Sexual dysfunction is common in both women and men with MS. In studies of men with MS, the following issues have been reported: erectile dysfunction (50% – 75%), ejaculatory dysfunction and/or orgasmic dysfunction (50%), reduced libido (39%), anorgasmia (37%). In women, the following has been reported:anorgasmia or hyporgasmia (37%), decreased vaginal lubrication (36%) and reduced libido (31%). Sexual dysfunction in MS is often multifactorial and includes lesion pathology (e.g. genital numbness/paresthesia, erectile dysfunction), hormone dysregulation, psychological factors (depression, etc.), fatigue/weakness, and medication side effects PDE-5 inhibitors have been shown to be effective in men, but treatment options in women are limited [18] Treatment Males PDE-5 inhibitors (e.g. sildenafil, tadalafil) - First-line Alprostadil (Caverject®, Muse®) - Second-line Testosterone therapy - if hypogonadism is present Females Hormone therapy - if hypogonadism is present Sildenafil - may be beneficial [5,18]
Bowel dysfunction
Overview Bowel dysfunction affects up to 70% of patients with MS and symptoms can range from chronic constipation to fecal incontinence Bowel dysfunction is often multifactorial, and in the case of constipation includes lesion pathology (e.g. anorectal hyposensitivity, pelvic floor dyssynergia, loss of supraspinal modulation), and medication side effects (particularly anticholinergics). Factors that may contribute to fecal incontinence include lesion pathology (e.g. anorectal hyposensitivity, anal sphincter weakness, loss of voluntary control of defecation), and uncontrolled colonic peristalsis. [5,19] Treatment Constipation Exercise and diet Abdominal massage Biofeedback Laxatives - psyllium fiber, polyethylene glycol (Miralax®), lactulose, bisacodyl Serotonin agonists - prucalopride (Motegrity®) Chloride channel activators - lubiprostone (Amitiza®) Guanylate cyclase agonists - linaclotide (Linzess®) Transanal irrigation and enemas Fecal incontinence Pelvic floor exercises Periodic evacuation of the rectum using enemas or suppositories Injectable anal bulking agents Sphincteroplasty Sacral nerve stimulator Colostomy or ileostomy in refractory cases [5,19]
Mood and cognition
Overview Mood and cognitive disorders are common in patients with MS. Treatment is generally the same as in patients without MS. Treatment Mood disorders Antidepressants - depression and anxiety Exercise - depression and anxiety Cognitive impairment Donepezil (Aricept®) - has had mixed results in studies [PMID 21519001, PMID 15534239] Memantine (Namenda®) - has shown no benefit in several studies [PMID 27000224, PMID 20483885] Pseudobulbar affect - sudden inappropriate laughing or crying Dextromethorphan/quinidine - available as Nuedexta®, or much cheaper as individual components [PMID 16634036]
Pain
Overview Pain is common in patients with MS affecting up to 60% of patients at some point during the course of their disease MS lesions can produce pain both directly and indirectly. Neuropathic pain in MS may include paresthesias in affected distributions, optic neuritis, and trigeminal neuralgia (affects up to 4% of MS patients). Musculoskeletal pain is common and may occur from spasticity, contractures, and mobility/posture issues. [5,8,20] Treatment Neuropathic pain Amitriptyline - First-line Duloxetine (Cymbalta®) - First-line Gabapentin (Neurontin®) - First-line Pregabalin (Lyrica®) - First-line Opiate medications - Second-line Trigeminal neuralgia Carbamazepine (Tegretol®) - First-line Oxcarbazepine (Trileptal®) - First-line Lamotrigine (Lamictal®) - Second-line Gabapentin (Neurontin®) - Second-line Pregabalin (Lyrica®) - Second-line Surgery - refractory cases Spasticity - see spasticity above [5,8]

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• FDA-APPROVED MEDICATIONS

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• OTHER TREATMENTS

• Haematopoietic stem cell transplant
• Haematopoietic stem cell transplants (HSCT) have been used to treat refractory MS. During a HSCT, stem cells are obtained from a donor (allogeneic) or the patient (autologous). The cells are typically taken from the bone marrow or peripheral blood. To obtain cells from the peripheral blood, a procedure called "mobilization" must be performed. During mobilization, the patient receives granulocyte colony-stimulating factor (G-CSF) +/- cytotoxic chemotherapy in order to increase the number of circulating stem cells.
• Before transplantation, ablative conditioning is performed where the patient is given high-dose chemotherapy and/or total body radiation in order to ablate the native immune system. Stem cells are then infused into the patient where they restore the bone marrow and reconstitute the immune system. To reduce the risks of ablative conditioning, lower intensity regimens called "nonmyeloablative regimens" have been developed. These regimens use lower doses of chemotherapy in order to reduce overall immune suppression.
• The best candidates for HSCT are patients who are young (≤ 50 years), ambulatory, have active relapsing–remitting MS, short disease duration (≤ 5 years), and ongoing relapses despite treatment
• In trials lasting up to 5 years, 70 - 80% of MS patients who have undergone HSCT have achieved complete suppression of disease activity
• See HSCT studies below for more [5,21]

• Exercise
• Exercise has been shown to be beneficial in the treatment of MS. It has also been shown to be beneficial for a number of MS symptoms including gait disturbance, fatigue, mood, cognition, and quality of life.
• All patients with MS should be encouraged to engage in regular exercise that includes both strength and endurance training. They should also be aware that exercise does not have any harmful effects on their condition. [22]

• Rituximab
• Rituximab is a B-cell depleting agent that is FDA-approved to treat rheumatoid arthritis and polyangiitis. Rituximab is similar to ocrelizumab in that they are both monoclonal antibodies that target CD20-expressing B-cells.
• Several studies have looked at the efficacy of rituximab in treating RR MS (PMID 18272891, PMID 27038238) and PP MS (PMID 19847908)

• Smoking
• Smoking is a strong risk factor for MS, and continued smoking after diagnosis is associated with increased progression to disability
• All patients with MS should be strongly advised to quit smoking [5,8]

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• STUDIES

• Head-to-head drug trials
• Fingolimod vs Interferon Beta-1a in Pediatric MS, NEJM (2018)
• Ocrelizumab vs Interferon Beta-1a in RR MS (2017), NEJM (2017)
• Alemtuzumab vs Interferon Beta in Treatment-resistant RR MS, Lancet (2012)
• Alemtuzumab vs Interferon Beta as First-line Treatment for RR MS, Lancet (2012)
• Fingolimod vs interferon beta for RR MS, NEJM (2010)
• Glatiramer Acetate vs Interferon Beta-1b in RR MS, Lancet Neurol (2009)
• Alemtuzumab vs Interferon Beta in RR MS, NEJM (2008)
• Natalizumab + Interferon beta vs Interferon beta in RR MS, NEJM (2006)

• Haematopoietic stem cell transplant (HSCT) trials
• HSCT vs Disease-modifying Therapy in RR MS, JAMA (2019)
• HSCT in Treatment-resistant RR MS, Neurology (2017)
• HSCT for aggressive MS, Lancet (2016)

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• PRICE ($) INFO

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• BIBLIOGRAPHY

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