The following discussion is for general informational purposes only and is not meant to provide the reader with specific medical advice. Please consult with your personal physician, or with a neurologist, for specific advice, guidance and information regarding your particular circumstances.

Introduction

Multiple Sclerosis is a neurologic disease associated with autoimmune mediated inflammation in the central nervous system and results in the breakdown of myelin, the protective insulation surrounding nerve fibers. The exact cause is unknown, but is likely due to a combination of genetic and environmental factors. Epidemiologic studies indicate that low serum levels of vitamin D, history of smoking, and infection with the Epstein-Barr virus may play a role in disease development. There does seem to be a genetic predisposition to the disease, though it is not directly inherited. It is estimated that nearly 1 million people in the United States have multiple sclerosis. Twice as many women as men are affected. Most people are diagnosed between the ages of 20 and 40, though new diagnoses can sometimes be made in children and older individuals. There have been improvements in diagnostic methods and major advances in medical treatment for multiple sclerosis over the last decade. This means people with multiple sclerosis can be diagnosed and treated earlier in the disease trajectory, leading to improved patient outcomes and reduction in disability.

Symptoms and Disease Characteristics

Symptoms of multiple sclerosis vary widely among people. They may include the following:

Motor symptoms

  • weakness, typically in one or more limbs on one side of the body
  • muscle cramps or spasms
  • tremor
  • loss of coordination
  • gait imbalance

Sensory symptoms

  • numbness, tingling, pain
  • L’hermitte’s sign (electrical shock-like sensation with neck flexion)

Other neurologic, psychiatric and constitutional symptoms

  • speech disturbances
  • blurry vision, double vision or loss of vision
  • dizziness
  • bladder and bowel problems
  • excessive fatigue
  • heat intolerance
  • cognitive impairment (e.g. difficulty with attention, memory, problem-solving)
  • depression and other psychiatric disturbances

Types of Multiple Sclerosis and Disease Course

Clinically Isolated Syndrome (CIS): a single, initial episode of neurologic symptoms caused by inflammation or demyelination in the central nervous system. CIS symptoms can be monofocal or multifocal and involve the optic nerves, brainstem, cerebral hemispheres, or spinal cord. The neurologic symptoms should last at least 24 hours, followed by complete or partial recovery. If CIS is accompanied by corresponding changes on Brain MRI, then the likelihood of developing multiple sclerosis is higher (between 60-80%).

Relapsing-Remitting Multiple Sclerosis (RRMS): Clearly defined acute attacks in the central nervous system developing over days to weeks followed by partial or complete recovery. The quiet periods between relapses may last months or even years. This is the most common form of multiple sclerosis, affecting about 80-85% of patients.

Primary Progressive Multiple Sclerosis (PPMS): Gradual onset of neurologic symptoms with slow deterioration and accumulation of disability over time. No clear relapsing events. About 10-15% of patients have a primary progressive course, and diagnosis is typically made in older patients.

Secondary Progressive Multiple Sclerosis (SPMS): This pattern begins with a relapsing-remitting course, but after about 10-20 years, the disease progressively worsens as evidenced by gradually increasing disability. This affects about 25-50% of patients with RRMS.

Progressive-Relapsing Multiple Sclerosis (PRMS): This type of MS is characterized by disease progression from the beginning of the diagnosis, but there are clear acute relapses as well, with or without full recovery.

The majority of people with multiple sclerosis have a relapsing and remitting disease course.  Relapses are characterized by new symptoms or worsening of old symptoms that are caused by new inflammatory MS activity in the central nervous system. However, sometimes, patients with MS can also experience what are called “pseudo-relapses.” These are worsened symptoms typically triggered by stress, fatigue, an underlying infection, or increase in body temperature (e.g. after exercise). “Pseudo-relapses” are not characterized by new inflammation in the central nervous system, but rather reflect the damage from previous inflammation.

Up to 50% of patients with relapsing remitting MS will eventually develop secondary progressive MS, which is characterized by a steady progression of symptoms without distinct relapses.

Diagnosis

The diagnosis of multiple sclerosis is based upon careful clinical history, physical examination, and imaging studies, typically a magnetic resonance imaging (MRI) scan of the brain, cervical and thoracic spine.  A lumbar puncture may also be done to detect characteristic abnormalities of the cerebrospinal fluid. Blood tests to check for other autoimmune or inflammatory diseases that can mimic multiple sclerosis are also performed. Computer-assisted electrodiagnostic tests, known as evoked responses, may also be helpful in diagnosing multiple sclerosis.

Multiple sclerosis mimics can include autoimmune/inflammatory disease such as Systemic Lupus Erythematosus (SLE), Sjogren's syndrome, vasculitis, and sarcoidosis. Other MS mimics include infectious diseases such as Lyme disease, syphillis, HIV, progressive multifocal leukoencephalopathy (PML), and Human T-cell lymphotropic virus-1 (HTLV-1). Finally, genetic disorders, vitamin deficiencies, or brain tumors can also present with similar symptoms, so thorough workup is essential to making a diagnosis.

There are also other demyelinating disorders that are not multiple sclerosis. Examples include Neuromyelitis optica (NMO) which is characterized by inflammation of the optic nerves (optic neuritis) and long lesions in the spinal cord. Acute disseminated encephalomyelitis (ADEM) is a single inflammatory attack on the CNS that occurs more commonly in children and is typically accompanied by fever and associated with a viral infection.

Treatment

Acute relapse treatment

Treatment of acute relapses typically involves high dose steroids that reduce the inflammation in the nervous system. While steroids do not alter the long term course of the disease, clinical studies have shown that they can shorten the relapse. Treatment with adrenocorticotropic hormone (ACTH) can be used for patients who are unable to tolerate steroids. Not all relapses require treatment, so a discussion with your treating neurologist is crucial.

Disease-modifying drugs

Though there is presently no cure for multiple sclerosis, there have been many new drugs approved over the last 2 decades to reduce the relapses and accumulation of disability in multiple sclerosis.

Beta interferons and copaxone (first generation MS drugs)

Beta-interferons were the first drugs approved for treatment of relapsing remitting multiple sclerosis (RRMS). They are administered by self-injection. They work by reducing the body's immune reaction (primarily T-cell inflammatory activity). Interferon beta 1b (Betaseron) was the first therapy approved for RRMS in 1993. The other interferons approved by the FDA for treatment of MS are Avonex (interferon beta 1a), Rebif (interferon beta 1a), Plegridy (peginterferon beta 1a), and Extavia (interferon beta 1b). Studies have shown patients taking these medications had about a 30% reduction in relapse rate.  Side effects of interferons can include flu-like symptoms (headache, fever/chills, myalgias, nausea, fatigue) and injection site reaction.  Blood cell count and liver enzymes need to be checked prior to starting the interferons, and periodically monitored by your treating neurologist.

Copaxone (glatiramer acetate) is a polymer that is similar to myelin basic protein, which is maintains the correct structure of myelin, and works by blocking myelin-damaging T-cells through a mechanism that is not completely understood. It was approved for treatment of multiple sclerosis in the US in 1997. Copaxone is a self-administered injection and is generally very well tolerated. The most common side effects are injection site reactions such as lipoatrophy.

Oral medications

Teriflunomide (Aubagio) was approved by the FDA in 2012. It works by disrupting the DNA synthesis of active T cells and subsequently reduces their proliferation. Teriflunomide reduces relapse rate by about 30% and is also shown to reduce the number and size of MRI lesions, and reduce the disability associated with MS.  Side effects include gastrointestinal upset, hair loss, paresthesias, rash, elevated liver enzymes and increased susceptibility to infections. It is teratogenic and considered pregnancy category X, so women of childbearing age must be counseled carefully. It is not recommended in patients with severe liver problems, immunodeficiency, or bone marrow disease (e.g. anemia, leukopenia). Liver enzymes are monitored closely (monthly for the first 6 months, and intermittently thereafter).

Dimethyl fumarate (Tecfidera) is an oral medication approved in 2013. Its exact mechanism of action is unclear but it seems to activate anti-inflammatory pathways and exert a neuroprotective effect. Dimethyl fumarate reduces the relapse rate by about 50% compared to placebo and is also shown to reduce the lesion burden on MRI and slow down the accumulation of disability. Common side effects include flushing and gastrointestinal upset, which are typically worst during the first month and improve thereafter. Cell counts and liver enzymes also need to be monitored while on tecfidera.

Monomethyl Fumarate (Bafiertam) is considered a bioequivalent alternative to dimethyl fumarate (Tecfidera). It was approved in April 2020, and is proposed to have less gastrointestinal side effects, though this has not been evaluated in clinical trials.

Diroximel fumarate (Vumerity) is also similar to dimethyl fumarate. However, Diroximel fumarate has been shown in clinical trials to have fewer gastrointestinal side effects. Otherwise, its efficacy and side effect profile are similar to that of dimethyl fumarate.

Fingolimod (Gilenya) is a once daily oral medication approved in 2010. It is a sphingosine 1-phosphate receptor modulator that sequesters T-cells in the lymph nodes and prevents their migration into the central nervous system. It reduces the number of relapses by about 50% compared to placebo. It is generally well tolerated, but safety concerns include first dose bradycardia (lowering of heart rate), increased risk of infection (specifically herpes virus infections), lymphopenia (extreme lowering of white blood cell count), elevated liver enzymes, and macular edema. The first dose must be monitored by a medical professional due to temporary changes in heart rate or blood pressure. Due to the possibility of macular edema, patients also need baseline evaluation by an ophthalmologist and repeat evaluation 3-4 months after initiation of the drug. Cell count and liver enzymes should be monitored. Severe exacerbation of disease has been reported after stopping Fingolimod, so please do not stop this medication without notifying your treating neurologist.

Siponimod (Mayzent) was approved by the FDA in March 2019 for treatment of relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and clinically isolated syndrome (CIS). It is a sphingosine-1-phosphate modulator similar to fingolimod but has a more targeted effect and therefore may lead to less side effects. Like fingolimod, it reduces relapse rate by about 50%, and studies also show reduction in disability in secondary progressive multiple sclerosis. It is contraindicated in patients who have certain cardiovascular issues such as prior myocardial infarction, stroke, or heart block. Patients should also be checked for CYPC9*3/*3 genotype because this genotype can lead to significantly increased siponimod plasma levels. While first dose cardiac monitoring is not required, it is recommended for patients with pre-existing cardiac issues. Cell count and liver enzymes should be checked and periodically monitored on this medication. Just like with fingolimod, exacerbation of disease is possible after stopping this treatment.

Ozanimod (Zeposia) was approved by the FDA in March 2020 for treatment of relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and clinically isolated syndrome (CIS). It is a sphingosine-1-phosphate modulator similar to fingolimod, but like Siponimod, has  a more targeted effect and therefore may lead to less side effects. Its efficacy and safety profile is similar to that of Siponimod, and monitoring of cell counts and liver enzymes is recommended. While it does not require first dose cardiac monitoring, a baseline EKG is still recommended to determine if there are pre-existing cardiac conditions.

Cladribine (Mavenclad) was approved by the FDA in March 2019 for the treatment of relapsing remitting multiple sclerosis and active secondary progressive multiple sclerosis. It works by suppressing both B-cell and T-cells in the immune system. It has a convenient dosing schedule (10 treatment days a year over 2 years). However, there are significant safety concerns including increased risk of malignancy, lymphopenia (decreased white blood cell counts), liver injury and fetal harm. For this reason, it is generally used only when alternate treatments have failed to control progression of multiple sclerosis.

Infusion Treatments

Natalizumab (Tysabri) is a monoclonal antibody that prevents lymphocyte migration across the blood-brain barrier and into the central nervous system. It was approved by the FDA for relapsing remitting and active secondary progressive multiple sclerosis in 2004, and is administered in monthly infusions. Tysabri has been shown in multiple studies to be highly effective in RRMS, with reduction in annualized relapse rate by about 80% compared to placebo. However, Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), which is a serious opportunistic brain infection caused by the John Cunningham virus (JCV). For this reason, patients must have a JCV titer checked prior to and during treatment with Tysabri to evaluate the risk for PML infection. If patients remain JCV negative, then the risk of infection remains low (1/10,000 patients) for about 8 years, regardless of other risk factors. However, if JCV titer is positive, then the risk for PML infection increases based on other risk factors (e.g. prior immunosuppresion).

Ocrelizumab (Ocrevus) is a monoclonal antibody directed against the CD20 antigen on B-cells which contribute to demyelination. It was approved by the FDA in 2017 for relapsing remitting and active secondary progressive multiple sclerosis. It is also the first and only medication approved by the FDA to treat primary progressive multiple sclerosis (PPMS). It is given initially as two infusions two weeks apart, and afterwards, administered once every 6 months. Studies have shown it reduces relapse rate by nearly 50% compared to Rebif, and there is also significant delay in disability progression. It is contraindicated in active Hepatitis B infections, so patients must be screened for this prior to initiation. The most common adverse reactions are respiratory tract infections, herpes-related infections, skin infections, and infusion reactions. To date, there has only been one case of progressive multifocal leukoencephalopathy (PML) directly associated with ocrelizumab.

Alemtuzumab (Lemtrada) is a monoclonal antibody directed against the CD52 antigen on lymphocytes. It was approved by the FDA in 2014 for treatment of relapsing remitting and active secondary progressive multiple sclerosis. It is given in two annual treatment courses. While it is very effective (decreased relapse rate by 55% compared to rebif), it has the potential for serious side effects including autoimmune hematologic and endocrine conditions, serious and sometimes life-threatening infusion reactions, and increased risk of malignancies. Stroke has also been reported. Due to the safety concerns, it is generally reserved for patients who have had an inadequate response to other treatments for MS.

New Injectable Treatments:

Ofatumumab (Kesimpta) is a monoconal antibody directed against CD20 antigen on B-cells. It was approved by the FDA in September 2020 for the treatment of relapsing remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndrome. It is the first MS therapy targeting B-cells that can be administered at home with once a month injections. It was shown to be superior to Aubagio in studies (demonstrating a greater than 50% reduction in annualized relapse rate and reduction in MRI lesions by about 80% compared to Aubagio). Side effects include upper respiratory tract infections, headaches, injection-related reactions, and more significantly, hepatitis B reactivation, herpes infection, and rarely progressive multifocal leukoencephalopathy.

In summary, choosing the right medication for multiple sclerosis is a complex decision that will involve looking at multiple factors such as disease activity, likelihood of progression, medication tolerability, and each patient’s unique needs.

Other medications for treatment of symptoms of multiple sclerosis:

Dalfampridine (Ampyra): this is an oral medication that is approved by the FDA to improve walking in patients with multiple sclerosis. It works by blocking potassium channels on the nerve fibers, which may improve the signal conduction in nerve fibers that have been damaged in MS. Side effects include urinary tract infections, gastrointestinal upset, dizziness, headaches, back pain, and sleep disruption. It is contraindicated in patients with moderate to severe renal impairment, and patients with history of seizures. About a third of patients notice that dalfampridine improves their mobility. This improvement is typically seen in 2-4 weeks, and assessed by walking speed. If patients do not exhibit an improvement in walking speed during this time, then the medication is not typically continued.

Baclofen, tizanidine, and cyclobenzaprine are muscle relaxants that can be used to treat muscle spasms, cramps, and pain related to the spasticity caused by multiple sclerosis. Common side effects include fatigue, dizziness, and weakness.

Anti-depressants such as duloxetine, amitriptyline, and nortriptyline can be used to help with nerve pain and to help stabilize mood. Side effects can include sleepiness, dizziness, urinary or gastrointestinal upset.

Seizure medications such as gabapentin, pregabalin, lamotrigine, and oxcarbazepine can also help with nerve pain.  Side effects can include sleepiness, dizziness, and weight gain.

Lifestyle recommendations

Food and diet: There is no special diet that has been proven to modify the course of MS. In general, MS specialists recommend that people follow the same heart healthy, high fiber, low fat diet that is recommended for all adults.  Cardiovascular risk factors such as high blood pressure and high cholesterol may be associated with MS worsening, so managing these conditions is very important.

Vitamin D is important for bone health, reducing inflammation, and helping support the immune system. Several epidemiological studies have shown low vitamin D is one of the risk factors that can contribute to the development of MS. Some studies have also shown that low vitamin D is associated with more MS activity. Sunlight exposure and foods such as fatty fish are good sources of vitamin D. MS patients often get their vitamin D levels checked, and if they are found to be deficient, this can be corrected by changes in diet, lifestyle, or through a vitamin D supplement. Of note, because vitamin D is fat-soluble, there is a chance of toxicity if high doses of vitamin D are ingested. Therefore, vitamin D supplementation must be done under the guidance of a doctor, and vitamin D level should be periodically monitored.

Exercise is also recommended to all MS patients in order to improve overall health. Aerobic exercise can reduce fatigue, improve mobility, mood, and cognitive function. Stretching exercises can reduce stiffness and also help with mobility. A physical therapist can help tailor an exercise plan according to the specific needs.

References

National Institute of Neurological Disorders and Stroke

The Use of Disease Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. A Consensus Paper by the Multiple Sclerosis Coalition

National MS Society

American Academy of Neurology