Multiple sclerosis was first described in 1868 by Jean-Marie Charcot. Thousands of patients are affected by this disease, which varies according to country and continent: it is common in Europe and North America but very rare in Africa. For the last fifteen years, the number of cases has increased in industrialized countries.

It is an inflammatory disease of the central nervous system (brain, bone marrow, and optic nerve) occurring most often between the ages of 20 and 40 years and causing a slowdown in the conduction of nerve impulses. It affects mainly women.

It is called “sclerosis” because the affected tissues in the brain and bone marrow become scarred, and “plaques” designate the brownish areas corresponding to the inflamed and then repaired areas that can be identified by MRI (Magnetic Resonance Imaging).

Let’s try to understand this disease better.

Definition of multiple sclerosis (MS)

Multiple sclerosis is an inflammatory autoimmune disease. This means that the immune system of people with MS goes awry and “attacks” its tissues. In the case of MS, it is the myelin (a biological membrane that wraps around nerve fibers to protect them and allow the conduction of nerve impulses).

At the beginning of the disease, the inflammation is transient, and there is a repair phase after the inflammatory attack. However, the repair is no longer possible over time, and degenerative changes dominate and are irreversible.

MS is a highly heterogeneous disease in symptoms, progression, and severity.

Different types of multiple sclerosis

Relapsing-remitting MS

In 85% of cases, MS is said to be relapsing-remitting. The disease begins with an inflammatory attack that destroys myelin. This attack is characterized by the appearance or worsening of neurological symptoms for more than 24 hours outside a period of fever or infection. It lasts a few days to a few weeks and then gradually subsides.

Relapsing-remitting MS (RRMS) is defined by successive relapses interspersed with periods of remission of varying lengths. In children, relapses are about three times more frequent than in adults (annual relapse rate of 1.13 versus 0.4 in adults), and 3 out of 4 relapsing MS cases are in women. Initially, the damage is repaired, but it is no longer repaired as time goes on.

Good to know: sometimes a rise in body temperature can react to old neurological symptoms, most often vision problems. This transient phenomenon, known as the “Uhthoff phenomenon”, is not a relapse since the symptoms disappear when the body temperature drops.

RMS is defined as very active in:

• Patients with a very active form of the disease despite complete and well-conducted treatment with at least one background MS therapy.
• Patients with severe and rapidly progressive RRMS are defined as 2 or more disabling relapses in one year associated with one or more enhanced lesions on brain MRI after gadolinium injection (contrast medium).

Secondary progressive MS

After about 15 years, 50% of relapsing-remitting MS progress to secondary progressive MS. The progression of the disease is no longer stepwise but continuous, with the appearance of an irreversible disability on which relapses are grafted.

Primary progressive MS

In 15% of cases, MS is “progressive” from the beginning of the disease. This happens mostly in people who have MS after the age of 40.

In this form of MS, men are affected as much as women. The primary clinical picture is slightly different: first of all, there are walking disorders with increasing difficulties and conditions of the urinary system.

Note: there are also a few isolated clinical syndromes that will only manifest themselves through one clinical episode in a lifetime and forms that do not evolve very much, characterized by a shallow level of disability after 20 or 30 years of the disease.

Causes of multiple sclerosis

The causes of MS remain unknown. However, there are probably several factors that cause the disease. 

Good to know: smoking triples the frequency of relapses, and smoking appears to be a factor that can worsen the level of disability. In addition, the level of vitamin D also plays a vital role in the risk of relapses since, when it is lower than usual, they are more frequent.

Environmental factors

The disease is 5 times more frequent in northern or temperate regions (North America, Europe) than in tropical or southern climates. The cause of this difference is unknown, but it could be that vitamin D plays a role.

Genetic factors

MS is not hereditary and cannot be passed from parents to their children. However, the first genetic cause of multiple sclerosis has been discovered (2016). Thus, the mutation of the NR1H3 gene (which produces the defective LXRA protein) is directly linked to the development of the disease (70% risk of developing MS). Nevertheless, this mutation affects only 1 ‰ of patients. In addition, more than 20 genes have been identified in recent years.

Other factors

Other factors are cited but more hypothetical: a virus or an infection, stress, trauma…

For example, one study showed that a head injury during adolescence was associated with a 22% increased risk of developing multiple sclerosis. People who had two or more TBIs would see this risk double.

Hepatitis B and HPV vaccines are also sometimes implicated. However, these vaccines are safe. It is thought that, in people who have had their multiple sclerosis begin following a vaccine, it is only a trigger and that the disease would have appeared anyway, but later.

Symptoms of MS

Although they vary from one individual to another and are also very variable in severity, the most common symptoms are

• Sensory disturbances;
• motor disorders;
• balance or walking problems
• abnormal fatigue;
• muscle spasms or contractures;
• visual disorders (optic neuritis);
• speech difficulties;
• Urinary and digestive system disorders (constipation);
• sexual disorders;
• partial or total paralysis of a part of the body;
• cognitive disorders;
• Emotional symptoms (mood changes, among others).

Good to know: schematically, one-third of the diseases reported are sensitivity disorders, 20% are visual disorders, and one-third are motor disorders.

Diagnosis of multiple sclerosis

There is no diagnostic test or biological markers specific to MS. There must be evidence of lesion dissemination (e.g., visual and motor impairment) and disease progression (at least two relapses) to diagnose MS.

However, it is essential to diagnose the disease as early as possible to start treatment as soon as possible.

For this, apart from the clinical examination, two tools are used:

MRI (Magnetic Resonance Imaging). It allows the detection of the location of the lesions and their evolutionary character thanks to the injection of contrast product (Gadolinium), which highlights active inflammation. On the other hand, it is impossible to assess the severity of the damage because the severity of the lesion is unrelated to the intensity of the symptoms. There are disability scales To evaluate this severity.

The lumbar puncture aims at studying the cerebrospinal fluid to highlight signs of inflammation.

Treatments for MS

There is no cure for multiple sclerosis. However, early multidisciplinary management of the disease can improve the patient’s quality of life. Moreover, MS is not considered to reduce the life span of patients compared to the general population (for some specialists, the life expectancy gap with the general population is 7 years – compared to more than 15 years more than 20 years ago).

Today, a distinction is made between treating MS symptoms and disease-modifying therapy to combat demyelination.

Treatment of flare-ups

Intravenous corticosteroids can be used to shorten the duration and severity of inflammatory flare-ups without impacting the disease’s overall progression. On the other hand, the side effects are sometimes significant.

In children, methylprednisolone (30 mg/kg/day with a maximum of 1 gram) is used for 3 to 5 days. Sometimes, oral corticosteroids can also be considered, even in very young children, as the demyelinating attacks are very inflammatory.

In adults, the combination of methylprednisolone and an immunoglobulin infusion does not show any additional efficacy. On the other hand, there is an improvement in children when the attacks are resistant to corticosteroids.

Background treatment

These aim to reduce the frequency of attacks and slow down demyelination. In newly diagnosed relapsing forms of MS, 5 years of treatment may be sufficient to significantly reduce the level of disability (hence the need for early treatment). On the other hand, these background treatments are not active on MS in the progressive form.

We use:

• immunomodulators (interferonsβ: Betaferon®, Avonex®, Rebif®, Extavia®) which allow a 30% reduction in relapses over two to three years (subcutaneous or intramuscular injections are used);
• immunosuppressants, particularly for rapid or severe forms of the disease and for very active relapsing-remitting multiple sclerosis (RRMS):
  • fingolimod (Gilenya®) or natalizumab (both intravenous);
  • ocrelizumab (Ocrevus®), an anti-CD20 monoclonal antibody (also intravenous);
  • mitoxantrone (Elsep® – Novantrone® and generics).

     

The choice between these 3 drugs is made in consultation with a resource and competence center, taking into account clinical data (a form of the disease, frequency of relapses, age of the patient), imaging, tolerance profile of the drugs (fingolimod has cardiac toxicity), their efficacy and patient preference.

Selective adhesion molecule inhibitors (glatiramer acetate: Copaxone®) reduce the activity of the immune system and thus slow the destruction of myelin (29% reduction in relapses over two-year periods).

Good to know: due to the estrogen-progesterone climate, relapses are generally less frequent during pregnancy.

The prescription and renewal of interferons and glatiramer acetate are reserved for specialists in neurology.

Cannabis extracts

Two cannabis extracts, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are combined in a medication (Sativex®) presented in the form of a spray. It has been available in most countries since 2018. It is used to treat symptoms induced by moderate or severe spasticity, occurring during multiple sclerosis in case of failure of other antispastic drugs and when they respond quickly.

After one month, this treatment is effective in more than 80% of patients, improving spasticity symptoms by at least 20%. However, only one out of two patients continues the treatment over the very long term (more than 18 months) because of the decrease in the symptomatic and adverse effects.

Management of sleep disorders

In addition, it is essential to manage any sleep disorders, as patients who do not sleep well will not be able to recover correctly, which will increase the frequency of relapses. Sleep is involved in regulating the permeability of the blood-brain barrier. A melatonin-based supplement can be an excellent solution for multiple sclerosis for people who cannot get enough sleep.

In the same vein, it is crucial to eliminate all foods that can increase this permeability, namely:

• salt;
• gluten
• milk proteins.

Note: the paleo and Seignalet diets are of definite interest in the fight against MS.

Second-line treatment in children

Approximately 50% of children with MS will switch to second-line therapy within three years of the first treatment. This change is due to either ineffectiveness of the initial treatment (in 28% of cases) or poor tolerability of the initial treatment (19% of cases).

The second-line treatment uses a monoclonal antibody, natalizumab (Tysabri®), but this molecule does not have marketing authorization in patients under 18 years of age. Furthermore, natalizumab is likely to cause (although very rarely) progressive multifocal leukoencephalopathy (PML), a formidable and often fatal complication of shingles. In addition, it exposes patients to severe and sometimes fatal opportunistic infections, hypersensitivity reactions, and liver damage.

Nevertheless, when it is practical, this treatment reduces more than 90% of the number of relapses and stabilization of motor disability (even an improvement in 23.4% of cases).

After 2 years, a continuation of treatment should be considered only after evaluation of the number of risk factors of the patient and regular reassessment of the benefit/risk ratio.

In addition, several other molecules that have shown efficacy in adults are being tested in children and adolescents (fingolimod, teriflunomide, or BG12). Their use should therefore be discussed with the reference center, as teriflunomide (Aubagio®) is particularly prone to severe and sometimes fatal adverse effects (liver damage, leukopenia, infections) and peripheral neuropathy. However, some patients may prefer them because they are easier to take as daily tablets.

Relief treatments

In parallel, many therapeutic strategies are used to relieve the various symptoms: urology, physiotherapy, psychotherapy… A whole team surrounds the neurologist to manage all aspects of the disease and improve patients’ quality of life.

In children with MS, it is helpful to supplement with vitamin D, as they usually have lower levels than others.

Good to know: Zinc supplementation of up to 15 mg per day over the long term can help combat symptoms and improve well-being.

Fatigue can also be fought with coenzyme Q10, which is effective as an antioxidant and circulatory stimulant. An essential element for cellular respiration, CoQ10 is also involved in the proper functioning of nerve cells (low levels of CoQ10 are widely associated with primary neurodegenerative diseases). It should be taken at 200 mg each morning or even more (up to 600 mg) if necessary.

Impact of Multiple Sclerosis

MS can significantly impact patients’ lives, who may experience several problems (urological, sexual, attentional problems, etc.), intense fatigue, disabling spasticity, and psychological suffering, sometimes related to difficulties with relationships or work. They may then find themselves unable to continue their professional activity. They have to find a way to adapt to a new rhythm of life and think earlier than others about when they will see their mobility decrease.

On the other hand, a patient with MS can consider pregnancy. However, certain precautions should be taken for women treated with Aubagio® (teriflunomide). This treatment has teratogenic and embryotoxic effects and should not be prescribed during pregnancy. In addition, due to its persistence in the body, which can be up to 2 years after stopping treatment, an accelerated elimination procedure (specific protocol based on colestyramine or activated charcoal) must be undertaken in the event of a desire for pregnancy or the occurrence of an unplanned pregnancy. The ANSM indicates that this accelerated elimination procedure is hardly ever respected…

Similarly, while interferons or glatiramer acetate are safe, other oral immunosuppressants (fingolimod, dimethyl fumarate) are formally contraindicated.

Finally, MS patients do not require any special prevention or diet.

Current research on multiple sclerosis

Research on multiple sclerosis is very active, both on the disease and its treatments. Numerous clinical trials are underway to find effective strategies for progressive forms of the disease. Researchers are looking at making the immune system tolerant to cells that produce myelin to remyelinate the damaged areas. They are also interested in retroviruses with research on monoclonal antibodies (neuroprotection) or the microbiota (intestinal flora), which would play a role in the immune system. In fact, in patients with multiple sclerosis, we observe an intestinal dysbiosis with depletion of bacteria such as Bacteriodacea and Prevotella and conversely an enrichment of other bacteria, such as Streptococcus and Pseudomonas.

We can also mention the research on stem cells.

There is still a long way to understand the disease and treat it. Even if the research undertaken so far has made it possible to improve the management of patients by making it multidisciplinary, it has also made it possible to identify the axes of the challenges to be met.

Ocrelizumab: a promising monoclonal antibody

For the time being, in 2019, the use of ocrelizumab (Ocrevus®) is limited to active relapsing forms of the disease and progressive conditions with marked inflammatory activity.

Ocrelizumab is a humanized monoclonal antibody that explicitly targets CD-20 receptors on the surface of B lymphocytes, reduces the relapse rate, and delays the progression to a secondarily progressive form of the disease (which occurs in 50% of patients). Indeed, the molecule slows down the appearance of new white matter lesions and reduces the relapse rate.

However, it should be noted that it slightly increases the risk of cancer, particularly in the breast (long-term follow-up of malignant tumors is planned), and entails a significant risk of infections and infusion reactions.

Studies are ongoing to evaluate its potential effectiveness in the early phase to limit the evolution towards a secondarily progressive phase (responsible for the handicap).

Note: If not used as first-line therapy, ocrelizumab may be used as an alternative to fingolimod, natalizumab, or in the event of failure of these products. However, no robust data are documenting its efficacy and safety in these clinical situations.

Other immunosuppressants

Two drugs are not currently marketed:

Mavenclad® (cladribine, an oral nucleoside analog with immunosuppressive activity), for which the clinical interest and safety data are insufficient to justify coverage by national solidarity, even though it indicates very active forms of MS;

Lemtrada® (alemtuzumab, an antibody directed against the CD52 glycoprotein located on the surface of lymphocytes) despite its being approved for community use as a 2nd or 3rd line treatment for very active forms of RRMS.

Pending re-evaluation by the EMA of Lemtrada’s marketing authorization following unexpected serious adverse events, its use is temporarily restricted to very active RRMS despite two disease-modifying therapies or when no other disease-modifying treatment is possible.

Finally, we are interested in siponimod (like fingolimod, a selective inhibitor of the sphingosine 1-phosphate receptor), which also seems to have an action in certain secondarily progressive MS.