Multiple Sclerosis (abbreviated MS) is also known as disseminated sclerosis or encephalomyelitis disseminata is an idiopathic disease of suspected autoimmune cause(s) where the body’s immune response attacks a person’s central nervous system resulting in demyelination. Onset usually occurs in young adults and is more prevalent in females1. It has a prevalence that ranges between two (2) and 150 per 100,000.
MS affects the human body by hindering the ability of nerve cells in the brain and spinal cord to communicate with each other. Under normal circumstances, nerve cells communicate by sending electrical signals (called action potentials) down long fibers known as axons. These axons are wrapped in an insulating substance known as myelin. In a person suffering from MS, the body’s immune system attacks and damages the myelin. When this happens, the axon(s) can no longer effectively conduct signals. The disease’s name ‘” Multiple Sclerosis ‘” refers to the scars (scleroses) in the white matter of the brain and spinal cord which are mainly composed of myelin. Although much is known about the mechanisms involved in the disease process, the exact cause remains unknown. Theories include both genetic problems and infection. Environmental risk factors have also been found.
Almost any neurological symptom can appear with MS and often progresses to physical and cognitive disability as well as neuropsychiatric disorder. MS can take several forms ‘” with new symptoms occurring either in discrete attacks (relapsing form) or slowly accumulating over time (progressive forms). In between attacks, symptoms may go away completely, but permanent neurological problems often occur as the disease advances.
There’s currently no known cure for MS. Treatment(s), instead, attempt to return function following an attack, prevent new attacks, and prevent disability. Drugs used to treat MS can cause adverse effects or be poorly tolerated and, as a result, many patients pursue alternative treatments ‘” some of which lack supporting scientific study. The prognosis of a person with MS is difficult to predict; it’s dependent on the subtype of the disease, the individual person’s disease characteristics, the initial symptoms and the degree of disability the person experiences as time advances. It should be noted, however, that the life expectancy of a person with MS is nearly the same as that of the unaffected population.
How is MS classified?
Several subtypes ‘” or patterns of progression ‘” have been described. Subtypes use the past course of the disease in an attempt to predict the future course. These are important, not only for the prognosis, but also in making therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society (http://www.nationalmssociety.org) standardized four (4) subtype definitions: relapsing remitting, secondary progressive, primary progressive, and progressive relapsing.
The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks may either resolve or leave sequela6. When deficits always resolve between attacks, this is sometimes referred to as benign MS.
Secondary progressive MS subtype is used to describe those patients with initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and remissions may occur. The median time between onset and conversion from relapsing-remitting to secondary progressive MS is nineteen (19) years.
The primary progressive subtype is used to describe the approximately 10% to 15% of individuals who never have remission after their initial MS symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The age of onset for the primary progressive subtype is later than other subtypes.
The progressive relapsing subtype is used to describe those individuals who, from onset, have a steady neurologic decline while also suffering clear superimposed attacks. This is the least common of all of the subtypes.
What are the signs and symptoms of MS?
Symptoms of MS usually appear in episodic acute periods of worsening (referred to as relapses, exacerbations, bouts, attacks, or “flare-ups”), in a gradually progressive deterioration of neurologic function, or in a combination of both.
The most common presentation of MS is the clinically isolated syndrome (CIS). In CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. It’s estimated that only between 30% to 70% of persons experiencing CIS later develop MS. The disease usually presents with sensorial (46% of cases), visual (33% of cases), cerebellar (30%), and motor (26% of cases) symptoms. Additional, rare, initial symptoms have also been reported including: aphasia (a disorder of the content of speech), psychosis11, and epilepsy. Patients seeking initial medical treatment commonly present with multiple symptoms. Often these signs and symptoms do not prompt the person to seek medical attention and are sometimes identified retrospectively after the diagnosis of MS has been made. In some cases, MS is incidentally identified during a neurological exam being performed due to other causes. Such cases are known as sub-clinical MS.
A person with MS can suffer almost (italics added) any neurological sign or symptom including changes in sensation (hypoesthesia or paraesthesia), muscle weakness, muscle spasm(s), difficulty in moving, difficulties with coordination and balance (ataxia15), problems with speech or swallowing, visual problems, fatigue, acute or chronic pain, and bladder or bowel difficulties. The extent of cognitive impairment varies from person to person, however, depression and/or mood instability are common.
MS relapses are unpredictable and often occur without warning or obvious inciting factors. Some attacks, however, are preceded by a common trigger or triggers. Research has shown that relapses occur more frequently during the spring and summer months. MS patients who suffer infections such as the common cold, influenza, or gastroenteritis have an increased risk of relapse. In addition, research has shown that pregnancy might affect to relapse at least until the last trimester when the risk seems to decrease. Other potential triggers have been been examined and found not to influence an MS relapse. For example, there is no evidence that vaccinations for influenza, hepatitis B, varicella18, tetanus, or tuberculosis (TB) increase the risk for relapse. Exposure to higher than usual ambient temperatures ‘” known as Uhthoff’s phenomenon – can exacerbate existing symptoms, however, has not been established as a relapse trigger.
What causes Multiple Sclerosis?
Epidemiological studies of MS have shed light on possible causes for the disease and researchers have developed theories to combine this data into plausible explanations, however, none have proved to be definitive. Currently, it appears that MS likely occurs at the result of a combination of both environmental and genetic factors.
MS is not considered a hereditary disease, however, a number of genetic variations have been shown to increase the risk of developing the disease. For example, the risk of acquiring the disease is higher for the relatives of a person with MS than it is in the general public. This risk is especially high in the case of siblings, parents, and children. In the case of monozygotic twins20, concordance occurs in only about thirty-five percent (35%) cases, and half-siblings have a lower risk of occurrence than full siblings indicating a polygenic origin.
Apart from familial studies, specific genes have been linked with MS. Differences in the Human Leukocyte Antigen (HLA) system (a group of genes in chromosome 6) which serves as the major histocompatibility complex have also been found to increase the possibility of suffering MS. Two other genes have also been shown to have a link to the occurrence of MS. These are the IL2RA and the IL7RA ‘” both of which are sub-units of the receptor for Interleukin 2 and Interleukin 7 respectively. The HLA complex is involved in antigen presentation, which is crucial to the functioning of the immune system while mutations in the IL2 and IL7 genes were already known to be associated with diabetes and other auto-immune conditions. These findings support the theory that MS is an auto-immune disease.
Even though genetic susceptibility can explain some of the geographic and epidemiological variations in the incidence of MS, such as the high appearance of the disease among some families or the risk decline with genetic distance, however, it does not count for other phenomena, such as the change in risk that occur with migration at an early age.
A possible explanation for this epidemiology finding could be that some type of infection ‘” produced by a widespread microbe rather than a rare pathogen ‘” is the origin of the disease. Different hypotheses have elaborated on the mechanism which would allow this to occur. One of these (the hygiene hypothesis) proposes that exposure to several infectious agents early in life is protective against MS. It further proposes that MS is an auto-immune reaction triggered in susceptible individuals by multiple infective micro-organisms with an increase in the risk of occurrence as the person ages. Yet another hypothesis, the prevalence hypothesis, proposes that the disease is due to a pathogen which is more common in regions of high MS prevalence. According to the hypothesis this pathogen is very common causing most individuals only an asymptomatic persistent infection. Only in a limited number of cases, and after many years since the original infection, does it result in demyelination. To date, the hygiene hypothesis has received more support than the prevalence hypothesis.
Evidence supporting viruses as the cause of MS includes the presence of oligoclonal bands23 in the brain and cerebrospinal fluid of most patients, the association of several viruses with the occurrence of human demyelinating encephalomyelitis, as well as the induction of demyelination in animals through viral infection. Human herpes are also a candidate group of viruses linked to MS; Varicella zoster ‘” which causes shingles in adults ‘” has been found at high levels in the cerebrospinal fluid of MS patients, but, by far, the most reproduced finding is the reduced risk of having the disease in persons who have never been infected with Epstein-Barr virus. This finding goes against the hygiene hypothesis since the non-infected have probably experienced a more hygienic upbringing.
Non-infectious environmental risk factors
MS is more common in people who live farther from the equator. One possible explanation for this lies in the fact that it has been proven that decreased exposure to sunlight has been linked with a higher risk of contracting MS. The result of the decreased exposure to sunlight is a decrease in vitamin D production and a higher possibility of developing MS.
Additionally severe stress might also be a risk factor in the development of MS, however, evidence to prove this is currently weak; smoking has also been shown to be an independent risk factor for developing MS. Association with occupational exposures and toxins ‘” primarily solvents ‘” has been evaluated, but a clear conclusion has yet to be reached.
What is the Pathophysiology of MS?
MS is an auto-immune disease
MS is currently believed to be an immune-mediated disorder with an initial trigger which may have a viral etiology. Damage is believed to be caused by the person’s own immune system which attacks the nervous system. Although it’s not known for sure, it’s believed that the attack could be the result of exposure to a molecule similar in structure to that one found in the immune system.
The name Multiple Sclerosis refers to the scars (scleroses) that form in the nervous system. These lesions most commonly involved areas of white matter located close to the ventricles of the cerebellum, brain stem, basal ganglia, and spinal cord as well as the optic nerve. The function of white matter is to carry signals between grey matter areas, where processing takes place, and the rest of the body.
Specifically MS destroys oligodendrocytes ‘” the cells responsible for creating and maintaining a fatty layer (the myelin sheath) which helps the neurons carry electric signals. The MS results in either a thinning of myelin and, as the disease advances, the cutting ‘” or transection ‘” of the neuron’s extensions or axons. Once the myelin is lost, the neuron can no longer effectively conduct electrical signals. There is a repair process called remyelination that takes place during the early stages phases of the disease, however, the oligodendrocytes cannot completely rebuild the cell’s myelin sheath. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons.
Blood-brain barrier breakdown
The blood-brain barrier is a capillary system that should (italics added) prevent the entrance of T-cells into the nervous system. The blood-brain barrier is normally not permeable to these type of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junction forming the barrier. Once the blood-brain barrier regains its integrity ‘” usually after the infection or virus clears ‘” the T cells are trapped inside the brain.
Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cells — a kind of lymphocyte. Lymphocytes are cells that play an important part in the body’s defenses. In MS, the T cells gain entry into the brain via the blood-brain barrier described above. However, recent evidence from animal models, also points to the role of B cells in addition to T cells in the development of the disease.
The T cells recognize myelin as a foreign body and attack it as if it were an invading virus. This triggers the inflammatory process, stimulating other immune cells and soluble factors like cytokines and anti-bodies. Leaks form in the blood-brain barrier which, in turn,
causes a number of other damaging effects such as swelling, activation of macrophages, and other destructive proteins.
How is MS diagnosed
Multiple Sclerosis can be difficult to diagnose since its signs and symptoms might be similar to other medical problems. Diagnostic criteria have been created to both ease and standardize the diagnostic process for a physician. Historically, both the Schumacher and Poser criteria were both popular. Currently, the McDonald criteria focuses on a demonstration with clinical, laboratory, and radiological data of the dissemination of MS lesions in time and space. A diagnosis cannot be made until other possible conditions have been ruled out and there is evidence of demyelinating events separated anatomically and in time.
Clinical data alone may be insufficient for a diagnosis of MS if an individual has suffered separate episodes of neurologic systems characteristic of MS. Since some people seek medical attention after only one attack, other testing may hasten and ease the diagnosis. Among the most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid (CSF), and evoked potentials. Magnetic resonance imaging (pictured above) of the brain and spine show areas of demyelination (lesions or plaques). Gadolinium ‘” a type of contrast ‘” can be administered intravenously to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the time of the evaluation.
Testing of cerebrospinal fluid (CSF) obtained by a lumbar puncture can provide evidence of chronic inflammation of the central nervous system. The CSF is tested for oligoclonal bands, which are an inflammation marker, and are found in between 75% and 85% of persons with MS. Since no known test is perfectly specific to MS, only biopsies or post-mortem examination can yield an absolutely certain diagnosis.
The nervous system of a person with MS responds less actively to stimulation of the optic nerve and sensory nerves due to the demyelination of such pathways. These brain responses can be examined using both visual and sensory evoked potentials.
How is MS treated
Although there is no known cure for MS, several therapies have proven helpful. The primary aims of therapy are: 1) returning function following an attack; 2) preventing new attacks; and 3) preventing disability. As is the case with any medical treatment, the medications used in the management of MS have several adverse side effects. Alternative treatments are pursued by some patients despite a shortage of supporting, comparable, replicated scientific study.
Management of acute attacks
During symptomatic attacks, the administration of high doses of intravenous corticosteroids28 such as methylprednisolone is the routine therapy for acute relapses. The goal of this type of treatment is to end the attack sooner and leave fewer lasting deficits. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. Potential side effects include: osteoporosis, and impaired memory ‘” the latter being reversible. Severe attacks, which do not respond to corticosteroids, might be treated by Plasmapheresis.
The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome or CIS. Several studies have shown that treatment with interferon during an initial attack can decrease the chance that a patient will develop clinical MS.
As of 2007, six (6) disease-modifying treatments have been approved by the regulatory agencies of different countries for RRMS. Three (3) are interferons30: two formulations of interferon beta-1a (trade names: Avonex, CinnoVex, ReciGen, and Rebif) and one of interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon). A fourth medication is glatiramer acelate (Copaxone), a non-interferon, non-steroidal immunomodulator. The fifth medication, mitoxantrone, is an immunosuppressant also used in chemotherapy, approved only in the United States, and largely for secondary progressive MS. The sixth one is natalizumab (marketed as Tysabri). All of these medications are modestly effective in decreasing the number of MS attacks as well as slowing the progression to disability, however, their efficacy rates (response rate) differ and studies of their long-term effects are still lacking.
Both the interferons and glatiramer are delivered by frequent injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular) for Avonex. Natalizumab and mitoxantrone are delivered by IV infusion at monthly intervals.
Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown positive side effects in patients with secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease as well as the frequency of relapses in patients in short-term follow-up. No treatment has been proven to modify the course of primary-progressive MS.
Managing the effects of MS
Although disease-modifying treatments reduce the progression rate of MS, they can’t stop it. As Multiple Sclerosis progresses, the symptomatology ‘” that is, the combined symptoms of the disease ‘” tends to increase. MS is associated with a variety of symptoms and functional deficits that ultimately result in a range of progressive impairments and disability. For that reason, management of these deficits is very important. Both drug therapy and neuro-rehabilitation have shown to ease the burden of some symptoms, however, neither influences the progression of the disease. For any patient with neurologic deficits, a multidisciplinary approach is key to both limiting and overcoming disability; the one problem involved with this lies in the fact that it’s difficult to specify a “core team” as patients with MS might need the help of almost any health profession or service at some point.
What is the prognosis for a person with MS?
The prognosis (the expected future course of the disease) for a person with MS depends the subtype of the disease; the person’s sex, age, and initial symptoms; and the degree of disability the person experiences. For example, a female with the relapsing-remitting subtype, who has optic-neuritis or sensory symptoms at onset, few attacks in the initial years, and early age of onset would have a better prognosis.