In this autoimmune disorder, myelin sheaths progressively degenerate in scattered foci in the brain. These areas are eventually replaced by plaques of hardened tissues, which can be observed through magnetic resonance imaging (MRI). The term "sclerosis" refers to "hardening".
Patients are most often in their 30's when symptoms first appear, although occasionally the disorder appears in childhood or indeed at any age. The first clinical signs are most likely to be sensory and motor symptoms, such as optic neuritis, diplopia, nystagmus (shown to right), paresthesias, muscle weakness and ataxia. At first, these are often mild.
Multiple sclerosis usually begins as a relapsing-remiting disorder, in which periods of symptoms are interspersed with periods of recovery. In most patients this eventually converts into a progressive phase, in which there is increasing axonal and neuronal loss. On average, a patient in the relapsing-remitting phase has about a 3% chance each year of converting to the progressive phase. Thus the median time for conversion to the progressive form is about 20 years. But there is considerable individual variation in the time-course of the disorder. A small percentage of the patients, for example, never go through a phase of remission, especially if they are older.
As the progressive phase advances, axons and entire neurons degenerate, leading to additional, increasingly severe symptoms, including paralysis, difficulty speaking, emotional problems, memory loss and autonomic problems. Symptoms can encompass most functions of the nervous system.
A careful neurological examination of the patient, of course, is important, although the individual symptoms can occur in various other neurological disorders.
As mentioned above, an MRI is an important tool. Before the imaging, gadolinium is often administered intravenously, because it will traverse the abnormal, leaky endothelium at the plaques, allowing the areas to be highlighted on the MRI.
Also, the visual evoked potential may be abnormal due to optic neuritis, which is one of the most common early symptoms. The electrical recording is similar to that of an electroencephalogram, but it is taken during a repetitive visual stimulus. Optic neuritis is suspected with pain in the eye and disrupted vision.
Also useful is a lumbar puncture to test the cerebrospinal fluid for signs of inflammation and certain antibodies. For example, there are typically antibodies in the CSF against myelin basic proteins, which are responsible for compacting the myelin. However, the antibody levels do not correlate well with the progression of multiple sclerosis.
The initial cause of the disorder is not known, although clearly both genetic and environmental factors play important roles. Various genetic loci have been identified, but these do not yet clearly connect with the pathogenesis. Multiple sclerosis is strikingly more common in temperate regions of the northern hemisphere, which also correlates with vitamin D levels. The highest rate is in Scotland. There also is a significant correlation with infection by the Epstein-Barr virus. To some, this points to a possible role for the virus in the initiation of multiple sclerosis; to others, it suggests that the microbial environment might influence the development of the corresponding immune cells.
There are two distinct phases in the pathogenesis of the disorder which correspond to the evolution of the symptoms. In the first relapsing phase, there are bursts of inflammation in foci in the white matter. The blood-brain barrier is disrupted in these areas. T cells and macrophages are prominent in the lesions. The CD4+ T cells are type I, and induce significant inflammation. While this is the traditional view of the pathogenesis of multiple sclerosis, the success of antibodies that reduce B cells indicates that B cells are also substantially involved in the pathogenesis.
The current idea is that this initial, focal inflammation is ultimately responsible for the later cascade of pathology that causes the neurodegeneration of the long-term disability.
As the myelin sheath degenerates, the action potentials slow and ultimately stop. Evidence suggests that new Na+ channels may then be placed in membrane previously covered by myelin, allowing the axons to function more or less as unmyelinated axons, with their much slower conduction. But also in the early phases, axons can regain function through partial remyelination.
As conduction in axons becomes marginal in multiple sclerosis, it may be readily upset by increases in body temperature during fever or exercise. The higher temperature speeds the opening and closing of the ion channels, shortening the action potential. This may be enough to block the conduction in the damaged axons. Cooling restores the conduction.
During an acute relapse, symptoms can be improved with corticosteriods (glucocorticoid), as is the case in many inflammatory and immunological disorders. But this does not alter the progression of the disorder.
Several types of drugs are called disease modifying drugs because that slow the progress of the disorder. (The options are actually significantly more complicated that listed below.)
The cytokine interferon beta-1 is often used to modify the immune response. It has an anti-inflammatory effect, including improving the integrity of the blood brain barrier. It usually causes flu-like side-effects.
More recently, ocrelizumab, which is an antibody that binds to a molecule on B cells and causes a reduction in their number, was found to be even more effective than interferon beta-1.
Glatiramer is a set of synthetic polypeptides that alters T cell function, possibly by mimicking myelin proteins. It must be injected regularly.
Natalizumab, which is a monoclonal antibody, blocks adhesion molecules in the endothelium, thus preventing entry of inflammatory cells into the lesion. It is also more effective than interferon beta-1, but carries a small but significant risk of a serious immunological disorder.
In 2010, fingolimod was approved as a disease modifying drug for multiple sclerosis. It is the only oral disease modifying treatment. Fingolimod is a phospholipid that is a chemical modification of a molecule produced by a fungus originally derived from Chinese medicine. It acts by suppressing or modifying the immune response.
Later in the disorder in the progressive phase, an immunosuppressant, such as methotrexate or various others, is often used. Monthly pulses of glucocorticoid might also be used.