Multiple Sclerosis

MULTIPLE SCLEROSIS

MS is the most prevalenat inflammatory disease of the CNS in humans, affecting 1 person per 1,000 adults. This disease affects women in a 2:1 ratio to men, and,  for the most part, respects the latitudi-nal geographic presentation; that is, it occurs mostly in the northern European population or those of northern European descent.

 The incidence of MS gradually decreases as one approaches the equator. MS increases in incidence as one moves south, away from the equator. Epidemio-logical studies have also determined that the risk rate is fixed at the age of puberty; that is, if a person moves from an area of high risk to low risk before the age of fif-teen that person takes on the risk rate of the new location. If a person moves after the age of 15, that person maintains the risk rate from the area he or she migrated from. The reverse is true in going from low-risk areas to high-risk areas. Epide-miologists have interpreted this to mean that the inciting event or exposure that will ultimately lead to the clinical picture of MS occurs decades before the dis-ease is manifested in the mid-twenties and thirties.

Some epidemiologists point to the geo-graphical parameters of the disease as evi-dence of a genetic predisposition. In fact, even within the northern latitudes, the Laplanders and Inuits are not susceptible to MS. Specific human leucocyte antigens (HLA) types, such as DR2, occur more fre-quently in MS patients than in the general population. Twin studies also support this hypothesis, with identical twins experienc-ing concordance for the disease at a rate twenty to fifty times higher than expected from the population as a whole.

Newer studies are focusing on the role of 25-hydroxy vitamin D, an immuno-modulating factor, in the pathogenesis of MS vis-à-vis the latitudinal gradient. High levels of vitamin 25-hydroxy vitamin D in the serum significantly lower the odds ratio of MS risk in large population studies. Pos-sibly, the higher exposure to sunlight in the equatorial latitudes enhances natural absorption of vitamin D from the skin, resulting in higher serum levels, which may protect against MS.

By definition, the disease must affect two parts of the CNS at two discrete periods. Historically, the neurological examination and patient’s clinical history were used to fulfill these criteria. More recently, the MRI scanner has become a powerful adjunct to the history and examination in these patients. Multiple areas of the CNS can now be imaged to confirm the presence of more than one lesion. Serial MRI scans can now confirm multiple episodes in time, even when the patient is asymptomatic. A scan may be performed at three-month intervals from the first symptom to deter-mine whether new lesions present them-selves. New evidence of inflammation fits the criterion for separate episodes in time and thus the definition of MS. This is called the McDonald criterion for MS and has strengthened the practice of treating patients earlier in the disease course before significant disability sets in.

Cerebrospinal fluid (CSF) analysis has also proven helpful in diagnosing MS. The CSF is usually normal in terms of protein and cells but may have a slight protein elevation or increase in lymphocytes, rarely more than 50 cells/ml. Spinal fluid analysis, which directs one to the diagnosis of MS, includes evidence of intrathecal synthesis of immunoglobulins and the presence of oligoclonal bands. These antibody bands, primarily IgG, are found in approximately 90 percent of patients at some point in their disease course. These antibodies are detected on an agarose gel in the presence of an electric field and isoelectric focusing. The bands present in the basic area of the gel were initially felt to show a spe-cific immune response to an autoantigen or infectious agent in MS patients. How-ever, years of investigation have detected no consistent antibody response in MS patients. In fact, the pattern differs from patient to patient. Newer interpretation for the presence of oligoclonal antibodies is that they represent polyclonal dysregu-lation, rather than B-cell populations with specific immune responses induced. None-theless, the oligoclonal bands are a use-ful adjunctive test in the diagnosis of MS. Other diseases, which can produce bands, can be readily ruled out by other means, such as syphilis with a rapid plasma reagin (RPR) test or Lyme disease with enzyme-linked immunosorbent assay (ELISA) and Western blotting against Borrelia antigens.

The symptoms of MS depend on their localization in the nervous system. If the optic nerves are affected, the patient can present with decreased vision, ranging from color blindness to total loss of vision, which is accompanied by pain due to eye move-ment. Lesions of the brain stem can present with double vision, trigeminal neuralgia, severe pain on the face, or speech or swal-lowing difficulties. Lesions in the spinal cord can present with numbness, tingling, or weakness of the upper or lower extremities, as well as bladder/bowel and sexual dys-function. Symptoms are often accompanied by severe fatigue, possibly caused by release of cytokines in the CNS. The symptoms are manifest because nerve conduction is significantly slowed in demyelinated fibers. Saltatory conduction between the nodes of Ranvier is disorganized, and the slowed conduction results in neurological symp-toms of nerve dysfunction.

In addition, local edema in the area of the plaque may interrupt function tempo-rarily. Some patients develop symptoms that last a few hours or less. It is believed that low-affinity antibodies present in MS directly interact with antigens com-posing the sodium channels on neurons directly. The attachment and subsequent freeing of the antibodies from these chan-nels may be responsible for a rapid change in symptoms not involving an entire autoimmune/inflammatory cascade.

This finding points to the premise that MS is not solely a disease of white matter and demyelinating pathology but may also be a neuronal disease as well. MRI scanning using the neuronal marker NAA (N-acetyl-aspartate) has demonstrated that neuronal dysfunction occurs earlier in MS patients than would be expected from destruction of neurons based only on demyelination secondarily. This may open up new ave-nues of therapy in the future, directed not only toward remyelination but also in the area of nerve growth factors as well.

The overall pathological lesion has been categorized as a demyelinated area within the CNS white matter, with the presence of inflammation, gliosis remyelination, or axonal pathology. More recently, the pathology of MS has been categorized into four distinct patterns. Two patterns show lesions induced by autoreactive T cells (type I), or T cells plus antibodies and complement (type II). These are similar to the pathology induced by animal models discussed later. Patterns III and IV appear to be caused more by a dystrophy of the oligodendrocyte, and apoptosis, rather than an autoimmune reaction. The pathol-ogies are homogeneous within the demy-elinated lesions in each patient but differ from patient to patient. This may suggest that different disease pathologies may be linked to one clinical state, MS, or that there are clinical subcategories of MS pre-sentations that may be clinically tied to the pathology, which is yet to be determined. This will ultimately reflect different treat-ment modalities for the different presenta-tions of MS.

Experimental allergic encephalomyeli-tis (EAE) in rodents, which has been the hallmark animal model of MS, is induced following immunization with whole myelin or antigens related to myelin (i.e., myelin oligodendrocyte glycoprotein, or MOG, or myelin basic protein, or MBP with complete Freund’s adjuvant). These myelin antigens are also cross-reactive with T cells and antibodies directed against the Semliki Forest virus, used to promote an immune-mediated demyelinating viral encephalitis model. Antibodies to MOG induce demy-elination in EAE and exacerbate the clinical disease, while antibodies to MBP reduce disease severity. A polymer of a peptide sequence of MBP is an approved immuno-modulating drug for MS in humans, which is believed to stabilize disease by chang-ing the T-cell repertoire from T_H1 to T_H2 in the CNS.

The pathogenesis of the EAE model involves immune cells migrating from the peripheral lymphoid system, where acti-vation takes place, to the CNS. These cells then mediate tissue damage in the CNS. In addition, epitope spreading occurs where autoreactive T cells and antibodies become more diverse.

This model also allows for the concept of microbial-induced autoimmune reactions in genetically susceptible mice strains with Theiler’s murine virus or Semliki Forest virus. Blood-brain barrier passage by CD4⁺ cells, CNS immigration, demyelination lesion induction, and clinical neurological deficit in the rodent have all been achieved in this model. However, the cause of per-manent neurological deficit in MS and EAE is still not entirely understood. CNS and inflammation and demyelination do not account for irreversible neurological symp-toms. Recently, axonal pathology has been also implicated not only in MS but also in EAE as well and may lead to future thera-pies. In terms of therapies for MS, many biologic agents are species specific, and nonhuman primates such as marmosets and rhesus monkeys are the more appropri-ate model to use. For studying MS, nonhu-man primates have proved the most useful model thus far, despite the history of EAE in rodents. They also provide species-spe-cific therapeutic options to be investigated, as well as an easier ability to do longitudi-nal sampling of body fluids.

Treatment of the disease is aimed at three levels. The first level, the use of intra-venous corticosteroids, is the treatment and shortening of acute attacks, such as visual loss with optic neuritis, a spinal cord syn-drome, or hemiparesis. Patients are also treated with oral steroids for less severe attacks, with the exception of optic neu-ritis. In addition to its anti-inflammatory properties, steroids may strengthen the blood-brain barrier and decrease edema in a lesion, causing a rapid reversal of symptoms.

The next level of therapy for patients is the daily management of ongoing symp-toms. This might include muscle relaxants for spasticity, amantadine, or modafinil for fatigue, antidepressants or anticon-vulsants for pain and mood changes, and anticholinergic medication for bladder spasticity and incontinence. Fortunately, most MS patients have a limited constella-tion of symptoms, but some require signifi-cant polypharmacy.

Ongoing physical therapy and a course of psychotherapy are often prescribed for patients. Physical therapy optimizes the muscle capabilities of the patient and has an effect on psychological well-being as well. Depression plays a major role in MS, but it is unclear whether it is a reactive or endogenous mood disorder. Nonetheless, suicide attempts are a considerable risk with MS patients and psychological coun-seling is often suggested.

Interferons and immunomodulating agents have become the mainstay of treat-ment of the long clinical course of MS. Specifically, IFN-β, given subcutaneously or intramuscularly has become recom-mended lifelong for patients at this time. Statistical significance was achieved in these patients, both in terms of MRI effects and the frequency and severity of attacks. The clinical relapse rate diminished by one-third, and MRI data suggest an even more dramatic drop in lesion volume (−17.3 percent) and number (−83 percent) compared with placebo. The literature is somewhat contradictory about the goal of slowing the gradual progression or wors-ening of the disease overall, but some stud-ies are able to confirm this finding. While interferons have several immunomodulat-ing effects and may also be antiviral, the main function of these medications in this setting may be to block adhesion of lym-phocytes and macrophages to the blood-brain barrier and thus limit trafficking into the CNS. Natalizumab, a newly approved immunomodulator in MS also inhibits the attachment of lymphocytes to the endothe-lial cells and limits trafficking of the cells across. It is an antibody directed against the integrin-4α adhesion molecule on lym-phocytes and monocytes.

Glatiramer acetate (Copaxone) has a similar effect profile in MS patients in terms of reduction of MRI lesions and clinical attack rate. The drug is a polypep-tide polymer of myelin, eight amino acids long, and is believe to function by a differ-ent mechanism from the interferons. The drug appears to act directly within the CNS by altering the immune profile from a helper to suppressor predominance. It is hoped that these immunomodulating agents will change the course of disease in the long term, especially if they are started early after diagnosis or presump-tive diagnosis.