Multiple sclerosis (MS) was first described by a French neurologist Jean-Martin Charcot in 1868. It is a chronic immune-mediated demyelination disease characterized by the damage of the fatty protein called myelin which is an insulting sheath that wraps around the axon in the central nervous system. The destruction of myelin or white matter of the brain affects the effectiveness of the signal transmission between the brain and the other parts of the body, leading to a wide range of neurological symptoms including the sensory, visual, motor, cognitive, bowel, bladder and sexual systems such as blurred vision, muscle weakness, loss of sensation, loss of coordination, difficulty in balance, memory problems, fatigue, speech and swallowing problems. The name multiple sclerosis refers to various (multiple) scar formation (scleroses) on the myelin sheaths.
The disease of multiple sclerosis is predominant in female patient rather than in male patient and the target group is often young adult between ages 20 to 45 years although the diagnoses in children and adult over 50 years old are relatively rare. MS has a higher prevalence in Caucasians than in other racial groups. Geographically, the prevalence and the incidence increase with increasing latitude from the equator. The northernmost and southernmost countries such as Canada, USA, Russia, New Zealand and parts of Australia are the area with high risk, while the equatorial countries such as Asia, South American and Africa generally have a lower risk MS.
Clinical courses of Multiple Sclerosis
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The United States National Multiple Sclerosis Society recognized four courses of multiple sclerosis which range from benign to progressive and incapacitation disorder (Lublin & Reingold, 1996). These subtypes of MS play an important role in the prognosis and therapeutic recommendations in treatment of MS.
Relapsing/Remitting Multiple Sclerosis (RRMS) is the most common course accounting for about 80% of patients present with acute but episodic attacks of worsening severity.
Secondary Progressive Multiple Sclerosis (SPMS) is the second most common one occurs in approximately 65% of patients and it is the progressive deterioration following the RRMS.
Primary Progressive Multiple Sclerosis (PPMS) is marked by gradual progressive deterioration in neurologic status and describes around 20% of individuals.
Progressive Relapsing Multiple Sclerosis (PRMS) is the least common and is characterized by a steady decline in neurologic function along with episodic acute attacks.
`Pathogenesis of multiple sclerosis
Recently, over thousand of articles have been published each year on multiple sclerosis. Most of the researchers are paying great efforts in investigating the etiology, diagnosis and treatments of MS. However the causes and pathogenesis of this demyelinatin disease are still poorly understood and there is no definite answer.
Multiple sclerosis is categorized as an autoimmune disease as it usually results from the attacks by patient's own immune system on the CNS.
The pathophysiological processes of MS involve inflammation, blood-brain barrier damage, demyelination and remyelination, oligodendrocyte destruction, astrocyte proliferation produce gliosis, and neuronal and axonal danage, resulting of the formation and accumulation of sclerotic plaque in the CNS. MS is characterized primarily as degenerative or infectious condition with secondary inflammation.
During the inflammatory phase, body's immune system plays a key role in the damage of myelin. T-cells and macrophages are activated as an immune response to attack the oligodendrocytes on the myelin sheath and resulting of demyelination. Furthermore, the conduction block by depolarization of the axonal plasma membrane causes axonal destruction in the neurodegenerative phase. Risk factors contributing to the pathogenesis of multiple sclerosis
Several studies have proposed that MS is the result of complex combination of genetic, environmental and infectious factors.
Recently, family study shows that the recurrence rate of MS is about 20% if there has close relatives such as siblings, parents or children are suffering from the disease and this rate is much higher than that has no genetic component. Furthermore, the concordance rate in monozygotic twins is 25%, while it is reduced to 5% in dizygotic twins which evidences that the susceptibility for developing MS is genetically associated (Compston and Coles, 2008).
Various publishes indicate that genetic is one of the risk factors involved in the developing of multiple sclerosis. Genetic studies show that MS contributing genetic links occur in alleles of the human leukocyte antigen (HLA) class II region of the major histocompatibility complex (MHC), with highly significant linkages to MHC confirmed on chromosome 6p21and the alleles are defined as HLA-DRB1*1501 and HLA-DQB*06026(Kantarci &Wingerchuk,2006). Recently, another gene locus for MS was identified as inerleukin-7 receptor Î± gene (IL7RA) (Gregory et al., 2007) which was confirmed by International Multiple Sclerosis Genetics Consortium (IMSGC). After then, the genome-wide association studies (GWAS) have described interleukin-2 receptor Î± gene (IL2RA) as an additional gene locus of MS ("IMSGC", 2009). Because of the genetic heterogeneity, different genes may be involved in different populations and different gene combinations may correspond to variations in disease severity, progression and symptoms (Zuvich, McCauley, Pericak-Vance & Haines, 2009).
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In order to further the knowledge of the genetics influencing MS and get better understanding of the genetic architecture of MS, some comprehensive analytic approaches such as common disease/common variant hypothesis (CDCV)(Pritchard, 2001) and multiple rare variants hypothesis(MRV)(Smith & Lusis,2002) should be used by researchers for examination. The former hypothesis proposes that susceptibility to common diseases is determined by a few common variants with lower penetrance while the latter hypothesis suggests that susceptibility is determined by a large number of rare variants with higher penetrance.
On the other side, since the concordance ratio in monozygotic twins is not 100%, this may suggest that MS is not entirely genetically controlled. Other factors such as environmental exposure may be involved in the disease susceptibility.
Among those environmental factors that contributing to the development of multiple sclerosis, vitamin D should be the most mentionable one. As previously discussed, epidemiological studies of geographic distribution of MS evidenced that the high prevalence and incidence in the countries which are farther from the equator is due to the low sunlight exposure and indicated the possible influence of vitamin D intake to the MS susceptibility(Ascherio & Munger, 2008); (Myhr, 2009). Further indications that the rate of MS relapse activity and degree of disability are inversely associated with the vitamin D serum level (Smolders, Menheeere, Kessels, Damoiseaux & Hupperts, 2008).
Recent studies implied that vitamin D can reduce the expression of the multiple sclerosis associated human leukocyte antigen class II allele and act as an immunomodulator in the anti-inflammatory processes through a single vitamin D receptor (Smolders, Damoiseaux Menheeere, & Hupperts, 2008);(Ramagopalan,et al., 2009). Another study evidenced that the seasonal circulation 25-hydroxyvitamin D (25(OH) D) level is regulated by genetic influences (Orton, et al., 2008).
One the other hand, if the risk of MS is linked with sunlight exposure, there should be a high incidence in the far north of Norway. However, the incidence in the north cities of Arctic Circle is lower than that of the south and it is plausibly explained by the high consumption of oily fish which is high in vitamin D3 and omega-3. Therefore, dietary habit is another environmental trigger which may contribute to the risk of MS (Kampman, Wilsgaard, Mellgren, 2007).
Still other commentators suggest that cigarette smoking is associated with the increased risk of MS and especially in female smokers by affecting the blood-brain barrier and immune system (Sundstrom, Nystrom & Hallmans, 2008); (Hossain at el., 2009)
There is suggested evidence that pathogen such as Chlamydophilia pneumiae has been implicated in MS as its DNA is found in the CSF of MS patient (Contini et al, 2010). Moreover, nearly all MS patients are seropositive for Epstein-Barr Virus (EBV) and antigenic mimicry is believed to be the pathogenesis of EBV in MS (Bagert, 2009)
Diagnosis of multiple sclerosis
In 2001, McDonald criteria were published and were subsequently revised in 2005. These latest diagnostic criteria were recommended as the standard diagnosis of multiple sclerosis by detection of disseminated disease both in time and localization, based on history of exacerbations and remissions, clinical signs and symptoms and usually supplemented by radiologic and laboratory test results (McDonald et al., 2001); (Polman et al., 2005).
Magnetic resonance imaging (MRI) can be used to detect the formation of lesions and plaques in the brain and spinal cord of the patient with or without clinical symptoms (Compston and Coles, 2008).
In the laboratory side, the examination of the cerebrospinal fluid for the presence of oligoclonal bands by protein electrophoresis can provide evidence of chronic inflammation of the CNS (Compston and Coles, 2008). Besides, measurement of the level of the antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) can show the occurrence of demyelination(Egg, Reindl, Deisenhammer, Linington & Berger, 2001).
The combining of MRI founding, clinical evidence and the presence of oligoclonal bands, the definite diagnosis of multiple sclerosis can be made (Compston and Coles, 2008).
Vitamin D binding protein (DBP) is the major plasma carrier protein of vitamin D. It is recently suggested that DBP is a potential biomarker for diagnosis of MS by proteomics analysis of its level in CSF of the patients (Qin, Qin & Liu, 2009).
Therapies of multiple sclerosis
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There is no known definitive cure for multiple sclerosis and the recent treatments are aimed at preventing the new MS attacks, returning function after attacks and slowing the onset of new symptom. Current treatment in MS involves the use of immunomodulatory and immunosuppressant drugs either sequentially or in combination. There are six parenteral formulations approved treatment for relapsing-remitting multiple sclerosis by reducing the rate of relapses, preventing the formation and progression of new lesions visible on MRI. The three interferon-ß agents (IFNß-1b, IFNß1a-SC, IFNß-1a IM) and glatiramer acetate are the commonly used first-line immunomodulatory drugs which are only administered by subcutaneous of intramuscular injection (Stüve, 2009). A study showed that there is a gender effect on the respond to interferon-ß treatment as male patients do not respond as well as females (Trojano et al., 2009). The second-line agents include an immunosuppressant drug named mitoxantrone which is also a chemotherapeutic agent, and Natalizumab is the first developed and approved monoclonal antibody for the MS treatment (Stüve, 2009).
Recently, several promising oral agents are still under investigation or awaiting for approval which include Cladribine, Teriflunomide, Laquinimod, Fingolimod and Fumaric acid. The other two currently evaluated injectable drugs are Alemtuzumab and PEGylated interferon beta (Kieseier, Wiendl, Hartung & Stüve, 2009)
New technologies and new treatments are expecting by both clinicians and patients, such as stem-cell biology which may contribute in the repair mechanism of multiple sclerosis by enhancing the remyelination (Vosoughi & Freedman, 2010). Furthermore, the approaches of the new developing therapies should provide improvement in efficacy with fewer side effects. In addition, oral treatments are awaited eagerly as they present clear advantage in terms of convenience over currently available injectable therapies. As a whole, genetic is the bulletin, and environment is the gun, supplementation of vitamin D with appropriate dosage may help to prevent the development of MS in the populations of the high risk areas and those with genetic components.