Multiple Sclerosis, Research Paper Example

Abstract

The purpose of this document is to offer a precise account of Multiple Sclerosis. The statement of problem related to this research reads ‘while theories pertaining to the etiology of multiple sclerosis predominantly focus on genetics and infection various environmental risks can be predisposing influences also. As such, this research explores the extent to which genetic and infection theories defining causative factors influencing the development of multiple sclerosis can really explain the pathophysiology of the disease. Consequently, the researcher will adapt a comparative analysis of the perspectives offered by theorists regarding emergence of multiple sclerosis among the twenty-first century female young adults. These will be matched with critiques from scientists advocating an environmental approach towards explaining the phenomenon as data relevant to its epidemiology; clinical symptoms; immunological concepts underlying the disease; therapy and management as well as current trends are explored.

Introduction

Description

Multiple sclerosis was not discovered as a disease until late 19the century. An English Physician by the name of Walter Moxon in 1873 along with American Dr. Edward Seguin in 1878 discovered multiple sclerosis as a dysfunction of the nervous system. They confirmed that it was more common in women than men. However, three notable signs of multiple sclerosis signs described as Charcot’s triad 1 being nystagmus, intention tremor, and telegraphic speech (scanning speech) have been attributed to French neurologist Jean-Martin Charcot (1825-1893). He  recognized cognition alterations, which was described as “marked enfeeblement of the memory” and “conceptions that formed slowly” (Clanet, 2008, p 58).  At the time these doctors did not project any sound etiology of the disease, but said that there was no evidence to support it being inherited. However, they confirmed that numerous diverse neurological irregularities were produced as symptoms of the condition (Terry et.al, 2012).

Multiple sclerosis (MS); disseminated sclerosis is also known as encephalomyelitis disseminata. Scientists have described it as an inflammatory condition characterized by formation of myelin sheaths around brain and spinal axons tissue. Ultimately, these tissues are destroyed through scarring; reduction in myelin to protect brain and spinal cord. Research is still being conducted regarding its etiology, Assumptions however have been that many predisposing genetic, environmental and infection factors could initiate the inflammation (Ascherio & Munger, 2007).

Other assumptions have been that there are mechanisms within the body chemistry, which are responsible for destruction of the immune system inhibiting production of myelin cells. Consequently, massive insidious nerve destruction occurs and nerve cells become incapable of functioning as communicators of impulses across nerve ending within the human body. Often when the etiology of a disease is obscure there is seldom a cure. Recent research has continued to advance ther theory that indeed multiple sclerosis affects more females than males (Nakahara et.al 2012)

To date scientists have advanced from repeated research that there is no discrimination as to which neurological symptoms can emerge due to nerve destruction in the brain and spinal cord which are the primary target organs. From observation there have been immense progressive physical and mental dysfunctions. In some cases memory irregularities could develop, but a difficultly exists classifying them as purely psychiatric because they may present in conjunction with various levels of other neurological abnormalities. As the disease evolves it converges into many misleading features increasing the challenge of addressing the real symptoms in devising modes of treatment intervention. Scientists have described this phenomenon as an escalation of new symptoms, which were not formerly associated with the initial presentation. They are termed relapsing forms and progressive forms respectively (Dymentet.al, 2004)

The period from when attacks begin end, and begin again symptoms may subside. However after these episodes permanent nerved damage occurs. As the disease advances symptoms worsens and exacerbations seems to occur leading up to when treatment becomes ineffective. This disease is more than 100 years old, but scientists have not been articulate in arriving at any profound etiology while numerous theories exist. They have not gone far beyond exploring mechanisms related to the disease process itself (Ascherio & Munger, 2007).

Nakahara, Maeda, Aiso and Suzuki (2012) offer evidence as they explain ‘Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy’ showing where without relevant etiology appropriate treatment cannot be adapted for MS intervention. These researchers argue that present interventions, disease modifying therapies (DMT) are aimed only at addressing the autoimmune etiology of the disease. As such, they merely focus on restoring function to affected nerves after symptoms become uncontrollable; control recurrence and limit the extent to which nerve damage produces disability (Nakahara et,al, 2012).

However, medications used to treat multiple sclerosis are not without their serious side effects, besides being poorly tolerated by patients. Consequently, patients turn to alternative medicine for relief. Precisely, since there are few studies conducted regarding alternative remedies these remedies are considered nonscientific and are not recommended even through patient report how successful these treatments have been in restoring nerve function (Gilden, 2005).

People diagnosed with multiple sclerosis live an average 5-10 years, less than persons who do not have the disease. There is an average of 2 persons affected by multiple sclerosis for every 150 per 100, 000 (Rosati, 2001).  However, data or theories have no value if they cannot be used to enhance an understanding of the disease ultimately providing better treatment methods, leading towards a cure. This research is expected to sensitize scientists into elaborating on present research practices in arriving at a consensus regarding the reality of multiple sclerosis etiology.

Epidemiology

Epidemiology infers a study of disease patterns that evaluates infection etiology; geographic, socioeconomic status, genetics and demographic variations. Often epidemiologists add to the multiple sclerosis body of knowledge through assessing relationships between these factors. Since there are no known causative factors for multiple sclerosis it is important that epidemiologists continue investigations regarding migration patterns. However, it must be understood that figures published in epidemiology records are all estimates. This is an attempt at establishing a more profound understanding regarding multiple sclerosis target populations across the world. It also helps identifying and explaining geographic locations containing highest and lowest multiple sclerosis rates (Merril, 2010).

The challenge facing the epidemiology of multiple sclerosis lays in the difficulty diagnosing the disease. No single distinct tests are being conducted in establishing a diagnosis for multiple sclerosis. As such, the argument is that diagnoses can be incorrect delayed or just bypassed. While MRI technology has been of great assistance in resolving difficult diagnoses epidemiologists question the accuracy of diagnoses produced from previous studies since they may not give a true representation of multiple sclerosis with the given population. More importantly, various methodologies used by specialists collecting data on the disease can greatly alter interpretations and outcomes. Due to these factors the epidemiology of multiple sclerosis is still in its infancy even though the disease is over 100 years old (Merril, 2010).

According to Orhun Kantarci and Dean Wingerchukb (2006) multiple sclerosis claims the health of approximately 1 000 000 people between 17 and 65 years old internationally. The 2000 projected multiple sclerosis prevalence rate among white US populations showed 191 per100 000. Alternatively, the US overall incidence rate and was 7.3 per 100 000 person in the same year. Further epidemiological studies supported the theory that multiple sclerosis is two times more common in women than men. It was discovered also that there is a tendency for a later onset of the disease among men. The prognosis for them is even worse for women. Scientists attribute this difference to gender-dependent and phenotypic variability factors which may create an etiological predisposition (Kantarci & Wingerchukb, 2006).

Multiple sclerosis care cost United States government an estimated $6.8 billion annually, which includes loss in productivity as well as actual health care interventions. A total life time cost is estimated at 2.2 million per patient (Kantarci & Wingerchukb, 2006).Similar epidemiological estimates exist around the world. There seems to be patterns of ‘a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere’ (Rosati, 2001, p 22). Multiple sclerosis is less prevalent among people who live close to the equator. Theories pertaining to climate, sunlight and vitamin D intake are variables used in relating possible causes in explaining this latitude gradient theory regarding geographic disposition multiple sclerosis prevalence among people living near to the equator (Rosati, 2001).

Overtime other variations have appeared, which forced epidemiologist to consider environment in combination with genetics. Multiple sclerosis was discovered to be prevalent among northern European populations and most common in certain ethnic groups such as ‘Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New Zealand M?ori’ (Rosati, 2001, p 22).

Childhood environmental factors were then considered as a single variable in the emergence of multiple sclerosis at a later stage in the child’s life. Consequently, epidemiologists began investigating numerous diverse migrant populations which revealed that once children were removed from the location before attaining 15 years of age it was less likely for him/her to develop the disease. When children remain in the geographic space the predisposition of contracting multiple sclerosis is sustained. Further investigations revealed that the birth season also had a relationship towards development of the disease which makes epidemiological estimation ns more complicated. This confirmed the vitamin D sunlight theory since people born in November were less likely to contact multiple sclerosis regardless the geographic location (Rosati, 2001).

Critics of the environmental epidemiological theory have contended that quantification of the assumptions is difficult because data derived is obtained mainly from retrospective case-control studies whereby subjects are exposed to the same environment and results may lack internal and external validity besides containing reliability issues. ‘A practical, albeit limited, design is a nested-cohort study in which a population cohort already identified for exposure to given factor(s) for another disease is exploited for excess of -NIS occurrence after sufficient follow- up’(Kantarci & Wingerchukb, 2006, p 249). While trying to make sense of the environmental theoretical epidemiological perspectives major advances have implicate viral exposure factors. Viruses identified are canine distemper virus, Epstein-Barr virus, and human herpes virus-6) (Kantarci & Wingerchukb, 2006).

Internationally, conclusions are that multiple sclerosis makes its first appearance in adults during their thirties. It can occur at any time in children. However, the primary progressive subtype appears later in people in their fifties.  The genetic epidemiology of multiple sclerosis seems to be overlapping with both environmental and viral/infections. Analysts have discovered that the only facts they have to support the genetic epidemiology are its high incidence among Northern Europeans in relation to indigenous populations from the ‘same geographic location, familial aggregation’(Kantarci & Wingerchukb, 2006, p 249). See appendix 1 and 2

Clinical signs and symptoms

Numerous signs and symptoms are associated with multiple sclerosis. However neurologists keep abreast of symptoms by applying the Expanded Disability Status Scale (EDSS).  EDSS gives a score total of a scale ranges from 0 to 10.

‘The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability.  The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. In addition, it also provides eight subscale measurements called Functional System (FS) scores. These subscale categories are listed below.  The levels of function within each category refer to the eight functional systems affected by MS’ (Kurtzke, 1983).

Pain

Pain is very common among multiple sclerosis patents and often appears after the first lesion is formed. In most occasions it is associated with the control mechanisms which regulate ascending and descending tracts in the anterolateral system. From 28 studies researchers proved taking a sample of 7101 multiple sclerosis patients that 63% complained of various degrees of pain. There were no significant differences in pain levels among men and women or people with greater disability than others.  Most pain occur as ‘headaches (43%), dysesthetic limb pain (26%), back pain (20%), painful spasms (15%), painful Lhermitte’s phenomenon (16%) and Trigeminal Neuralgia (3%)’ (Foley et.al, 2013, p 632).

Emotional disturbance

Emotional disturbance manifests as clinical depression. This can extend into a life time complication. Present incidence rates range between 40–50% per person diagnosed with multiple sclerosis. Brain imaging studies have tried to relate findings to depression when brain lesions are found. More importantly, most neurologists have associated these brain lesions with neuropathology of the left anterior temporal/parietal regions. It is very important development that is worth monitoring carefully because emotional disturbance is responsible for 15% of deaths emerging from suicide. As such, patients are closely evaluated when signs anger, anxiety, hopelessness, and frustration surface (Siegert, Abernethy, 2005).

Bladder and Bowel irritability

Bladder disturbances occur in 70% of all multiple sclerosis patients. It presents as frequency, hesitancy and incontinence which can affect maintenance of personal hygiene. Bowel issues appear in 70% of the multiple sclerosis patients, 50% suffer from constipation 30% fecal incontinence (DasGupta & Fowler, 2003).

Cognitive disturbances

40%- 60% of multiple sclerosis patients encounter cognitive difficulties. It ranges from simple degrees of forgetfulness to severe loss of memory. Other cognitive difficulties are attention deficit; neurological fatigue; processing speed and visual spatial ability alterations (Ebers, 2008).

Impaired Mobility

Mobility changes become evident when walking, moving, getting off and on the bed and balancing. Research has shown that between the onset of the disease and 5 years 50% of patient score 6 on the EDSS scale. 10 years living with multiple sclerosis 25% of patients can attain just a score of 6 on the Expanded Disability Status Scale (EDSS). This makes using a walker and other methods of mobility support necessary. Within 30 years, 83% of patients use walking aids (DasGupta & Fowler, 2003).

Speech difficulties

Speech could become slurred and tone of voice altered.

Muscle Tremor and Ataxia

Ataxia coincides with muscle tremors. Clumsy movement occurs creating difficulty in maintaining a steady gait. Muscle tremors are often uncontrollable involuntary episodes of shaking.

Transverse myelitis 

When multiple sclerosis begins invading deep into spinal cord tissue lower body functions become impaired. These include bladder/irritability as well as sexual potency in males. Inability to have an erecting is possible along with ejaculation difficulties

Spasticity

Spasticity manifests as both a sign and symptom. Muscles, especially, in the extremities become very stiff and immobile.

Diagnosis

Researchers have posited that multiple sclerosis is difficult to diagnose since confirmation of the disease cannot be made on clinical symptoms alone. Signs and symptoms may resemble many other neurological disorders. To facilitate diagnosis during the early stages scientists have designed standardized criteria. They include Schumacher, Poser and McDonald criteria.

Schumacher’s criterion is a neurological examination detecting central nervous system abnormalities involving two or more systemic dysfunctions. Often white matter abnormalities are evident in brain and spinal tissue. In 1983 these criteria were modified by Poser accounting for clinically definite; laboratory supported definite; clinically probable and laboratory supported probable multiple sclerosis (Royal College of Physicians of London, 2004).

McDonald criteria are the ones presently used in most health care institutions across the world for making a more accurate multiple sclerosis diagnosis. It includes a

• Diagnostic criteria for suspected MS (two or more attacks)
• Diagnostic criteria for suspected MS (monosymptomatic)
• Diagnostic criteria for suspected MS (single attack)
• Diagnostic criteria for suspected MS (progressive from onset)

However, Schäffler, Köpke , Winkler , Schippling , Inglese , Fischer and, Heesen (2011) have reprted that the development of a new diagnostic criteria for multiple sclerosis was recently proposed after a systematic literature review  revealed that present accuracy issues made some tests invalid. The aim of this study was to validate diagnostic studies and clarify the value of diagnostic test used in offering a diagnosis. They included in their review a minimum of 40 patients who were traced for 2 years. This limitation existed in all the studies reviewed since they significantly lacked a gold standard measurement for validating the diagnostic tests that were used in those trials. A second relapse phase was adopted as a surrogate in relapsing-remitting multiple sclerosis testing. However, the lengthy 5 year follow-up created difficulty in detecting all cases. Also, quite a few studies contained various levels of validity and reliability issues. Notably, a selection bias was identified due to the indistinct classification of a clinically isolated syndrome (Schäffler et.al, 2011).

Based on these limitations, ‘sensitivity of magnetic resonance imaging (MRI) criteria was between 35% and 100%, and specificity was between 36% and 92%; Cerebrospinal fluid (CSF) oligoclonal banding showed sensitivities between 69% and 91% with specificities between 59% and 94%; combination studies of MRI and CSF indicate enhanced sensitivity (56-100%) and specificity (53-96%)’ (Schäffler et.al, 2011, 153). The researchers did not find justification in conclusions derived in the literature review studies. Further they suggest that ‘a combination of simplified MRI criteria with CSF might be the best approach for an early MS diagnosis’ (Schäffler et.al, 2011, 153).

Prognosis

While there is no cure for multiple sclerosis it has not been considered a fatal disease even though it severely affects a person’s quality of life. Serious disability does not occur until about 20 years after onset of the disease. Women seem to have a better prognosis than males. Factors affecting each patient’s prognosis regarding quality and length of life relate  to  adherence of health promotion strategies that will limit symptoms , doctor’s  appointment  follow up ; compliance with medication management to reduce progression of the disease. Generally life expectancy is reduced by 5-10 years with careful intervention strategies (Murray, 2002).

Immunological concepts underlying Multiple sclerosis

Immunology relates to the body’s defense mechanisms in counteracting  the activity of invading agents. For every disease entity that enters the human internal environment there are diverse strategies employed by the immune system in a comprehensive effort to interrupt the intended invasion consequences. Consequently, the immune system builds up resistance by developing immunity to the invading organisms. There are mainly five types of immunological responses that can emerge from this activity. They are humoral immunity; cell-mediated immunity; innate (or Natural Immunity); acquired immunity, and non-specific immunity (Nakahara et.al, 2006).

Humoral immunity

Humoral immunity is also known as antibody-mediated system being mediated macromolecules located in extracellular fluids like secreted antibodies, antimicrobial peptides and complement proteins. Usually, humoral immunity reacts with substances in body fluid humors (Nakahara et.al, 2006).

Cell-mediated immunity

Cell-mediated immunity does not rely on producing antibodies in order to defend the body against harmful organisms. Instead it activates phagocytes, antigen-specific cytotoxic T-lymphocytes, and disperses numerous cytokines in an antigen response (Nakahara et.al, 2006).

Innate or Natural Immunity

Innate immunity is the body’s evolutionary natural mechanism used to fight invading foreign species. This is the dominant and oldest type of immunity among living creatures including unicellular organism such as amoeba, fungi, plants and insects (Nakahara et.al, 2006).

Acquired immunity

Acquired immunity emerges after exposure to a foreign organism. It is also known as adaptive immunity due to somatic hypermutation or accelerated somatic mutations), and V (D) J recombination, which is actually a genetic antigen receptor recombination that cannot be reversed (Nakahara et.al, 2006).

Non-specific immunity

Non-specific immunity means that the immunological response is antigen independent and unspecified. However, distinct mechanisms are activated. They include establishing anatomical barriers, stimulation of secretory molecules and integrating cellular components.  Recognizable mechanical anatomical barriers include the internal epithelia tissue such as the skin.  Intestinal mobility along with oscillation of broncho-pulmonary cilia is chemicalized because chemical messages are transmitted through biological agents present in skin, intestines and nervous system.

Dominant Immunological concepts associated with multiple sclerosis are connected to the pathogenesis of this disease. Some basic traditional immunological concepts pertaining to multiple sclerosis are:-

• Relapsing MS
• Secondary progressive MS.
• Progressive MS.
• Progressive relapsing MS

While these are the four major immunological concepts that intermingle in explaining the pathophysiology of each stage collectively in facilitating the discussion other will be highlighted. Significantly, coinciding with the five types of immunological responses that can emerge from antigen antibody interaction are humoral immunity; cell-mediated immunity; innate (or Natural Immunity); acquired immunity, and non-specific immunity. Therefore, the terms that will be explained in this section are:

• Demyelinization
• Cell-Mediated Immunity
• Humoral Immunity
• Immunoregulatory Cells

Relapsing MS is a serious symptom which progresses into a chronic inflammatory demyelinating central nervous system disorder manifesting as morphological inflammation, demyelination, axonal loss and gliosis. There is massive infiltration of heterogeneous cellular population; and soluble mediators of the immune system are activated. These include T cells, B cells, macrophages and mi croglia, cytokines, chemokines, antibodies which stimulate  humoral immunity; cell-mediated immunity; innate (or Natural Immunity); acquired immunity, and non-specific immunity (Nakahara et.al, 2006).

Demyelinization

Research has shown where a lymphocytes subset identified as T helper cells specifically the Th1 and Th17 play a major role in development of multiple sclerosis lesions. Also the Interleukin 12 protein causes differentiation of naive T cells producing inflammatory T cells. When there is over production of Interleukin 12 it initiates inflammatory increases that occur in patients with persistent multiple sclerosis relapses. Patients who are not affected by multiple sclerosis their lymphocytes develop innate immunity to recognize and distinguish cells what cells belong to the body and those which are foreigner (Nakahara et.al, 2006).

Lymphocytes, in the body of a person afflicted by multiple sclerosis cannot differentiate between healthy and non-healthy cells. They attack cells in the central nervous system as foreigners such as viruses, bacteria, fungi triggering inflammatory responses as if it were a cell-mediated immunity conflict. In this process other immune cells such as cytokines and antibodies are activated and join in the inflammatory battle. Importantly, most myelin-recognizing T cells are family to a terminally differentiated subset known as co-stimulation-independent effector-memory T cells (Nakahara et.al, 2006).   See appendix 5

Cell-Mediated Immunity

T cells are responsible compromising an estimated 10% of the all inflammatory cells found as active participants in demyelinating multiple sclerosis lesions. Scientists have already proven that the EAE model can adequately be transferred by injecting an animal with myelin-specific CD4+ T cells. Therefore, the acceptable assumption has been that Multiple Sclerosis is foremost a CD4+ T-cell-mediated disease. It was advised that caution must be taken when interpreting these results because CD4+ T cells can play an important role in a disease stage-specific context. Importantly, they cells are absent in chronic Multiple Sclerosis lesions apart from the T-cell repertoire shows changes (Awad & Stüve 2010).

Different T cell subtypes play significant roles in the pathogenesis of autoimmune diseases such as multiple sclerosis. Extensive studies have been conducted to validate these interactions. These diverse subpopulations contain distinct cytokine products.  ‘TH1 CD4 + cells secrete interferon gamma, tumor necrosis factor ?, IL-2, and nitric oxide’ (Awad & Stüve 2010, p, 168).  TH1 cells are responsible for activating cell-mediated immunity. Alternatively, TH2 CD4+ cells secrete IL-4, IL-5, IL-6, IL-10, IL-13. They transform the growth factor ?.  TH2 cells in humans function as a regulator agent when certain inflammatory conditions occur (Awad & Stüve 2010).

The human system does not contain distinct TH1-TH 2 dichotomy. This adds to the complexity of explaining cell mediated immunity. Significantly, there is an overlap expression of cytokine between two subtypes TH1-TH 2 dichotomy which is a subtype of CD4+ cells. These cells have been implicated in the autoimmunity as TH17 cells. They express as proinflammatory cytokine IL-17. RNA (mRNA) encoding IL-17 messengers were detected in blood at very high levels cerebro spinal fluid (CSF) and brain parenchyma of multiple sclerosis patients in active stages of the disease (Awad & Stüve 2010).

This phenomenon is highly suggestive of the major role cell mediated immunity plays in progression of multiple sclerosis as an immunopathogenesis factor in the disease sequence.  More importantly, it is worth noting that even though multiple sclerosis is often perceived as a CD4+-mediated autoimmune disease, there are CD8+ T cells implications in its pathology. Precisely, scientists have confirmed that clonal and oligoclonal expansion of CD8+ T cells consistently have appeared in plaques obtained from multiple sclerosis patients during diagnostic testing. In a few situations when evaluations were conducted, CD8+ T cells were found to have outnumbered CD4+ T cells (Awad & Stüve 2010).

Again this is highly suggestive of suggesting cytotoxic T cells probably participation in starting this inflammatory interaction. Another factor worthy of consideration is the knowledge that T lymphocytes express ?/? receptors were detected in various quantities when cerebro spinal fluid (CSF) of multiple sclerosis patients experiencing early stages of the disease. However, patients who had the disease for a longer time emerging into the chronic stages, CD8+ T cells were not found. The distinction lays in a probability that these cells play a role in the early development of the disease when cell medicate immune response is being activated.  More clarification on this phenomenon is pending while the pathogenic role of CD8+ T cells in multiple sclerosis progression is further explored (Awad & Stüve 2010).

Humoral Immunity

Scientists posit that despite the autoimmune process in multiple is perceptive mainly from the premise of it being mediated by T cells; there is just as much evidence to suggest a great degree humoral immunity activity is also involved in the progression of disease process. Fundamentally, scientists discover that there have been interactions with an antigen driven B-cell response in multiple sclerosis patients’ cerebro spinal fluid. This is highly suggestive that B- cells are implicated in the immunopathogenesis of the disease. Also, oligoclonal immunoglobulin production persists in the cerebro spinal fluid of multiple sclerosis patients. Subsequently, growth of secondary lymphoid brain tissue was detected during diagnostic evaluations in multiple sclerosis patients experiencing secondary progressive stages of the disease. Some research studies have even shown a direct relationship between intrathecal immunoglobulin levels and severity of the disease when patients present with secondary progressive multiple sclerosis (Awad & Stüve 2010).

Scientists have continued probing for evidence of humoral immunity implication. Researchers have also detected B cells in brain cerebro spinal fluid of secondary progressive multiple sclerosis patients. There has been constant isolation of B cells in the cerebro spinal fluid of patients with secondary progressive multiple sclerosis. Evidence of clonal expansion along with extensive somatic mutation in B-cell receptor genes was observed. This phenomenon expresses the characteristic features of an antigen-driven response. Precisely, the assumption is that B-cell selection might have been initiated in peripheral lymph nodes or in lymphoid follicles of the central nervous system (Awad & Stüve 2010).

Further studies related to investigating B-cell compartment of cerebro spinal fluid in multiple sclerosis reveal that B-cell differentiation is confirmed in the central nervous system of individuals suffering from multiple sclerosis. The dominant antibodies happen to be short-living plasmablasts. Interestingly it is not plasma cells. Precisely, plasma cells are actually the predominant antibody secreting cell found in multiple sclerosis patients’ cerebro spinal fluid. More importantly, the phenomenon whereby upregulation of costimulatory molecules on plasma cells within central nervous system  occurs is indicative the potential of such cells to sustain their T-cell activation.  Scientifically, B cells have been known as potent antigen-presenting cells. Assumptions are that they might feature prominently in T-cell antigenic stimulation. Scientists conclude that B cell and humoral immunity might be the main factors responsible for initiating and sustaining multiple the sclerosis disease process (Awad & Stüve 2010).

Immunoregulatory Cells

Studies have revealed that isolating myelin-reactive T cells from peripheral blood of healthy subjects is highly suggestive that, perhaps, decreasing regulatory cells interactions is the basic immunopathology concepts in multiple sclerosis evolution and not he presence or absence  of self-reactive T cells.  Scientifically,   it has been accepted that regulatory cells play a major role in controlling intensity when immune response are activated by maintaining self-tolerance. Importantly, it has been proven that CD4+ TH2 cells are active in anti-inflammatory cytokines production. They are IL-4, IL-5, and IL-13. Precisely, this CD4+ TH2 has the ability of lowering regulatory function of macrophages (Awad & Stüve 2010).

Further developments show where a relatively little subpopulation of CD4+ T cells were identified to be naturally occurring regulatory T (CD4+CD25+Treg) cells. It is believed that they are vital participants in the immune homeostasis process too. Certainly, they were found to be expressing CD25 which is an important component of the IL-2 receptor. However, preclinical trials have revealed that Treg cells’ absence was closely associated with the emergence of autoimmunity. Overwhelming evidence exists to prove that inadequate Treg-cell activity could be a main contributory element in multiple sclerosis etiopathogenesis. Essentially, studies show where  CD4+CD25+Treg cells effector function  emerging out of multiple sclerosis patients’ peripheral blood samples of patients was deficient in comparison to CD4+CD25+Treg cells from subjects who were not afflicted by the disease (Awad & Stüve 2010).

While these findings scientifically seem profound critics argue there are no differences in Treg cell concentration and constitution in the cerebro spinal fluid among patients afflicted by multiple sclerosis and those who were healthy. A larger study conducted on 73 multiple sclerosis researchers discovered that Treg cell concentration was identical with that of healthy volunteers. . The notable difference detected was that the Treg cells obtained from multiple sclerosis patients demonstrated reduction suppressive potential on the ‘immune response directed against myelin antigens’ (Awad & Stüve 2010, p 201). Yet, in another study this theory was refuted since, there were higher Treg cell counts in multiple sclerosis patients than in the control. Alternatively,  appeared the potential of these cells suppress MBP-induced proliferation was less effective (Awad & Stüve 2010)

Explaining the functional differences of Treg cells activity in multiple sclerosis patents and healthy subjects there has been reports of activity in RRMS and progressive stages of the diseases too.  For example, Forkhead box p3 (FOXp3) has been identified as a popular transcriptional factor. Its main role has been detected being a valuable participant in Treg-cell-suppressive molecular programmer activity (Awad & Stüve 2010)

Many preclinical studies have supported many of these theories in confirming the linkage between autoimmunity and absence of FOXp3. An association was also discovered with ectopic FOXp3 expression conferring suppressive function on CD4+CD25+Treg cells. Further linkages posit a relationship showing significant reductions in FOXp3 mRNA transcripts and protein levels. Importantly, this occurred without any concordant decrease in CD4+CD25+Treg representation in multiple sclerosis patents. FOXp3+CD4+CD25+Treg cells popularly create infiltrations when cerebro spinal fluid of subjects afflicted with neuro inflammatory diseases. Comparatively, this multiple sclerosis patients isolated more FOXp3+CD4+CD25+Treg cells   than patients afflicted by dementia, stoke  or  any other neurological disease. In addition it was observed that Treg activity seem to be compromised when peripheral blood samples are used for the analysis in multiple sclerosis patients unlike other non-affected clients.

Therapy and management

There is no cure for multiple sclerosis. However, scientists continue to experiment with drugs and therapies, which can be useful in relieving symptoms. For example, David Virley (2005) conducted studies to explore strategies involved in ‘Developing Therapeutics for the Treatment of Multiple Sclerosis.’ The author posited that many animal models have been used in developing therapeutic interventions for treating relapsing multiple sclerosis. The aim of preclinical research was mainly to identify and validate novel targets that are the most appropriate mimics for the specific clinical situation. Animal models therefore, become valuable subjects in establishing drug development processes that help select suitable human subjects for therapeutic interventions. This process provides the proof-of-concept for continuance of clinical trials. The author further contended that ‘although there is no gold standard model of multiple sclerosis, experimental autoimmune/allergic encephalomyelitis (EAE) models simulate the clinical and pathological hallmarks of multiple sclerosis in various guises and can provide the necessary predictive index for clinical therapeutic application’  (Virley, 2005, p 639).

EAE was induced by generating T-cell-mediated immunity into central nervous system antigens, which was easily modeled in rodents such as rats, mice, and guinea pigs. Whole CNS homogenate (spinal cord) t purified protein and peptides were combined in preparing the autoantigen for the experiment (Virley, 20050.  ‘Myelin basic protein (MBP), proteolipid protein, myelin oligodendrocyte glycoprotein (MOG), S100?, and glial fibrillary acidic protein as well as specific peptides from respective parent proteins are encephalitogenic in the appropriate host, as the major histocompatability complex (MHC) is one of the major determinants of immune responsiveness and disease susceptibility to these self-antigen’ (Virley, 2005, p 639).

The author concluded that the pathogenic autoimmune mechanism steps that initiate and magnify EAE and MS damage tissue sequences are:-

• Activation of autoreactive CD4+ T-cells in the periphery to an antigen;
• Transmigration of proinflammatory T-cells and monocytes through the blood brain barrier (BBB)
• Amplification of local inflammation and activation of resident antigen-presenting cells (APCs), such as microglia; and 4) destruction of oligodendrocytes, myelin sheath, and axons culminating in demyelination and axonal pathology (Virley, 2005, p 639).

Current Drug Therapies

The foregoing trials have emerged into distinct therapies, which are now active treatment management intervention s for multiple sclerosis. To date there are only five Food and Drug Administration (FDA) approved therapeutic treatments for relapsing – remitting multiple sclerosis. They include ‘two interferon (IFN)-?1a agents (Avonex and Rebif), one IFN-?1b (Betaseron), glatiramer acetate (GA) (Copaxone) and Mitoxanthrone (Novantrone)’ (Virley, 2005, p 639).

Patents suffering from secondary progressive multiple cyclophosphamide (Cytoxan) and mitoxanthrone are the drugs of choice. There are no extreme benefits in using these two drugs or severe toxicity. However, the main drugs used are corticosteroids, IFN? and GA (Virley, 2005).

Corticosteroids

Corticosteroids are administered to raise a patient’s tolerance level tolerance during an attack and speed up recovery. Long term therapies are more effective even though short-term interventions can be useful. However, to maintain a longer period between remissions it is always better to continue treatment over a longer period of time.  Patents often receive significant results even when the clinical course of multiple sclerosis may change to secondary progressive stage. Even with so many drug trials and pre-trials being conducted scientists are still not yet sure what are the actual effects of corticosteroid on the immune system are (Virley, 2005).

However, preclinical research evidence has verified quite a few putative mechanisms. They embody ‘an inhibition of the Th1 immune response reduction in BBB molecules and protection of oligodendrocytes from cytokine-induced cell death’ (Virley, 2005, p 639). EAE models validated the suppressive interactions produced by corticosteroid treatment in relation to clinical course disruption of multiple sclerosis, T-cell migration dampening its antigens response suppression during expression of adhesion utilization of anti-glucocorticoid, RU 38486 (mifepristone). It was revealed that these interactions have intensified as well as reversed steroid-induced inhibition of disease (Virley, 2005).

While corticosteroids have been so effective in the treatment of multiple sclerosis in both short and long term its side effected should not be underestimated. For example, extended use can initiate transient mood changes headache, gastrointestinal disturbances, and myalgias.  Decrease in bone density can occur overtime if patients must be treated for extended periods of time. Ultimately, osteoporosis could become a real problem increasing risks for fractures and infections. When side effects have become so progressive, the patient ought to be reassessed. Often the attending physician may consider either reducing or discontinuing treatment temporarily (Virley, 2005).

IFN-?

IFN-? therapies emerged after over 25 years of clinical trials. The aim was finding how multiple sclerosis would respond to IFNs if it is truly a virally mediated disease. Importantly the   antiviral assumption became invalid after clinical trial assessments, which revealed that IFN? worsened symptoms.  This was highly suggestive, that IFN?  was more influential in multiple sclerosis pathological process. it meant that IFN?, like other IFNs, is a species-specific glycoprotein with numerous biological properties. Actually, the mechanism producing these interactions is not fully understood from a scientific perspective poorly. However assumptions have been that immunomodulatory as an alternative to antiviral and antiproliferative makes much sense in deriving at an alternative proposition (Virley, 2005).

Importantly, IFN?-1a is exactly like the natural IFN-?, but IFN?-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFN?-1b displays comparative biological activity to IFN?-1a. Therefore, putative responses of IFN? on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFN?, tumor necrosis factor (TNF)?, interleukin (IL)-12. The lymphotoxin secretion has been identified in the sequence of controlling monocyte activation; inhibiting disruption of BBB. Consequently, the entry of lymphocytes into the CNS is reduced; antigen presentation is reduced to T-cells; and up-regulation of anti-inflammatory cytokines occurs; TGF? and IL-10 (Virley, 2005).

EAE pre-trial models have validated the use of IFN? by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFN? formulations. Important findings indicate a one third relapse reduction rate when higher doses are administered. The onset has been observed to be rapid. Precisely, relapses occurred at a rate of 1 per year and few weeks for MRI disease activity. Conversely, there were huge inflammatory changes measured through MRI activity; accumulation of MRI disease burden was significantly slowed down. Besides, there were magnificent results shown by patients regarding relapses (Virley, 2005).

This novel treatment is not without its adverse side effects. Some include, flu-like symptoms along with reactions emerging at the site where injections are administered. If patients do not respond to the drug after six months of therapeutic intervention, the IFN? therapy is usually discontinued. Some patients who are already disabled with progressive or relapses occurring at a rate of more than one per year are treated with a combination of combination three or more courses of corticosteroids over a 1-year period. In addition some patents encounter extreme feelings of depression leading towards suicidal inclinations. Drug toxicity can also become a problem with patients becoming noncompliant. This initiates physicians’ decisions of considering alternatives. Neutralizing antibodies in IFN? effectiveness ought to be addressed as an adverse reaction during treatment. This can lead to long term complications. As such, it must not be ignored if patients complain of reactions or it shows up in diagnostic testing (Virley, 20 05).

Glatiramer acetate – GA

GA is considered a non-IFN, nonsteroidal therapy. It is made from synthetic random base copolymers mixtures containing four amino acids namely glutamic acid, alanine, lysine, and tyrosine). The molar ratio was highly specific. Trials researched investigated the GA’s potential encephalitogenic role using EAE animal models. However, surprisingly, it was discovered that GA suppressed their acute and chronic clinical and pathological hallmarks. Importantly, translation of impacts was clinically beneficial. Importantly, GA provided evidence in the initial phase II trial as being a suitable agent for reducing relapse rates by 76% in patients with relapsing-remitting multiple sclerosis. A 5 year follow up intervention treatment confirmed

GA benefits as being capable of sustaining the initial influence on relapses in multiple sclerosis patients. The progression of the disease into the secondary stages was significantly slowed. Patients did not enter into disability as quickly as when other drug therapies were used. Also, when the Lesion burden was assessed through MRI it validated the value of GA in helping patients during the relapsing-remitting episodes. It was discovered that GA greatly reduced  frequency  rates of lesion load  and new enhancing lesions when baseline pretreatment measures are compared (Virley, 2005).

Since then numerous mechanisms were advanced as being responsible for these fascinating results observed by GA’s intervention in the disease process. First its biological activity relapsing-in remitting MS was noted as a valuable factor. Then the antigen-specific induction suppressor T cell was remarkable. Thirdly, a MBP competitive inhibition was distinctly observed as a benefit. There was also a relationship of the interactions to -peptides from antigen-presenting cells (Virley, 2005).

It must be noted that regardless of how beneficial a new drug therapy may be in treating a disease there are always adverse effects, which must be considered in its administration. GA is no exception even though the tolerance level in multiple sclerosis patients is great. However, subcutaneous administrations could become harmful due to increasing incidences observed whereby injection site reactions occurred in the majority of cases and they were localized proving that it was the drug interaction with human skin (Virley, 2005).

The overall picture being communicated in the use of this drug pertains towards it being the most tolerable in terms of side effects when compared to other therapies. Reduced propensity in the development of depression, neutralizing antibodies and menstrual disorders was far less when compared to other drugs now available for treating multiple sclerosis. Despite these developments, however, it is still important for continued research in extending to multiple sclerosis patients more options. While there is no cure for the condition medical science can provide the best relief it could through timely and efficient intervention therapies that work (Virley, 2005).

Ultimately, these interventions should aim at not only providing relief, but secure sustained drug benefits reducing symptoms of multiple sclerosis, which shows that treatments are becoming more effective. Patents should be taking lower doses and experiencing fewer side effects. As such, pharmaceutical and biotechnology industries are challenged to provide this service to the multiple sclerosis community of patients. Essentially, numerous alternative disease-modifying strategies are emerging. They will be reviewed in the following pages of this document (Virley, 2005).

For example, Pietro Iaffaldano (2012) and a group of researchers conducted studies regarding the ‘Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study.’ These researchers contend that Natalizumab reduced relapse rate as well as magnetic resonance imaging reactions in patients experiencing Relapsing-Remitting Multiple Sclerosis (RRMS). However, its impact on fatigue cognition in patients affected by multiple sclerosis need to be validated though scientific research. There the purpose of a prospective, open-label, observational study was intended as an  evaluation relating probable impacts  natalizumab had on cognition and fatigue when measured in patients experiencing Relapsing-Remitting Multiple Sclerosis  after being treated continuous for two years (Iaffaldano et.al, 2012).

Researchers examined cognitive performances by applying  ‘Rao’s Brief Repeatable Battery (BRB) device, the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months’ (Iaffaldano, 2012, p  201).   When patients did not respond favorable to at least 3 BRM and ST 3 they revived a cognitively impaired (CI) classification. Every 12months the Fatigue Severity Scale (FSS) was administered. This assessed the patient’s ability to self-reported incidences of fatigue. A total of 1 53 patients participated in 1 and 2 year-natalizumab continuous treatment (Iaffaldano et.al, 2012).

Result revealed that after one year treatment the amount of’ CI sampled patients decreased from 29% (29/100) at baseline to 19% (19/100) (p=0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, p<0.0001 and 3.61±1.56, p=0.008). These significant effects were confirmed in the subgroup of patients treated up to two year.’ (Iaffaldano et.al, 2012, p. 201). From these results researchers concluded that

In the short-term Natalizumab can be successfully used as a treatment which could, ultimately reduce incidences of cognitive difficulties and fatigue in patients experiencing Relapsing-Remitting Multiple Sclerosis (Iaffaldano et.al, 2012).

Examples of Novel Therapeutic Challenges for Multiple sclerosis

Blockade of lymphocyte migration

Very late antigen-4: natalizumab (Tysabri) and small molecule antagonists. There is widespread evidence implicating very late antigen-4 (VLA-4, ?4-?1 integrin) in this process, via its interaction with receptors like vascular cell adhesion molecule 1 (VCAM-1) and the CS1 fibronectin domain (Virley, 2005).

Immunomodulatory agents

Interest recently has emerged regarding development of novel Immunosuppressants. Trials have been conducted and they have been actually used in treatment of many autoimmune diseases such as psoriasis and rheumatoid arthritis. They reduced exacerbations keeping progression (Virley, 2005).

Anti-inflammatory agents

‘Cycloxygenase-1 and -2 (COX-1 and COX-2 or prostaglandin H synthases 1 and 2) catalyze the conversion of arachidonic acid and oxygen to generate inflammatory prostaglandins such as PGE2, PGD2, PGF2a, and thromboxane’ (Virley, 2005, p 201).

Neuroprotective and neuroregenerative therapeutic strategies

Achievements in repair of myelin and immense neuroprotection though therapeutic interventions can be interpreted major research breakthrough in the attempt at providing more beneficial therapies that reverse permanent neurological disability associated multiple sclerosis.

Potential combinations of therapeutic strategies

The heterogenic influences of clinical response as well as pathological hallmarks contained in recent multiple sclerosis drug development it would be wise considering combining therapeutic strategies that differentiate concentrating of specific aspects of the disease such as cognition memory and fatigue as espoused by Iaffaldano and his team of researchers. An area of precedence is a development stage whereby each agent independently offers a benefit distinct from the others, but is still valuable when combined in adding synergistic value to the therapeutic intervention. This approach would be extremely beneficial for patients who seldom respond favorable to therapies now available on health care markets across the country and world (Virley, 2005, p 201).

Conclusion

While theories pertaining to the etiology/epidemiology/immunology of multiple sclerosis predominantly focus on genetics and infection various environmental risks can be predisposing influences also. As such, this research explored the extent to which genetic and infection theories defining causative factors influencing the development of multiple sclerosis can really explain the pathophysiology of this disease. Consequently, the researcher adapted a comparative analysis of the perspectives offered by theorists in discussion of epidemiology regarding emergence of multiple sclerosis among the predominantly, female young adults twenty-first century population. These were matched with critiques from scientists advocating an environmental approach towards explaining the phenomenon as data relevant to its epidemiology; clinical symptoms; immunological concepts underlying the disease; therapy and management, and current trends are being explored.

Current Trends

Precisely, Ascherio and Munger (2007) ‘Environmental risk factors for multiple sclerosis Part I: the role of infection’ contend that even through genetic susceptibility play a role in the acquisition of multiple sclerosis among families studies show where personal hygiene significantly affect occurrence of the disease. Further, they advance that genetics and environment alone cannot account explicitly for the MS frequency among geographic variations when risk changes with migration are taken into consideration. Supportive epidemiological findings highlights the “hygiene hypothesis,” showing the additional role Epstein-Barr virus (EBV) plays as evidence for MS risk factor (Ascherio & Munger, 2007)

Another piece of research literature by the same authors ‘Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors focusing on the environment explains that the change risk factor among migrants gives profound evidence for M.S environmental determinants. Then researchers defined environment to mean variations in diet and social behavior. Main contributory factors were sunlight and cigarette smoking (Ascherio & Munger, 2007)

Dyment, Ebers, and Sadovnick, (2004) took a stand in ‘Genetics of multiple sclerosis.’      They argue that while environment and infection may play a role many genes appear to be linked to  MS etiology. They mentioned ‘HLA classes I and II, T-cell receptor beta, CTLA4, ICAM1, and SH2D2A’ (Dyment et.al, 2004, pp 110). These researchers advanced that future development in the MS genetic science largely depends on continuous research making data available as evidence. Also the development of appropriate statistical measurements and research methodologies could be valuable (Dyment et.al, 2004).

George Ebers (2008) focused on ‘Environmental factors and multiple sclerosis’ in reporting that studies conducted in Canada show where environmental factors influence the distribution of MS in specific geographic locations. The researcher cited migration studies to prove that the increase incidence of MS in Canada relates to longitudinal sex ratio expansion among immigrants within the country. This was compared to studies conducted in Australia where similar geographic patterns exist. It was discovered that by modifying the environment it reduced 80% of cases. It was concluded that while genetics play a major role there are predominant environmental factors associated with MS incidences in certain geographic locations (Ebers, 2008).

Gavin Giovannonia and George Ebers (2007) posit that ‘genes and environmental factors lead to tissue injury by autoimmune mechanisms, implicated by strong circumstantial evidence’ (Giovannonia and Ebers, 2007 pp, 261). They further contend that it is difficult to identify the specific genes responsible for MS without examining the associating influences of the environment. Actually, they argue that the impact of genes on MS emergence is modest. Additional studies were cited emphasizing irregularities in confirming the genetic theory of MS etiology (Giovannonia and Ebers, 2007).

Nakahara, Maeda, Aiso and Suzuki (2012) offer evidence as they explain ‘Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy’ showing where without relevant etiology appropriate treatment cannot be adapted for MS intervention. These researchers argue that present interventions, disease modifying therapies (DMT) are aimed at addressing the autoimmune etiology of the disease. These therapies are designed to reduce inflammation, but their long term effect is uncertain. Hence, a re-evaluation of both pathogenesis and etiology is suggested (Nakahara et.al, 2012).

Rosati offered insights to say that the childhood environmental factor was a single variable in the emergence of multiple sclerosis at a later stage in the child’s life. Consequently, epidemiologists began investigating numerous diverse migrant populations which revealed that once children were removed from the location before attaining 15 years of age it was less likely for him/her to develop the disease. When children remain in the geographic space the predisposition of contracting multiple sclerosis is sustained. Further investigations revealed that the birth season also had a relationship towards development of the disease which makes epidemiological estimation ns more complicated. This confirmed the vitamin D sunlight theory since people born in November were less likely to contact multiple sclerosis regardless the geographic location (Rosati, 2001).

Consequently, this study’s importance pertains to advancements into understanding multiple sclerosis’ etiology, pathophysiology/immunology and treatment. As explained in the foregoing principal pieces of research literature theories relating the etiology of MS are numerous. However, theories have no value if they cannot be used to enhance an understanding of the disease ultimately providing better treatment methods, leading towards a cure.

Current therapeutic trends predict that the ideal treatment for multiple sclerosis must consist of techniques aimed at increasing disease-causing/sustaining antigen(s) tolerance. Ultimately, it is expected that long-term therapy would be obviated. This is important because amidst  numerous continuous drug trials scientist still contend that none of them seem to have considerable effects on resolutions of a disease which is over 100 years old. Justifiably establishing coordination between activated T cells and B cells in the pathophysiology of multiple sclerosis is highly recommended for targeting the two cell population. These include resting and dividing cells together. The strategy may necessitate, taking control of the disease process itself (Awad & Stüve, 2010).

Whatever emerges from these assumptions scientist must bear in mind that other immune cell populations are playing a major role also in the sequel of this disease. They intimate and perpetuate the process. Therefore, the final proposition of this theory advanced that amplifying or sparing the pool of regulatory cells which act as mediators of immune suppression would be valuable a valuable intervention. This however must be embraced without compromising immune surveillance in the treatment of this disease (Awad & Stüve, 2010). In concluding these deliberations pertaining to current trends in multiple sclerosis therapeutic management it is expected that this research project sensitize scientists into elaborating on present research practices in order for a consensus be reached regarding the reality of multiple sclerosis etiology and its pathological implications.

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