Categories
Medicine and Health

Multiple sclerosis

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.

Medicine and Health: Multiple Sclerosis

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 Māori’ (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)        Flowchart Icon  
  • Diagnostic criteria for suspected MS (monosymptomatic)         Flowchart Icon
  • Diagnostic criteria for suspected MS (single attack)                   Flowchart Icon
  • Diagnostic criteria for suspected MS (progressive from onset)      Flowchart Icon

                             (Royal College of Physicians of London, 2004)

               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.

                   DominantImmunological 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 α, 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 β.  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 γ/δ 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), S100β, 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).

(See Appendix 4).

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)-β1a agents (Avonex and Rebif), one IFN-β1b (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, IFNβ 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-β

          IFN-β 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 IFNγ worsened symptoms.  This was highly suggestive, that IFNγ  was more influential in multiple sclerosis pathological process. it meant that IFNβ, 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, IFNβ-1a is exactly like the natural IFN-β, but IFNβ-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFNβ-1b displays comparative biological activity to IFNβ-1a. Therefore, putative responses of IFNβ on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFNγ, tumor necrosis factor (TNF)α, 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; TGFβ and IL-10 (Virley, 2005).

        EAE pre-trial models have validated the use of IFNβ by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFNβ 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 IFNβ 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 IFNβ 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, α4-β1 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 mustconsist oftechniques 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.

References

Ascherio, A., & Munger, K (2007). Environmental risk factors for multiple sclerosis. Part I: the

                      role of infection. Ann. Neurol. 61(4); 288–99

Ascherio, A., & Munger, K. (2007). Environmental risk factors for multiple sclerosis. Part II:

                     Noninfectious factors. Ann. Neurol.  61(6); 504–13.

Awad, M., & Stüve, O. (2010). Immunopathogenesis of Multiple Sclerosis: New Insights and

                    Therapeutic Implications. Lifelong Learning in Neurology. 16(5); 166-180

Clanet M (2008). Jean-Martin Charcot. 1825 to 1893. Int MS J 15 (2), 59–61.

DasGupta, R., & Fowler, C. (2003). Bladder, bowel and sexual dysfunction in multiple  

                       sclerosis: management strategies.  Drugs, 63 (2): 153–66.

Dyment, A; Ebers, G; Sadovnick, A. (2004).  Genetics of multiple sclerosis. Lancet

                                 Neurol  3( 92). (2004): 104–10.

 Ebers, G. (2008). Environmental factors and multiple sclerosis. Lancet Neurol  

                              7 (3). 268–277.

Foley, P. Vesterinen, H. Laird, B. (2013). Prevalence and natural history of pain in adults with

                       multiple sclerosis: Systematic review and meta-analysis. Pain 154 (5): 632– 42

Gilden, D (2005). Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

                                    195–202.

Giovannoni, G; Ebers, G. (2007). Multiple sclerosis: the environment and causation. Curr

                                Opin Neurol. 20( 3); 261-8.

Kantarci, O., & Wingerchukb, D. (2006). Epidemiology and natural history of multiple sclerosis:

                             new insights. New York. Lippincott Williams & Wilkins

Kurtzke, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability

                          status scale (EDSS). Neurology, 33 (11); 1444–52.

Iaffaldano, P. Viterbo, G. Paolicelli, D. ( 2012). Impact of Natalizumab on Cognitive

               Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label,

                  Two Years Observational Study. PLoS . 7(4)

Merril, R. (2010). An Introduction to Epidemiology, (5th Edition). Jones and Bartlett

                   Publishing.

Murray, J (2002). Infection as a cause of multiple sclerosis. Theories abound because no one

                         knows the answers yet. BMJ. 325(7373).(2002). 1128.

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N ( 2012). Current concepts in multiple

                             sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in

                           allergy & immunology  42(1); 26–34.

 Oksenberg, J., & Barcellos, L (2000). The complex genetic etiology of multiple sclerosis.

                           Journal of NeuroVirology. 6(2), S10 ± S14

Rosati G (2001). The prevalence of multiple sclerosis in the world: an update. Neurol. Sci. 22

                (2): 117–39.

Royal College of Physicians London (2004) Multiple Sclerosis: National Clinical Guideline for

                Diagnosis and Management in Primary and Secondary Care. NICE Clinical

              Guidelines, No. 8.National Collaborating Centre for Chronic Conditions (UK).

               London

   Schäffler, N. Köpke, S. Winkler, L. Schippling, S. Inglese, M. Fischer, K.,  & Heesen, C.

      (2011). Accuracy of diagnostic tests in multiple sclerosis–a systematic review. Acta Neurol

                      Scand. 124(3), 151-64

Siegert, R., Abernethy, D. (2005). Depression in multiple sclerosis: a review. J. Neurol.

                     Neurosurg. Psychiatr. 76 (4): 469–75.

Terry, R. Miller, S. Getts, D., & Muller, M. (2012). Current Theories for Multiple Sclerosis

                    Pathogenesis and Treatment. Free Press New York. 2012.

 Virley, D. (2005). Developing Therapeutics for the Treatment of Multiple Sclerosis. NeuroRx.

                 2(4): 638–649.

Appendix 1

Table 1 Multiple sclerosis as a genetic disease

———————————————————————————

1. Racial clustering of MS cases. Resistant ethnic groups residing in high risk regions

2. Familial aggregation of MS cases. Increased relative risk to sibs (ls=20±40)

3. Low incidence of conjugal MS

4. MS sibling pairs tend to cluster by age of onset, rather than

year of onset

5. High disease concordance in monozygotic twins (25±30%) compared with dizygotic twins and non-twin siblings (3±5%)

6. No detectable effect of shared environment on MS susceptibility in first-degree non-biological relatives (spouses, adop-tees)

7. Suggestive correlations between certain polymorphic loci and disease susceptibility

————————————————————————————

Appendix 2

Table 2 Confounding factors in genetic studies of multiple

Sclerosis

————————————————————————————————-

1. Aetiologic heterogeneity identical genes, different phenotypes

2. Genetic heterogeneity Different genes, identical phenotypes

3. Unknown genetic parameters Single versus multiple genes Dominant versus recessive mode of inheritance incomplete penetrance

4. Epistatic gene interactions

5. Post-genomic mechanisms

6. Unidentied non-heritable (environmental) factors

——————————————————————————————————————

(Oksenberg & Barcellos, 2000).

Appendix 3

Medicine and Health: Multiple Sclerosis

Name of Author

Outline

Introduction

•          Description

•          Epidemiology

•          Clinical signs and symptoms

•          Diagnosis

•          Prognosis

Immunological concepts underlying the disease

Therapy and management

Conclusion

•          Current Trends

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.

Medicine and Health: Multiple Sclerosis

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 Māori’ (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)        Flowchart Icon  
  • Diagnostic criteria for suspected MS (monosymptomatic)         Flowchart Icon
  • Diagnostic criteria for suspected MS (single attack)                   Flowchart Icon
  • Diagnostic criteria for suspected MS (progressive from onset)      Flowchart Icon

                             (Royal College of Physicians of London, 2004)

               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.

                   DominantImmunological 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 α, 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 β.  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 γ/δ 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), S100β, 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).

(See Appendix 4).

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)-β1a agents (Avonex and Rebif), one IFN-β1b (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, IFNβ 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-β

          IFN-β 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 IFNγ worsened symptoms.  This was highly suggestive, that IFNγ  was more influential in multiple sclerosis pathological process. it meant that IFNβ, 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, IFNβ-1a is exactly like the natural IFN-β, but IFNβ-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFNβ-1b displays comparative biological activity to IFNβ-1a. Therefore, putative responses of IFNβ on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFNγ, tumor necrosis factor (TNF)α, 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; TGFβ and IL-10 (Virley, 2005).

        EAE pre-trial models have validated the use of IFNβ by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFNβ 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 IFNβ 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 IFNβ 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, α4-β1 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 mustconsist oftechniques 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.

References

Ascherio, A., & Munger, K (2007). Environmental risk factors for multiple sclerosis. Part I: the

                      role of infection. Ann. Neurol. 61(4); 288–99

Ascherio, A., & Munger, K. (2007). Environmental risk factors for multiple sclerosis. Part II:

                     Noninfectious factors. Ann. Neurol.  61(6); 504–13.

Awad, M., & Stüve, O. (2010). Immunopathogenesis of Multiple Sclerosis: New Insights and

                    Therapeutic Implications. Lifelong Learning in Neurology. 16(5); 166-180

Clanet M (2008). Jean-Martin Charcot. 1825 to 1893. Int MS J 15 (2), 59–61.

DasGupta, R., & Fowler, C. (2003). Bladder, bowel and sexual dysfunction in multiple  

                       sclerosis: management strategies.  Drugs, 63 (2): 153–66.

Dyment, A; Ebers, G; Sadovnick, A. (2004).  Genetics of multiple sclerosis. Lancet

                                 Neurol  3( 92). (2004): 104–10.

 Ebers, G. (2008). Environmental factors and multiple sclerosis. Lancet Neurol  

                              7 (3). 268–277.

Foley, P. Vesterinen, H. Laird, B. (2013). Prevalence and natural history of pain in adults with

                       multiple sclerosis: Systematic review and meta-analysis. Pain 154 (5): 632– 42

Gilden, D (2005). Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

                                    195–202.

Giovannoni, G; Ebers, G. (2007). Multiple sclerosis: the environment and causation. Curr

                                Opin Neurol. 20( 3); 261-8.

Kantarci, O., & Wingerchukb, D. (2006). Epidemiology and natural history of multiple sclerosis:

                             new insights. New York. Lippincott Williams & Wilkins

Kurtzke, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability

                          status scale (EDSS). Neurology, 33 (11); 1444–52.

Iaffaldano, P. Viterbo, G. Paolicelli, D. ( 2012). Impact of Natalizumab on Cognitive

               Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label,

                  Two Years Observational Study. PLoS . 7(4)

Merril, R. (2010). An Introduction to Epidemiology, (5th Edition). Jones and Bartlett

                   Publishing.

Murray, J (2002). Infection as a cause of multiple sclerosis. Theories abound because no one

                         knows the answers yet. BMJ. 325(7373).(2002). 1128.

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N ( 2012). Current concepts in multiple

                             sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in

                           allergy & immunology  42(1); 26–34.

 Oksenberg, J., & Barcellos, L (2000). The complex genetic etiology of multiple sclerosis.

                           Journal of NeuroVirology. 6(2), S10 ± S14

Rosati G (2001). The prevalence of multiple sclerosis in the world: an update. Neurol. Sci. 22

                (2): 117–39.

Royal College of Physicians London (2004) Multiple Sclerosis: National Clinical Guideline for

                Diagnosis and Management in Primary and Secondary Care. NICE Clinical

              Guidelines, No. 8.National Collaborating Centre for Chronic Conditions (UK).

               London

   Schäffler, N. Köpke, S. Winkler, L. Schippling, S. Inglese, M. Fischer, K.,  & Heesen, C.

      (2011). Accuracy of diagnostic tests in multiple sclerosis–a systematic review. Acta Neurol

                      Scand. 124(3), 151-64

Siegert, R., Abernethy, D. (2005). Depression in multiple sclerosis: a review. J. Neurol.

                     Neurosurg. Psychiatr. 76 (4): 469–75.

Terry, R. Miller, S. Getts, D., & Muller, M. (2012). Current Theories for Multiple Sclerosis

                    Pathogenesis and Treatment. Free Press New York. 2012.

 Virley, D. (2005). Developing Therapeutics for the Treatment of Multiple Sclerosis. NeuroRx.

                 2(4): 638–649.

Appendix 1

Table 1 Multiple sclerosis as a genetic disease

———————————————————————————

1. Racial clustering of MS cases. Resistant ethnic groups residing in high risk regions

2. Familial aggregation of MS cases. Increased relative risk to sibs (ls=20±40)

3. Low incidence of conjugal MS

4. MS sibling pairs tend to cluster by age of onset, rather than

year of onset

5. High disease concordance in monozygotic twins (25±30%) compared with dizygotic twins and non-twin siblings (3±5%)

6. No detectable effect of shared environment on MS susceptibility in first-degree non-biological relatives (spouses, adop-tees)

7. Suggestive correlations between certain polymorphic loci and disease susceptibility

————————————————————————————

Appendix 2

Table 2 Confounding factors in genetic studies of multiple

Sclerosis

————————————————————————————————-

1. Aetiologic heterogeneity identical genes, different phenotypes

2. Genetic heterogeneity Different genes, identical phenotypes

3. Unknown genetic parameters Single versus multiple genes Dominant versus recessive mode of inheritance incomplete penetrance

4. Epistatic gene interactions

5. Post-genomic mechanisms

6. Unidentied non-heritable (environmental) factors

——————————————————————————————————————

(Oksenberg & Barcellos, 2000).

Appendix 3

http://upload.wikimedia.org/wikipedia/commons/thumb/3/3c/Ms_progression_types.svg/300px-Ms_progression_types.svg.png

                     Diagram showing immunological concepts underlying Multiple sclerosis                   

                     Progression of subtypes (Oksenberg et.al, 2000).                        

FIG. 1.

      Schematic view of the putative pathogenic steps in MS. 1: Activation of autoreactive T cells by antigen presenting cells in the periphery. 2: Migration of T cells and monocytes through the blood brain barrier. 3: Amplification of local inflammation and destruction of oligodendrocytes, myelin sheath, and axons culminating in demyelination and axonal pathology (Virley, 2005, p 639).                                         Appendix 5   – Demyelinization

Medicine and Health: Multiple Sclerosis

Name of Author

Outline

Introduction

•          Description

•          Epidemiology

•          Clinical signs and symptoms

•          Diagnosis

•          Prognosis

Immunological concepts underlying the disease

Therapy and management

Conclusion

•          Current Trends

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.

Medicine and Health: Multiple Sclerosis

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 Māori’ (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)        Flowchart Icon  
  • Diagnostic criteria for suspected MS (monosymptomatic)         Flowchart Icon
  • Diagnostic criteria for suspected MS (single attack)                   Flowchart Icon
  • Diagnostic criteria for suspected MS (progressive from onset)      Flowchart Icon

                             (Royal College of Physicians of London, 2004)

               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.

                   DominantImmunological 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 α, 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 β.  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 γ/δ 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), S100β, 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).

(See Appendix 4).

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)-β1a agents (Avonex and Rebif), one IFN-β1b (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, IFNβ 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-β

          IFN-β 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 IFNγ worsened symptoms.  This was highly suggestive, that IFNγ  was more influential in multiple sclerosis pathological process. it meant that IFNβ, 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, IFNβ-1a is exactly like the natural IFN-β, but IFNβ-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFNβ-1b displays comparative biological activity to IFNβ-1a. Therefore, putative responses of IFNβ on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFNγ, tumor necrosis factor (TNF)α, 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; TGFβ and IL-10 (Virley, 2005).

        EAE pre-trial models have validated the use of IFNβ by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFNβ 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 IFNβ 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 IFNβ 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, α4-β1 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 mustconsist oftechniques 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.

References

Ascherio, A., & Munger, K (2007). Environmental risk factors for multiple sclerosis. Part I: the

                      role of infection. Ann. Neurol. 61(4); 288–99

Ascherio, A., & Munger, K. (2007). Environmental risk factors for multiple sclerosis. Part II:

                     Noninfectious factors. Ann. Neurol.  61(6); 504–13.

Awad, M., & Stüve, O. (2010). Immunopathogenesis of Multiple Sclerosis: New Insights and

                    Therapeutic Implications. Lifelong Learning in Neurology. 16(5); 166-180

Clanet M (2008). Jean-Martin Charcot. 1825 to 1893. Int MS J 15 (2), 59–61.

DasGupta, R., & Fowler, C. (2003). Bladder, bowel and sexual dysfunction in multiple  

                       sclerosis: management strategies.  Drugs, 63 (2): 153–66.

Dyment, A; Ebers, G; Sadovnick, A. (2004).  Genetics of multiple sclerosis. Lancet

                                 Neurol  3( 92). (2004): 104–10.

 Ebers, G. (2008). Environmental factors and multiple sclerosis. Lancet Neurol  

                              7 (3). 268–277.

Foley, P. Vesterinen, H. Laird, B. (2013). Prevalence and natural history of pain in adults with

                       multiple sclerosis: Systematic review and meta-analysis. Pain 154 (5): 632– 42

Gilden, D (2005). Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

                                    195–202.

Giovannoni, G; Ebers, G. (2007). Multiple sclerosis: the environment and causation. Curr

                                Opin Neurol. 20( 3); 261-8.

Kantarci, O., & Wingerchukb, D. (2006). Epidemiology and natural history of multiple sclerosis:

                             new insights. New York. Lippincott Williams & Wilkins

Kurtzke, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability

                          status scale (EDSS). Neurology, 33 (11); 1444–52.

Iaffaldano, P. Viterbo, G. Paolicelli, D. ( 2012). Impact of Natalizumab on Cognitive

               Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label,

                  Two Years Observational Study. PLoS . 7(4)

Merril, R. (2010). An Introduction to Epidemiology, (5th Edition). Jones and Bartlett

                   Publishing.

Murray, J (2002). Infection as a cause of multiple sclerosis. Theories abound because no one

                         knows the answers yet. BMJ. 325(7373).(2002). 1128.

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N ( 2012). Current concepts in multiple

                             sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in

                           allergy & immunology  42(1); 26–34.

 Oksenberg, J., & Barcellos, L (2000). The complex genetic etiology of multiple sclerosis.

                           Journal of NeuroVirology. 6(2), S10 ± S14

Rosati G (2001). The prevalence of multiple sclerosis in the world: an update. Neurol. Sci. 22

                (2): 117–39.

Royal College of Physicians London (2004) Multiple Sclerosis: National Clinical Guideline for

                Diagnosis and Management in Primary and Secondary Care. NICE Clinical

              Guidelines, No. 8.National Collaborating Centre for Chronic Conditions (UK).

               London

   Schäffler, N. Köpke, S. Winkler, L. Schippling, S. Inglese, M. Fischer, K.,  & Heesen, C.

      (2011). Accuracy of diagnostic tests in multiple sclerosis–a systematic review. Acta Neurol

                      Scand. 124(3), 151-64

Siegert, R., Abernethy, D. (2005). Depression in multiple sclerosis: a review. J. Neurol.

                     Neurosurg. Psychiatr. 76 (4): 469–75.

Terry, R. Miller, S. Getts, D., & Muller, M. (2012). Current Theories for Multiple Sclerosis

                    Pathogenesis and Treatment. Free Press New York. 2012.

 Virley, D. (2005). Developing Therapeutics for the Treatment of Multiple Sclerosis. NeuroRx.

                 2(4): 638–649.

Appendix 1

Table 1 Multiple sclerosis as a genetic disease

———————————————————————————

1. Racial clustering of MS cases. Resistant ethnic groups residing in high risk regions

2. Familial aggregation of MS cases. Increased relative risk to sibs (ls=20±40)

3. Low incidence of conjugal MS

4. MS sibling pairs tend to cluster by age of onset, rather than

year of onset

5. High disease concordance in monozygotic twins (25±30%) compared with dizygotic twins and non-twin siblings (3±5%)

6. No detectable effect of shared environment on MS susceptibility in first-degree non-biological relatives (spouses, adop-tees)

7. Suggestive correlations between certain polymorphic loci and disease susceptibility

————————————————————————————

Appendix 2

Table 2 Confounding factors in genetic studies of multiple

Sclerosis

————————————————————————————————-

1. Aetiologic heterogeneity identical genes, different phenotypes

2. Genetic heterogeneity Different genes, identical phenotypes

3. Unknown genetic parameters Single versus multiple genes Dominant versus recessive mode of inheritance incomplete penetrance

4. Epistatic gene interactions

5. Post-genomic mechanisms

6. Unidentied non-heritable (environmental) factors

——————————————————————————————————————

(Oksenberg & Barcellos, 2000).

Appendix 3

http://upload.wikimedia.org/wikipedia/commons/thumb/3/3c/Ms_progression_types.svg/300px-Ms_progression_types.svg.png

                     Diagram showing immunological concepts underlying Multiple sclerosis                   

                     Progression of subtypes (Oksenberg et.al, 2000).                        

FIG. 1.

      Schematic view of the putative pathogenic steps in MS. 1: Activation of autoreactive T cells by antigen presenting cells in the periphery. 2: Migration of T cells and monocytes through the blood brain barrier. 3: Amplification of local inflammation and destruction of oligodendrocytes, myelin sheath, and axons culminating in demyelination and axonal pathology (Virley, 2005, p 639).                                         Appendix 5   – Demyelinization

Medicine and Health: Multiple Sclerosis

Name of Author

Outline

Introduction

•          Description

•          Epidemiology

•          Clinical signs and symptoms

•          Diagnosis

•          Prognosis

Immunological concepts underlying the disease

Therapy and management

Conclusion

•          Current Trends

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.

Medicine and Health: Multiple Sclerosis

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 Māori’ (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)        Flowchart Icon  
  • Diagnostic criteria for suspected MS (monosymptomatic)         Flowchart Icon
  • Diagnostic criteria for suspected MS (single attack)                   Flowchart Icon
  • Diagnostic criteria for suspected MS (progressive from onset)      Flowchart Icon

                             (Royal College of Physicians of London, 2004)

               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.

                   DominantImmunological 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 α, 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 β.  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 γ/δ 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), S100β, 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).

(See Appendix 4).

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)-β1a agents (Avonex and Rebif), one IFN-β1b (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, IFNβ 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-β

          IFN-β 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 IFNγ worsened symptoms.  This was highly suggestive, that IFNγ  was more influential in multiple sclerosis pathological process. it meant that IFNβ, 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, IFNβ-1a is exactly like the natural IFN-β, but IFNβ-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFNβ-1b displays comparative biological activity to IFNβ-1a. Therefore, putative responses of IFNβ on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFNγ, tumor necrosis factor (TNF)α, 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; TGFβ and IL-10 (Virley, 2005).

        EAE pre-trial models have validated the use of IFNβ by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFNβ 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 IFNβ 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 IFNβ 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, α4-β1 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 mustconsist oftechniques 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.

References

Ascherio, A., & Munger, K (2007). Environmental risk factors for multiple sclerosis. Part I: the

                      role of infection. Ann. Neurol. 61(4); 288–99

Ascherio, A., & Munger, K. (2007). Environmental risk factors for multiple sclerosis. Part II:

                     Noninfectious factors. Ann. Neurol.  61(6); 504–13.

Awad, M., & Stüve, O. (2010). Immunopathogenesis of Multiple Sclerosis: New Insights and

                    Therapeutic Implications. Lifelong Learning in Neurology. 16(5); 166-180

Clanet M (2008). Jean-Martin Charcot. 1825 to 1893. Int MS J 15 (2), 59–61.

DasGupta, R., & Fowler, C. (2003). Bladder, bowel and sexual dysfunction in multiple  

                       sclerosis: management strategies.  Drugs, 63 (2): 153–66.

Dyment, A; Ebers, G; Sadovnick, A. (2004).  Genetics of multiple sclerosis. Lancet

                                 Neurol  3( 92). (2004): 104–10.

 Ebers, G. (2008). Environmental factors and multiple sclerosis. Lancet Neurol  

                              7 (3). 268–277.

Foley, P. Vesterinen, H. Laird, B. (2013). Prevalence and natural history of pain in adults with

                       multiple sclerosis: Systematic review and meta-analysis. Pain 154 (5): 632– 42

Gilden, D (2005). Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

                                    195–202.

Giovannoni, G; Ebers, G. (2007). Multiple sclerosis: the environment and causation. Curr

                                Opin Neurol. 20( 3); 261-8.

Kantarci, O., & Wingerchukb, D. (2006). Epidemiology and natural history of multiple sclerosis:

                             new insights. New York. Lippincott Williams & Wilkins

Kurtzke, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability

                          status scale (EDSS). Neurology, 33 (11); 1444–52.

Iaffaldano, P. Viterbo, G. Paolicelli, D. ( 2012). Impact of Natalizumab on Cognitive

               Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label,

                  Two Years Observational Study. PLoS . 7(4)

Merril, R. (2010). An Introduction to Epidemiology, (5th Edition). Jones and Bartlett

                   Publishing.

Murray, J (2002). Infection as a cause of multiple sclerosis. Theories abound because no one

                         knows the answers yet. BMJ. 325(7373).(2002). 1128.

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N ( 2012). Current concepts in multiple

                             sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in

                           allergy & immunology  42(1); 26–34.

 Oksenberg, J., & Barcellos, L (2000). The complex genetic etiology of multiple sclerosis.

                           Journal of NeuroVirology. 6(2), S10 ± S14

Rosati G (2001). The prevalence of multiple sclerosis in the world: an update. Neurol. Sci. 22

                (2): 117–39.

Royal College of Physicians London (2004) Multiple Sclerosis: National Clinical Guideline for

                Diagnosis and Management in Primary and Secondary Care. NICE Clinical

              Guidelines, No. 8.National Collaborating Centre for Chronic Conditions (UK).

               London

   Schäffler, N. Köpke, S. Winkler, L. Schippling, S. Inglese, M. Fischer, K.,  & Heesen, C.

      (2011). Accuracy of diagnostic tests in multiple sclerosis–a systematic review. Acta Neurol

                      Scand. 124(3), 151-64

Siegert, R., Abernethy, D. (2005). Depression in multiple sclerosis: a review. J. Neurol.

                     Neurosurg. Psychiatr. 76 (4): 469–75.

Terry, R. Miller, S. Getts, D., & Muller, M. (2012). Current Theories for Multiple Sclerosis

                    Pathogenesis and Treatment. Free Press New York. 2012.

 Virley, D. (2005). Developing Therapeutics for the Treatment of Multiple Sclerosis. NeuroRx.

                 2(4): 638–649.

Appendix 1

Table 1 Multiple sclerosis as a genetic disease

———————————————————————————

1. Racial clustering of MS cases. Resistant ethnic groups residing in high risk regions

2. Familial aggregation of MS cases. Increased relative risk to sibs (ls=20±40)

3. Low incidence of conjugal MS

4. MS sibling pairs tend to cluster by age of onset, rather than

year of onset

5. High disease concordance in monozygotic twins (25±30%) compared with dizygotic twins and non-twin siblings (3±5%)

6. No detectable effect of shared environment on MS susceptibility in first-degree non-biological relatives (spouses, adop-tees)

7. Suggestive correlations between certain polymorphic loci and disease susceptibility

————————————————————————————

Appendix 2

Table 2 Confounding factors in genetic studies of multiple

Sclerosis

————————————————————————————————-

1. Aetiologic heterogeneity identical genes, different phenotypes

2. Genetic heterogeneity Different genes, identical phenotypes

3. Unknown genetic parameters Single versus multiple genes Dominant versus recessive mode of inheritance incomplete penetrance

4. Epistatic gene interactions

5. Post-genomic mechanisms

6. Unidentied non-heritable (environmental) factors

——————————————————————————————————————

(Oksenberg & Barcellos, 2000).

Appendix 3

http://upload.wikimedia.org/wikipedia/commons/thumb/3/3c/Ms_progression_types.svg/300px-Ms_progression_types.svg.png

                     Diagram showing immunological concepts underlying Multiple sclerosis                   

                     Progression of subtypes (Oksenberg et.al, 2000).                        

FIG. 1.

      Schematic view of the putative pathogenic steps in MS. 1: Activation of autoreactive T cells by antigen presenting cells in the periphery. 2: Migration of T cells and monocytes through the blood brain barrier. 3: Amplification of local inflammation and destruction of oligodendrocytes, myelin sheath, and axons culminating in demyelination and axonal pathology (Virley, 2005, p 639).                                         Appendix 5   – Demyelinization

Medicine and Health: Multiple Sclerosis

Name of Author

Outline

Introduction

•          Description

•          Epidemiology

•          Clinical signs and symptoms

•          Diagnosis

•          Prognosis

Immunological concepts underlying the disease

Therapy and management

Conclusion

•          Current Trends

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.

Medicine and Health: Multiple Sclerosis

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 Māori’ (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)        Flowchart Icon  
  • Diagnostic criteria for suspected MS (monosymptomatic)         Flowchart Icon
  • Diagnostic criteria for suspected MS (single attack)                   Flowchart Icon
  • Diagnostic criteria for suspected MS (progressive from onset)      Flowchart Icon

                             (Royal College of Physicians of London, 2004)

               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.

                   DominantImmunological 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 α, 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 β.  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 γ/δ 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), S100β, 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).

(See Appendix 4).

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)-β1a agents (Avonex and Rebif), one IFN-β1b (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, IFNβ 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-β

          IFN-β 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 IFNγ worsened symptoms.  This was highly suggestive, that IFNγ  was more influential in multiple sclerosis pathological process. it meant that IFNβ, 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, IFNβ-1a is exactly like the natural IFN-β, but IFNβ-1b differs in having two amino acids as well as not being glycosylated. Despite these insidious structural differences IFNβ-1b displays comparative biological activity to IFNβ-1a. Therefore, putative responses of IFNβ on the progression of multiple sclerosis is believed to be related primarily to its  antiinflammatory influences, which demonstrates as dampening the stimulatory impact of IFNγ, tumor necrosis factor (TNF)α, 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; TGFβ and IL-10 (Virley, 2005).

        EAE pre-trial models have validated the use of IFNβ by proving its influence in limiting the   progression of multiple sclerosis. Supportively, clinical trials were done using both IFNβ 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 IFNβ 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 IFNβ 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, α4-β1 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 mustconsist oftechniques 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.

References

Ascherio, A., & Munger, K (2007). Environmental risk factors for multiple sclerosis. Part I: the

                      role of infection. Ann. Neurol. 61(4); 288–99

Ascherio, A., & Munger, K. (2007). Environmental risk factors for multiple sclerosis. Part II:

                     Noninfectious factors. Ann. Neurol.  61(6); 504–13.

Awad, M., & Stüve, O. (2010). Immunopathogenesis of Multiple Sclerosis: New Insights and

                    Therapeutic Implications. Lifelong Learning in Neurology. 16(5); 166-180

Clanet M (2008). Jean-Martin Charcot. 1825 to 1893. Int MS J 15 (2), 59–61.

DasGupta, R., & Fowler, C. (2003). Bladder, bowel and sexual dysfunction in multiple  

                       sclerosis: management strategies.  Drugs, 63 (2): 153–66.

Dyment, A; Ebers, G; Sadovnick, A. (2004).  Genetics of multiple sclerosis. Lancet

                                 Neurol  3( 92). (2004): 104–10.

 Ebers, G. (2008). Environmental factors and multiple sclerosis. Lancet Neurol  

                              7 (3). 268–277.

Foley, P. Vesterinen, H. Laird, B. (2013). Prevalence and natural history of pain in adults with

                       multiple sclerosis: Systematic review and meta-analysis. Pain 154 (5): 632– 42

Gilden, D (2005). Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

                                    195–202.

Giovannoni, G; Ebers, G. (2007). Multiple sclerosis: the environment and causation. Curr

                                Opin Neurol. 20( 3); 261-8.

Kantarci, O., & Wingerchukb, D. (2006). Epidemiology and natural history of multiple sclerosis:

                             new insights. New York. Lippincott Williams & Wilkins

Kurtzke, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability

                          status scale (EDSS). Neurology, 33 (11); 1444–52.

Iaffaldano, P. Viterbo, G. Paolicelli, D. ( 2012). Impact of Natalizumab on Cognitive

               Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label,

                  Two Years Observational Study. PLoS . 7(4)

Merril, R. (2010). An Introduction to Epidemiology, (5th Edition). Jones and Bartlett

                   Publishing.

Murray, J (2002). Infection as a cause of multiple sclerosis. Theories abound because no one

                         knows the answers yet. BMJ. 325(7373).(2002). 1128.

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N ( 2012). Current concepts in multiple

                             sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in

                           allergy & immunology  42(1); 26–34.

 Oksenberg, J., & Barcellos, L (2000). The complex genetic etiology of multiple sclerosis.

                           Journal of NeuroVirology. 6(2), S10 ± S14

Rosati G (2001). The prevalence of multiple sclerosis in the world: an update. Neurol. Sci. 22

                (2): 117–39.

Royal College of Physicians London (2004) Multiple Sclerosis: National Clinical Guideline for

                Diagnosis and Management in Primary and Secondary Care. NICE Clinical

              Guidelines, No. 8.National Collaborating Centre for Chronic Conditions (UK).

               London

   Schäffler, N. Köpke, S. Winkler, L. Schippling, S. Inglese, M. Fischer, K.,  & Heesen, C.

      (2011). Accuracy of diagnostic tests in multiple sclerosis–a systematic review. Acta Neurol

                      Scand. 124(3), 151-64

Siegert, R., Abernethy, D. (2005). Depression in multiple sclerosis: a review. J. Neurol.

                     Neurosurg. Psychiatr. 76 (4): 469–75.

Terry, R. Miller, S. Getts, D., & Muller, M. (2012). Current Theories for Multiple Sclerosis

                    Pathogenesis and Treatment. Free Press New York. 2012.

 Virley, D. (2005). Developing Therapeutics for the Treatment of Multiple Sclerosis. NeuroRx.

                 2(4): 638–649.

Appendix 1

Table 1 Multiple sclerosis as a genetic disease

———————————————————————————

1. Racial clustering of MS cases. Resistant ethnic groups residing in high risk regions

2. Familial aggregation of MS cases. Increased relative risk to sibs (ls=20±40)

3. Low incidence of conjugal MS

4. MS sibling pairs tend to cluster by age of onset, rather than

year of onset

5. High disease concordance in monozygotic twins (25±30%) compared with dizygotic twins and non-twin siblings (3±5%)

6. No detectable effect of shared environment on MS susceptibility in first-degree non-biological relatives (spouses, adop-tees)

7. Suggestive correlations between certain polymorphic loci and disease susceptibility

————————————————————————————

Appendix 2

Table 2 Confounding factors in genetic studies of multiple

Sclerosis

————————————————————————————————-

1. Aetiologic heterogeneity identical genes, different phenotypes

2. Genetic heterogeneity Different genes, identical phenotypes

3. Unknown genetic parameters Single versus multiple genes Dominant versus recessive mode of inheritance incomplete penetrance

4. Epistatic gene interactions

5. Post-genomic mechanisms

6. Unidentied non-heritable (environmental) factors

——————————————————————————————————————

(Oksenberg & Barcellos, 2000).

Appendix 3

   s                        

Diagram showing immunological concepts underlying Multiple sclerosis               Progression of subtypes (Oksenberg et.al, 2000).                        

      Schematic view of the putative pathogenic steps in MS. 1: Activation of autoreactive T cells by antigen presenting cells in the periphery. 2: Migration of T cells and monocytes through the blood brain barrier. 3: Amplification of local inflammation and destruction of oligodendrocytes, myelin sheath, and axons culminating in demyelination and axonal pathology (Virley, 2005, p 639).                                

         Appendix 5   – Demyelinization

Categories
Medicine and Health

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.

                    My justification for selecting this topic and the investigation approach lays in the premise that so far medical science is inconclusive regarding causes for multiple sclerosis within our generation and beyond (Murray, 2002). More importantly, there is no cure for this disease. Often when an etiology is unknown scientist find it difficult to detect a cure. Contemporary measures are aimed at treating symptoms while no profound interventions are made to reduce incidences of debilitating of the disease which has a short life expectancy profile after its initial diagnosis (Terry et.al, 2012). Hence, it is imperative that a consensus be reached and health promotion measures designed for controlling multiple sclerosis among high risk populations. This can only be achieved if the predisposing factors have been clearly identified (Gilden, 2005)

                    Six principal pieces of literature will be embraced in this research project pertaining to the etiology of multiple sclerosis from a genetic, infection and environmental perspective. 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. Supportive epidemiological findings highlights the “hygiene hypothesis,” showing the additional role Epstein-Barr virus (EBV) 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 predominant environmental factors are 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).

                    Consequently, the study’s importance pertains towards advancements into understanding multiple sclerosis’ etiology, pathophysiology 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. This research is expected to sensitize scientists into elaborating on present research practices in arriving at a consensus regarding the reality of MS etiology.

Works cited

Ascherio A, Munger K. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61(4) 2007). 288–99 Print

Ascherio A, Munger K. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann. Neurol.  61(6). (2007): 504–13. Print

Dyment, A; Ebers, G; Sadovnick, A.  Genetics of multiple sclerosis. Lancet

Neurol  3( 92). (2004): 104–10. Print

 Ebers, George. Environmental factors and multiple sclerosis. Lancet Neurol   

7 (3). (2008):268–277. Print

Gilden D. Infectious causes of multiple sclerosis. The Lancet Neurology 4  (3)

(2005): 195–202.Print

Giovannoni, G; Ebers, G. Multiple sclerosis: the environment and causation. Curr

Opin Neurol. 20( 3). (2007): 261-8.Print

Murray, Jock. Infection as a cause of multiple sclerosis. Theories abound because no one knows the answers yet. BMJ. 325(7373).(2002). 1128.Print

Nakahara, J; Maeda, M; Aiso, S; Suzuki, N (February 2012). Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy. Clinical reviews in allergy & immunology  42(1). (2012) 26–34. Print

 Terry, Racheal; Miller, Stephen; Getts, Daniel Muller, Marcus. Current Theories for Multiple Sclerosis Pathogenesis and Treatment. Free Press New York. 2. Print

Categories
History

Őtzi: Uncovering the Iceman

In September of 1991 two hikers in the Őtzal Alps near South Tyrol, Italy came across the frozen body of a man. Although the hikers first suspected that it was the body of someone who had recently died, it turned out to be the corpse of a man who had been frozen in that spot for thousands of years. The frozen was given the nickname Őtzi because of the region where it was discovered, although he also became known as the Iceman. Researchers believe that Őtzi is over 5000 years old, and that he lived during the Neolithic period known as the Copper Age. Because his body was so well-preserved in the ice and snow, scientists have been able to learn many things about how he lived, and even about how he died.

            Although the elements eventually stripped away all of Őtzi’s hair, some of his hairs were found stuck in his clothing, and researchers have been able to determine that he had short, dark, curly hair that had been recently trimmed prior to his death (Conklin, 2005, p.137). Some of Őtzi’s clothes were damaged or destroyed during the process of removing him from the ice, but the remnants of what was destroyed as well as the articles of clothing that were preserved offered many clues about his life. Őtzi appeared to be well-prepared for traveling, as he was wearing soft leather shoes and a jacket made of leather or animal hide (Conklin, p.137). He had been carrying some sort of large backpack, though it had been damaged over the centuries, so it is not clear what was inside it, although it does offer evidence that Őtzi was traveling for some purpose (Conklin, p.137).

            Őtzi was wearing a small leather pouch that contained several items, such as pieces of flint, some unfinished arrowheads, grass string, and a hole punch or awl that may have been used for sewing leather (iceman.it, n.d.). In addition to the items in the pouch, Őtzi was carrying a large bow that had not been strung yet, a flint knife in a grass sheath, and a copper axe. Although the people who have studied Őtzi have used a number of different techniques to determine how old he is and to learn about his health and his way of life, the copper axe offers some clues. Őtzi was alive in the period known as the Copper Age, but in the typical settlement that people from that period often lived, it would not have been common for everyone to have copper axes or other tools (Conklin, p.135). Some researchers believe that this axe is evidence that Őtzi was an important person, and may have been a shaman, a medicine man, or some other significant figure among his people (Hales, 2000, p.86). Along with the items of clothing and tools that were found with Őtzi, researchers also found several different types of food, such as pieces of animal meat and pieces of plum or some other form of fruit. The presence of the fruit may indicate that Őtzi died in autumn, when the growing season had ended but fresh fruit was still available (Hales, p.86).

            There were a number of areas that had been settled in the region between what is now Switzerland and Italy, and the people of this period usually lived by farming and hunting. Agriculture would not have been particularly advanced, but archaeologists have found evidence that people raised sheep and goats, planted grains and other crops, and had carts with wheels and other basic farming tools. These people had the capacity to cook and to bake bread, and there was evidence that Őtzi ate a significant amount of grains in his life, as the grains had worn down his teeth (iceman.it, n.d.).

            Researchers used a number of scientific techniques to study Őtzi. Although the existence of his axe made it clear right away that he was at least several thousand years old, it was not until Carbon-14 dating techniques were used that it was possible to make a fairly accurate assessment of his age. The results of the test showed that Őtzi had lived sometime between 3350 and 3100 B.C., and had been trapped in that spot for over 5,000 years (iceman.it, n.d.). Other studies of his internal organs showed that he still had food in his system when he died, meaning that he had eaten recently, and that he showed signs of parasitic infections (Conklin, p.138). Some of the plants and food items Őtzi had with him may have been intended for use as medicine to fight symptoms of parasites.

            X-rays of Őtzi’s body showed a number of interesting things, including the fact that he had signs of arthritis in his hips, knees, and ankles. The most significant find uncovered by the X-rays, however, was the presence of a small flint spearhead or arrowhead embedded below his left shoulder (Gay and Whittington, 2002, p.20). The discovery of this spearhead has led researchers to believe that Őtzi may have been attacked while traveling, and that his death was a result of blood loss (Gay and Whittington, p.20). It is unlikely that it will ever be known for certain how Őtzi died, but this theory seems as plausible as any other possibility. Other tests and studies have determined that Őtzi was approximately 45 years old at the time of his death, which would have been a relatively old age for a man of his era.

            It is not known exactly which culture Őtzi lived in, though there were several different cultures scattered throughout the region that had developed the use of stone and metal tools and the ability to make ceramics. The museum exhibit featuring Őtzi’s body also makes information available about how he and people from his time lived. The cultures from this time and place are described as “cults of the dead,” and funeral ceremonies, burial rituals, and graves were all central parts of the culture (iceman.it, n.d.). Őtzi’s people buried important items with the dead, such as weapons and tools, so that the spirits of the dead would be prepared for the afterlife. Some people of this time buried bodies in mass graves, and others built stone crypts. The graves of the dead would be visited for prayers and rituals on a regular basis. Őtzi had a number of tattoos on his back and legs, which may have been put there as part of some sort of religious ceremony, or in the belief that they would help with the pain of the arthritis he had in those areas (Gay and Whittington, p.21).

            The settlements and communities of the Copper Age had other ceremonial sites besides graves, and religion was a central part of life for people from Őtzi’s time period. The people of this time would have worshipped the spirits of deceased ancestors and engaged in rituals to commune with the spirit world and to ask for acceptance in the afterlife (iceman.it, n.d.). Natural forces, such as the wind and rain, would be believed to be controlled by the gods. Because Őtzi was carrying the copper axe, it is possible that he was a religious figure among his people, and he may have been traveling on some important mission or quest. It is impossible to know everything about his life, but the remarkable condition of his preserved body has mean that Őtzi has been able to tell us many things about how people lived thousands of years ago.

Works Cited

Conklin, Wendy. Mysteries in History. Westminster, CA: Teacher Created Resources, 2005. Print.

Gay, Kathlyn, and Christine Whittington. Body Marks: Tattooing, Piercing, and Scarification. Brookfield, CT: Millbrook Press, 2002. Print.

Hales, Sheila. Developing Literacy Skills: Pack Unit 1. Oxford, UK: Heinemann, 2000. Print. “Ötzi – the Iceman | Ötzi – South Tyrol Museum of Archaeology.” Home | Ötzi – South Tyrol Museum of Archaeology. N.p., 2013. Web. 15 June 2013.

Categories
Art

The Rebirth of Art: Renaissance and Baroque

Chapter Two of “The Annotated Mona Lisa” explores the historical periods known as the Renaissance and the Baroque. Artistic expression in the Middle Ages abandoned many of the traditions of the Classical period, and focused primarily on cathedrals and other architectural works that were intended to glorify God rather than the human form and the natural world. At the dawn of the Renaissance, the world “came back to life,” and artists once again began to focus on anatomical accuracy and capturing the human form and the natural world realistically and accurately. Many works of art from these historical periods reflected the rebirth of humanity’s interest in knowledge, learning and exploration.

            Leonardo Da Vinci, of Florence, Italy is one of the most well-known and respected artists of the Renaissance era. Only a small number of Da Vinci’s paintings still survive, and one of those surviving paintings is one of the most famous works of art in history: The Mona Lisa. This portrait of a young woman was painted with oil on canvas, and was “one of the first easel paintings intended to be framed and hung on a wall” (Strickland and Boswell, 2007, p.34). Da Vinci’s work on the Mona Lisa incorporated several of the new techniques seen in Renaissance-era paintings, such as the use of light and dark known as chiaroscuro and the use of linear perspective that drew all the lines on the painting to a distant point hidden by the young woman’s head. These techniques made her image appear much more lifelike than earlier, more two-dimensional techniques, were capable of doing.

            Another famous work of Michelangelo’s, and one that was done on a very different scale, is “The Last Supper,” a fresco that portrays the last meal Jesus shared with his disciples. The wall-sized mural, painted in Milan, uses perspective and chiaroscuro techniques and a pyramidal structure to place Jesus at the center of the image as all the lines converge at his head. The other figures in the image are captured in various poses that make them appear very lifelike, revealing “the fundamental character and psychological state of each apostle” (Strickland and Boswell, p.35).

            Along with these well-known works from Da Vinci the chapter covers other artists and works from the Renaissance and Baroque periods, and demonstrates that many of the contemporary elements of art as they are known today were developed in these eras. I would define many of the works of art produced during these periods as exciting new forms of artistic expression that set the standard for what it mean to be an artist, and formed the foundation of the contemporary world of art.

Works Cited

Strickland, Carol, and John Boswell. The Annotated Mona Lisa: A Crash Course in Art History, from Prehistoric to Post-Modern. Kansas City, Mo: Andrews McMeel, 2007. Print.

Categories
Art

The Birth of Art and the Birth of Humanity

For tens of thousands of years humans have expressed themselves through works of art. Human predecessors such as the Neanderthals developed the capacity to make and use tools, but this capacity was limited to practical purposes, such as hunting. As Neanderthals were supplanted by Cro-Magnons, and later by Homo sapiens, the capacity for making and using tools was developed beyond simple practicality. These early humans and their Cro-Magnon predecessors used their tool-making capability to create paintings, sculptures, and architectural works. I see all three of these as forms of artistic expression. With the development of artistry, humans were able to express ideas and emotions that transcended the immediate physical world. Whether the form is sculpture, painting, architecture, or other more contemporary forms, art provides a means for expressing the ideas and emotions that define what it means to be human.

            Whether the form of artistic expression is a small and simple carving or a grand and elaborate architectural creation, each work captures the intention of the artists or artists, and signals to those who view it or who make use of it messages about both the individuals and the culture that produced it. One of the earliest known sculptural works that still exists today is a small carved figurine representing a stylized female form known as the Venus of Willendorf. This carving is believed to be more than 20,000 years old, and clearly shows that artists of the era were able to represent the human form in a realistic manner. This figure of a large-breasted and full-figure female is believed to represent fertility (Strickland and Boswell, 2007. p.4); my impression of this figure is that it may not only represent literal fertility associated with pregnancy and child-birth, but it may represent fertility as associated with health, vitality, and abundance. The female form is well-rounded, but she does not necessarily appear to be pregnant; she may just appear to be well-fed. In time when the challenges of life would have made it difficult for hunter-gatherers to always maintain a steady food supply, it may have been unlikely that many actual women would develop such proportions. In that sense, then, this figure might have represented an ideal, rather than serving as a realistic depiction of the human form.

            From the palm-sized fertility idol the Roman Colosseum, works of art have assumed countless forms, shapes, and sizes. The Colosseum was built for the practical purposes of hosting gladiatorial combat and other events, but it was not designed solely with such practical purposes in mind. While the Colosseum’s design was remarkably efficient, and allowed tens of thousands of people to quickly enter and exit the building (Strickland and Boswell, 2007, p.18), it was also crafted with aesthetic beauty. The Romans developed the capacity to build arches and other architectural features for a variety of uses, and I am just as impressed by the beauty and symmetry of these designs as I am by their functionality and practicality. The Colosseum uses a variety of arches in its design, serving to highlight the significance of the arch to the Romans. The Romans saw the arch as a powerful symbol, infused with “magic” (Strickland and Handy, 2001, n.p.); conquering generals returning from battle would pass through one of these magical arches to “purge themselves of hostility” (Strickland and Handy, 2001, n.p.) as they prepared to leave their military lives behind them. I cannot help but see a connection between the practical, physical strength of the Roman arches and the manner in which they resonated on an emotional level for the Romans, as if their ability to support things in the physical world was mirrored by the manner in which they supported the spiritual and magical components of the Roman culture and imagination.

            Strickland and Handy (2001, p.x) state that “the story of architecture is also the story of human history,” an assertion which only reinforces my sense that art forms such as painting and sculpture are not separate from architecture; rather, all three are simply different forms of art. If architecture is the “story of human history,” so too is the ability to carve fertility idols or paint scenes of hunting expeditions on cave walls. In each of these various forms of art, human beings have expressed their capacity to transcend the moment, and to connect with something larger than themselves. It is this capacity for transcendence that makes us, in fact, human.

Works Cited

Strickland, Carol, and John Boswell. The Annotated Mona Lisa: A Crash Course in Art History, from Prehistoric to Post-Modern. Kansas City, Mo: Andrews McMeel, 2007. Print.

Strickland, Carol, and Amy Handy. The Annotated Arch: A Crash Course in the History of Architecture. Kansas City, MO: Andrews McMeel Pub, 2001. Print.

Categories
Accounting

Interpretation of Sarbanes-Oxley Act

Over the course of the decade, there have been many publicized corporate scandals from the much publicized downfall of Enron, to WorldCom, Arthur Anderson, Tyco International, and a host of other major corporations that scandals rocked the accounting world. These companies were cooking the books, hiding accounting practices not reported in audits, and stealing from clients. From the number of corporations involved in scandals, thousands lost their jobs, and millions more lost their trust in major corporations. Out of this mistrust, President Bush acted in a reasonable response by creating the Sarbanes-Oxley Act of 2002 that was enacted in July 2002. This new law targeted other major corporations with the primary goal of protecting investors and the public in providing accurate and true reporting of auditing and accounting services. These were set in place in order to restore confidence in major corporations, and honestly the government that mostly bails these companies out.

Congress actions in passing the law were out of growing public scrutiny of auditing services that were mostly done internally, turning a blind out to the misdeeds of the executives and the heads of the companies. The little guys which were usually the lower level employees were the ones that were left without jobs. This is where the public was most upset about that the CEO’s and executives were riding high, but the lower employees were left broke and without benefits. The requirements in SOX, have shifted the focused on the importance of outside auditing firms double checking the company’s books, and the growing importance of the Securities and Exchange Commission in getting back public trust.

According to the textbook, Irwin suggest that Sarbanes-Oxley Act was to hold businesses accountable for their auditing duty. When all these scandals happen the bigger question was, “where were the auditors?” (Louwers, 2013) This question is crucial in understanding the importance of how these companies were able to commit fraudulent activities long before being caught. Attention was only brought because of whistleblowers, or suspicions from the SEC. Auditing is the key in holding businesses to the standards that the SEC has entrusted in them to follow the letter of the law in operating within the United States. Internal audits that are done by the company is how most of the companies are able to get by. Internal audits are supposed to ensure the public of a company’s honesty. “Internal auditing is an independent, objective assurance and consulting activity that adds value to and improves and organization’s operations.” (Louwers, 2013) The end result of the SOX is to provide insurance to investors that the company is operating legitimately.

The impact of the law for the future is meant to be positive for investors, studies have proven that SOX has not only instilled faith in investors, but has uncovered other scandals, such as Value Line, that was committing fraud for over 20 years was discovered by the SEC credit from the SOX. (Bhaktavatsalam, Condon, 2009) However there has been criticism that SOX has prevented IPO’s and foreign investors from entering the market. Many representatives have asked for a repeal that feel are hurting the U.S economy. However the future impact is unseen as many have believed including investors that the law supports a market and business culture that breeds honesty in operations that show the public that they are able to remain successful and turn a profit in a legitimate fashion that contributes to the economy.

References

Bhaktavatsalam, Sree Vidya, Condon, Christopher. “Value Line Settlement Marks End of Buttner Reign.” (2009). Bloomberg. Retrieved from http://www.bloomberg.com/apps/news?pid=newsarchive&sid=aPpxj3FdB0uM

Landers, Guy. “What is Sarbanes-Oxley?” (2003). McGraw-Hill. New York, NY

Louwers, T. Auditing & Assurance Services. 5th edition. (2013). McGraw-Hill

Categories
History

Geographic and environmental influences on developing civilizations

The geography and environment influenced the development of early civilizations in a great way; this was evidenced in the way the beliefs, the cultures and the practices were coined. Geography and environment influenced the internal characters and perceptions of man during the ancient periods. Elements such as political power, religious belief and economic sustainability during those days were mainly derived from the environmental facets and geographic elements. It is in the light of the above facts that this study highlights how geography and environment influenced human thoughts, societal settings, religious beliefs and politics. The study takes a comparative stance by looking at various regions such as Egypt, India, China, Greece, Western Asia and Rome (Heinrich von Treitschke, 225).

            Geography claims to own scientific thoughts that were cultivated by the ancient people in the above mentioned regions, take a case scenario of climatic difficulties in Egypt due to the desert where the scientific solution available to the Ancient Egyptians was the invention of water irrigations methods that saw them harness water from River Nile for agricultural and domestic purposes. The Egyptian case highlights the advent of hydraulic civilization which was mainly influenced by the environment and climatic conditions.

            In India geographic and climatic patterns affected the not only their settlements but also the rise of political kingdoms and emperors. Climatic elements such as monsoons winds and rainfall patterns around the Himalayan Mountains had a great impact on the peoples believes. The ancient Indians believed that little rainfall was due to their failure to obey their laws of their gods. The geographic vastness of the Indian region can also be attributed to the collapse of early political powers such as Harrapan civilizations which were founded in Mohenjo Dero, historians believe that the collapse of these civilizations was due to poor organization of political power due to the vastness of the region.

Geographical remoteness during the ancient periods calls for the question of geographical proximity, take the case scenario of Greek peninsula and the Greeks located in such regions. The conquest of peninsula by the Turkish influenced the culture of the Greeks who lived in those areas; this therefore explains sources of Greek culture in some Asiatic and Turkish settings. The element of political rivalry in the ancient times was vested on the natural environmental resources and geographical proximity. This is also manifested in the advancement of the Roman Empire into areas of central Europe. The Roman Empire had strong political powers that were consolidated by the rich natural resources and favorable climatic conditions. Heinrich von Treitschke, 225).

            The influence of geography and environment on the development of ancient civilizations was also evidence in the development of art and craft of the ancient periods, take the case scenario of ancient Greek where art was used to communicate the feelings of the people towards the rulers and the climatic changes. Egypt takes a lead in the development as regards to the issue of arts; Pyramids were built to honor the pharaohs where they kept after passing a way with a lot of food preservations(Geraham. Chisholm, 342).

            Hydraulic civilization is better placed to explain the advent and development of ancient China, for instance history shows that early settlements in China started in the along the Yellow River also known as Huang He. The people depended on the river for their livelihoods, natural features such as hills and mountains were believed to be the homes of the gods.

Works cited

Heinrich von Treitschke, Politik,. Leipzig,. This whole chapter on Land und Leute is suggestive.           Vol. 1, p. 225. 2009.

Geraham. Chisholm, The Relativity of Geographic Advantages, Scottish Geog. Mag., Vol. XIII,           No. 9, Sept. 2010.

Categories
American History

A New Look at the Failures and Successes of Reconstruction

The era of U.S. history known as Reconstruction brought rapid and significant changes to the South in the aftermath of the Civil War. While the moderate policies of Abraham Lincoln, and later Andrew Johnson, supported a deliberate and relatively slow process of promoting political and economic change in the South, a more radical contingent of Republicans pushed for rapid change and a virtually complete overhaul of the politics and economics of the South. These Radical Republicans supported the rights of post-slavery Freedmen, affording them the right to vote and to engage in political activity. By most accounts, the era of Reconstruction was a failure, and many of the policies and changes pushed by the Radical Republicans were quickly reversed. Historians disagree about what forces were primarily responsible for the failure of Reconstruction; some maintain that individual and institutional racism undermined the Reconstruction efforts, while others assert that larger economic policies were the root cause of the failure of many components of Reconstruction. The truth seems to lie somewhere in between these competing views or Reconstruction: racism, economics, and politics were all factors in the failure of some aspects of Reconstruction, though it may be too simple to say that any one factor was the most significant, just as it may be an oversimplification to see Reconstruction as a complete failure.

            LeeAnna Keith writes about the battle at the Colfax Courthouse in Louisiana, and points to this event as a tipping point when the efforts by the Radical Republicans to overhaul the political and economic systems of the Southern states began to fail. The Colfax Courthouse had become a symbol to many disgruntled Whites in the South of the newfound political and economic freedoms afforded to the Freedmen (the former slaves) by the Radical Republicans in Congress. Anger and distrust was building among many Whites, and an organized group of men, some of whom belonged to groups like the “Old Time Ku Klux Klan” attacked the Freedmen who were holed up in the Courthouse on April 5, 1873. Dozens, or possibly hundreds, of Blacks were killed in the attack. According to historians such as Keith, this assault and slaughter became a symbol and a rallying cry for the Whites who opposed Reconstruction, and would mark the beginning of a growing movement to bring an end to the changes imposed on the South by Congress.

            Historian Heather Cox Richardson takes a different view on the failures of Reconstruction, claiming that political and economic circumstances in the North had as much or more to do with the situation as did the racism of Southern Whites. Richardson argues that Whites in the North opposed aspects of the labor movement associated with Freedmen, such as the redistribution of property and other decisions that the Northern Whites believed showed special favoritism to Southern Blacks. While many Whites in the North supported the notion of granting “Civil Rights” to Blacks, these rights were specifically about the rights to own property, to vote, to use the legal system, and other similar processes. At the same time, many Whites in the North believed that Freedmen, as well as some politicians, were attempting to write and pass legislation that would afford Blacks privileges that had not been individually earned. The opposition to this was based on the belief that Whites had to earn their own places in society and that the laws should not be used to grant Blacks special favors or privileges.

            Discrimination against Blacks by Northern Whites may not have been as strong or as violent as that of Southern Whites, but many in the North still opposed the idea that Blacks and Whites were socially equal, and believed that Radical Republicans who were trying to enforce the rights associated with labor were also trying to push for social equality for Blacks that was not earned. In a sense, the racism of Southern Whites and Northern Whites helped to undermine Reconstruction, and when combined formed a force of opposition that was too great for the changes of Reconstruction to withstand. Despite the fact that many of the changes brought about by Reconstruction were undone or reversed, however, those few years of relative freedom for many Blacks gave them a glimpse of the possibilities that could be theirs. This realization did not die with the end of Reconstruction, and would serve to support the eventual rebirth of the civil rights movement in the following century. By that measure, then, Reconstruction was not entirely a failure, though it would take nearly a century before the rights of Blacks that had been lost at the end of reconstruction would eventually be restored.

Categories
Psychology

Reading Report

Source: Rutter, M., & O’Connor, T.G. (2004). Are there biological programming effects for psychological development? Findings from a study of Romanian adoptees. Developmental Psychology. 40.1, 81-94.

Problem: “The key question is whether, given the high quality of the later environment,

there were any persisting sequelae (among Romanian orphans who were later adopted into British homes) and, if there were, to what they might be due.” (p.81)

Procedure: The researchers began this study with an examination of a selection of children who lived in the difficult and challenging conditions presented in a number of Romanian orphanages from birth to ages four and five. The basic premise of their study was that these children, who were adopted out of these orphanages and into middle-class British homes, made an appropriate group of test subjects for research into what, if any,  effect(s) the difficult conditions in which they lived for their first few years of life would have on their development and behavior in adolescence and adulthood after they were adopted. The researchers considered three possible mediators for persisting psychosocial adversity (i.e.- developmental and/or behavioral issues) among the Romanian adoptees. The first was that ongoing psychosocial adversity, if it was demonstrated,  was a result of current conditions in their new environments; the second was that early-age cognitive processing either would or would not allow children to process and adapt to their early environments in positive ways; the third was that early adversity would bring about lasting physiological, psychological, and developmental changes that would make it impossible (or at least less likely) for these adoptees to avoid psychosocial adversity later in life. The researchers posited several hypotheses based on these three factors, with the aim of determining whether any of the three appeared to provide an adequate explanation for the presence or lack of post-adoption psychosocial adversity

In order to test their premises, the researchers drew from the “324 children adopted into UK families (from other countries) between February 1990 and September 1992” (p.84). Of this pool, 144 children were selected who had lived “in very depriving institutions and who were adopted into UK families at various ages up to 42 months” (p.84). The comparison sample consisted of 54 UK-born children who had been adopted at or near birth into UK families. The study considered a number of developmental measures, including physical measurements of height and weight at birth and at the time of the study, as well as information available about each child’s height and weight at various points in between. A number of psychological tests were administered as well, primarily intended to assess the existence of attachment disorders and psychological development disorders.

Findings: the study concluded that there was a strong association between early deprivation and poor physical, cognitive, and psychological development after adoption. The researchers found that most of the children demonstrated a “catch-up” (p.89) period in the first few years of life in their new homes where they tended to make notable improvements both physically and psychologically. This catch-up period seemed to last an average of 2-2.5 years, with any subsequently-remaining physical, psychological, or cognitive deficits appearing to become permanent.

The researchers concluded that early deprivation was an accurate determinant of lasting physiological and psychological adversity, and that subsequent environmental improvements were not adequate for completely reversing the damage of such early deprivation. Reaction: This study seems to demonstrate in very clear terms how important the first few years of life are in terms of physical and psychological development. When adverse conditions exist in this period of life, the damage can be severe, and regardless of whether later conditions are less adverse, much of the damage done in early childhood cannot be overcome or reversed.

Categories
Accounting

Balanced Scorecard Theory

Key performance indicators, financial assessments, return on investment, project schedules, budget estimates and a plethora of other tools and metrics are used to measure quantitative and qualitative variables in performance.  While there are key performance indicators and other metrics to manage, understand and provide data to make informed decisions there is still a need to have a more granular view on what is expected of the group being measured and the expected outcomes of the performance.  There are multiple areas that can be measured and analyzed to provide the data required to make informed business decisions.  These areas can be defined as financial, external, internal and growth.  By applying metrics across a broad spectrum of opportunities each area of the business can be measured and compared between each other.  This scorecard method allows insight into key metrics of the organization and allows a concise and focused effort that ultimately aligns the strategic intent of the organization to the defined measurements of the organization. 

Balanced Scorecard Definition

The objective of the balanced scorecard is to provide a quick and powerful tool so that anyone in the organization that has the need to know or understand the performance of their specific function can view and gain the perspective needed (Kaplan, R. and Norton, D).  This visual assessment allows for the managers and leaders of the organization to make informed business decisions to take the appropriate actions.  These actions taken by leadership would drive the change in the organization based upon achieving the performance standards outlined on the balanced scorecard (Monk, E., and Wagner, B).  This tool is used as a planning tool that aligns those actions on the tactical business operations level to the strategic intent of the business.  Prior to the utilization of the balanced scorecard theory businesses relied heavily on financial measurements to drive actions within the organization (Kanaracus, C.).  While this did provide a certain level of validity to the management decisions it did not provide the full picture required to make those tough business decisions in an ever changing and dynamic environment.

The early implementation of the balanced scorecard, although not officially named balanced scorecard until the 1990’s, was used by the General Electric Company in the 1950’s (Cooper, D. F., Grey, S., Raymond, G., and Walker, P).  The General Electric Company was driving toward a new and innovative way to align what was happening in the business and how to make changes in the manufacturing process to impact the final results of their process.  By measuring different variables in the organization the sourcing buyers, engineers, manufacturing team leaders and other members of the manufacturing and sourcing supply chains could make decisions based on these financial and non-financial key performance indicators to better their metrics.  Each change was then compiled into a scorecard to determine the strategic health of the organization.  The intention of the balanced scorecard has remained the same over the years but the ability to define metrics, measure variables and report results have become increasing intricate and beneficial across multiple business units in virtually all industries.

Balanced Scorecard Perspectives

The essence of the Balanced Scorecard Theory is to provide a fair and balanced approach that deviated from the original metrics associated with the business decisions.  The balance comes from defining metrics that work in a complimentary fashion as opposed to a financial centric focus that was previously used.  There were some inherent weaknesses and opaque perspectives that came from the pure financial view and the balanced scorecard approach provided a balance to the over strategic performance of the organization.  The balance also is seen as taking a different perspective on the company as noted before.  The four areas encapsulate the business in unique ways and can provide insight and vision into an area of the business that would be completed overlooked by other functions of the business (Leach, L).  The first are is the financial portion.  While this has always been included in the views and analysis of companies since the beginning of trade, the financial perspective is crucial to business decisions.  The question on what should be measured is based on how the success of the company is view by the shareholders of the company.  Financially, what is important to those with a vested interest in the success of the company?  The answers to this question will help drive the metrics needed to drive the objectives, measures, targets to the measures and the projects or programs that will drive these changes.

While the financial portion is aligned, measured and analyzed there are three other areas that need to be taken into account.  The next is the customer’s view.  This could be customers within the same organization or those customers in the traditional sense that are utilizing the final good or service as intended by the organization’s business model.  The leaders of the business must have a vision on what the organization will do in the future.  This could be growth in certain sectors of the business or expansion into new markets or product opportunities.  The vision is established by leadership so that the projects, objectives and efforts of the organization can drive the results required.  With the customer section of the balanced scorecard, the focus is centered on the ability to achieve the vision of leadership and how the customer measures that success.  These objectives are viewed as key performance indicators from the perspective of the customer. These objectives could be increased efforts for after hour support or availability of web-based applications.  These types of focus areas would drive the objectives, metrics and actions of the organization to meet the criteria outlined by the customer’s perspective.  This external view of the organization can shed light onto areas that may be neglected based on the mere fact that those creating the metrics and defining key targets do not have the external focus necessary to drive those types of changes.  Also without metrics based on these external focuses the business is not as likely to allocated resources to those types of projects considering they do not have the support or focus needed to be successful.  Without a measurement it is hard to determine progress or definitive results and benefits from a project (Prencipe, Davies, and Hobday).

After looking externally to drive results, the next area is internally focused based on processes, procedures and core capabilities.  The internal focus looks at the business functions that provide value to the organization, product or service that are seen as critical to satisfy the shareholders, customers, leadership and other entities that are reliant or collaborative with the business processes.  In order to satisfy those requirements, what business processes and functions are needed to run at the optimal performance level?  This question will drive the goals and objectives as well as the level of the target assigned to that objective.  Another area of focus for the balanced scorecard is neglected most of all in terms of a pure financial analysis of the company.  This area is the growth of the organization.  This growth is more than real estate, capital, work force or markets but it focuses on talent, agility, change management, functional expertise, adaptability and learning.  These areas are measured by their ability to improve the organization and change to meet the vision of the organization.

With all four areas the objectives there is a focus on building the objectives, measurements, target metrics and the projects.  Each perspective of the balanced scorecard will result in the definition of key requirements of the perspective.  These areas start with the objectives of the perspective.  These objectives are the outlined end states that are required from each perspective.  The end state is the deliverable or result of the business.  Within the objectives there are examples for each perspective.  The customer perspective could entail the view that each customer should have access to their accounts regardless of the core business hours.  This objective is from the customer’s perspective but does not have a definitive measurement around it.  The objectives tie into the measureable statistic of that objective.  For this example the measurement could become the amount of time the system is available each day.  This is the measurable aspect of the objective.  The metric is simple, measureable, attainable, relevant and simple.  These criteria should be present in all the measurable metric criteria on the balanced scorecard.  With the objective identified and the key performance measure outlined there must be a line or target established so that the person or group reviewing the balanced scorecard know how they are performing against the outlined indicators.  This target is established and provides that much needed sanity check for the team.  This target drives actions.  The actions required by the business lead to projects or other initiatives of the organization so that they can make the necessary adjustments to meet the objectives, measures and targets of the organization.

Alignment and Benefits

The vision and strategy is in the epicenter of this balanced scorecard.  Since the business has an overall view of the internal processes, external customer centric view, financial health and metrics of the organization and the growth metrics assigned there is an overall view of the business and its performance.  The crucial portion of all those metrics is how they measure the health of the organization, the progress toward the business’ vision and the success of maintaining those efforts to ensure a sustainable operating model.  The vision of the business and the results of the business’s financial and operational actions are linked together through the actions taken based on the balanced scorecard.  This strategic mapping of tactical actions to the vision of the organization is facilitate by the insight and guidance offered by the balanced scorecard.

As the objectives lead to metrics and the metrics establish targets which ultimately lead to the initiatives and projects of the organization there is a logical and deliberate map from the smallest enhancement project to the overall vision of the organization.  This linkage is one of the major benefits of the balanced scorecard and its application to business.  The actions on the lowest level of the organization have a direct correlation to the successful implementation and intent of the leadership of the organization.  Not only is the purpose and intent of those actions attached to the vision the actions are also measured and reported upon with the visibility required to garner the support and input by the key leadership positions.

The benefits of the using the balanced scorecard are just as varied as the inputs of the perspectives.  The overall objective and benefit of the balanced scorecard includes the ability to monitor, track and align the actions of the organization with definitive deliverables align to the vision of the organization.  Strategically aligning these actions allows the limited resources of time, funding and people to be adequately and effectively allocated to the project and programs that benefit the organization in the most impactful manner.  This alignment of key performance indicators aligns all levels of the organization and instills a sense of purpose knowing that the operation of a specific functional area of the organization is executing has purpose and direction.  The alignment of the vision to the operationalize functions also creates an opportunity for increased communication and collaboration between units since their scorecard metrics are also aligned with the vision of the organization.  This increased opportunity lends itself to increased creativity and innovation to solve real world issues and still understand what the end state must be and what key performance indicators are measuring success (Highsmith, J. A., & Highsmith, J.).  This clear picture of what success is and what areas require focus can facilitate the problem solving aspect of business and allow the ingenuity and innovation of the organization to solve those problems.

The balanced scorecard, if executed correctly, can create value within itself that could potentially create a competitive advantage.  This advantage comes from the inherent ability to create the translation between the vision of the leadership to the concrete and achievable actions throughout the organization.  The balanced scorecard also creates the opportunity to improve business processes, make informed decisions on business tactics and reduce the amount of noise in the data analysis and alignment process.  This is accomplished by analyzing already established business metrics that are continually reported upon and the variations from one reporting cycle to the next can be traced by to specific actions that occurred through the projects outlined in the scorecard.  Clarity and visibility into the key functions of the operations that are driving the key performance indicators allows a greater command and control upon the inputs of the operation and the manipulation of the expected results.  Understanding the needs of the company and how they align to the organizational vision can create that much needed clarity advantage throughout the organization (Kaplan, R. and Norton, D).

While the benefits of the balanced scorecard include the visibility into four different areas of the business including finance, internal business processes, customer or external focus and growth as well as the alignment to the vision of the organization there are still some potential disadvantages to the scorecard.  To execute the balanced scorecard there is a tremendous amount of preparation and planning to effectively and efficiently implement the use of the balanced scorecard.  The vision of the organization must be firm and established and the objectives of the organization must be clear and understood by those developing the balanced scorecard.  The balanced scorecard is also not the only tool needed to run the business.  While the tool is very useful it is not an all-encompassing metric and analysis tool to base all business decisions upon.

Case Study

Through the understanding of what the balanced scorecard stands for and looking to implement the tool into the organizational culture, the case study hits on some of the key fundamentals of the advantages and disadvantages of the balanced scorecard theory.  The advantages are sought out by the company to create that strategic alignment and visibility needed to be successful but the forethought and effort for the development of those metrics; deliverables and targets were not fully vetted and aligned with the vision of the company.  The Young, Martinez and Cheung (YMC) firm developed a set of strategic objectives which are aligned with the position of the firm and their core values.  The first step is complete but there still needs to have a measureable assigned to each strategic goal.  With each objective listed below there is a corresponding measure for that objective.

Financial

  1. Steadily increase the firm’s revenues and profits

Measure: 

  1. Determine the operating profit of the organization
  2. Determine the Revenue generated by services by function
  3. Determine Earnings before interest and tax            

Customer

  1. Understand the firm’s customers and their needs.

Measure:

  1. Count the number of customer complaints
  2. Count the types of services used by the customer
  3. Quantify the services provided by function
  4. Value customer service over self-interest.

Measure:

  1. Calculate work level for core operations
  2. Calculate Pro-Bono effort

Internal Business Process

  1. Encourage knowledge sharing among the legal staff

Measure:

  1. Track knowledge management inputs
  2. Track knowledge management views
  3. Calculate knowledge transfer/exchange session held
  4. Communicate with each other openly, honestly, and often

Measure:

  1. Count the number of brown bag lunch sessions
  2. Determine number of round table discussions held
  3. Count the number of closed door offices
  4. Empower staff to make decisions that benefit clients

Measure:

  1. Review quantity of decision review boards
  2. Quantify types of decisions being reviewed up the chain of command
  3. Measure the dollar amount associated with each decision type

Organizational Learning

  1. Maintain an open and collaborative environment that attracts and retains the best legal staff.

Measure:

  1. Count employee turnover
  2. Calculate case winning percentage
  3. Calculate settlement winning percentage
  4. Quantify attendance and sick leave
  5. Seek staff diversity

Measure:

  1. Calculate education
  2. Calculate experience in core business functions

While these measures are not all encompassing of the metrics required they are specific to each one of the objectives and are aligned with the vision of the company.  From those metrics a target will be established and from that target the company would know how to allocate their resources to fund and support the initiatives needed to meet those targets.

            The law firm can use the balanced scorecard to evaluate staff and make key business decisions regarding their performance and what the expectation are regarding their level of effort in different areas of the business.  With each different perspective there are measureable areas that can help guide the staff and provide a visual cue into what success looks like.  The balanced scorecard is utilized as more than a dashboard to key metrics.  The balanced scorecard allows the staff to determine the actions, efforts and level of performance required to meet the targets set forth by the organization.  These targets would provide the baseline measurement on the performance of the staff.  While the balanced scorecard can encapsulate what is required by the staff it must also be understood that many intangible assets of an employee must also be taken into consideration by the evaluating team.

Performance Based Incentives

When reviewing staff based upon the balanced scorecard there is a by-product of that analysis.  There is an inherent prioritization or rack-and-stack of staff on how well they execute the tasks outlined in the metrics of the balanced scorecard.  The question then becomes how to reward the high performers and how to raise the performance of those on the opposite end of the spectrum.  The balanced scorecard is an effective way to tie performance indicators from multiple different perspectives to the performance results of the staff.  This correlation provides a framework for tying compensation to the balanced scorecard results.  With the metrics that are individually based and focused this is possible but there are also other metrics that must be met as a group or functional area of the organization that cannot be tied back to a specific individual.  This could be a great way to promote incentive pay to user change in the organization but there is a fine line between driving results and pay for performance.  These types of decisions will also need to incorporate the culture of the organization and the type of environment the organization is trying to build.  The metrics will drive the actions of the organization and that can have a positive or negative impact depending on the end state deliverable.

Application

As previously discussed the application of the balanced scorecard is focused on the strategic alignment with the vision of the organization and the actions of the staff to achieve that vision.  The arduous part of utilizing the balanced scorecard is the preparation and implementation of the management tool.  There are key areas that must be taken into consideration for the implementation of the tool.  The first is the buy-in from leadership of the organization. The balanced scorecard is a top down implementation that requires the foundation to be laid and supported by leadership.  The success of the balanced scorecard hinges upon the correlation between the actions derived from the projects and the vision of the organization. To employ the balanced scorecard there must be an understanding of what results the organization wants to achieve from the implementation of the scorecard.  The objectives, metrics, targets and projects that result from the implementation of the scorecard are the real drivers of the change and the scorecard is the vessel into the visibility of that change.  The effort to commercialize the idea throughout the organization will also provide the opportunity to garner feedback and critical information on what to measure, how to measure it and what the intended results are.

            The balanced scorecard is a tool that will allow the strategic mapping of the vision developed by leadership to the key performance indicators that visually depict what success looks like for the organization.  The alignment of key functional actions throughout the organization will provide a synergistic approach to achieving success.  The balanced scorecard is the management tool that can provide that guidance and feedback needed to allocate resources to achieve the outcomes outlined by leadership in the vision.

Works Citied

Cooper, D. F., Grey, S., Raymond, G., and Walker, P. Project risk management guidelines, managing risk in large projects and complex procurements. John Wiley & Sons. 2005. Print.

Highsmith, J. A., & Highsmith, J. Agile project management, creating innovative products. Addison-Wesley Professional. Print.

Kanaracus, C. Survey finds erp software project overruns ‘distressingly common’. 22 June. 2013. Web. http://www.cio.com/article/710777/Survey_Finds_ERP_Software_Project_Overruns_39_distressingly_Common_39_?taxonomyId=3009

Leach, L. P. “Critical chain project management”. Norwood, MA: Artech House, INC. 2005. Print.

Magal, S. R., and Word, J. (2011). Integrated business processes with erp systems. RRD/Jefferson City: Wiley. 2011. Print.

Miller, D. “Building a project work breakdown structure: visualizing objectives, deliverables, activities, and schedules.” ESI international Project Management Series. Auerbach Publications. (2009). Print.

Monk, E., and Wagner, B. Concepts in enterprise resource planning. (3 ed.). Boston, MA: Course Technology Cengage Learning. 2009. Print.

Prencipe, A., A. Davies, and M. Hobday. The business of systems integration. Oxford University Press, USA, 2007. Print.

Project Management Institute. “A Guide to the Project Management Body of Knowledge (PMBOK Guide) Fourth Edition.” Project Management Institute. Newtown Square, PA. (2008). Print.

Kaplan, R. and Norton, D. “Using the Balanced Scorecard as a Strategic Management System,” Harvard Business Review (January-February 1996): 76. Print.

Wheelen, T. L., and Hunger, D. Strategic management and business policy, achieving sustainability. (12th ed.). Upper Saddle River, NJ: Pearson College Div. 2010. Print.

Categories
English

The Struggle of Human Rights

Introduction

            The speech of Eleanor Roosewelt in Paris, Sorbonne is written in a way that it is able to create engagement with the audience, get people connected and emphasize the importance of preserving human rights. The below essay is going to examine the rhetorical tools used by Eleanor Roosevelt.

            Logos. The main thesis of the speech; the importance of maintaining freedom and human rights is clearly communicated through the speech. The speaker says:

            “I believe, of our chance of peace in the future, and for the strengthening of the United   Nations organization to the point where it can maintain peace in the future “. She clearly wants to ensure that world politics and the United Nations step up against totalitarian dictatorial states like the USSR.

            Ethos. The credibility of Eleanor Roosevelt is also addressed in the speech. As the longest serving First Lady an author and an equality activist. She stepped up several times before against discrimination.

            Pathos. Pathos is the rhetorical tool that is used the most throughout the speech. This is what creates a real connection with the audience. Talking about past historical issues like the French Revolution in front of an audience in Paris is a great choice, just like involving current issues, like the lack of freedom of speech in many parts of the world, especially in the USSR.

            Style of Speech. The speech examined in this essay is definitely written in a Toulmin style, as the moral argument is already decided and one can suppose that the audience already agrees with the statement that freedom of speech and human rights are values that are important for democratic societies. She also confirms: “The decisive importance of this issue was fully recognized by the founders of the United Nations at San Francisco.”

References

Roosevelt, Eleanor. (1948) “The Struggle for Human Rights.” American Rhetoric. 2011. Web. 11          May 2012. School of Liberal Arts. (web) The Rhetorical Triangle: Understanding and Using Logos, Ethos

Categories
English

Banning Smoking in Public Places

The topic of the Rogerian essay is the argument for banning smoking in public places. Bringing in scientific research results, the authors would like to address human rights and freedom issues and argue that everyone has the right for clear fresh air without 3000 different toxins. While smokers’ have the right to enjoy their habit if they choose to, the public’s interest is more important in this case than individual rights.

            Background Knowledge. I have examined newspaper and academic publications regarding smoking ban in America. As a non-smoker, I understand that people with heart and respiratory conditions can be affected by cigarette smoke. With friends who are asthmatic I know that cigarette smoke can worsen several people’s condition. Indeed, if I go to a club or party where smoking is allowed, my clothes and hair immediately need to be washed, because of the smell.

            Research Plan. In the first phase, I would like to review newspaper publications on the issue; argumentative articles on each side. The second phase would be to check the validity of the claims using peer-reviewed journals detailing research results on second-hand smoking and its effect on people’s health. I will use search terms “second-hand smoking” and “ban smoking in public”. Debate.org would be a good starting point, as it is a website that addresses both sides of the argument. The CDC website would provide facts and overview about the health risks of second-hand smoking on different population groups. It also provides references for future research including scientific study publications. The WHO report covering the statistics of 192 countries would also provide the author with a solid proof to back up the argument for banning smoking in public places.

References

Centers for Disease Control and Prevention. (web) Smoking and Tobacco Use.                    <http://www.cdc.gov/tobacco/data_statistics/fact_sheets/secondhand_smoke/general_facts> [Accessed: 12/6/13]

Debate.org Website. History and Debate of Smoking Ban. Web. <http://www.debate.org/tobacco-            rights/> [Accessed: 12/6/13] Oberg, M., Jaakkola, M., Woodward, A., Pergua, A., Pruss-Ustun, A. (2010) Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from          192 countries. WHO. Web.             <http://www.who.int/quantifying_ehimpacts/publications/smoking.pdf>  [Accessed:

Categories
Religion Sociology

How does religion influence human being

Religion plays an important role in everyday life. A person’s religious beliefs can affect various aspects of his/her life. Religion is not always about accepting or living by a certain set of beliefs, but it can be about the way those beliefs indirectly influences one’s life. Religious beliefs may instil morals and values in a person that will in turn influence the decisions he/she makes about the type of life he/she leads. Religion is defined as a set of beliefs, cultural systems, or views of the world that relates the human being to the supernatural realm. Numerous studies have been conducted to determine why religion plays such an important aspect in society. Great debates have been pursued about various religions and the people who practice them. Religion has a much greater impact on society than the average person realizes. Human society is built on religion, so even if one doesn’t believe in a particular religion, he/she is still inadvertently affected by a religious society. Consequently, almost every aspect of one’s daily life is influenced in some way by one religion or another. One of the greatest influences that religion has on everyday life is the fact that many of the laws and social and cultural beliefs that are practiced are based upon religious teachings. These laws are the foundation of the society that humans know. Because these laws govern our daily behaviour, in essence humans are behaving according to religious doctrine. Religious beliefs are an intricate part of each human being that shapes their social interaction, family life, type of job they work, whether or not they attend religious services, the role they play in society as a female or male, and their economic life.

Religious beliefs help to keep and maintain order in society. Religious practices also help to comfort humans and explain why tragic events happen. By nature humans are naturally sociable creatures. Humans learn from each other and often work better with the help and ideas of others. Without religion, people would not be able to live together and function in society. Religious beliefs govern the way people interact with one another in society. Religion is used by society members to comfort one another in time of crisis. Religious groups ban together to pray when tragic events happen. Many religious people admit that they are able to face a world of crime and violence because of their strong religious beliefs. Religious beliefs are used in to comfort bereaved families. Funeral, wakes, tributes, memorials, and other rituals all have their foundations in one religion or another. Many of the Ten Commandments are actual state laws that one could be penalized for violating. Nonetheless, most cultures have vowed to separate church and state. One religious belief can also affect one’s social status. Many time in small town when someone is seeking political office, one of the aspects of their lives that is mentioned is their religious affiliation. In order to live productively in society together, humans must be able to resolve conflict in a peaceful manner. Again, religion plays a role in conflict resolution. Must religions have a set of guidelines that govern how conflicts should be resolved among believers. Most religious believers follow these guidelines and only revert to state law when no other actions can be taken.

Religion also affects aspects of family life. The act of marriage is a religious convention. Whether or not a couple gets married, has children, divorces, use contraceptives, or attends some type of religious services each week all depends upon religion. With nearly fifty percent of all marriages today ending in divorce, many scholars are examining whether or not a family’s religious beliefs has an effect on its cohesiveness. Marriages end in divorce over many dilemmas from money to the best way to raise and discipline children. Many studies have concluded that families that practice religious beliefs and rituals together tend to be happier and more loving. When couples have religious grounding in their relationship they tend to not argue as much as couple who do not because many religions have the role of each person in the relationship outlined. If each person is willing to abide by the guidelines set for him/her, the possibility of arguing of the general government of the family is slim. Statistics also show that children who come from loving, two parent homes have a better chance at success than their counterparts. Religious people feel that these statistics are no mistake because a higher being designed it that way. Many religions have guidelines as to the role of the mother and father. Many religions convey that the role of the woman is to bear children, while the role of the man is to provide the finances. Disciplining children has become a huge controversy lately. The law says that whipping is a crime, while many religions teach that discipline is necessary. Nonetheless, it is quite obvious that in order for a marriage to work, the couple must be operating under some type of guidelines.

One’s profession may be influenced by religious beliefs. Many people were taught that an honest dollar was a good dollar, but many people refuse to work certain types of jobs due to their religious beliefs. There have been many heated debates in the news lately about abortions and casinos. Many religions teach that abortions are wrong because it is murder. As a result, people who support this will not work for physicians or clinics that perform abortions. They may feel that if they work in a place that performs abortions that they are somehow condoning the action. Likewise, many people will not accept the services of a doctor or nurse that performs or assists in the act of abortion. Religious people often ask their doctor or nurse these questions before eliciting their services. Likewise, many religions profess that gambling is wrong too. Consequently, no matter how desperate a person may be for a job, he or she will not take a job at a casino because of religious beliefs. Another example is massage parlours. There are an endless number of religions that convey that the woman’s body should be covered properly and not seen by strange men. Most women at massage parlours wear very skimpy clothing to elicit male customers. Likewise, some women do not patronize massage parlours out of fear of being stereotyped.

Attending some type of religious service is a religious ritual. Surveys have confirmed that a high percentage of people attend some type of religious service on a regular basis. In some instances, people don’t attend religious services because they believe in the particular religion, but because it has become a routine for them. They grew up attending a service and they continued when they were grown. As a result, they now attend with their family. Or, attending a religious service may be expected by the community in which they live. Many people attend services because everyone else in their neighbourhood does or because people they work with attend the same service. Whatever the reason may be, people seem to go. Some people even attend more than one service per week. Although many people are unaware of it, in some denominations people hold offices in their religious establishments. With these offices comes societal and economic prestige.  Some religious organizations demand that their member donate a certain percentage of their family’s earnings.

The role of males and female in society has been determined for years. As children, humans are taught that some roles are feminine, while others are masculine. Female children are given dolls and male children are given trucks. These teachings stem from the false assumption that women are naturally passive and men are naturally aggressive. Nonetheless, societal roles are being transformed in today’s society. Women are going out and working while men stay home and take care of the home and children. There are men who decide to become school teachers and women who want are professional truck drivers.  The way people teach their children about these roles are rooted in religious beliefs. As a result, humans grow into the roles they will have later in life. Sadly, those people who do not fit into the cookie cutter design are ostracized by society. The religious connotation of these roles is still state law in many places. The institution of marriage is defined as a woman and man in many states today; the same way it is defined in most religions. People who object to these rules are deemed deviants and trouble makers.

Deciding to live meagrely or extravagant is also rooted in religious beliefs. Most people who are religious practices decide to live meagrely. Living extravagantly is seen as a waste by most religions. Donating to charities, volunteering, tithing, and helping the poor in general are seen as wealth to religious people. In most religions, the main teacher was of poor upbringings. For example, in Christianity, Christ was poor. He didn’t own anything and live the life of a nomad, moving from place to place. As a result of this teaching, and others like it, many people believe it is a sin to be wealthy.

The roots of religious practices are manifested in various aspects of human life. Even people who profess that they are not religious are still inadvertently affected by religion. Every member of the civilized world is subject to societal laws, and depending upon where one lives those laws could come directly from some religious teaching. Some type of religion has been present to humans from the very beginning of existence. Many practices have evolved and changed over time, but can be traced back to one particular religion or another. Much research has been conducted to try to uncover the meaning of it all, but one definitive meaning has remained elusive. People who practice religious beliefs seem happier, content with life, and more purpose driven than people who do not practice at all. Religion affects how members of society interact with one another. It determines if one will get married or cohabitate. Religion determines the type of job or career one pursues.  Religion affects all aspects of one life both directly and indirectly.

Categories
English

Overcoming Obstacles

A Turn of Events

My early experiences in life led me to adopt a motivated mindset to overcome daunting obstacles and achieve my goals. If there is anything I have learned to realize about the reality of life is that, ‘nothing is naturally that easy to accomplish’. Through the years of struggling to achieve my dream of becoming the first one in the family to finish a college degree, I found out that nothing is free in this world and every single matter that gives one a sense of achievement should be handled with proper application of effort and hard work.

Everything was going smoothly. My mother had her job and was able to put me in school thus providing me the education that I need to achieve my dreams. I thought then that everything would remain as ‘easy’ as it seems. However, everything changed one my single mother came in the house one night looking drenched and powerless. She lost her job. She looked at me with no words, but it was as if I can hear her say “how can I support you now?”  I was speechless, all I could do was try to figure out how I would be able to ease her paid. The hardships began to come in like flood. It became hard to put even just the simplest meal in the table for the family to share. I realized that at this point, I had to stand up for my own sake and be stronger as I am to face larger challenges as these problems come sweeping our family.  I knew that this was the only thing I could do to make sure my mother’s pain could be eased somehow.

Part of my step towards achieving my goal is dedicated to putting my attention focused on my studies. I admit it was not easy to keep my attention on my studies amidst all the different conditions I had to deal with in relation to my mother and my family as a whole. I needed all the help I can get. Sadly, my teachers were preoccupied with their own problems. I had to learn matters on my own and become dedicated to my studies. Financial problems became the main hindrance to my goal but I pursued my dream any way I could anyway.

As I entered college, my dream became even harder to achieve as the financial support I needed pressured me at an even harder cause. I then resorted to searching for the most possible scholarships available that I could apply for; working while learning also became a stepping-stone towards the completion of my goals. Relatively, nothing was easy; but I know I do have to undergo all these trials. I always keep in my mind the words of my mother as she says ‘nothing comes from nothing, every good thing comes from another good thing’, I figure, if I keep on choosing the good path then perhaps I would finally be able to reap the fruits of my efforts later on in life. My determination apparently was not enough for me to achieve my dreams. Every single desire should be worked upon, every single step towards my goal should be seriously taken into consideration and every obstacle should be realized as opportunities towards growth and a closer bridge towards what I want to achieve.

Through the years, I realized that with one twist of events in my much easier life when I was younger, everything could take another phase and my determination immediately grew. It was as if I was forced to become a lot more mature at such an early age. To some, such an experience might seem specifically devastating. To me though, such part of my life became the turning point of everything, a realization of what I really want and a source of indication on the path that I want to take as I grow into age. My mother, my inspiration, gave me the most compelling source strength allowing me to see through the bright side of life even though everything started to seem shattered. As my mother never gave up on me or on the idea of giving me what I needed as an advancing student, I learned not to give up on myself either. I knew I had to stand up and it was not only for me nor for my dream, but for my mother and my family who I want to lead in a much better state of living as I tend to graduate from college and gain a better job that would allow me to give them the American dream that my mother longed to realize for us when we were still young.