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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

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                              7 (3). 268–277.

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

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                             new insights. New York. Lippincott Williams & Wilkins

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                  Two Years Observational Study. PLoS . 7(4)

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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

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                      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.

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                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.

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                    Pathogenesis and Treatment. Free Press New York. 2012.

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                 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.

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      (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

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                              7 (3). 268–277.

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

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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

SOUTHEAST ASIAN HISTORY

Southeast Asian countries, which largely include China and its neighboring countries, are greatly known for their being highly cultural and traditional. This basically imposes the idea that suggests that such countries depend much on how their ancestors tried to manage their communities through the utilization of religious principles alongside the oldest guidelines that are provided by their ‘elders’. Considering their background culture as a huge element towards the particular progress that they would want to incur, such regions give high regard to direction and proper guidelines that are provided to them through the history of their people. As noted, imperialist aggression shattered the fond dreams of the Chinese about learning from the West. It was very odd — why were the teachers always committing aggression against their pupil? The Chinese learned a good deal from the West, but they could not make it work and were never able

to realize their ideals (Mao Tse Tung, 3). This is the reason why the Chinese nation strongly depends on the aspects of communism and the principles by which it directs the society. In relation to this matter, this is practically the reason why the Chinese community [and all other nations noted to be related to their race] specifically follow the administration’s direction. They do believe that the constricts provided through the governance under a communist administration would provide them the chance to follow the path towards progress. Between the years 1945 towards 1947, this was evidently shown through the lifestyle of the people within the said region in Asia. Practically, this change has affected the overall economic condition of the country. People had the chance to seek the manner by which they were to actually take a role in relation to the path of progress that the country’s government wants to take as dictated by the administrators. Relatively though, while they were given the option to become excellent in what they are good in, they were not given the liberty to chose what they want to be excellent in. Nevertheless, this form of manipulation specifically boosted the economic status of the nations in the region.

            Children are categorized according to what they can do, lead to schools that help them perfect the said conditions of expertise. They are directed to become the perfect individuals who could make the society they are living in particularly ‘a better place to live in’. In a way, this approach of governance is considered as a restriction on the manner by which the rights of the people to freedom is recognized. Relatively though, for the administrators, this approach was one of the reasons why China and all its neighboring countries were able to withstand the different conditions that the years beyond 1947 offered them. Overall, it could be realized that even though the approach of the western countries towards progress was different, the path chosen by the Southeast Asians have become the best choice for their administration and their people as they embrace development towards a new and modern age.

References:

Mao Tse Tung. On the People’s Democratic Dictatorship: In commemoration of the twenty-eighth anniversary of the communist party of China. Selected Works of Mao Tse Tung.

1900: A Preview of the Twentieth Century.

Categories
Legal Issues

Government Investigations and Access to Information

The Fourth Amendment to the U.S. Constitution states that “The right of the people to be secure in their persons, houses, papers, and effects, against unreasonable searches and seizures, shall not be violated, and no Warrants shall issue, but upon probable cause, supported by Oath or affirmation, and particularly describing the place to be searched, and the persons or things to be seized.” This amendment is an important proscription against the potential overreach of governments or public agencies seeking information from private citizens, businesses, and other organizations. Government agencies attempting to make a legal case against an individual or an organization must adhere to legal restrictions and guidelines in their efforts to obtain information useful in investigations and legal proceedings. The public’s right of access to information is also limited and restricted, with laws such as the Freedom of Information Act (FOIA) proscribing what, when, and how information is to be made public.

Governments have a number of ways in which to gather information. In the context of government oversight and regulation of industries, financial sectors, and other areas of concern, the means by which regulators and government agencies can and does vary according to particular circumstances and situations. At the most basic level, regulators often receive (and transmit) information to and from those that are subject to such regulation. Put simply, “regulators talk to the regulated”(Carter and Harrington, 2000). The information gathered this way is often “communicated in an informal manner and on a voluntary basis,” (Carter and Harrington) and it is this typical form of information-gathering that underpins much of government oversight and regulation.

In instances where the government is attempting to bring a legal case against a business of organization over which it has regulatory power, the need for access to information is of significant concern; acquiring information is what gives regulators the requisite power to successfully prosecute such cases. As an example of how regulatory agencies exert power and gather information in the context of legal proceedings, it will be helpful to examine several specific instances of such activities by a government agency. While the Drug Enforcement Agency (DEA) is responsible at the federal level for the U.S.’ efforts to combat the problems associated with illegal drugs, it is also responsible for regulatory oversight of the handling of legally-prescribed controlled medications. In recent years, the abuse of prescription pain medications and other prescription drugs has received significant attention in the media, and has prompted both greater scrutiny and legal action on the part of the DEA (dea.gov, 2013). When conducting investigations related to the handling and dispensation of medications subject to the Controlled Substances Act (CSA) the DEA must use a number of methods to acquire useful and necessary information.

At its core, the most fundamental question about the government’s interest in acquiring information is whether or not the request is reasonable. Government agencies and representatives who seek information from private citizens or from businesses and other organizations must have a reasonable purpose for asking for such information (Carter and Harrington). If the request for information or access might potentially turn up evidence that a crime or crimes have been committed, it is sometimes necessary to determine if the request for access is reasonable before such access is granted. For example, if the Occupational Safety and Health Administration wishes to carry out an inspection of a business, the OSHA representative typically needs a warrant (Carter and Harrington). If consent for the inspection is granted without a representative of the business requesting a warrant, the information uncovered in the inspection is typically useful and admissible in legal proceedings. If the request to produce a warrant is denied, then the business does not have to grant consent for the search unless and until OSHA is granted a warrant.

In the context of DEA oversight of the handling of legally-prescribed controlled substances, the agency is legally afforded strict control and oversight of the activities of physicians and other prescribers, pharmacists and pharmacies, wholesale and retail distributors of such medications, and the companies that manufacture these medications (dea.gov). A significant body of regulatory procedures, guidelines, and laws has been established that are intended to assure that the activities of these various actors are transparent and that the information related to such activity is easily and readily available to the DEA. Officials from the DEA and the U.S. Department of Justice (DOJ) have used this information to build cases against individuals and organizations that have violated the relevant policies and laws related to the handling of controlled prescription medications; when such information is not forthcoming, these same officials have used the lack of information as the substantive standard for demonstrating a reasonable need for this information (justice.gov, 2013).

In recent years the state of Florida has received intense scrutiny from the DEA for activities within the state that fail to adhere to the guidelines and laws that regulate the handling and dispensation of a number of medications covered by the CSA. According to DEA officials and government prosecutors, Florida has been home to a significant number of so-called “pill mills” (dea.gov); these pill mills are doctor’s offices that prescribe (and sometimes even dispense) pain medications and other controlled substances at rates that the DEA considers to be outside the boundaries of legitimate medical use. These medications are subject to widespread abuse by addicts, and the DEA has charged that the pill mills are contributing to the problem by flooding the streets of Florida with these medications (dea.gov).

Oversight of these medications is supposed to be strict, with doctors limiting the amount of medications they prescribe, pharmacists and pharmacies watching for prescriptions in amounts that should raise red flags, and distributors flagging orders from pharmacies that appear to be excessive. In a recent case that was settled between the DEA and Walgreen’s pharmacy, a large national chain, Walgreen’s agreed to pay a fine of $80 million and to overhaul its methods of handling and dispensing controlled medications (dea.gov). Among the charges that the DEA leveled against Walgreen’s were accusations that the chain and several of its individual pharmacy locations had failed to maintain adequate records and failed to notify the DEA, per statutory regulation, about suspicious prescriptions at the retail level and excessive orders at the distribution level (dea.gov). It is this sort of information that would –or at least should- normally be communicated between the regulated and regulators. When discrepancies in records and errors in reporting were uncovered by the DEA, these failures served as the foundation of the agency’s requests for the warrants needed to uncover more information and ultimately to successfully prosecute their case.

Although the DEA has made the argument that the availability of these controlled medications on the streets poses a significant public health risk, there are a number of factors that make it difficult, or sometimes impossible, for the public to acquire information related to the activities of the DEA both in terms of these investigations and of the overall activities of the agency. The Freedom of Information Act (FOIA), which ostensibly makes it possible for the public to request information about the activities of government, does not always assure that such requests will be met. A number of organizations and individuals who have made FOIA requests to the DEA and DOJ about the activities of the DEA have been denied; according to a recent report, the rate at which such FOIA requests about the DEA have been denied has jumped 114% since the beginning of the administration of President Barack Obama (Rumsey, 2012). Other legal restrictions, such as those that protect the privacy of patients’ medical records, further limit the amount of information available to journalists and other investigators where the DEA is concerned.

There are laws that further protect and enhance the rights of the public to access information about some aspects of the medical and pharmaceutical industries. The Sunshine Act for physicians provides transparency of payments from pharmaceutical companies to physicians, which can expose instances where physicians are receiving payments from the same companies whose medications these doctors are dispensing (healthcaredatasolutions.com). Sunshine Laws offer little in the way of providing access to information about the activities of the DEA, however, despite the fact that the activities of this agency may be as significant an area of public concern as are the activities of the individuals and organizations the DEA regulates. In any instance where information is useful and necessary, whether for use by the government of for the edification of the public, there are a number of laws that are intended to ensure such access.

References

Carter, L. H., & Harrington, C. B. (2000). Administrative law and politics: Cases and comments. New York, NY: Longman.

DEA.gov / Denver News Releases, 05/30/13. (2013, May 30). Retrieved from http://www.justice.gov/dea/divisions/den/2013/den061213.shtml

Pharma Compliance: License Verification | Healthcare Data Solutions | Healthcare Data Solutions. (2012). Retrieved from http://www.healthcaredatasolutions.com/hdsverify.html

Rumsey, M. (2012, July 17). The News Without Transparency: DEA FOIA rejections have increased 114 percent since the end of Bush administration – Sunlight Foundation Blog. Retrieved from http://sunlightfoundation.com/blog/2012/07/17/the-news-without-transparency-dea-foia-rejections-have-increased-114-percent-since-the-end-of-bush-administration/

Walgreens agrees to pay a record settlement for civil penalties under the Controlled Substances Act. (2013, June 11). Retrieved from http://www.justice.gov/usao/co/news/2013/jun/6-11-13.html

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
Ethics

Painkillers “Walgreens”

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
English

Environmental Issues

DiMento, JFC, Doughman, PM. (2007). Climate Change: What It Means for Us, Our Children, and Our Grandchildren. The MIT Press, p. 3. Retrieved from           http://books.google.com/books?id=PXJIqCkb7YIC&printsec=frontcover&source=gbs_g   e_summary_r&cad=0#v=onepage&q&f=false

One of the major reasons that the world has yet to make progress towards slowing down and reversing human effects on the earth is due to social reasons. Many politicians argue that enacting climate change policy is too expensive and not worthwhile. In the United States, the division between the political opinions of Democrats and Republicans is a major contributing factor to this situation. Typically, Republicans claim that global warming is a hoax while Democrats actively advocate for environmental policies.

Knight J, KenneyJJ, Folland C, Harris G, Jones GS, Palmer M, Parker D, Scaife A. (2009). Do              Global Temperature Trends Over the Last Decade Falsify Climate Predictions?   Bull.Amer.Meteor.Soc,. 90 (8): S75–S79. Retrieved from   http://www.metoffice.gov.uk/media/pdf/j/j/global_temperatures_09.pdf

Global warming is typically thought of a process that involves the constant warming the earth’s surface. This study shows that global temperature change has slowed down within the last decade. Despite this, there is clear evidence that there has been climate change over a long time period and this is especially apparent when we graph temperature changes over each year.

NOAA. (2007). Patterns of greenhouse warming. GFDL Climate Modeling Research Highlights.             Retrieved from http://www.gfdl.noaa.gov/cms-filesystem-            action/user_files/kd/pdf/gfdlhighlight_vol1n6.pdf

This pamphlet summarizes the findings of the Geophysical Fluid Dynamics Laboratory. These studies traced the patterns of greenhouse warming and concluded that summer warming over continents may be accompanied by drier soils, the most warming is expected to occur during the winter in North America and north-central Asia, warming in this century will occur more over land than oceans, and the increase of surface air temperatures in response to increasing greenhouse gas levels will not be geographically uniform.

Raupach R, Marland G, Ciais P, Le Quéré C, Canadell G,  Klepper G, Field B. (2007). Global   and regional drivers of accelerating CO2 emissions. Proceedings of the National          Academy of Sciences, 104 (24): 10288–10293. Retrieved from           http://www.pnas.org/content/104/24/10288

Carbon dioxide emissions are responsible for trapping heat in the atmosphere which is directly responsible for causing the Greenhouse Effect. These emissions have been increasing over the years as a result of several factors including more frequent use of fossil fuels and industrial processes. The article discusses the distribution of carbon dioxide emissions across the world, reasons for its release, and provides information on the growth of this practice.

Wentz FJ, Ricciardulli L, Hilburn K, Mears C. (2007). How Much More Rain Will Global         Warming Bring? Science, 317 (5835): 233–5. Retrieved from             http://www.sciencemag.org/content/317/5835/233.abstract

This article discusses the relationship between global warming and rain. It has been determined using climate models and scientific observation that the amount of water stored in the atmosphere will increase as the surface of the earth becomes warmer. While former studies indicate that precipitation will be released at only a portion of this rate, the group discovered that precipitation and surface warming have a direct relationship and an increase in one will lead to a proportional increase in the other. Therefore, global warming will cause a greater extent of precipitation.

Categories
Healthcare

Advantages and disadvantages of the hospital payment systems

Outline

Advantages and disadvantages of the following hospital payment systems on cost containment and provider behavior:

  • Fee-for-service
  • Per diem
  • The DRG-based payment system (i.e., Medicare’s Inpatient Prospective Payment System)
  • Capitation

Fee-for-service:-

         A major advantage of the Fee-for-service (FFS) payment model is that services are paid for separately and not together as other plans. Importantly, it is beneficial to both hospital and the provider since through this payment system earnings can be increased because it patients are charged for each intervention. For example, if a patient had a surgery, the surgeon is paid for the operation whereas the hospital stay is recorded separately benefiting from the procedure. Hence, opportunities to provide more care since these are billed individually. In countries such as Japan fee –for-Service Payment methods are connected to national pricing to contain cost within health care organization

      A notable disadvantage of this method, however, is that patients tend to be offered treatment, which unnecessary, but are added because the physician can derive a fee for the service. In this case the emphasis flows away from quality care towards quantity care critics argue that it is not cost effective because the focus in on quality and not quality. As such, whether patients are heard regarding their complaints is unimportant to both hospital and physician. Subsequently, efficiently is greatly compromised since the goal is more towards improving the censuses and not quality of care (Fuchs, 2009).           

            Per diem:-

         Per diem is a limited model of the prospective payment technique whereby patients pay a daily price or rate for their health care services when hospitalized. Reimbursement is through a third party payer. An example of this system and its advantages for healthcare organizations, especially, hospitals is one practiced by the Indian Health Service whereby they found it useful to combine these payment strategies with supplemental health insurance plans. It has been executed with such dexterity that the payment system has been a tradition in that society regarding fairness of reimbursing physicians for services rendered to patients who are being hospitalized for extended periods of time (Casto & Layman, 2006).

        Critics argue that the method can be exploitive to patients because providers do take advantage of the opportunity to increase the days patients remain hospitalized or hospitalize patients unnecessarily. While all of this may be true the system is cost effective because calculations of daily rates are far less complicated than coding charges per service. Therefore, cost is contained and the health care facility makes a greater profit than in many other payment methods (Casto & Layman, 2006).

Capitation:-

     A great advantage of capitation payment method in health care relates to the third party payer reimbursement strategy. This is calculated based on providers being afixed a certain amount per given period, per capita amount for a period’ (Casto & Layman, 2006, p 4). The terminology per capita pertains to per head or on per person per month (PMPM). Usually, this is the amount of money paid to the provider or hospital on a monthly basis one the client/patient is enrolled in the health insurance plan. It means that providers receive payment for services of all group members regardless of whether the patient is seen or not. Therefore, this is a tremendous advantage for maintenance organizations (Hughes et.al, 2004).

      Consequently, the amount of services has no effect on payment as it relates to increase because there is a set amount of money allotted to the organization or provider for that period. As such, if the entered into an agreement to offer a certain amount of services within a given period of a set of employees this is the payment that will be received. This a notable disadvantage, but it can still contain cost to patients in long term care facilities (Casto & Layman, 2006).

The DRG-based payment system (i.e., Medicare’s Inpatient Prospective Payment System)

         An advantage of DRG-based payment system is the assignment of a specific DRG weight by Centers of Medicare Services to each patient’s accessibility of care profile. This weight gives an estimate regarding the services that are available to that Medicare recipient in the DRG program. It also helps the medical record department to align these resources to those received by other recipients. The purpose of all these weights is mainly for accurately giving account of cost differences among various treatments administered by care providers during hospitalization. Conditions that cost more are ascribed a higher DRG weight for accountability. Examples of weight ranges are ‘the fiscal year 2001 the DRG weights ranges were .5422 for a concussion (DRG 32) to 1.4966 for viral meningitis (DRG 21) to 19.0098 for a heart transplant (DRG 103).29’ (Blount & Waters 2001, p 12).

          However, while the weight assignment is a great advantage of cost containment to hospitals and providers non – physician services provided by hospitals cannot be reimbursed though this system. The organization or provider has to access another resource for submitting such costs directly for reimbursement through PPS (Blount & Waters 2001).

References

 Blount, L. L., & Waters, J.( 2001). Managing the Reimbursement Process. 3rd ed. Chicago:

                  AMA Press

Casto, B., & Layman, E. (2006). Principles of Healthcare Reimbursement. American Health

                  Information Management Association

Fuchs, V. (2009). Eliminating waste’ in health care. Journal of the American Medical

              Association, 302 (22), 2481–2482

 Hughes, J. Averill, F.  Eisenhandler, J. Goldfield, N.Muldoon, J.  Neff, M., & Gay. J. (2004).

           Clinical risk groups (CRGs): A classification system for risk-adjusted

            capitation-based payment and health care management.

            Medical Care 42 (1): 81

Categories
Healthcare

Nursing

Introduction

             The case study for this lesson encompasses hospitalization costs of a 70 year old woman who underwent kidney transplant at a general hospital. She accumulated a total of $150,000 in Medicare-approved charges associated with the procedure. This report outlines individual cost pertaining to the DRG Description Case Weight; 115; Permanent Cardiac Pacemaker; 3.5513; 302 Kidney Transplant 4.1370 and 441 Hand Procedure/Surgery 0.8785. Related to the surgery itself cost will be calculated for operating; capital payment for the hospital. Considerations regarding whether the hospital will be eligible for Medicare outlier payments and the total payment the hospital can receive form the entire procedure.

Case study Application

          The DRG Description Case weight refers to the diagnostic related group (DRG), which classifies hospital inpatient cases for Medicare services. Specifically, DRGs classify all human diseases based on the ‘affected organ system, surgical, procedures performed on patients, morbidity, and sex of the patient’ (Gottlober, 2001, p 2). This classification taken in to consideration an additional eight primary diagnoses along with six procedures performed during Mr. Smith’s hospitalizations. Consequently when a weight is assigned to Mrs. Smith’s procedures it shows the Medicare resources available to her when compared to other recipients with the same condition/ disease. The more intense the disease condition the greater is the weight (Gottlober, 2001).  

         Precisely, 115; Permanent Cardiac Pacemaker; 3.5513; 302 Kidney Transplant 4.1370 and 441 Hand Procedure/Surgery 0.8785 has a less weight than Kidney Transplant and they both have a stronger weight than Hand Procedure/ Surgery.115,302 and 441 are codes provided to each procedure, which indicate the cost ascription of each service. Calculations for each DRG are modified from time to time. However, in the standard methods charge for individual DRG is calculated by adding up all charges for cases within that particular DRG (Gapenski, 2009).

       After arriving at this figure that amount is divided by the number of classified cases contained in the DRG. Prior to this process, though, patient charges are standardized and the effects of regional area wage differences along with indirect medical education costs if the institution is a training hospital are removed. In this case The San Francisco General Hospital is not a teaching facility, but is located in a large urban geographic location. Also, additional payments to hospitals that treat a large percentage of low income patients are removed. (Gapenski, 2008).

      In applying the wage criteria to hospital costs, this accounts for the greatest care expenditure. Center for Medicare Service usually adjusts this cost according to the patient’s income level. Teaching institutions carry a higher cost which could escalate prices for patients even when bring more profit to the institution. There are three other conditions which can affect Mrs. Smith’s the overall cost. They include whether San Francisco General Hospital is located more than 35 miles in proximity to another hospital. Secondly, whether San Francisco General Hospital the only so inpatient hospital servicing that geographic location or if San Francisco General Hospital was designated “critical access hospital’’ by the Secretary (Blount & Waters, 2001).

           In relation to the Kidney Transplant the operating payment to be paid to the hospital requires a six step calculation. Step 1 is calculating the Standard rate; Step 2 Adjusting for the Wage Index Factor; Step 3. Adjusting for the DRG Weight; Step 4 Disproportionate Share Payment ; Step 5 Indirect Medical Education Payment and Step 6 Outlier Payments

Step 1 Calculating the Standard rate

A large Urban area is used because San Francisco General Hospital is located there

Labor related $22,809.18 Non-labor related $10,141.85

Step 2 Adjusting for the Wage Index Factor

$22,809.18 x 1.4193 = $3987.07 (adjusted labor rate for San Francisco) $34,987.07 + $21,141.85= $55,128.92 — Generic Hospital’s Adjusted Base Rate

Step 3 Adjusting for the DRG Weight

Based on the codes

($33,987.07 + $21,141.85) x (1.8128) = $91,297.71

Step 4 Disproportionate Share Payment

This rate is 0.1413. Generic’s base payment rate is multiplied by this rate. ($91,297.71) x (1+ 0.1413) = $100,611.47

Step 5 Indirect Medical Education Payment

The adjustment factor for Indirect Medical Education is 0.0744. This rate is added to the DSH factor plus 1 to give the Hospital an adjustment rate of: 1 + 0.1413 + 0.0744 = 1.2157. The payment the hospital can expect to receive for this case is: $9,297.71 x 1.2157 = $11,303.23

Step 6 Outlier Payments

$150,000 If  Mrs. Smith/’s cost of care exceeded the payment rate by $14,050, the hospital can apply for Outlier Payments

(Blount & Waters, 2001).

Conclusion

What is the operating payment to be paid to the hospital?

This is calculated applying the following formula

DRG Relative Weight x ((Labor Related Large Urban Standardized Amount x Core-Based Statistical Area [CBSA] wage index) + (Nonlabor Related National Large Urban Standardized Amount x Cost of Living Adjustment)) x (1+ Indirect Medical Education + Disproportionate Share Hospital).

What is the capital payment to be paid to the hospital?

This is calculated using the following formula:-

(DRG Relative Rate x Federal Capital Rate x Large Urban Add-On x Geographic Cost Adjustment Factor x Cost of Living Adjustment) x (1+ Indirect Medical Education + Disproportionate Share Hospital)

Will the hospital be eligible for the Medicare outlier payment?  

No because Mrs. Smith’s care does not exceed the pay rate by $14,050,

What is the total payment to the hospital?

$100,611.47

References

Blount, L. L., & Waters, J. ( 2001). Managing the Reimbursement Process. 3rd ed. Chicago:

                  AMA Press

Gapenski, L. (2009). Cases in Healthcare Finance (4th edition). Boston: McGraw Hill-Irwin

                               McGraw-Hill Irwin

Gapenski, L.C. (2008). Healthcare finance: an introduction to accounting and financial

                  management (4th ed.). Chicago, IL: Health Administration Press.

 Gottlober, P. (2001) Medicare Hospital Prospective Payment System: How DRG Rates Are

                       Calculated and Updated. Office of Inspector General Office of Evaluation and                         Inspections Region IX

Categories
Business

The Art of Negotiation

Negotiations of a contract to gain consensus between parties is ultimately the clarification and agreement on what is going to be provided regarding the requirements and what will be exchanged for meeting those requirements prior to the actual efforts taking place.  The process to arrive at the desired end state is a balance of the art of negotiation and science of managing psychological and behavioral activities to manage and control the negotiation and communication.  The art of negotiation involves understanding how to create the behavioral and psychological reactions and interactions of the parties involved and to establish the bond or relationship between the parties of the negotiation.  In regard to the science or tactical side of the negotiation, it is imperative to understand the tools available to the negotiator as well as the knowledge and understanding of what negotiations actually involve. 

There are two types of negotiations, the integrative and distributive.  The distributive negotiation sees negotiation as dividing a fixed amount of items and is by definition finite.  This is representative of haggling for the best price or the best offer.  This is a tug-of-war between the buyer and the seller in which only a certain amount of ground can be gained or lost.  The distributive negotiation is more about keeping key information secret and not allowing any leverage to the other negotiation party.  Integrative negotiations are based on cooperation collaboration for a mutually beneficial objective.  These types of negotiations provide a win-win scenario which is normally used in trouble-shooting, problem solving or finding a resolution to a complex issue with multiple facets.  Distributive negotiations would be used when buying a vehicle or purchasing a house whereas integrative negotiations would be used when selling land to a new corporation that will bring new business opportunities to a community.

Understanding the two sides of negotiation will allow the negotiator to focus on the interactions between themselves and the other parties.  It is important for the negotiator to fully understand the requirements of the negotiation as well as they process required to achieve the requirements.  By understanding the process and ensuring a level of preparedness prior to negotiation the negotiator can focus on those behaviors that can provide a benefit or advantage in the negotiation.  There are certain triggers and reactions that a negotiator can focus on to place the other party at ease and build a bond between each side.  The negotiator must build a relationship while also watching for the pitfalls or roadblocks that could obstruct the pursuit of the desired end state.  These roadblocks include but are not limited to situations such as unsolicited criticism, whether good or mal-intentioned, and potential diversification issues that could lead to barriers in communication, understanding or acceptance of the proposed negotiations.  The negotiator must understand with whom they are communicating with, how their communication is interpreted and if it is received as intended.  Communication is key to negotiations.

Understanding the two sides of negotiation will allow the negotiator to focus on the interactions between themselves and the other parties.  It is important for the negotiator to fully understand the requirements of the negotiation as well as they process required to achieve the requirements.  By understanding the process and ensuring a level of preparedness prior to negotiation the negotiator can focus on those behaviors that can provide a benefit or advantage in the negotiation.  There are certain triggers and reactions that a negotiator can focus on to place the other party at ease and build a bond between each side.  The negotiator must build a relationship while also watching for the pitfalls or roadblocks that could obstruct the pursuit of the desired end state.  These roadblocks include but are not limited to situations such as unsolicited criticism, whether good or mal-intentioned, and potential diversification issues that could lead to barriers in communication, understanding or acceptance of the proposed negotiations.  The negotiator must understand with whom they are communicating with, how their communication is interpreted and if it is received as intended.  Communication is key to negotiations.

The appropriate communication method is not only a vessel to provide key information but it is also a basis for tactical operations within the negotiation as well as the tool to effectively and efficiently close the negotiation with a beneficial outcome.  Each person receives and perceives communication in different ways.  A message could be misinterpreted through subtle changes in the way the message is received.  The message can be altered in multiple ways.  This includes both verbal and non-verbal cues.  These communicative aspects of the negotiation are tools that can promote the success of the negotiation or derail the intentions.  Tailoring messages to specific parties becomes easier with experience and increased involvement with the parties in the negotiation.  These interactions create the psychological and behavioral bonds needed to achieve an on-going and strategically mutual relationship.  Building the relationships between each party also provides the ability for the negotiation teams to bridge the gaps between distance and culture.  As more communication occurs, the better the teams begin to know and understand one another.  Through this collaboration the bond that is built also facilitates the negotiation (Goldman & Shapiro, 2012).

OUTLINE

Thesis Statement:  Research shows successful negotiations are dependent upon the behavioral as well as psychological triggers of the negotiation process because an agreeable personality is crucial in communication, humans generally do not react well to criticism and cultural diversity will present challenges if not understood.

I.  Introduction to Successful Negotiations

a. Definition of the Negotiation (Templar, Herring, Thompson, & Fadem, 2012).

i. Negotiations of a contract to gain consensus between parties is ultimately the clarification and agreement on what is going to be provided regarding the requirements and what will be exchanged for meeting those requirements prior to the actual efforts taking place (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

ii. Negotiations are a balance between hard and soft skills (Gallagher, R. S. 2009).

iii. It is imperative to understand the tools available to the negotiator (Gallagher, R. S. 2009).

iv. Knowledge and awareness are key tools to the negotiator (Barry, B., & Friedman, R. A. 1998). 

iii. There are two types of negotiations, the integrative and distributive (Barry, B., & Friedman, R. A. 1998).

a. The purpose of Negotiations (Templar, Herring, Thompson, & Fadem, 2012).

            i. The purpose is to create a situation in which a party gains what they need. (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

            ii. The relationship can be win/lose, lose/lose or win/win           (Kochan & Lipsky, 2003).

II. The role of an agreeable personality (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

a. Understanding each side of the negotiation is imperative and allows the negotiator to focus on the interactions between themselves and the other parties (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

b. Understanding the process and ensuring a level of preparedness prior to negotiation the negotiator can focus on those behaviors that can provide a benefit or advantage in the negotiation (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

c. The Negotiator must build a relationship while also watching for the pitfalls or roadblocks that could obstruct the pursuit of the desired end state (Goldman, B. M., & Shapiro, D. L. (Eds.) 2012).

d. Communication is critical to successful negotiations (Long, Fisher & McGinn, 2012).

i. Clarity is the key to communication (Patton, 2011).

            ii. Concise communication facilitates negotiations (Patton, 2011).

            iii. The communication must be understood by sender and receiver (Patton, 2011).

 e. Utilizing a straightforward tactic alleviates unnecessary communication and interference that could hinder the process and negate the potential successful conclusion of the negotiation(DeRue, Conlon, Moon, and Willaby, 2009).

f. Straightforwardness sets the tone for the negotiation and creates a slight competitive advantage for the first party by creating a feeling of superiority, credibility and steadfastness (DeRue, Conlon, Moon, and Willaby, 2009).

III. The role of criticism.

  1. Fully understand the requirements of the negotiation as well as they process required to achieve the requirements (Templar, Herring, Thompson, & Fadem, 2012).
  2. Preparedness leads to successful negotiations(Templar, Herring, Thompson, & Fadem, 2012).
  3. Criticism is both a positive and negative tool (Patton, 2011).

i. Unsolicited Criticism puts the other party on the defensive and risks the relationship (Patton, 2011).

ii. Constructive Feedback builds the relationship and moves a potential pitfall to a building experience (Patton, 2011).

  • There are multiple pitfalls in negotiations (Barry, B., & Friedman, R. A. 1998).

i. Unsolicited Criticism (Patton, 2011).

ii. Diversity issues (Gallagher, 2009).

iii. Language Barriers (Gallagher, 2009).

iv. Un-communicated needs (Gallagher, 2009).

v. Misunderstandings (Gallagher, 2009).

III. Cultural diversity.

  1. Key interactions create the psychological and behavioral bonds needed to achieve an on-going and strategically mutual relationship (Goldman & Shapiro, 2012).
  2. There are many aspects of negotiation(Templar, Herring, Thompson, & Fadem, 2012).

i. Communication is important and the ability to create concise, clear and understandable communication is the keystone to the negotiation process (Patton, 2011).

  • Methods of Tactics.

i. The appropriate communication method is not only a vessel to provide key information but it is also a basis for tactical operations within the negotiation as well as the tool to effectively and efficiently close the negotiation with a beneficial outcome (Goldman & Shapiro, 2012).

ii. Diversity between cultures can lead to natural barriers (Kochan & Lipsky, 2003).

iii. Collaborative efforts create the bond that facilitates the negotiation (Goldman & Shapiro, 2012).

Negotiations expand beyond the requirements of one party and the acceptance of requirements by the other.  There is an underlying requirement to ensure the appropriate method of communication is used while also presenting that communication in a straightforward manner.  This straightforward method of communicating the requirements of what one needs enables a slight advantage in the negotiation.  The clear, concise and accurate description of the requirements establishes a level of credibility in the knowledge and understanding of the negotiating party and creates a scenario that is slightly in favor of the straightforward party.  This type of tactic utilizes the psychological and behavioral tendencies of negotiating parties to create an advantage and every advantage in a negotiation will help facilitate the ability to achieve the desired results.  Building relationships is also crucial in taking the negotiations to a higher level of expectations and results.  Understanding how people communicate and what cultural and diversity issues can strain interactions between parties will allow the ability to mitigate those risks and work on the core negotiations.  Eliminating the noise of communication and the barriers of poor delivery and receipt of that communication allows for a pure and focused negotiation on the key points of the requirements.  Understanding what negotiations include, maintaining a prepared and straightforward negotiation style while also maintaining clear and unobstructed communication will all play into the art of negotiation.

References

Barry, B., & Friedman, R. A. (1998). Bargainer characteristics in distributive and integrative negotiation. Journal of Personality and Social Psychology, 74(2), 345. Retrieved from: http://psycnet.apa.org/journals/psp/74/2/345/

DeRue, D. S., Conlon, D. E., Moon, H., & Willaby, H. W. (2009). When is straightforwardness a liability in negotiations? The role of integrative potential and structural power. Journal of Applied Psychology, 94(4), 1032. Retrieved from: http://psycnet.apa.org/journals/apl/94/4/1032/

Gallagher, R. S. (2009). How to tell anyone anything: breakthrough techniques for handling difficult conversations at work. American Management Association, New York. Retrieved from: http://books.google.co.uk/books?hl=en&lr=&id=aY6OR71CvIAC&oi=fnd&pg=PR7&dq=Gallgher,+R.+S.+(2009).+How+to+tell+anyone+anything:+Breakthrough+techniques+for+handling+&ots=wo-QGSdsQJ&sig=aa6IcwyopTAXs5ngHDI_afZ7nTA#v=onepage&q=summary&f=false

 Goldman, B. M., & Shapiro, D. L. (Eds.). (2012). The Psychology of negotiations in the 21st century workplace: new challenges and new solutions. Routledge Academic. Retrieved from: http://books.google.co.uk/books?hl=en&lr=&id=Zz-h37LKklcC&oi=fnd&pg=PP2&dq=The+Psychology+of+Negotiations+in+the+21st+Century+Workplace:+New+Challenges+and+New+Solutions+&ots=jTyVPMfh9o&sig=D6WOkfyn9Vosg_3fv-1e6iPADkk 

Kochan, T. A., & Lipsky, D. B. (2003). Negotiations and change: from the workplace to society. Cornel University Press, New York. Retrieved from: http://books.google.co.uk/books?hl=en&lr=&id=jj2UzQLKfUcC&oi=fnd&pg=PR9&dq=Negotiations+and+Change:+From+the+Workplace+to+Society+&ots=h28DsMzMGS&sig=JJ3eBQvrdyDl8dVaGKmDgzOdrbA 

Kulik, C. T., & Olekalns, M. (2012). Negotiating the gender divide lessons from the negotiation and organizational behavior literatures. Journal of Management, 38(4), 1387-1415. Retrieved from: http://jom.sagepub.com/content/38/4/1387.short

Lewicki, R. J., Saunders, D. M., & Minton, J. W. (1999). Negotiation: readings, exercises, and cases. Irwin/The McGraw-Hill Companies. Retrieved from: http://psycnet.apa.org/psycinfo/1998-07764-000 

Long, E. L., Fisher, C., & McGinn, K. L. (2012). Negotiation processes as sources of (and solutions to) inter-organizational conflict (No. 12-107). Harvard Business School Working Paper. Retrieved from: http://hbswk.hbs.edu/item/6983.html 

Patton, B. (2011). Gaining ground in difficult negotiations: training advanced negotiation & difficult conversations (Vol. 1). Maklu Pub. Retrieved from: http://books.google.co.uk/books?hl=en&lr=&id=xiZYUMw6j70C&oi=fnd&pg=PA6&dq=+Bargaining+for+Advantage:+Negotiation+Strategies+for+Reasonable+People+2nd+Edition+by+G.+Richard+Shell&ots=Tx4jWs2iKk&sig=aQveGPNVHIB0ht_-JIPUJzPwEdI#v=onepage&q=Bargaining%20for%20Advantage%3A%20Negotiation%20Strategies%20for%20Reasonable%20People%202nd%20Edition%20by%20G.%20Richard%20Shell&f=false 

Templar, R., Herring, J. J., Thompson, L., & Fadem, T. J. (2012). Negotiating to win: strategies and skills for every situation (collection). FT Press. Retrieved from: http://books.google.co.uk/books?hl=en&lr=&id=tPBSj1WlQpIC&oi=fnd&pg=PT1&dq=The+Truth+About+Negotiations+by+Leigh+L.+Thompson&ots=CrLodMnsdL&sig=Lgik2nUr2f21s8wEI_9SsPtNk5w   Thompson, L. L., Wang, J., & Gunia, B. C. (2010). Negotiation. Annual Review of Psychology, 61, 491-515. Retrieved from: http://www.annualreviews.org/doi/abs/10.1146/annurev.psych.093008.100458?journalCode=psych