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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
Medicine and Health

Pneumocephalus

Introduction

Millions of people around the world suffer from neurological injuries that can be the cause for serious concern. In some instances, millions ignore the injuries and the warning signs associated with head traumas. Head traumas are a serious injury that have side effects that can range from headaches, dizziness, and other conditions that are best checked in case of damage to the brain or the spinal cord. Pneumocephalus is a condition that can be complicated to diagnose. When patients go in to get checked out the most common complaint is headaches that tend to be neurological symptoms that are related to the buildup of air that places pressure on the brain. Only in the case of MRI scan can doctors determine if there is a serious neurological problem that will show images of the brain and skull. Pneumocephalus is an emergency situation in which there is no outlet for the air that has buildup in the skull. Pnemocephalus is present within the intracranial compartments of the cranial vault that can cause serious complications including the disruption of the brain.

Categories
Medicine and Health

Diabetic Ketoacidosis (DKA) And Hyperosmolar non-ketotic coma (HONK) Treatment and Patient Education (PPT)

Diabetic Ketoacidosis (DKA) And Hyperosmolar non-ketotic coma (HONK) Treatment and Patient Education

Categories
Medicine and Health

Global Concerns Regarding Novel Influenza A (H7N9) Virus Infections

The scare over the possibility of having another medical dilemma has been increased in relation to the entrant of the news about the H7N9. The article written by Timothy Uyeki specifically gives a specific implication on how such scare has been detected and what current studies have already been implicated to make sure that the control over its spread is to be effective enough especially when it comes to manifesting a major public health resolution. Like that of the Avian Flu (AH1N1), the H7N9 is also sourced out from animals. Once the distribution of the virus becomes rampant, there is a scare that it might not be controllable anymore. Consistently, utilizing the research and journal of Gao as reference to the discussion, Uyeki tries to outline the different procedures taken into consideration to discover the different strands of the virus as well as its characteristics in relation to how its genome could be distributed in a rapid pace.

Categories
Medicine and Health

Managing Staff

The location of a healthcare supervisor differs based on the ability that he or she performs in. For instance, in big hospitals a healthcare supervisor can manage just one division and would work mutually along with many other healthcare professionals to make sure the good procedure of the facility. On the other hand, smaller clinics healthcare supervisors can be accountable for handling the whole facility.

Healthcare manager position

The role of a healthcare supervisor also differs in accordance to his or her location.  Some areas of specialty can include:

– Clinical supervisor – makes and equip rules and regulations of a particular Researchers assess the personnel performance make a budget.  Frequently have specialist practical knowledge that fits the office he or she is handling. For instance, if the scientific supervisor is handling the actual remedy office, he or she will usually have practical knowledge or education in the field of therapy.

–  Health information supervisor – maintains individual report and creates definite they are securely stored, that  needs remaining existing on the latest government rules and system as well as on how to utilize current software technology.

Categories
Medicine and Health

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs. An Article Critique

The emergence of Medicaid program is to make sure that the lower-end earners in the overall status of the economy are still given the chance to be provided with the best healthcare that they need to protect themselves and the integrity of their health. However, because of financial subsidy, there are instances when the ones who present their Medicaid to the hospitals are given a much less expensive choice of medicine so they could afford to buy the said health requirements. Notably though, there are instances when such low-amount medicines also have low-grade effect on the patients if not even ready to offer specific side effects that could harm the patients directly.

Categories
Medicine and Health

Critical Review Form- Qualitative Studies

CITATION:

 

 

Bagby, M. S., Dickie, V. A., Baranek, G. T. (2012). How sensory experiences of children with and without autism affect family occupations. The American Journal of Occupational Therapy, 66, 78-86. doi: 10.5014/ajot.2012.000604

 

 

 

 

 

 

Comments

 

STUDY PURPOSE:

 

Was the purpose and/or research question stated clearly?

yes

no

 

 

 

Outline the purpose of the study and/or research question.

The goal of this study was to use a grounded theory approach, one in which inductive reasoning is used to develop a theory from the collected data, to generate a theory to differentiate the family occupations and routines of those families with autistic children from those families with only typically developing children.

 

LITERATURE:

 

Was relevant background literature reviewed?

yes

no

 

 

 

Describe the justification of the need for this study. Was it clear and compelling?

The rationale for this study was quite compelling. The authors noted that little literature has attempted to understand how sensory experiences impact family occupations, and to understand the similarities between families with autistic children and those with only typically developing children.  This study addresses both of those gaps in the literature.  The importance of understanding family occupations rests on the grounds that previous studies have shown that parents of autistic children have to restructure family life to cope with dailiy life experiences, particularly sensory experiences.

 

 

 

How does the study apply to your practice and/or to your research question? Is it worth continuing this review?[1]

The epidemic level growth in autism means that encountering this condition on a reasonably regular basis is a near-certainty.  This study presents important theoretical basis for developing appropriate interventions for such patients. Thus, it is important to continue with this paper.

 

 

 

STUDY DESIGN:

 

What was the design?

phenomenology

ethnography

grounded theory

participatory action research

other

_     _____________

 

 

Was the design appropriate for the study question? (i.e., rationale) Explain.

The study design was very appropriate for the study question.  The author used semi-structured interviews of parents of children with autism as well as parents of typically developing children; the two groups were aga- and gender-matched.  Open-ended questions combined with pre-scripted prompts and probes were used to understand how the children’s sensory experiences impacted family routines and occupations.  From the data collected, a theory was constructed in the analysis section of the paper.

 

Was a theoretical perspective identified?

yes

no

 

Describe the theoretical or philosophical perspective for this study e.g., researcher’s perspective.

A grounded theoretical study such as described in this paper, does not start from a pre-established theory, but instead uses the data collection to define a new theory based on the evidence collected. The researchers noted that there was little in the literature that compared family occupations of those families with an autistic child compared to those families with only typically developing children. They were attempting to close that gap. Thus, the purpose of this paper was to construct a theory addressing this issue.  Thus, the theoretical basis was in the conclusion of the paper, rather than an a priori theory  used to design the study.

 

 

 

 

Method(s) used:

participant observation

interviews

 document review

focus groups

other

_     _____________

 

 

Describe the method(s) used to answer the research question. Are the methods congruent with the philosophical underpinnings and purpose?

The methodology was one of semi-structured interviews.  All interviews were conducted by a single researcher for consistency.  These interview transcripts were then encoded into a set of 110 codes representing concepts and categories.  The codes were grouped into causal conditions, phenomena; context; interviewing conditions; action-interaction strategies; and consequences.  Further, three core categories were developed along with defining potential emerging themes.  This methodology is well defined as appropriate in a grounded theoretical approach.  The methods chosen were congruent with their intentions to define a theory a posteriori rather than a priori.

 

SAMPLING:

 

Was the process of purposeful selection described?

yes

no

 

Describe sampling methods used. Was the sampling method appropriate to the study purpose or research question?

The samples were chosen via a variety of methods, starting from participants in a much larger prior study.  The reseearchers noted that the recruitment was done via e-mail lists and word of mouth.  The researchers also noted the exclusion and inclusion criteria for the  two groups.

This is generally appropriate, however, the sample used in this study is extremely small (only 6 in each group) and the selection is a convenience sample of those meeting the criteria.  No information is provided regarding how many other potential participants, also meeting the appropriate criteria, were excluded from this study orwhether the first 6 were simply the ones chosen for participation.

 

 

 

 

 

Was sampling done until redundancy in data was reached?[2]

yes

no

not addressed

 

Are the participants described in adequate detail? How is the sample applicable to your practice or research question? Is it worth continuing?

The participants were described in reasonable detail.  Note that the participants in the study were actually the parents of the autistic children (and the parents of the typically developing children). The ideintifying information used to describe the participants included the age of the chid, the gender of the child, and the mother’s level of education.  Children’sages ranged from 2 yr 4 mo. to 8 yr 6 mo.  Of the 12 participating mothers, 7 had graduate degrees, 1 had a bachelor’s degree, and 2 had associate degrees. Only 2 had only a high school diploma and none were high school dropouts.  This very high level of education most likely reflects the university-town context in which the study was conducted.

The families of this study are not directly similar to families that are likely to occur in my future practice, which are unlikely to have so much advanced education as these participants. As noted in the study, the degree to which the study’s conclusions generalize to other populations cannot be determined by this research.  However, it is unclear if that socio-economic difference makes a serious impact on the relevance of the study.  Thus, it is worth continuing to consider this paper.  This also provides an opportunity for me to consider for future reasearch to determine if similar results would be obtained from more demographically common participants, i.e., those from a lower educational and/or socioeconomic group.

 

 

 

 

Was informed consent obtained?

yes

no

not addressed

 

The study clearly states both that parents received informed consent and that the study was approved by the institutional review board of the researchers’ university.

 

 

 

DATA COLLECTION:

 

Descriptive Clarity

Clear & complete description of

site:                         yes   no

participants:          yes   no

 

Role of researcher & relationship with participants:

yes  no

 

Identification of assumptions and biases of researcher:

yes  no

 

 

Describe the context of the study. Was it sufficient for understanding of the “whole” picture?

The context of the study was briefly described as “telephone or face-to-face interviews.”  No indication was given regarding which participants were interviewed in person and which over the phone. Furthermore, the parents were only interviewed once, and only the mothers were interviewed.  Participants were paid either $25-$75 for parents of autistic children or $5 for parents of typically developing children.  The children received a toy. It is difficult to determine if the data collected is sufficient to understand the whole picture since the raw data was not made available in the study. The answer to that has to be “indeterminate” based solely on the information available in the study.

 

 

 

 

 

What was missing and how does that influence your understanding of the research?

One key missing piece would be the perspectives of other family members, such as fathers, or older siblings.  This study did not address those at all.  Also the high level of education of the participants in the study makes it hard to know how well the authors’ results generalize to other populations.

 

Procedural Rigour

Procedural rigor was used in data collection strategies?

yes

no

not addressed

 

 

 

Do the researchers provide adequate information about data collection procedures e.g., gaining access to the site, field notes, training data gatherers? Describe any flexibility in the design & data collection methods.

The researchers explain their data collection process with some degree of rigor, but it could be improved. For example, only “example” questions used in the interviews were provided rather than a list of all the open-ended questions used.

 

 

 

 

 

 

DATA ANALYSES:

 

Analytical Rigour

Data analyses were inductive?

yes    no   not addressed

 

Findings were consistent with & reflective of data?

yes   no

 

Describe method(s) of data analysis. Were the methods appropriate? What were the findings?

The data analysis, as noted earlier, used grounded theoretical approaches to encoding the interview transcripts. Care was taken by the researchers to confirm the encoding using a variety of self-check schemes.

The authors describe their results under three themes of ‘what families choose to do”, “how families prepare” and “extent to which experiences, meanings, and feelings are shared.”  In each theme, they describe the differences and commonalities between the two groups, citing occasional specifics from one interview or another.   In the first theme, they noted all families modified their activities based on their child’s developmental level.  In the second theme they noted that the degree of preparation varied based on the degree of sensory-intensity of the activities, with families with autistic children having to do more detailed and broader preparation.  In the third theme, the researchers noted that feelings, meaning, and experiences were shared less often in families with autistic children.

 

 

 

 

 

 

 

 

 

 

Auditability

Decision trail developed?

yes   no   not addressed

 

Process of analyzing the data was described adequately?

yes   no   not addressed

 

Describe the decisions of the researcher re: transformation of data to codes/themes. Outline the rationale given for development of themes.

The authors described the encoding process with a fair degree of detail, including providing detail on the software used to identify the themes and categories.  While the authors detailed their process, they were less clear on the specificsof their data analysis in terms of listing the categories and themes that emergedin the encoding process.  What is stated in the paper is that their creation of three “core categories” attempted to cature the central phenomenon of the interview.  They also noted that Bagby (the interviewing researcher) used Charmaz’s memo technique to define potential emerging themes, to label interesting quotes, and to determine the most salient elements of the interviews. Since the core categories and groupings are not clearly stated in the paper, it is difficult to be specific about the authors’  rationale beyond stating that they complied with accepted interview analysis techniques.

 

 

 

 

 

 

Theoretical Connections

Did a meaningful picture of the phenomenon under study emerge?

yes

no

 

 

 

How were concepts under study clarified & refined, and relationships made clear? Describe any conceptual frameworks that emerged.

The authors came to three key conclusions about how  children’s sensory experiences affected family occupations.  These were: (1) decisions about what the family did or did not do; (2) how the family prepared for activities and events; and (3) the extent of sharing of experiences, feelings, and meanings.  The focus was on the children under study and their parents, but there may be additional (or alternative) impacts on siblings that were not studied.

The authors do not clearly state their new theoretical framework in this paper, unfortunately. They do say that they have developed one, but as described in the paper it is somewhat vague and difficult to explain simply. In essence, the authors concluded that having a child with autism (1) restricted the types and number of activities the family participates in; (2) reduces the sharing of experiences within the family; (3) significantly increases the degree of preparation required to perform an occupation; (4) dramatically increases the sensory experiences the autisitc child has.  In addition, the authors concluded that a typically developing child having a “bad” day modified the family’s responses to be more similar to those of a family with autistic children, thus partly bridging the gap between the occupations of the two types of families.

 

 

 

 

 

 

 

OVERALL RIGOUR

Was there evidence of the four components of trustworthiness?

Credibility              yes  no Transferability       yes  no

Dependability        yes  no

Comfirmability      yes  no

 

 

 

For each of the components of trustworthiness, identify what the researcher used to ensure each.

For credibility, the authors carefully delineated their methodology and the care taken to properly analyze the data.  For transferability, which is the weakest link in this study, the authors noted that their sample is quite small and that it derived from an atypically educated segment of the general population.  For dependability, the authors noted their efforts to ccheck and cross-check their coding of the interviews to ensure that it was correctly performed.  Confirmability was not directly addressed by this study.

 

 

 

 

 

What meaning and relevance does this study have for your practice or research question?

The study provides some guides for developing strategies that address a child’s sensory processing as an important factor in determining family activities and occupations.  In particular, the authors noted the many similarities between typically developing children and autistic children. Thus there is relevance both for families of autistic children and typically developing children.

 

 

 

 

CONCLUSIONS & IMPLICATIONS

 

Conclusions were appropriate given the study findings?

yes  no

 

The findings contributed to theory development & future OT practice/ research?

yes  no

 

 

 

What did the study conclude? What were the implications of the findings for occupational therapy (practice & research)? What were the main limitations in the study?

This study provided insight into how families cope with children’s sensory experiences, whether the children are autistic or not.  Unfortunately, the conclusions are fairly general rather than specific.  It is less clear that the conclusions are non-obvious.  For example, one conclusion is that family routines are important in all families.  A second is that parents with autistic children limit family activities and locations while families with typically developing children tended to expand their children’s sensory experiences. The third conclusion was that family occupations were affected to the extent to which they were shared.  These conclusions seem fairly self-evident rather ones that are novel or that break new ground.  On the other hand, the authors also present some excellent suggestions for OT practice that are worth taking into consideration when dealing with families with children, autistic or not.

The implications for OT practice are clearly defined by the authors and can be summarized as: (1) consider both positive & negative impacts of the child’s sensory experiences on the family; (2) educate parents on these impacts and offer coaching to help them optimize their strategies to cope with the child’s responses; (3) provide strategies to plan and prepare for activities, while being sensitive to the parents’ stress levels; (4) help parents understand their child’s sensory experiences and help them minimize confusion, worry, and feelins of inadequacy, particularly with an autistic child; (5) beware of using clinical jargon with parents or or pathologizing the child; (6) provide management strategies rather than attempt to change the child; (7) identify occupations that can overcome uncomfortable sensory experiences for the child; and (8) establish positive sensory routines that promote shared experiences.

The key limitations of this study were the extremely small sample size, the high educational level of participants (which limits its generalizability), and the lack of inclusion of family members other than mothers in the interviews.

 

[1] When doing critical reviews, there are strategic points in the process at which you may decide the research is not applicable to your practice and question. You may decide then that it is not worthwhile to continue with the review.

[2] Throughout the form, “no” means the authors explicitly state reasons for not doing it; “not addressed” should be ticked if there is no mention of the issue.

Categories
Medicine and Health

Barriers to Medication Compliance with Bipolar Patients

Table of Contents

Introduction.. 3

Research Question. 5

Theoretical Basis for Study…………………………………………………………………………………. 6

Significance of Study. 6

Literature Review… 8

Medication Compliance. 8

Factors Affecting Compliance. 10

Issues in Non-Compliance. 12

Methodology.. 14

Research Design. 14

Sample. 15

Procedure. 15

Human Subject Issues……………………………………………………………………………………….. 15

Findings. 17

Discussion.. 20

Limitations. 22

Conclusions. 23

Implications for Clinical Practice. 23

References. 25

 

Barriers to Medication Compliance with Bipolar Patients

Introduction

Bipolar disorder (BPD) is a serious disease that afflicts approximately six million Americans. Two types of BPD are recognized, BPD type I (BPD-I), which is the more severe form of the condition including at least one manic or mixed manic/depressive episode, and BPD-type II (BPD-II) in which the manic episodes are more moderate or hypomanic; the level of depressive symptoms may be as severe as in BPD-I, however (Puri & Gilmore, 2011). BPD-II is closely associated with a prevalence of anxiety disorders, and longer or more frequent depressive phases (Puri & Gilmore, 2011).

BPD is a serious illness, and frequently is found in patients with other psychiatric disorders such as substance abuse, anxiety, ADHD, eating disorders, and others (Sansone & Sansone, 2011). Other issues are that BPD patients are at substantially higher risk of suicide (both attempts and completions) than patients with other psychiatric disorders, with as many as one in five attempting suicide at least once in their lifetime, and untreated BPD patients have a suicide rate twenty to thirty times higher than in the general population (Sansone & Sansone, 2011). Thus, BPD may be the most lethal of all psychiatric disorders (Sansone & Sansone, 2011).

Diagnosing BPD is challenging because it primarily presents in the depressive part of the cycle and thus is often mistaken for simple depression (Baldessarini et al, 2010).  Some distinguishing characteristics of BPD are that it is almost equally prevalent in males as females; it often appears in adolescence or early adult years particularly in cases with a family history of mood disorders (Baldessarini et al., 2010). BPD-I appears at younger ages than BPD-II, and BPD-II generally appears at younger ages than depression (Baldessarini et al., 2010).  BPD also has a high recurrence rates, with substantial mood shifts about once or twice a year typically, and, in some patients, even more rapid cycling of four or more episodes a year  (Baldessarini et al., 2010). As a result of these and other difficulties, it is often five to ten years after initial symptoms before correct diagnosis and treatment is begun  (Baldessarini et al., 2010).

However, the treatment of BPD is controversial. Guidelines suggest that treating BPD patients solely with an antidepressant is not a good idea because it may induce a manic state—yet multiple studies offer evidence exists that fluoxetine in depressed BPD-II patients is actually reasonably effective on at least a short-term basis for depressed phases (Sansone & Sansone, 2011). The treatment for the manic episodes in BPD patients is equally controversial, with antipsychotics and lithium being notorious for their side effects.  Common side effects, including weight gain, increases the risk formedical complications such as hypertension, hyperlipidemia, diabetes, asthma, and joint pain (Sansone & Sansone, 2011).  Given the current epidemic of obesity in this country, weight gain associated with their BPD treatment regimens, reported in about 30% of BPD patients, is itself a serious problem, with nearly one in five developing hyperlipidemia and 8.6% developing diabetes (Baldessarini, Perry & Pike, 2008). Psychiatrists note that critically needed improvements in available treatments including the need for better mood stabilization, medications that do not lead to weight gain, and better treatment for depression that does not respond to current treatments (Baldessarini, Perry & Pike, 2008).

A diagnosis of BPD can be expensive for the patient and third-party payers. Hassan and Lage (2009) report that caregiving costs associated with BPD are nearly $5 billion a year, while lost productivity within the family as a result of relapses was $6.2 billion a year (Hassan & Lage, 2009). Thus, controlling relapses via medication is important for BPD patients. The medications used to treat BPD can be expensive. Many of the newer BPD medications are brand-name rather than generic, making them more expensive. In addition, some BPD medications such as some of the antipsychotics also require regular laboratory tests as part of the dosage monitoring process, making them even more expensive for patients (Sansone & Sanson, 2011).  Qiu, Fu, Liu, and Chirstiensen (2010), however, investigated the actual annual medical expenses of BPD patients in one state (North Carolina) using Medicaid data. They found that prescribing atypical antipsychotic medications alone had higher medication costs, but lower overall medical care costs than those receiving only a mood stabilizer, making the overall cost of those two options approximately equivalent. The most expensive treatment option from a third-party payer perspective was that of combining antipsychotic medications with a mood stabilizer (Qiu et al., 2010).

Patients report that the greatest frustrations of having BPD are mood swings, depression, the need to take medication daily, the stigma of being “mentally ill,” difficulty with interpersonal relationships, and medication side effects (Baldessarini, Perry & Pike, 2008). The result of these frustrations with their condition can lead some patients to be non-compliant with their treatment program.

Research Question

The questions raised by these issues regarding BPD result in some serious treatment questions, specifically:

What reasons do patients cite for not being compliant with their BPD medication regimens?

The objective behind this research question is to better understand noncompliance from the patient’s perspective, and thus have an understanding of what interventions may be most useful in improving patient compliance. The approach that will be taken is one of a qualitative study to determine patient rationales for their noncompliance. The issue is of particular importance in an advanced nursing practice since understanding why patients do not comply with their medications directly impacts providing quality patient care. If nurses can better understand the rationales patients have for not taking their medications, strategies can be developed to overcome these barriers to proper compliance with the patients’ medication regimens.

Theoretical Basis for Study

Categories
Medicine and Health

Autogenous Tooth Transplantation: Five Year Re-evaluation of a Vital Transplant

Introduction

The concept of tooth transplantation for many is not realistic due to the narrow indications for its use. Required is strict selection of patients combined with appropriate surgical technique for success to be realized. The consideration of the transplant as a clinical option has been eliminated due to the predictability of implant dentistry. However, the long-term prognosis of dental implants in addition to how these implants accommodate to the changing natural dentition during the process of aging is yet unknown. This study re-evaluates the autogenous tooth transplant and the role it may play as a treatment plan option. In addition, this study highlights the indication for autogeneous tooth transplantation using a case report as an example. Review of the recommended surgical technique and success rates will be discussed.

According Andresen, et al ( 2001) (1) results reported in a long term study of 370 transplanted premolars, the state of most development that is optimal for this procedures is “three-quarters root formation in which the apex is wide open and the follicle covering the root surface is thick and resistant to trauma.” (Andresen, et al, 2001, p.134) When the transplantation has been carried out It is very important to monitor eruption and periodontal and pulpal healing.” (Andresen et al, 2001, p.134)  Eruption will take place after several months, periodontal ligament healing can be verified after six weeks. (Andresen, et al, 2001, p.134) The growth of additional root can be verified in the majority of cases however, in approximately one-third of transplanted premolars there will be arrest of root formation results. If the tooth is graphed after 75% root formation has taken place there will generally be no practical implications for the long-term survival of the implant. (Andresen, et al, 2001, paraphrased) This procedure is highly predictable and dependent on the state of root formation, which has been confirmed during long-term studies. (Andresen, et al, 2001, paraphrased)

For many, the concept of tooth transplantation may not be realistic due to the narrow indications for its use. Strict patient selection in addition to appropriate surgical technique is required for success.  The predictability of implant dentistry has virtually eliminated consideration of the transplant as a clinical option.  However, the long-term prognosis of dental implants and how they accommodate to the changing natural dentition during the aging process yet remains to be seen. This paper re-evaluates the autogenous tooth transplant and the role it may play as a treatment plan option.  This article highlights the indication for autogenous tooth transplantation using a case report as an example.  Review of the recommended surgical technique and success rates will be discussed.

Work by Apfel, Hale and Miller in the 1950’s was the first to well document the successful autogenous tooth transplant and establish the surgical techniques along with indications for autogenous tooth transplantation.   Third molars with incomplete root formation were moved to other sockets of extracted teeth and as by the high success rate reported in the studies over the last decade autogenous tooth transplantation has demonstrated to be a viable option for tooth replacement under the right condition.

Background

The work of Clokie, Yau, and Chano (2001) (3) entitled “Autogenous Tooth Transplantation: An Alternative to Dental Implant Placement” reports that the earliest reports of tooth transplantation occurred in slaves in ancient Egypt who were compelled to provide their teeth to the pharaohs. This procedure is reported as having been abandoned due to “problems of histocompatibility” and this was replaced with autotransplantation. (p.92) Patient selection is of critical importance in successful autotransplantation. Patients must be healthy and capable of following post-operative instructions and able to keep follow-up appointments. In addition, patients should “demonstrate an acceptable level of oral hygiene and be amenable to regular dental care.” (Clokie, Yau, and Chano, 2001. (p.93)(3)  The most important factor is the patient having a suitable recipient site and donor tooth. (Clokie, Yau, and Chano, 2001, p.93) (3)

Dentistry has been historically primary concerned about tooth extracting and provision of prosthesis for edentulous areas. In the past, animal teeth, ivory, bone and human teeth extracted from the deceased has been sued as denture material but due to discoloration none of these material were found acceptable with reasons stated as “discoloration, bad odor and structural weakness.” (Andreason, 2001, p.170) Tooth transplantation was conducted exclusively on the upper classes until the latter part of the 19th century, since only the upper classes could afford such treatment. In the 1950s information about autotransplantation began to appear with the concept being that following extraction of a first molar that was unrestorable due to severe decay that an impacted developing third molar could be transplanted to replace the extracted tooth with a 50% success rate. Failure was due to the  lack of development of the transplanted tooth and autotransplantation was then considered only a temporary treatment. Autotransplantation  has gained attention since recent research on periodontal ligament healing following autotransplantation has made provision of information that can be applied to the procedure.

Case Report

During a routine orthodontic examination of an 11-year male it was found that both lower mandibular central incisors were congenitally missing. The patient was referred for evaluation of an erupting maxillary single rooted supernumerary tooth in the buccal vestibule adjacent to tooth #10, class III mobility of the retained primary mandibular central incisors and congenitally missing mandibular central incisors 24 and 25. Radiographic examination revealed a retained primary dentition at the sites of congenitally missing teeth 24 and 25 in addition to the presence of a maxillary single rooted supernumerary tooth with incomplete root formation.

Since the maxillary supernumerary tooth was to be extracted, it was decided to attempt an autogenous tooth transplant of the upper supernumerary single rooted tooth to site of the retained primary and congenitally missing central mandibular incisors.  The space allotment would require enamel plasty of the maxillary supernumerary tooth prior to inverting and planting into the recipient site.

Indications

Qualities of candidates for autogenous tooth transplantation include patients who are systemically in good health and acceptable for oral surgical procedures; show good oral hygiene practices; have donor teeth and who choose autogenous tooth transplant procedures over other treatment modalities. Indications for donor teeth include adequate viable periodontal ligament and that can be extracted with minimal damage to the periodontal ligament.  Single rooted teeth without surface concavities are the best candidates.  Nonworking, mal-positioned, dislocated, tilted or impacted teeth qualify well. Recipient site indications include alveolar ridges with sufficient height and width to receive the donor tooth or teeth.

Contraindications

Categories
Medicine and Health

Heart Failure

Medically speaking, heart failure is a condition in which the heart cannot pump enough blood in relation to the venous return and the metabolic requirements of body tissues. Extreme exertion may cause heart failure in persons with normal hearts if there exists a discrepancy between the needs of the body and the volume of blood pumped by the heart. Heart failure may also be categorized as cardiac mechanical failure, myocardial failure, and arrhythmic failure.

Categories
Medicine and Health

Obesity in America

It is often said that Americans are the best marketers in the world. It doesn’t take much effort to understand why it may be true, given the sheer number of American brands that are world famous including Coca Cola, Pepsi, Heinz, Mars, Snickers, McDonald’s, Nike, and IBM. These brands have played a huge role in converting America into a consumerist society where almost every citizen has easy and convenient access to junk food and drinks. There are often more McDonald’s, Burger Kings, and KFCs in some small cities in America than there are in entire countries elsewhere in the world. The result has been a devastating rise in obesity which has imposed both huge economic and social on the American society. In addition, technology has made our lives even more convenient and growing competition has been leading to even busier work lifestyle. Thus, obesity crisis in America is not due to any single factor but the outcome of multiple factors including unhealthy diet, lack of physical activity, and genetic influences

Categories
Medicine and Health

Pros and Cons of Animal Research

Pros

The Animal Model and Human Benefits

            In the world of scientific research few topics can inspire debate like the use of animals for experimental purposes (Hobson-West, 2010). There are passionate proponents of both sides of the dispute that have outlined the major themes that sustain the issue. For example, the concept raises several questions about important factors like cruelty and potential benefits for both humans and animals. Many types of animals from small to large are subjected to tests on a daily basis, demonstrating that the topic applies to creatures throughout the animal kingdom. Since humans are part of this group, whether or not we like to acknowledge it, animal testing has been fundamentally supported by the idea that testing on animals provides results that are applicable to humans. As this theory has come to be supported by evidence, it represents a primary pro of animal research.

Categories
Medicine and Health

Ethics of Clinical Research and Medical Care

Clinical research and medical care both rely on ethics to maintain safety and moral integrity.  When involving human subjects, a strong ethical code is crucial.  Since science and medicine are interdependent on one another, clinical research and medical ethics both strive for progress in the healthcare field, though their methods and guidelines may differ.