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A Study of Multiple Sclerosis: Description by Alex Dunedin
It was a French neurologist at the Salpetriere in Paris, Jean Martin Charcot, who first described multiple sclerosis in 1868. He noted the accumulation of inflammatory cells in a perivascular distribution within the brain and spinal cord white matter of patients with intermittent episodes of neurologic dysfunction. This led to the term ‘sclerose en plaque disseminees’, or Multiple Sclerosis (MS) [12]. In 1933, Thomas Rivers at the Rockefeller Institute demonstrated experimental autoimmune encephalomyelitis, an autoimmune demyelinating disease in mammals. He achieved this with the repeated injection of rabbit brain and spinal cord into primates. This has led to the generally accepted hypothesis that multiple sclerosis is secondary to an autoimmune response to self antigens in a host [12].
Thomas Rivers at the Rockefeller Institute
In 1948, Elvin Kabat made the observation that there were increases in oligoclonal immunoglobulin in the Cerebrospinal Fluid (CSF) of patients with multiple sclerosis. This provided further evidence of the inflammatory nature of the disease. In the past 50 years, several studies focusing on twins have explored the possibility of a genetic factor as having an involvement in multiple sclerosis [12].
Multiple Sclerosis is the most common idiopathic inflammatory disease of the central nervous system. The distinction between multiple sclerosis and other benign or fulminant inflammatory demyelinating disorders is based on quantitative, rather than qualitative, differences in chronicity and severity [4].
Multiple Sclerosis is postulated as being unlikely to be a single disease entity. The term has been used to encompass a spectrum of heterogeneous disorders which produce a similar clinical picture. The clinical picture involves diverse pathologies and damage mechanisms including inflammation, demyelination, remyelination, axon injury and loss, oligodendrocyte and neuron loss, and astrocyte gliosis [42].
Four distinct immunopathologic patterns within acute plaques have been described. Principle damage mechanisms in multiple sclerosis may also change over time. Multiple Sclerosis is recognized as variable and unpredictable. Central Nervous System damage remains hidden for a long time so that clinical evaluation does not assess disease activity status very well. This is especially true for the early disease phases [42]. It has been hypothesized that multiple sclerosis is caused by a combination of genetic (polygenic) predisposition and exogenous factors (viral or bacterial infection) that induces an inappropriate immune response to one or more central nervous system autoantigens [67]. Scanning electron micrograph of T lymphocyte (right), a platelet (center) and a red blood cell (left) Multiple sclerosis is more common in females and often first manifests clinical symptoms during young adulthood. Relapses or “attacks” typically present subacutely, with symptoms developing over hours to several days, persisting for several days or weeks, and then gradually dissipating. The attacks are likely caused by the traffic of myelin reactive T cells into the central nervous system, causing acute inflammation with associated edema [12]. High dose steroids quickly abolishes multiple sclerosis symptoms. Acute edema and its subsequent resolution underlie the clinical relapse and remission respectively. Studies in Acute Disseminated Encephalomyelitis (ADEM) in humans and Experimental Autoimmune Encephalomyelitis (EAE) in rodents suggest that immunologically acute attacks are self-limited by regulatory T cells [12].
http://pmj.bmj.com/content/79/927/11.full.pdf
Multiple sclerosis and experimental autoimmune encephalomyelitis are both immune mediated diseases of the central nervous system. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss [24].
Multiple sclerosis is an inflammatory disease largely limited to the central nervous system white matter. The central nervous system inflammation varies among different patients, and consists of variable degrees of T lymphocytes, macrophages, B lymphocytes, and antibodies at the leading edge of the white matter destruction [25]. The association of multiple sclerosis with Major Histocompatibility Complex genes (MHC), inflammatory white matter infiltrates, similarities with animal models, and the observation that multiple sclerosis can be treated with immunomodulatory and immunosuppressive therapies is the foundation of the autoimmunity hypothesis in the disease pathology. Activated CD4+ myelin reactive T cells are major mediators of the disease [26].
Clinical Picture
The clinical picture involves diverse pathologies and damage mechanisms including inflammation, demyelination, remyelination, axon injury and loss, oligodendrocyte and neuron loss, and astrocyte gliosis. Four distinct immunopathologic patterns within acute plaques have been described. Principle damage mechanisms in multiple sclerosis may also change over time. Multiple sclerosis is recognized as variable and unpredictable [42]. Central nervous system damage remains occult for a long time so that clinical evaluation does not assess disease activity status very well. This is especially true for the early disease phases. Frequent magnetic resonance imaging (MRI) studies indicate that 80% to 90% of new MRI brain lesions are not associated with definable relapses [42].
‘Dawson’s Fingers’ pattern appearing on an MRI scan in Multiple Sclerosis
Experimentally, global disease measures (brain and cervical spinal cord atrophy, whole brain n-acetylaspartate on magnetic resonance spectroscopy, magnetic transfer and diffusion tensor histograms) detect extensive but subtle abnormalities in normal appearing brain tissue in addition to the macroscopic plaques. This occurs even in early disease stages. The inability to evaluate the true extent of injury in daily practice makes accurate prognosis difficult [42].
Diagnosis is based on a set of core clinical principles supported by laboratory testing which typically includes appropriate blood work, Magnetic Resonance Imaging, CSF (cerebrospinal fluid) analysis, and sometimes evoked potential testing [42].
The most important demyelinating disease is multiple sclerosis because of its frequency. It is more common in women than men, familial aggregation sometimes occurs, and it has a higher incidence among carriers of HLA3 and HLA7 of the human leukocyte antigen (HLA) system. It is an autoimmune disease that may be triggered by a viral infection and is characterized by demyelinating inflammatory foci [69]. The typical feature of multiple sclerosis is the temporally unrelated occurrence of completely different neuronal deficits, caused by lesions in different parts of the brain. Some of the lesions may partly regress when the local inflammatory process has subsided and the nerves (in the case of intact axons) have been remyelinated [69]. Multiple sclerosis has inflammatory and degenerative components. Inflammation which corresponds to the progressive phase is at its maximum in the beginning and falls over time. Neurodegeneration which corresponds to the progressive phase is present at all timepoints but is unmasked late. Multiple sclerosis involves simultaneous destruction and repair procedures. Multiple sclerosis is an organ specific disease with pathology confined to the central nervous system. The only consistent systemic abnormality is immune system activation [42].
In the search for potential multiple sclerosis biomarkers research has been divided into several broad categories:
Immune System Changes
Blood brain barrier disruption
Demyelination
Oxidative stress, excitotoxicity
Axonal/neuronal damage
Gliosis
Remyelination, repair
Plaques of Multiple Sclerosis
In multiple sclerosis there are multiple plaques of demyelination within the brain and spinal cord. Plaques are ‘disseminated in time and place’, hence the old name ‘disseminated sclerosis’ [95]. Multiple sclerosis is a syndrome of progressive nerve disturbances that usually occurs early in adult life. It is caused by gradual loss of the myelin sheath which surrounds the nerve cell. This process is termed demyelination [96].
Multiple sclerosis, gross: Classic multiple sclerosis (Charcot-type) grossly shows well-demarcated tan-gray patches of demyelination. Plaques are often present adjacent to the lateral angles of the lateral ventricles (pictured), optic nerves, floor of the fourth ventricle, brain stem and spinal cord. They may vary in shape, number and distribution and can occur anywhere in white matter, at gray-white junctions or even within cortical/deep gray matter. Taken from: http://www.urmc.rochester.edu/libraries/courses/neuroslides/lab3a/slide097.cfm
Oligodendrocytes form the myelin sheath around the axons of CNS nerve cells. One of the key functions of the myelin sheath is to facilitate the transmission of the nerve impulse. Without the myelin sheath, nerve function is lost. Symptoms correspond to the nerves that have lost their sheath [96]. Multiple sclerosis is a chronic disease of the central nervous system characterized by inflammation, myelin and axonal destruction, intermittent disability, and eventual chronic progressive neurological deterioration [78]. Multiple sclerosis is viewed as a largely subclinical inflammatory disease in its early stage. Periodic relapses punctuate the early course in most cases, but do not accurately reflect the severity of the underlying pathology. As viewed by imaging studies, multiple sclerosis is a continuously active, albeit fluctuating disease process, which results in severe brain tissue injury and brain atrophy alarmingly early in the disease course [78].
After years of fluctuating inflammation with related tissue injury, progressive neurological disability ensues relatively late in the disease. The pathological targets in multiple sclerosis are now known to include neurons and axons in addition to myelin, and progressive axonal loss is thought responsible for progressive neurological disability commonly observed in later stages [78].
Multiple sclerosis is characterized by multiple symptomsandsigns of brain and spinal cord dysfunction that are disseminated in both time and space. Its pathological hallmark is demyelination and axonal lesions. A relapse is the appearance of a new neurological disturbance, or the reappearance of one previously present, lasting at least 24 hours. All such disturbances arising within a one month period are counted as a relapse. The relapse rate is the number of relapses per year. Clear improvement of neurological function is termed remission [65].
Involvement of Immune Cells
Cell subpopulation studies have focused on blood; peripheral cells show increased activation markers. In a prospective study of 40 untreated patients with relapsing and progressive multiple sclerosis followed for one year, changes in activated T cell populations in the blood were correlated with clinical and MRI disease activity [42].
In relapsing multiple sclerosis, increases in CD4+ CD25+ cells correlated with clinical attacks while increases in CD25+ and CD4+ I3+ cells correlated with increased Expanded Disability Status Scale (EDSS). Increases in CD4+ CD26+ cells in relapsing patients, and increases in CD4+ I3+ cells in Secondary Progressive Multiple Sclerosis (SPMS) patients correlated with a simultaneous increase in Gd+ lesions [42]. Increase in I3+ cells in SPMS correlated with a simultaneous increase in T2 lesion volume, while in progressive multiple sclerosis, increase in CD26+ and CD4+ CD26+ cells correlated with increased lesion burden. Decrease in CD4+I3+ cells correlated with an increase in Gd+ lesions and more new Gd+ lesions [42]. In contrast to these activation markers, changes in CD3+ and CD4+ T cells did not correlate with clinical or MRI measures. In a cross sectional study, kinin B1 receptor mRNA transcripts and protein were significantly upregulated on circulating lymphocytes during active disease in relapsing and Secondary Progressive patients compared to stable multiple sclerosis and controls [42]. In a follow up study examining serial blood samples from 6 relapsing multiple sclerosis patients, increase in the kinin B1 actin mRNA preceded or were simultaneous with increase in Expanded Disability Status Scale (EDSS), clinical relapses, T2 lesion volume, and increased percentage of interleukin 2 receptor positive CD4+ T cells, CD26+ and MHC class II peripheral mononuclear cells. These are leukocyte activation markers [42]. It has been reported that increased Cerebrospinal Fluid (CSF) actin and tubulin in progressive multiple sclerosis correlated with EDSS [42]. Increased kinin B1 actin mRNA did not correlate with Gd+ lesions. B1 receptor mRNA levels were much lower and more stable in controls than in the multiple sclerosis group. In a study of CD10 (neutral endopeptidase) and CD13 (aminopeptidase N) activation markers on peripheral mononuclear cells, both markers were significantly higher in acute relapsing and progressive multiple sclerosis compared to patients in remission and Other Neurological Disease (OND) [42].
Incidence
It has been demonstrated that exogenous 1,25-dihydroxyvitamin D3 (The hormonal form of vitamin D3) can completely prevent Experimental Autoimmune Encephalomyelitis (EAE) [16]. It has been put forward that a crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D3 in skin [16]. The disease occurs primarily in populations above and below the latitudes 40° North and 40° South respectively [64].
Two peculiar anomalies fit this model of thinking; one of that in Switzerland with high multiple sclerosis rates at low altitudes, and low multiple sclerosis rates at high altitudes. Ultraviolet light (UV) intensity is higher at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low multiple sclerosis rates at higher altitudes [16]. The other geographic anomaly is that of Norway where there is found a high prevalence inland and a lower prevalence along the coast. This datum also fits the proposed model of thinking in that on the Norwegian coast, fish is consumed at high rates and fish oils are high in vitamin D3 [16]. It is suggested that corroboration of the hypothesis would implicate 1,25-dihydroxyvitamin D3 as having great therapeutic potential in patients with multiple sclerosis [16].
After trauma, multiple sclerosis is the major neurologic disease of young adults. Multiple sclerosis affected at least 350,000 [77] to 400,000 Americans in 2006. Multiple sclerosis affects up to two million people worldwide. Patient numbers appear to be increasing, not just within industrialized countries and Caucasian populations, but also in underdeveloped parts of the world and non Caucasian cultures [42].
Multiple sclerosis affects mostly women (65% of total population affected).
Women most affected at beginning of 20’s and men at end of 20’s [72].
Prevalence: 50 to 100 cases per 100,000 persons, increasing in higher latitudes.
It is the most common demyelinating disease in humans.
Predominant age: Young adults 17-35 years old [73].
Multiple sclerosis is the most common demyelinating disorder and cause of neurological disability in young adults between 20 and 40 years old. Multiple sclerosis has a higher prevalence in Caucasians from northern temperate climates and females [77]. Multiple sclerosis prevalence varies widely, but has a pattern of incidence which is directly proportional to distance of residence from the equator. At latitudes of 50-65ºN (roughly from southern England to Iceland) prevalence is 60 – 100 per 100,000; at latitudes less than 30ºN prevalence is below 10/100,000. At the equator multiple sclerosis is a rarity [95]. In the southern hemisphere this trend is similar – increasing prevalence with distance from the equator. Overall, in Europe and North America, the annual incidence is 2-10 per 100,000 making it the most common neurological disease in young adults. First degree relatives of a patient are reported to have an increased chance of developing multiple sclerosis, without a clear cut pattern of inheritance [95]. Concordance rate is 31% in monozygotic twins. Immigrants from low to high prevalence zones acquire the prevalence of their destination, provided they arrive before the age of 10. The commonest age of onset is between 20 and 45 years, a diagnosis before puberty or after 60 years is rare. Multiple sclerosis is more common in women [95]. In about two-thirds of the cases, onset is between ages twenty and forty (rarely is the onset after age fifty), and women have a higher incidence rate than men (sixty percent female to forty percent male). The frequency of multiple sclerosis appears to be increasing [96]. It appears that the initial event in the development of multiple sclerosis may occur in early life. It has a geographical incidence and the observation has been made that people who move from a low-risk area to a high-risk area before age fifteen have a higher risk of developing multiple sclerosis, whereas those who make the same move after age fifteen retain their low risk [96]. Areas with the highest frequency rates are all located in the higher latitudes, in both the northern and southern hemispheres (50 to 100 cases per 100,000 in the tropics). These high-risk areas include the northern United States, Canada, Great Britain, Scandinavia, northern Europe, New Zealand, and Tasmania. An interesting exception to this geographic distribution is Japan where multiple sclerosis is uncommon [96].
Cause
Multiple sclerosis is an inflammatory disease limited to the central nervous system white matter. The central nervous system inflammation varies among different patients, and consists of variable degrees of T lymphocytes, macrophages, B lymphocytes, and antibodies at the leading edge of the white matter destruction [25]. There are proposed two possibilities regarding the initiating event in multiple sclerosis. The first is that the central nervous system white matter is structurally normal, and that an autoimmune response initiated by autoreactive T cells, as shown possible by the Experimental Autoimmune Encephalomyelitis (EAE) model, mediates the initial inflammatory insult [25]. The second possibility is that the inflammation is a result of some alteration of the central nervous system white matter, which could be the result of a microbial central nervous system infection. This distinction between an autoimmune hypothesis where the central nervous system white matter is normal, and the microbial hypothesis where there is an infected central nervous system with regard to the etiology of multiple sclerosis may be blurred [25]. The pathogenesis of multiple sclerosis remains in debate despite many years of study. Well observed facts that multiple sclerosis plaques are invariably located around blood vessels and that alterations of the blood brain barrier permeabililty is an obligatory step in the development of the plaque [36].
C. M. Poser of Harvard Medical School has suggested it may result from a variety of environmental factors among which are mentioned trauma to the nervous system, as well as immunological changes resulting from viral infections and vaccinations [36].
The cause of multiple sclerosis is thought to be multifactorial. The etiology of multiple sclerosis is considered to involve genetic, environmental, infective, and immunological factors which affect the integrity of a normally assembled myelin sheath, either directly or indirectly resulting in demyelination [40].
Some sort of environmental trigger (infectious, dietary, climatic) has been implicated [64]. It has also been suggested that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease [16].
Latitude on the globe Thus under low sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3 providing a susceptibility for multiple sclerosis. This theory can account for the striking geographic distribution of multiple sclerosis, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres [16]. Efforts to transmit multiple sclerosis experimentally have been uniformly unsuccessful. However, an abnormal immune response in many multiple sclerosis patients produces increased titres of serum and CSF antibodies to many common viruses, particularly measles [95]. Titre also titer is the noun for: (1) Concentration of a substance in solution or the strength of such a substance determined by titration. (2) The minimum volume needed to cause a particular result in titration. [From the French ‘titre’, from Old French title, title] A zoonose (or zoonosis) is any infectious disease that is able to be transmitted from other animals, both wild and domestic, to humans or from humans to animals (the latter is sometimes called reverse zoonosis). The word is derived from the Greek words zòon (animal) and nosos (ill). Many serious diseases fall under this category. Some epidemic transmissible zoonoses, such as scrapie (demyelinating disease in sheep), have noted similarities to multiple sclerosis. Chlamydia has also been questioned as a cause [95]. Many hypotheses have been forwarded regarding the incidence and geographic patterns, these include solar exposure, genetics, diet, and other environmental factors. Many causative factors have been sited [96]:
Viral Infection
Autoimmune Reaction
Diet
Excessive Lipid Peroxidation
The etiology of multiple sclerosis is currently widely regarded as unknown. It is believed that it is the result of an autoimmune process triggered by infection or other environmental factors in individuals with genetic predisposition. There is some evidence that Epstein-Barr virus (EBV) infection may increase the risk of multiple sclerosis [73].
Genetics
The Major Histocompatibility Complex (MHC) is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproductive success.
To date, the MHC gene region is the only area of the human genome clearly associated with the disease, though the precise genes in that region responsible for multiple sclerosis are not as yet known [12]. Increased prevalence of multiple sclerosis is found with halotypes DR2, DQW1, DQA1, DQB1, A3 and B7 of the major histocompatibility complex [73]. Approximately 15-20% of multiple sclerosis patients have a family history of multiple sclerosis, but large extended pedigrees are uncommon, with most multiple sclerosis families having no more than two or three affected individuals. Studies in twins and conjugal pairs suggest that much of this familial clustering is the result of shared genetic risk factors, while studies of migrants and apparent epidemics indicate a clear role for environmental factors [12].
Detailed population based studies of familial recurrence risk have provided estimates for familial clustering with the ratio of the risk of disease in the siblings of an affected individual compared with the general population. It has become clear that this represents a complex genetic disease with no clear mode of inheritance [12].
Studies in families with multiple sib-pairs with multiple sclerosis have not been deemed very successful. To date, the only confirmed genetic feature to emerge from these efforts is the association and linkage of the disease with alleles and haplotypes from the MHC on chromosome 6p21. In the mid 1990’s whole genome screens for linkage were published [12]. A whole genome association scan, while attractive, is only beginning to be feasible as the cost of genotyping continues to decrease. It is also possible that such an approach may fail because multiple sclerosis may be the result of more than the one genetic syndrome that it is generally believed to be, or that hundreds or even thousands of genes, each representing only a fractional risk factor, are associated with the occurrence of multiple sclerosis [12]. In a study of 357 family histories of patients, adequate information was obtained on 1971 first degree relatives. 55 patients (15. 4%) had first degree relatives with multiple sclerosis (n=22, 6. 2%), another autoimmune disorder (n=30, 8. 4%), or both (n=3, 0. 8%). 16 families (4. 5%) had at least 3 first degree relatives who had multiple sclerosis or another autoimmune disorder. Multiple sclerosis, Grave’s disease, rheumatoid arthritis, vitiligo, type 1 insulin dependent diabetes mellitus and uveitis were the most common autoimmune disorders in these families [32].
Categorisation
Multiple sclerosis is postulated as being unlikely to be a single disease entity. The term has been used to encompass a spectrum of heterogeneous disorders which produce a similar clinical picture. There are several disease subtypes characterized by relapsing or progressive courses. Despite distinct clinical and laboratory features based on group analysis, which suggest basic biologic differences, no biomarkers have been identified for clinical subtypes [42].
Multiple sclerosis can be broadly divided into two major forms of the disease:
The early relapsing remitting type, where there is an average of 1-5 attacks per year clinically and 10 new lesions a year by magnetic resonance imaging (MRI).
The chronic progressive multiple sclerosis tends to have fewer new MRI lesions, as measured by dye leaking through the blood vessels (gadolinium enhancement), an indication of acute inflammation [25].
An approximated one third of patients with relapsing remitting disease and approximately 10% of multiple sclerosis patients begin with progressive disease without any previous relapsing remitting events (primary-progressive multiple sclerosis) [25]. In 60% of patients, multiple sclerosis begins as a relapsing remitting disease and evolves secondarily into a progressive neurological illness [4].
Further subcategorisations have been made by some: In relapsing remitting multiple sclerosis (80% of patients), signs and symptoms evolve over a period of several days, stabilize and then improve spontaneously or in response to corticosteroids [73]. In primary progressive multiple sclerosis, manifestations gradually worsen from disease onset without relapses [73]. In secondary progressive multiple sclerosis, after an intial relapsing remitting course, manifestations worsen gradually with or without superimposed acute relapses. In progressive relapsing multiple sclerosis, manifestations gradally worsen from disease onset with subsequent superimposed relapses [73]. There are several forms of the disease that may change the course of management and are therefore important to recognize. Most patients will have a months long, to years long disease free period after their first exacerbation [64]. Four pathologic categories of the disease were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation [12]. Two patterns (I and II) showed close similarities to T cell mediated or T cell plus antibody-mediated autoimmune encephalomyelitis, respectively. Patterns III and IV were highly suggestive of a vasculopathy or primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. The pattern of pathology tended to be the same in multiple lesions from any single individual with multiple sclerosis [12]. Different clinical courses of multiple sclerosis have been defined, including Relapsing Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS), Primary Progressive Multiple Sclerosis (PPMS), and Progressive Relapsing Multiple Sclerosis (PRMS) [77]. Multiple sclerosis is often recognized by the clinically different patterns of:
Relapsing and remitting multiple sclerosis 80-90%
Primary progressive multiple sclerosis 10-20% Secondary progressive multiple sclerosis – this follows on from relapsing remitting multiple sclerosis
Fulminant multiple sclerosis <10% – runs a sudden or severe course over some months [95]
Relapsing remitting multiple sclerosis is characterized by discrete episodes of neurological symptoms followed by a variable degree of recovery and accounts for up to 85% of the initial presentations [77]. This group of patients has demonstrated the best response to treatment, however, more than 50% of relapsing remitting multiple sclerosis patients go on to display continuous, progressive symptoms characteristic of secondary progressive multiple sclerosis within 10 years (up to 90% within 25 years) [77].
By contrast, primary progressive multiple sclerosis is characterized by a steady decline in neurological function from onset, without superimposed attacks and is found in 10% of multiple sclerosis patients [77]. At its onset, multiple sclerosis can be clinically categorized as either relapsing remitting multiple sclerosis (RRMS), observed in 85-90% of patients, or Primary Progressive (PPMS). In relapsing remitting multiple sclerosis, progression is characterized by relapses of active disease with incomplete recovery during periods of remission [64]. With time, the extent of recovery from attacks is often decreased and baseline neurological disability accrues. In some patients the progression of disease becomes more aggressive, so that a consistent worsening of function occurs. This form of the disease is termed secondary progressive disease [64]. Approximately 40% of replasing-remitting patients stop having attacks and develop a progressive neurodegenerative disorder related to the chronic central nervous system inflammation termed secondary progressive multiple sclerosis. The evolution to this secondary progressive form of the disease is associated with significantly fewer gadolinium-enhanced lesions and a decrease in brain parenchymal volume. While earlier relapsing remitting multiple sclerosis is sensitive to immunosuppression, as time goes on, responsiveness to immunotherapy decreases and may in fact disappear in secondary progressive multiple sclerosis [12].
It has been proposed that rather than conceiving multiple sclerosis as first a relapsing remitting and then a secondary progressive disease, multiple sclerosis is a continuum where these are acute inflammatory events early on with secondary induction of a neurodegenerative process refractory to immunologic intervention [12].
Secondary progressive multiple sclerosis is seen in over 50% of cases 6 to 10 years after onset, thus initially it is manifest as remitting-relapsing and later is manifest as chronically progressive multiple sclerosis. Recurrences, mild remissions, and plateau phases may occur with this form [65]. In the least common form, patients symptoms are progressive from the onset of disease with the early onset of disability. This form is termed Primary Progressive Multiple Sclerosis (PPMS) [64]. The primary progressive form of multiple sclerosis is characterized from the onset by the absence of acute attacks and instead involves a gradual clinical decline. This form of the disease is associated with a lack of response to any form of immunotherapy [12]. Professor Reinhard Rohkamm in his textbook the Color Atlas of Neurology presents us with a further unusual categorisation of the disease with ‘progressively remitting relapsing multiple sclerosis’. The form is reported as rare and that complete remission may or may not occur after relapses. Symptoms are described as having a tendency to worsen from one relapse to the next. The course of multiple sclerosis varies greatly from one individual to another, but two basic types of course can be identified [65]: Relapsing Remitting: Relapsing remitting is found in 66-85% of cases and is most common when onset is before age 25. It has well defined relapses separated by periods of nearly complete recovery with or without residual symptoms. It typically does not progress during remission. Chronic Progressive: Chronic progressive multiple sclerosis may be divided into 3 types:
Primary chronic progressive
Secondary progressive
Progressively remitting-relapsing.
Bibliography:
This thesis and work comes from a much larger document which is why the bibliography is presented in the sporadic numbering which you see in this website post. Every attempt has been made to give clear routes back to the original source of knowledge for each statement so that the work is presented in a forensic way. This means that the original text can be scrutinised and compared as to the version which is found in this digital version. It is also noted that there are curricular learning resources included throughout the above text, including links out to explain terminology, videos from the internet, and other knowledge resources. These are not listed in the bibliography below but should be regarded as added and self evidence sources which are their to aid in developing an understanding of the overall thesis and medical condition.
Reference 4:
The Evolution of Multiple Sclerosis Natural history of multiple sclerosis Dr Brian G. Weinshenker, MD Department of Neurology, Mayo Clinic, Rochester, MN Correspondence to Brian G. Weinshenker, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis David A. Hafler The Journal of Clinical Investigation September 1999, Volume 104, Number 5527 Harvard Medical School and Brigham and Women’s Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. E-mail: hafler@cnd. bwh. harvard. edu. Pages: 599–610.
Reference 26:
The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis Journal Journal of Clinical Immunology Publisher: Springer Netherlands ISSN: 0271-9142 (Print) 1573-2592 (Online) Issue: Volume 21, Number 2, March, 2001 DOI: 10. 1023/A:1011064007686 Pages: 81-92 The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis Kevin C. O’connor1, Amit Bar-Or1 and David A. Hafler [1] 1: Harvard Medical School, Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women”s Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts, 02115
Pathogenesis of multiple sclerosis; A critical reappraisal C. M. Poser Department of Neurology, Harvard Medical School, 330 Brookline Avenue, 02215 Boston, MA, USA; Neurological Unit, Beth Israel Hospital, 330 Brookline Avenue, 02215 Boston, MA, USA Pathogenesis of multiple sclerosis Journal: Acta Neuropathologica Publisher: Springer Berlin / Heidelberg ISSN: 0001-6322 (Print) 1432-0533 (Online) Issue: Volume 71, Numbers 1-2 / March, 1986 Category: Review Article DOI: 10. 1007/BF00687954 Pages: 1-10
Reference 40:
Myelin in multiple sclerosis is developmentally immature. M A Moscarello, D D Wood, C Ackerley, and C Boulias J Clin Invest. 1994 July; 94(1): 146–154. Division of Biochemistry Research, Hospital for Sick Children, Toronto, Ontario, Canada.
Reference 42:
Handbook of Multiple Sclerosis 4th edition Edited by Stuart D. Cook, P. K. Coyle Department of Neurology, School of Medicine, State University of New York at Stony Brook Stony Brook, New York, USA ISBN-13: 978-1-57444-827-6 (alk. paper) ISBN-10: 1-57444-827-7 Published 2006 Shelfmark: HB3. 207. 4. 145 P223 – Multiple Sclerosis Biomarkers
Reference 64:
Neurology – Page 303 Clinical Vignettes for the USMLE Step 2 CK: Pre-test Self-assessment and Review (PreTest Clinical Science) Published by: McGraw-Hill Education – Europe Paperback 01 Aug 2006 ISBN13: 9780071464031 ISBN10: 0071464034
Reference 65:
Multiple Sclerosis – Page 214 Color Atlas of Neurology Professor Reinhard Rohkamm, M. D. Neurological Clinic; Nordwest-Krankenhaus Sanderbusch; Sande, Germany ISBN 3-13-130931-8 (GTV) ISBN 1-58890-191-2 (TNY) This book is an authorized translation of the 2nd German edition published and copyrighted 2003 by Georg Thieme Verlag, Stuttgart, Germany. Title of the German edition: Taschenatlas Neurologie Original translator: Suzyon O’Neal Wandrey, Berlin, Germany Translator/editor: Ethan Taub, M. D., Zürich, Switzerland
Reference 67:
Multiple Sclerosis – Page 218 Color Atlas of Neurology Professor Reinhard Rohkamm, M. D. Neurological Clinic; Nordwest-Krankenhaus Sanderbusch; Sande, Germany ISBN 3-13-130931-8 (GTV) ISBN 1-58890-191-2 (TNY) This book is an authorized translation of the 2nd German edition published and copyrighted 2003 by Georg Thieme Verlag, Stuttgart, Germany. Title of the German edition: Taschenatlas Neurologie Original translator: Suzyon O’Neal Wandrey, Berlin, Germany Translator/editor: Ethan Taub, M. D., Zürich, Switzerland
Reference 69:
Neuromuscular and Sensory Systems; Demyelination – Page 302 Color atlas of pathophysiology Stefan Silbernagl, Florian Lang; illustrations by Rüdiger Gay and Astried Rothenburger ; [translated by Gerald R. Graham]. p. ; cm. Includes bibliographical references and index. ISBN 3131165510 (GTV) – ISBN 0-86577-866-3 (TNY) Translated by: Gerald R. Graham, B. A., M. D., Whaddon, UK This book is an authorized translation of the German edition published and copyrighted 1998 by Georg Thieme Verlag, Stuttgart, Germany. Title of the German edition: Taschenatlas der Pathophysiologie
