Multiple Sclerosis Case Studies
Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic neurodegenerative disorder in the central nervous system that, effecting young adults, leading to non-traumatic disabilities. This disease starts as an auto-immune disease in which CD4 T cells cross the blood brain barrier and attack myelin sheaths of olygodendrocytes resulting in demyelination (Gandhi et al., 2010; Lund et al., 2013). Initially this is a transient process and re-myelination occurs, so initial stage of the disease is characterized by neurological dysfunctions that eventually recover. However this re-myelination is not permanent (Compston and Coles, 2008; Wakerley et al., 2012). The continuous immune attacks cause serious pathological changes of myelin sheaths hence disease progression and development of serious disabilities . (Makris et al., 2013; …show more content…
Wakerley et al., 2012; Hafler, 2004; Nylander and Hafler, 2012; Eshaghi et al., 2013). Peak age of the initial diagnosis of MS is 30 and the disease progress overtime causing a in decline in health and even mortality (Makris et al., 2013). Though it is subjective the average decrease in life expectancy of a patient with MS is 5 to 10 years after the disease is being diagnosed (Keegan and Noseworthy, 2002). Disabilities caused by the disease vary between patients and depend on the abnormalities of the neuronal track that is affected (Leray et al., 2010). Some disabilities include numbness, muscle atrophy and MS is often characterized by secondary depression as a result of the deteriorating physical health (Makris et al., 2013). Even though the disease was clinically diagnosed in the early 19th century, up to this date its cause is yet to be known (Nylander and Hafler, 2012). However, it is clear that genetic susceptibility and environmental factors play key roles in inducing the disease (Compston and Coles, 2008). Studies about MS show that discussing about the implication of these two factors separately is unproductive but the interplay between these factors together with cultural conditions cause the disease (Wakerley et al., 2012; Makris et al., 2013).
Finding a geographical pattern in MS worldwide is a difficult task even today as it is unevenly distributed across the globe. MS has a prevalence rate of 83 per 100 000 individuals in the world with higher rate in northern countries. Europe has the highest prevalence of 193 per 100 000 individuals (Pugliatti et al., 2006). Australia and North America comes after Europe, which is a country at high risk for MS. However, Asian countries lie in the low risk category. Nevertheless, like every degenerative disease, in every population females are more prone to the disease than males (ratio 1:2). This ratio is found to gradually increase but it is not clear whether this is an increase due to females being more susceptible to the disease or more accurate diagnosis due to development of technology and awareness (Pugliatti et al., 2006; Koch-Henriksen and S√∏rensen, 2010).
In1970s scientists were first able to recognize MS risk genes in MHC region of chromosome 6 (Nylander and Hafler, 2012). Despite of the lacking reproducibility in the search for MS risk genes for years, about four years ago, scientists were able to discover the exact location of the strongest MS related genes on chromosome 6, HLA (Human leukocyte antigen)region. Three culprit genes were identified on HLA region of the HLA-DR2 haplotype on chromosome 6p21; HLADRB1*1501 (encoding HLA-DR2b), HLADRB5*0101 (encoding HLADR2a) and HLADQB1*0602 (encoding HLA-DQ6), even though significant amount of details yet to be revealed. Research findings also reveal that among the three genes, the main susceptible gene to MS is HLADRBi*1501 (Sadovnick, 2012). The role of genetics in MS is unequivocal however, segregation analysis shows no clear mode of inheritance making MS a complex disease. There is a non-linear relationship between familial recurrence and the degree of relatedness, making the first, second and even the third degree relatives of a MS patient more prone to get MS than a healthy individual (Sadovnick, 2012; Hoppenbrouwers and Hintzen, 2011). Even though genetics plays a major role in developing MS, the interrelation between genetic susceptibility and the environmental factors is crucial for one to acquire the disease (Compston and Coles, 2008). The most relative environmental factors are vitamin D deficiency/ less exposure to sunlight, and pre- exposure to viruses like Epstein-Barr (EBV), and the geographical area that a person spent their early life (upto 15 years) (Ascherio and Munger, 2007; Compston and Coles, 2008). Some studies hypothise that vitamin D deficiency and EBV separately alter the gene expressions which then lead to development of MS (Edge; Hoppenbrouwers and Hintzen, 2011). The most recent findings reveal that even childhood obesity also plays a part in acquiring the disease in later in their life (Munger, 2013).( one of the new findings).Some studies hypothise that vitamin D deficiency and EBV separately alter the gene expressions which then lead to development of MS(Edge; Hoppenbrouwers and Hintzen, 2011).
The disease starts off as T helper cell 1 (TH1) begin to secrete interleukin 17 and 22 which then penetrate the blood brain barrier and auto reactive CD 4 T lymphocytes cross the blood brain barrier as well (Lund et al., 2013; Makris et al., 2013). Subsequently these cells release Tumor necrosis factor (TNF) – α, interferon (INF) - γ and interleukins which enhances the activity of macrophages and B lymphocytes (Makris et al., 2013; Compston and Coles, 2008; Lund et al., 2013). Local inflammation of the brain ensues, resulting in lymphocytes to damage myelin sheaths of the olygodendrocytes hence demyelination. At the initial stage, of the damaged is repaired through re-myelination and no pathophysiological changes are visible (Compston and Coles, 2008; Makris et al., 2013). However, after few cycles of demyelination and re-myelination the capacity of the tissue repair exhausts causing in less successful re-myelination and later formation of sclerotic plaque which is the hall mark of the disease. Pathological conditions are a result of reduced saltatory conduction and subsequent reduction in conduction velocities over nerve fibres due to myelin sheath damage. For several years physiology of the disease cause was at a controversial stage. Despite of the theory of auto immune response then leading to de- myelination, some scientists believed that it is the initial abnormal neuron that induce the infiltration of CD4 T cells (Makris et al., 2013; Compston and Coles, 2008; Gandhi et al., 2010). However, most recent findings reveal that later hypothesis is incorrect ( ref....). T, but there are four patterns of immunopathology that can be found in four forms of lesions, concluding mechanism of demyelination in different subgroups of the disease can be different (Ref...?).
There is a vast range of symptoms and signs of MS, andas these can be directly related to the anatomical site of the focal inflammation within the CNS. At an initial stage of the disease, symptoms are not durable as proper re-myelination occurs so and are restricted to numbness, fatigue, dizziness, clumsiness, and visual disturbances. However, as the disease progress, numbness or weakness in one or more of the limbs, optic neuritis, brainstem symptoms such as diplopia or bertigo, gait disturbances, and with spinal code involvement loss of bladder control occurs apart from the initial symptoms. In some patients, cognitive decline and seizures are prominent as axonal injury and lesion load increase (Makris et al., 2013).
There are four major stages of Multiple sclerosis. Initial stage is the clinically isolated syndrome (CIS), which is characterised by episodes of demyelination and re-myelination cycles. 60% of the individuals who reached this stage will develop into MS within 20 years. At CIS stage, several sites are affected and if non affected sites are accompanied by white matter abnormalities detected by MRI, the disease develop into the second stage within a couple of years (Makris et al., 2013; Compston and Coles, 2008). Relapsing Remitting MS (RRMS) is the stage where acute immune attacks demyelinate neurons and focal neurological deficits are formed due to imperfect re-myelination. RRMS is the most common form of MS (65% of the patients have this type) and characterises by having relapses/visible symptoms and gaps in between where no or less symptoms are visible. There are two main types of RRMS; malignant MS and Benign MS. Malignant MS is characterised by frequent relapses increasing disabilities whereas Malignant MS course with infrequent relapses and limited disabilities (Menon et al., 2013). RRMS then progress into secondary progressive MS (SPMS) that show progressive pattern of the disease with relapses and remissions time to time. During the transient period of RRMS to SPMS patient’s health deteriorate. Unlike SPMS Primary progressive MS (PPMS) is characterised by gradual deterioration starting from the onset of the disease and occasional relapses and remissions (Compston and Coles, 2008; Wakerley et al., 2012; Makris et al., 2013).
Clinical and para clinical assessments are used to diagnose MS. Mc Donald criteria has been used for years for clinical diagnosis of MS with high degree of both specificity and sensitivity (Compston and Coles, 2008; Keegan and Noseworthy, 2002). This criteria specifically focuses on two characteristics; Lhermitte’s symptom and (an electrical sensation running down the spine or limbs on neck flexion) and the Uhthoff phenomenon (transient worsening of symptoms and signs when core body temperature increases, such as after exercise or a hot bath). Despite the fact that diagnosis can be made based only on clinical grounds, international panel on diagnosing MS stated the importance of paraclinical assessments like magnetic resonance imaging (MRI), on diagnosing the disease. They further explain how paraclinical assessments can supplement, support and even replace clinical criteria, in the revision of MC Donald criteria in 2010 (Mendon√ßa et al., 2012; Compston and Coles, 2008).
There are no current treatments to cure MS. Present medications can only reduce the progression, symptoms and the frequency of an attacks of the disease. Due to this reason, the early treatments and long term follow ups can pause/reduce demyelination and can increase the quality of life of a MS patient (Compston and Coles, 2008). There are two main types of treatments; first line treatments and second line treatments. Interferon β and Glatiramer Acetate are the most common first line treatments and Natalizumab (Tysabri), Fingolimod and Alemtuzumab could be considered as second line treatments. Depending on the severity, personal preferences, and individual susceptibilities, sometimes treatments starts with first line treatment then gradually move on to using second line basis. Nevertheless, treatments can start strait with second line basis (Morris and Yiannikas, 2012).
MS is one of the main neurodegenerative diseases in the world that lead to physical ? disabilities, however due to its complexity, years of studies have only being able to reveal few facts about the disease. Advances in the technology have led to most important new findings about the disease, even though the cause of the disease is yet to be known. MS patients around the world are waiting for scientist till that day comes, as it would be a break through to find a proper cure forto this dreadful disease.
Ascherio, A.
& Munger, K. L. 2007. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Annals of neurology, 61, 504-513.
Compston, A. & Coles, A. 2008. Multiple sclerosis. Lancet, 372, 1502-17.
Edge, L. Vitamin D: hope on the horizon for MS prevention?
Eshaghi, A., Bodini, B., Ridgway, G. R., García-Lorenzo, D., Tozer, D., Sahraian, M. A., Thompson, A. J. & Ciccarelli, O. 2013. Temporal and spatial evolution of grey matter atrophy in primary progressive multiple sclerosis. NeuroImage.
Gandhi, R., Laroni, A. & Weiner, H. L. 2010. Role of the innate immune system in the pathogenesis of multiple sclerosis. Journal of neuroimmunology, 221, 7-14.
Hafler, D. A. 2004. Multiple sclerosis. The Journal of Clinical Investigation, 113, 788-794.
Hoppenbrouwers, I. A. & Hintzen, R. Q. 2011. Genetics of multiple sclerosis. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1812, 194-201.
Keegan, B. M. & Noseworthy, J. H. 2002. Multiple sclerosis. Annu Rev Med, 53, 285-302.
Koch-Henriksen, N. & S√∏Rensen, P. S. 2010. The changing demographic pattern of multiple sclerosis epidemiology. The Lancet Neurology, 9,
520-532.
Leray, E., Yaouanq, J., Le Page, E., Coustans, M., Laplaud, D., Oger, J. L. & Edan, G. 2010. Evidence for a two-stage disability progression in multiple sclerosis. Brain, 133, 1900-1913.
Lund, H., Krakauer, M., Skimminge, A., Sellebjerg, F., Garde, E., Siebner, H. R., Paulson, O. B., Hesse, D. & Hanson, L. G. 2013. Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis. PLoS One, 8, e56375.
Makris, A., Piperopoulos, A. & Karmaniolou, I. 2013. Multiple sclerosis: basic knowledge and new insights in perioperative management. Journal of anesthesia, 1-12.
Mendon√Sa, N., Parreira, T., Sena, A. & Sousa, L. V. 2012. Differential diagnosis of multiple sclerosis, is Moyamoya in? Neurology, Psychiatry and Brain Research.
Menon, S., Shirani, A., Zhao, Y., Oger, J., Traboulsee, A., Freedman, M. S. & Tremlett, H. 2013. Characterising aggressive multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry.
Morris, K. & Yiannikas, C. 2012. Treatment Update in Multiple Sclerosis. Current allergy and asthma reports, 12, 246-254.
Munger, K. L. 2013. Childhood obesity is a risk factor for multiple sclerosis. Multiple Sclerosis Journal, 1352458513507357.
Nylander, A. & Hafler, D. A. 2012. Multiple sclerosis. The Journal of Clinical Investigation, 122, 1180-1188.
Pugliatti, M., Rosati, G., Carton, H., Riise, T., Drulovic, J., VéCsei, L. S. & Milanov, I. 2006. The epidemiology of multiple sclerosis in Europe. European journal of neurology, 13, 700-722.
Sadovnick, A. D. 2012. Genetic background of multiple sclerosis. Autoimmunity reviews, 11, 163-166.
Wakerley, B., Nicholas, R. & Malik, O. 2012. Multiple sclerosis. Medicine, 40, 523-528.
Multiple Sclerosis (MS) is a chronic neurodegenerative disorder in the central nervous system that, effecting young adults, leading to non-traumatic disabilities. This disease starts as an auto-immune disease in which CD4 T cells cross the blood brain barrier and attack myelin sheaths of olygodendrocytes resulting in demyelination (Gandhi et al., 2010; Lund et al., 2013). Initially this is a transient process and re-myelination occurs, so initial stage of the disease is characterized by neurological dysfunctions that eventually recover. However this re-myelination is not permanent (Compston and Coles, 2008; Wakerley et al., 2012). The continuous immune attacks cause serious pathological changes of myelin sheaths hence disease progression and development of serious disabilities . (Makris et al., 2013; …show more content…
Wakerley et al., 2012; Hafler, 2004; Nylander and Hafler, 2012; Eshaghi et al., 2013). Peak age of the initial diagnosis of MS is 30 and the disease progress overtime causing a in decline in health and even mortality (Makris et al., 2013). Though it is subjective the average decrease in life expectancy of a patient with MS is 5 to 10 years after the disease is being diagnosed (Keegan and Noseworthy, 2002). Disabilities caused by the disease vary between patients and depend on the abnormalities of the neuronal track that is affected (Leray et al., 2010). Some disabilities include numbness, muscle atrophy and MS is often characterized by secondary depression as a result of the deteriorating physical health (Makris et al., 2013). Even though the disease was clinically diagnosed in the early 19th century, up to this date its cause is yet to be known (Nylander and Hafler, 2012). However, it is clear that genetic susceptibility and environmental factors play key roles in inducing the disease (Compston and Coles, 2008). Studies about MS show that discussing about the implication of these two factors separately is unproductive but the interplay between these factors together with cultural conditions cause the disease (Wakerley et al., 2012; Makris et al., 2013).
Finding a geographical pattern in MS worldwide is a difficult task even today as it is unevenly distributed across the globe. MS has a prevalence rate of 83 per 100 000 individuals in the world with higher rate in northern countries. Europe has the highest prevalence of 193 per 100 000 individuals (Pugliatti et al., 2006). Australia and North America comes after Europe, which is a country at high risk for MS. However, Asian countries lie in the low risk category. Nevertheless, like every degenerative disease, in every population females are more prone to the disease than males (ratio 1:2). This ratio is found to gradually increase but it is not clear whether this is an increase due to females being more susceptible to the disease or more accurate diagnosis due to development of technology and awareness (Pugliatti et al., 2006; Koch-Henriksen and S√∏rensen, 2010).
In1970s scientists were first able to recognize MS risk genes in MHC region of chromosome 6 (Nylander and Hafler, 2012). Despite of the lacking reproducibility in the search for MS risk genes for years, about four years ago, scientists were able to discover the exact location of the strongest MS related genes on chromosome 6, HLA (Human leukocyte antigen)region. Three culprit genes were identified on HLA region of the HLA-DR2 haplotype on chromosome 6p21; HLADRB1*1501 (encoding HLA-DR2b), HLADRB5*0101 (encoding HLADR2a) and HLADQB1*0602 (encoding HLA-DQ6), even though significant amount of details yet to be revealed. Research findings also reveal that among the three genes, the main susceptible gene to MS is HLADRBi*1501 (Sadovnick, 2012). The role of genetics in MS is unequivocal however, segregation analysis shows no clear mode of inheritance making MS a complex disease. There is a non-linear relationship between familial recurrence and the degree of relatedness, making the first, second and even the third degree relatives of a MS patient more prone to get MS than a healthy individual (Sadovnick, 2012; Hoppenbrouwers and Hintzen, 2011). Even though genetics plays a major role in developing MS, the interrelation between genetic susceptibility and the environmental factors is crucial for one to acquire the disease (Compston and Coles, 2008). The most relative environmental factors are vitamin D deficiency/ less exposure to sunlight, and pre- exposure to viruses like Epstein-Barr (EBV), and the geographical area that a person spent their early life (upto 15 years) (Ascherio and Munger, 2007; Compston and Coles, 2008). Some studies hypothise that vitamin D deficiency and EBV separately alter the gene expressions which then lead to development of MS (Edge; Hoppenbrouwers and Hintzen, 2011). The most recent findings reveal that even childhood obesity also plays a part in acquiring the disease in later in their life (Munger, 2013).( one of the new findings).Some studies hypothise that vitamin D deficiency and EBV separately alter the gene expressions which then lead to development of MS(Edge; Hoppenbrouwers and Hintzen, 2011).
The disease starts off as T helper cell 1 (TH1) begin to secrete interleukin 17 and 22 which then penetrate the blood brain barrier and auto reactive CD 4 T lymphocytes cross the blood brain barrier as well (Lund et al., 2013; Makris et al., 2013). Subsequently these cells release Tumor necrosis factor (TNF) – α, interferon (INF) - γ and interleukins which enhances the activity of macrophages and B lymphocytes (Makris et al., 2013; Compston and Coles, 2008; Lund et al., 2013). Local inflammation of the brain ensues, resulting in lymphocytes to damage myelin sheaths of the olygodendrocytes hence demyelination. At the initial stage, of the damaged is repaired through re-myelination and no pathophysiological changes are visible (Compston and Coles, 2008; Makris et al., 2013). However, after few cycles of demyelination and re-myelination the capacity of the tissue repair exhausts causing in less successful re-myelination and later formation of sclerotic plaque which is the hall mark of the disease. Pathological conditions are a result of reduced saltatory conduction and subsequent reduction in conduction velocities over nerve fibres due to myelin sheath damage. For several years physiology of the disease cause was at a controversial stage. Despite of the theory of auto immune response then leading to de- myelination, some scientists believed that it is the initial abnormal neuron that induce the infiltration of CD4 T cells (Makris et al., 2013; Compston and Coles, 2008; Gandhi et al., 2010). However, most recent findings reveal that later hypothesis is incorrect ( ref....). T, but there are four patterns of immunopathology that can be found in four forms of lesions, concluding mechanism of demyelination in different subgroups of the disease can be different (Ref...?).
There is a vast range of symptoms and signs of MS, andas these can be directly related to the anatomical site of the focal inflammation within the CNS. At an initial stage of the disease, symptoms are not durable as proper re-myelination occurs so and are restricted to numbness, fatigue, dizziness, clumsiness, and visual disturbances. However, as the disease progress, numbness or weakness in one or more of the limbs, optic neuritis, brainstem symptoms such as diplopia or bertigo, gait disturbances, and with spinal code involvement loss of bladder control occurs apart from the initial symptoms. In some patients, cognitive decline and seizures are prominent as axonal injury and lesion load increase (Makris et al., 2013).
There are four major stages of Multiple sclerosis. Initial stage is the clinically isolated syndrome (CIS), which is characterised by episodes of demyelination and re-myelination cycles. 60% of the individuals who reached this stage will develop into MS within 20 years. At CIS stage, several sites are affected and if non affected sites are accompanied by white matter abnormalities detected by MRI, the disease develop into the second stage within a couple of years (Makris et al., 2013; Compston and Coles, 2008). Relapsing Remitting MS (RRMS) is the stage where acute immune attacks demyelinate neurons and focal neurological deficits are formed due to imperfect re-myelination. RRMS is the most common form of MS (65% of the patients have this type) and characterises by having relapses/visible symptoms and gaps in between where no or less symptoms are visible. There are two main types of RRMS; malignant MS and Benign MS. Malignant MS is characterised by frequent relapses increasing disabilities whereas Malignant MS course with infrequent relapses and limited disabilities (Menon et al., 2013). RRMS then progress into secondary progressive MS (SPMS) that show progressive pattern of the disease with relapses and remissions time to time. During the transient period of RRMS to SPMS patient’s health deteriorate. Unlike SPMS Primary progressive MS (PPMS) is characterised by gradual deterioration starting from the onset of the disease and occasional relapses and remissions (Compston and Coles, 2008; Wakerley et al., 2012; Makris et al., 2013).
Clinical and para clinical assessments are used to diagnose MS. Mc Donald criteria has been used for years for clinical diagnosis of MS with high degree of both specificity and sensitivity (Compston and Coles, 2008; Keegan and Noseworthy, 2002). This criteria specifically focuses on two characteristics; Lhermitte’s symptom and (an electrical sensation running down the spine or limbs on neck flexion) and the Uhthoff phenomenon (transient worsening of symptoms and signs when core body temperature increases, such as after exercise or a hot bath). Despite the fact that diagnosis can be made based only on clinical grounds, international panel on diagnosing MS stated the importance of paraclinical assessments like magnetic resonance imaging (MRI), on diagnosing the disease. They further explain how paraclinical assessments can supplement, support and even replace clinical criteria, in the revision of MC Donald criteria in 2010 (Mendon√ßa et al., 2012; Compston and Coles, 2008).
There are no current treatments to cure MS. Present medications can only reduce the progression, symptoms and the frequency of an attacks of the disease. Due to this reason, the early treatments and long term follow ups can pause/reduce demyelination and can increase the quality of life of a MS patient (Compston and Coles, 2008). There are two main types of treatments; first line treatments and second line treatments. Interferon β and Glatiramer Acetate are the most common first line treatments and Natalizumab (Tysabri), Fingolimod and Alemtuzumab could be considered as second line treatments. Depending on the severity, personal preferences, and individual susceptibilities, sometimes treatments starts with first line treatment then gradually move on to using second line basis. Nevertheless, treatments can start strait with second line basis (Morris and Yiannikas, 2012).
MS is one of the main neurodegenerative diseases in the world that lead to physical ? disabilities, however due to its complexity, years of studies have only being able to reveal few facts about the disease. Advances in the technology have led to most important new findings about the disease, even though the cause of the disease is yet to be known. MS patients around the world are waiting for scientist till that day comes, as it would be a break through to find a proper cure forto this dreadful disease.
Ascherio, A.
& Munger, K. L. 2007. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Annals of neurology, 61, 504-513.
Compston, A. & Coles, A. 2008. Multiple sclerosis. Lancet, 372, 1502-17.
Edge, L. Vitamin D: hope on the horizon for MS prevention?
Eshaghi, A., Bodini, B., Ridgway, G. R., García-Lorenzo, D., Tozer, D., Sahraian, M. A., Thompson, A. J. & Ciccarelli, O. 2013. Temporal and spatial evolution of grey matter atrophy in primary progressive multiple sclerosis. NeuroImage.
Gandhi, R., Laroni, A. & Weiner, H. L. 2010. Role of the innate immune system in the pathogenesis of multiple sclerosis. Journal of neuroimmunology, 221, 7-14.
Hafler, D. A. 2004. Multiple sclerosis. The Journal of Clinical Investigation, 113, 788-794.
Hoppenbrouwers, I. A. & Hintzen, R. Q. 2011. Genetics of multiple sclerosis. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1812, 194-201.
Keegan, B. M. & Noseworthy, J. H. 2002. Multiple sclerosis. Annu Rev Med, 53, 285-302.
Koch-Henriksen, N. & S√∏Rensen, P. S. 2010. The changing demographic pattern of multiple sclerosis epidemiology. The Lancet Neurology, 9,
520-532.
Leray, E., Yaouanq, J., Le Page, E., Coustans, M., Laplaud, D., Oger, J. L. & Edan, G. 2010. Evidence for a two-stage disability progression in multiple sclerosis. Brain, 133, 1900-1913.
Lund, H., Krakauer, M., Skimminge, A., Sellebjerg, F., Garde, E., Siebner, H. R., Paulson, O. B., Hesse, D. & Hanson, L. G. 2013. Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis. PLoS One, 8, e56375.
Makris, A., Piperopoulos, A. & Karmaniolou, I. 2013. Multiple sclerosis: basic knowledge and new insights in perioperative management. Journal of anesthesia, 1-12.
Mendon√Sa, N., Parreira, T., Sena, A. & Sousa, L. V. 2012. Differential diagnosis of multiple sclerosis, is Moyamoya in? Neurology, Psychiatry and Brain Research.
Menon, S., Shirani, A., Zhao, Y., Oger, J., Traboulsee, A., Freedman, M. S. & Tremlett, H. 2013. Characterising aggressive multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry.
Morris, K. & Yiannikas, C. 2012. Treatment Update in Multiple Sclerosis. Current allergy and asthma reports, 12, 246-254.
Munger, K. L. 2013. Childhood obesity is a risk factor for multiple sclerosis. Multiple Sclerosis Journal, 1352458513507357.
Nylander, A. & Hafler, D. A. 2012. Multiple sclerosis. The Journal of Clinical Investigation, 122, 1180-1188.
Pugliatti, M., Rosati, G., Carton, H., Riise, T., Drulovic, J., VéCsei, L. S. & Milanov, I. 2006. The epidemiology of multiple sclerosis in Europe. European journal of neurology, 13, 700-722.
Sadovnick, A. D. 2012. Genetic background of multiple sclerosis. Autoimmunity reviews, 11, 163-166.
Wakerley, B., Nicholas, R. & Malik, O. 2012. Multiple sclerosis. Medicine, 40, 523-528.