Differences
This shows you the differences between two versions of the page.
| Both sides previous revision Previous revision Next revision | Previous revision | ||
|
group_5_presentation_1_-_multiple_sclerosis [2016/09/25 19:16] jogendm |
group_5_presentation_1_-_multiple_sclerosis [2018/01/25 15:18] (current) |
||
|---|---|---|---|
| Line 57: | Line 57: | ||
| {{:ms-mri_t1_535x314-01.jpg|}} | {{:ms-mri_t1_535x314-01.jpg|}} | ||
| - | Figure 1: A T1-weighted MRI demonstrating permanent lesions in a MS patient. The dark spots | + | **Figure 1**: A T1-weighted MRI demonstrating permanent lesions in a MS patient. The dark spots |
| in the scan are the lesions. (Source: Spinms, 2016) | in the scan are the lesions. (Source: Spinms, 2016) | ||
| Line 82: | Line 82: | ||
| * Primary progressive (PPMS) | * Primary progressive (PPMS) | ||
| - | Clinically Isolated Syndrome refers to a first episode where there is inflammatory demyelination in the CNS. It is not yet considered MS, but could become MS if further activity occurs. In the relapse and remitting stage this indicates good health followed by an immediate change in symptoms. Secondary progressive MS occurs after the relapse and remitting stage. At this point there are more symptoms that are progressively getting worse. Primary progressive MS is the steady development of symptoms that will eventually become worse as the diseases progresses. RRMS, SPMS, and PPMS can be active or not active depending on if there is evidence of relapse or disease activity present. | + | Clinically Isolated Syndrome refers to a first episode where there is inflammatory demyelination in the CNS. It is not yet considered MS, but could become MS if further activity occurs. In the relapse and remitting stage this indicates good health followed by an immediate change in symptoms. Secondary progressive MS occurs after the relapse and remitting stage. At this point there are more symptoms that are progressively getting worse. Primary progressive MS is the steady development of symptoms that will eventually become worse as the diseases progresses. RRMS, SPMS, and PPMS can be active or not active depending on if there is evidence of relapse or disease activity present (Hedley, 2012). |
| </style> | </style> | ||
| Line 97: | Line 97: | ||
| Initially, for the T cells to cause lesion formation, they need to penetrate the Blood-brain barrier. The Blood-brain barrier consists of endothelial cells, tight junctions and basement membrane (Löscher and Potschka, 2005). The immune system cells travels through blood vessels which also contain endothelial cells. The Blood-brain barrier has selective permeability and prevents the immune system cells from entering the brain (Wingerchuk et al., 2001). However, when triggered by a virus such as Epstein Barr Virus (EBV), the Blood-brain barrier can be penetrated by T cells that can be autoreactive or be programmed to attack myelin protein present on the axons of the neurons (Wu and Alvarez, 2011). | Initially, for the T cells to cause lesion formation, they need to penetrate the Blood-brain barrier. The Blood-brain barrier consists of endothelial cells, tight junctions and basement membrane (Löscher and Potschka, 2005). The immune system cells travels through blood vessels which also contain endothelial cells. The Blood-brain barrier has selective permeability and prevents the immune system cells from entering the brain (Wingerchuk et al., 2001). However, when triggered by a virus such as Epstein Barr Virus (EBV), the Blood-brain barrier can be penetrated by T cells that can be autoreactive or be programmed to attack myelin protein present on the axons of the neurons (Wu and Alvarez, 2011). | ||
| - | Inflammation in the area due to a virus or foreign substances causes more T cells and macrophages to be recruited into the Blood-brain barrier due to the help of increased expression of adhesion molecules (Wingerchuk et al., 2001). Then, activated and non-activated T cells can secrete Matrix metalloproteinases (MMPs) which cause the degradation of the extracellular matrix, therefore weakening the Blood-brain barrier and allowing for other leukocytes and macrophages to enter (Wingerchuk et al., 2001). Inside the Central Nervous System, T cells can be activated by Antigen Presenting Cells and antibodies, therefore releasing an increased amount of chemokines and cytokines, which can recruit a much larger inflammatory response and lead to initiation of lesion formation (Wingerchuk et al., 2001).<sup>[X]</sup>. | + | Inflammation in the area due to a virus or foreign substances causes more T cells and macrophages to be recruited into the Blood-brain barrier due to the help of increased expression of adhesion molecules (Wingerchuk et al., 2001). Then, activated and non-activated T cells can secrete Matrix metalloproteinases (MMPs) which cause the degradation of the extracellular matrix, therefore weakening the Blood-brain barrier and allowing for other leukocytes and macrophages to enter, as highlighted in //Figure 2// (Wingerchuk et al., 2001). Inside the Central Nervous System, T cells can be activated by Antigen Presenting Cells and antibodies, therefore releasing an increased amount of chemokines and cytokines, which can recruit a much larger inflammatory response and lead to initiation of lesion formation (Wingerchuk et al., 2001). |
| </style> | </style> | ||
| <style float-left> | <style float-left> | ||
| - | {{:screen_shot_2016-09-23_at_7.57.09_pm.png|Figure X: Illustrates the mechanism used by T cells to penetrate the Blood-brain Barrier. | + | {{:screen_shot_2016-09-23_at_7.57.09_pm.png|Figure 2: Illustrates the mechanism used by T cells to penetrate the Blood-brain Barrier. |
| (Source: Wingerchuk et al., 2001)}} | (Source: Wingerchuk et al., 2001)}} | ||
| - | **Figure X**: Illustrates the mechanism used by T cells to penetrate the Blood-brain | + | **Figure 2**: Illustrates the mechanism used by T cells to penetrate the Blood-brain. |
| Barrier (Source: Wingerchuk et al., 2001). | Barrier (Source: Wingerchuk et al., 2001). | ||
| Line 115: | Line 115: | ||
| **Lesions:** | **Lesions:** | ||
| In Multiple Sclerosis, lesions will be formed in the white matter of the brain due to demyelination of neurons in the Central Nervous System. Demyelination or lesion formation can occur in any area, but most often occurs in the periventricular regions, optic nerves, brainstem, cerebellum and spinal cord (Wingerchuk et al., 2001). Demyelination usually occurs due to an autoimmune response by T cells towards myelin protein and oligodendrocytes, which are responsible for synthesizing myelin protein (Wu and Alvarez, 2011). | In Multiple Sclerosis, lesions will be formed in the white matter of the brain due to demyelination of neurons in the Central Nervous System. Demyelination or lesion formation can occur in any area, but most often occurs in the periventricular regions, optic nerves, brainstem, cerebellum and spinal cord (Wingerchuk et al., 2001). Demyelination usually occurs due to an autoimmune response by T cells towards myelin protein and oligodendrocytes, which are responsible for synthesizing myelin protein (Wu and Alvarez, 2011). | ||
| - | <sup>[X]</sup>. | + | |
| Different type of lesions: (Wu and Alvarez, 2011) | Different type of lesions: (Wu and Alvarez, 2011) | ||
| Line 123: | Line 123: | ||
| * **Pattern III:** Loss of Oligodendrocytes and myelin glycoprotein | * **Pattern III:** Loss of Oligodendrocytes and myelin glycoprotein | ||
| * **Pattern IV:** Oligodendrocytes dystrophy and absence of remyelination | * **Pattern IV:** Oligodendrocytes dystrophy and absence of remyelination | ||
| - | <sup>[X]</sup>. | + | |
| </style> | </style> | ||
| <style float-right> | <style float-right> | ||
| - | {{:screen_shot_2016-09-23_at_7.53.57_pm.png|Figure X: Illustrates the inflammatory response towards myelin protein, thus causing formation of lesions (Source: Luzzio, (n.d.).)}} | + | {{:screen_shot_2016-09-23_at_7.53.57_pm.png|Figure 3: Illustrates the inflammatory response towards myelin protein, thus causing formation of lesions (Source: Luzzio, (n.d.).)}} |
| - | **Figure X**: Illustrates the inflammatory response towards myelin | + | **Figure 3**: Illustrates the inflammatory response towards myelin |
| protein, thus causing formation of lesions (Source: Luzzio, (n.d.)). | protein, thus causing formation of lesions (Source: Luzzio, (n.d.)). | ||
| Line 140: | Line 140: | ||
| <style justify> | <style justify> | ||
| **Lesion Formation Mechanism: (Brosnan)** | **Lesion Formation Mechanism: (Brosnan)** | ||
| - | One of the proposed mechanisms of lesion formation was further examined by Brosnan and Raine (1996). They proposed that CD4 T cells were activated outside the Blood-brain barrier by Antigen presenting cells to either myelin protein or oligodendrocytes. The CD4 T cells would enter the Blood-brain barrier and the activated CD4 T cells would recognize antigens presented by microglial cells, which are the macrophages in the Blood-brain barrier or B cells antibodies (Brosnan and Raine, 1996). Once the MHC class 2 receptor recognition and costimulation occur, the CD4 T cells can now release cytokines such as TNF-alpha, gamma-IFN and IL-17. Then the activated microglial cell releases free radicals, nitric oxide, proteases which can cause destruction of tissue in Central Nervous System and recruit more of an inflammation response. This can ultimately cause irreversible tissue and axonal damage and therefore leading to the formation of lesions (Brosnan and Raine, 1996).<sup>[X]</sup> [Figure X]. | + | One of the proposed mechanisms of lesion formation was further examined by Brosnan and Raine (1996) and is illustrated below in //Figure 3//. They proposed that CD4 T cells were activated outside the Blood-brain barrier by Antigen presenting cells to either myelin protein or oligodendrocytes. The CD4 T cells would enter the Blood-brain barrier and the activated CD4 T cells would recognize antigens presented by microglial cells, which are the macrophages in the Blood-brain barrier or B cells antibodies (Brosnan and Raine, 1996). Once the MHC class 2 receptor recognition and costimulation occur, the CD4 T cells can now release cytokines such as TNF-alpha, gamma-IFN and IL-17. Then the activated microglial cell releases free radicals, nitric oxide, proteases which can cause destruction of tissue in Central Nervous System and recruit more of an inflammation response. This can ultimately cause irreversible tissue and axonal damage and therefore leading to the formation of lesions (Brosnan and Raine, 1996). |
| </style> | </style> | ||
| Line 146: | Line 146: | ||
| <style float-left> | <style float-left> | ||
| - | {{:screen_shot_2016-09-23_at_8.10.04_pm.png|Figure X:Demonstrates the location and as well as the immune cells involved in the production of IL-17 | + | {{:screen_shot_2016-09-23_at_8.10.04_pm.png|Figure 4:Demonstrates the location and as well as the immune cells involved in the production of IL-17 |
| (Source: Tzartos et al., 2008).}} | (Source: Tzartos et al., 2008).}} | ||
| - | **Figure X**: Demonstrates the location and as well as the immune cells involved | + | **Figure 4**: Demonstrates the location and as well as the immune cells involved |
| in the production of IL-17 (Source: Tzartos et al., 2008). | in the production of IL-17 (Source: Tzartos et al., 2008). | ||
| Line 159: | Line 159: | ||
| **Inflammation:** | **Inflammation:** | ||
| The attacks by the T-cells on myelin cause inflammatory processes, triggering other immune cells, cytokines and antibodies. The Blood-brain barrier starts to swell as well as macrophages are activated along with cytokines and other destructive proteins (Wu and Alvarez, 2011). | The attacks by the T-cells on myelin cause inflammatory processes, triggering other immune cells, cytokines and antibodies. The Blood-brain barrier starts to swell as well as macrophages are activated along with cytokines and other destructive proteins (Wu and Alvarez, 2011). | ||
| - | <sup>[X]</sup> | + | |
| </style> | </style> | ||
| Line 165: | Line 165: | ||
| **Effect of Demyelination:** | **Effect of Demyelination:** | ||
| After demyelination, the nerve tissue is damaged and the axons are not able to conduct action potentials effectively due to loss of myelin, which ultimately acts as an insulator. This prevents the body to communicate with the Central Nervous System effectively, therefore causing numbness in certain areas of the body (Smith and McDonald, 1999). | After demyelination, the nerve tissue is damaged and the axons are not able to conduct action potentials effectively due to loss of myelin, which ultimately acts as an insulator. This prevents the body to communicate with the Central Nervous System effectively, therefore causing numbness in certain areas of the body (Smith and McDonald, 1999). | ||
| - | <sup>[X]</sup> | + | |
| <style float-right> | <style float-right> | ||
| - | {{:screen_shot_2016-09-23_at_8.03.06_pm.png|Figure X: Illustrates the expression of CD3 T cells and as well as the activity of the CD3 T cells based on IL-17 production in patients with different stages of MS. | + | {{:screen_shot_2016-09-23_at_8.03.06_pm.png|Figure 5: Illustrates the expression of CD3 T cells and as well as the activity of the CD3 T cells based on IL-17 production in patients with different stages of MS. |
| (Source: Tzartos et al., 2008)}} | (Source: Tzartos et al., 2008)}} | ||
| - | **Figure X:** Illustrates the expression | + | **Figure 5:** Illustrates the expression |
| of CD3 T cells and as well as the | of CD3 T cells and as well as the | ||
| Line 187: | Line 187: | ||
| <style justify> | <style justify> | ||
| **Evidence Supporting Immune-mediated Pathophysiology:** | **Evidence Supporting Immune-mediated Pathophysiology:** | ||
| - | In an experiment conducted by Tzartos et al. (2008), they wanted to explore specifically which immune system factors and cells were involved in demyelination as well as the role of Interleukin-17 in demyelination (Tzartos et al., 2008). Initially, they wanted to determine whether T cells, astrocytes, microglia/macrophages, oligodendrocytes were able to produce IL-17, since there were earlier reports that IL-17 is present in higher concentrations in MS tissues. They used in situ hybridization and immunofluorescent-labelled IL-17 mRNA (Tzartos et al., 2008). In addition, they also labelled the interested cells and used an overlap imaging technique to show where IL-17 was present and therefore indicating its production . Astrocytes, T cells, oligodendrocytes all overlapped with IL-17 expression while microglia/macrophages did not (Tzartos et al., 2008). ( Fig X- T cells showed the largest expression, while astrocytes and oligodendrocytes showed small amount). In another experiment, they then wanted to see whether there was an increase of activity of CD3 T cell involved ( Th17 cells) in lesions/plaques and compare this to normal nerve tissue. They also looked at IL-17 to assess the activity of the activated Th17 cells (Tzartos et al., 2008). Using tissue samples from the perivascular areas of acute lesions, active borders of chronic active lesions, inactive lesions, inactive areas of chronic active lesions and as well as NAWM in MS patients(normal appearing white matter), they observed that there was increased amount of IL-17 cytokine and CD3 T cells in MS patient tissues samples compared to the non MS brain (control variable) . This indicated that IL-17 is largely involved in the inflammatory response in MS (Tzartos et al., 2008). In addition, they looked at alternative method to quantify the presence of IL-17 in MS patient brain sample. They compared the densities and were able to conclude the similar results as previously reported. Therefore, demonstrating that IL-17 and CD3 T cells were involved in carrying out an inflammatory response leading to demyelination of neurons (Tzartos et al., 2008). Fig <sup>[X]</sup> | + | In an experiment conducted by Tzartos et al. (2008), they wanted to explore specifically which immune system factors and cells were involved in demyelination as well as the role of Interleukin-17 in demyelination (Tzartos et al., 2008). Initially, they wanted to determine whether T cells, astrocytes, microglia/macrophages, oligodendrocytes were able to produce IL-17, since there were earlier reports that IL-17 is present in higher concentrations in MS tissues. They used in situ hybridization and immunofluorescent-labelled IL-17 mRNA (Tzartos et al., 2008). In addition, they also labelled the interested cells and used an overlap imaging technique to show where IL-17 was present and therefore indicating its production . Astrocytes, T cells, oligodendrocytes all overlapped with IL-17 expression while microglia/macrophages did not, as shown in //Figure 4// (Tzartos et al., 2008). In another experiment, they then wanted to see whether there was an increase of activity of CD3 T cell involved ( Th17 cells) in lesions and compare this to normal nerve tissue. They also looked at IL-17 to assess the activity of the activated Th17 cells (Tzartos et al., 2008). Using tissue samples from the perivascular areas of acute lesions, active borders of chronic active lesions, inactive lesions, inactive areas of chronic active lesions and as well as NAWM in MS patients(normal appearing white matter), they observed that there was increased amount of IL-17 cytokine and CD3 T cells in MS patient tissues samples compared to the non MS brain (control variable), highlighted in //Figure 5// below. This indicated that IL-17 is largely involved in the inflammatory response in MS (Tzartos et al., 2008). In addition, they looked at alternative method to quantify the presence of IL-17 in MS patient brain sample. They compared the densities from //Figure 6// and were able to conclude the similar results as previously reported. Therefore, demonstrating that IL-17 and CD3 T cells were involved in carrying out an inflammatory response leading to demyelination of neurons (Tzartos et al., 2008). |
| </style> | </style> | ||
| <style float-left> | <style float-left> | ||
| - | {{:zjh0010875050004.jpg|Figure X:Illustrates the observed expression as a density for both CD3 T cells and IL-17 based on the different stages of MS (Source: Tzartos et al., 2008).}} | + | {{:zjh0010875050004.jpg|Figure 6:Illustrates the observed expression as a density for both CD3 T cells and IL-17 based on the different stages of MS (Source: Tzartos et al., 2008).}} |
| - | **Figure X:** Illustrates the observed expression as a density for both CD3 T cells and | + | **Figure 6:** Illustrates the observed expression as a density for both CD3 T cells and |
| IL-17 based on the different stages of MS (Source: Tzartos et al., 2008). | IL-17 based on the different stages of MS (Source: Tzartos et al., 2008). | ||
| Line 242: | Line 242: | ||
| >Glatiramer acetate is thought to alter the immune processes believed to be responsible for the pathogenesis of MS, however its mechanism is not fully known. (Hedley, 2012) Studies have shown that there is delay of progression from CIS to “clinically definite MS” in MS patients for up to three years with use of glatiramer acetate. (Hedley, 2012) This treatment reduces the number and severity of relapses, and the formation of new lesions on a brain MRI, however its effects on long-term progression are not clear. (Hedley, 2012) Adverse effects of glatiramer acetate minor and mainly consist of injection site reactions, seen in 70% of patients. (Hedley, 2012) Other less common side effects include lipoatrophy, flushing, shortness of breath, chest tightness, and palpitations. (Hillman, 2014) | >Glatiramer acetate is thought to alter the immune processes believed to be responsible for the pathogenesis of MS, however its mechanism is not fully known. (Hedley, 2012) Studies have shown that there is delay of progression from CIS to “clinically definite MS” in MS patients for up to three years with use of glatiramer acetate. (Hedley, 2012) This treatment reduces the number and severity of relapses, and the formation of new lesions on a brain MRI, however its effects on long-term progression are not clear. (Hedley, 2012) Adverse effects of glatiramer acetate minor and mainly consist of injection site reactions, seen in 70% of patients. (Hedley, 2012) Other less common side effects include lipoatrophy, flushing, shortness of breath, chest tightness, and palpitations. (Hillman, 2014) | ||
| - | Deciding on which treatment to use (interferon beta or glatiramer acetate) depends on patient preference in type and frequency of injection. (See Figure **X**) | + | Deciding on which treatment to use (interferon beta or glatiramer acetate) depends on patient preference in type and frequency of injection. (See Figure 7) |
| </style> | </style> | ||
| Line 250: | Line 250: | ||
| {{:table_01.png|}} | {{:table_01.png|}} | ||
| - |  **Figure X**: The dosing, frequency, and route of administration for the ACB-R therapies. (Source: Hillman & Khorassani, 2014) | + |  **Figure 7**: The dosing, frequency, and route of administration for the ACB-R therapies. (Source: Hillman & Khorassani, 2014) |
| </style> | </style> | ||
| Line 296: | Line 296: | ||
| {{:treadmill_training.jpg|}} | {{:treadmill_training.jpg|}} | ||
| - | **Figure X**: Body weight assisted treadmill training. There is physical assistance for each | + | **Figure 8**: Body weight assisted treadmill training. There is physical assistance for each |
| leg due to impaired walking ability. (Source: http://agelessphysio.com) | leg due to impaired walking ability. (Source: http://agelessphysio.com) | ||
| Line 310: | Line 310: | ||
| __Walking Ability__ | __Walking Ability__ | ||
| - | > A common symptom of MS is impaired walking ability. Dalfampridine (Fampyra or Ampyra) can be used to improve walking ability. Dalfampridine is a potassium channel blocker that enhances conduction along demyelinated nerve fibres. (Hillman, 2014) In phase 3 clinical trials, walking speed was increased by about 25% within weeks in MS patients. (Hedley, 2012) There are, however, side effects such as a greater risk of seizures, anxiety, insomnia, dizziness, and tremor. (Hedley, 2012) In terms of physical therapy, exercise through treadmill training has been shown to improve walking endurance and velocity. (Amato & Portaccio, 2012) (See Figure **X**) | + | > A common symptom of MS is impaired walking ability. Dalfampridine (Fampyra or Ampyra) can be used to improve walking ability. Dalfampridine is a potassium channel blocker that enhances conduction along demyelinated nerve fibres. (Hillman, 2014) In phase 3 clinical trials, walking speed was increased by about 25% within weeks in MS patients. (Hedley, 2012) There are, however, side effects such as a greater risk of seizures, anxiety, insomnia, dizziness, and tremor. (Hedley, 2012) In terms of physical therapy, exercise through treadmill training has been shown to improve walking endurance and velocity. (Amato & Portaccio, 2012) (See Figure 8) |
| __Depression__ | __Depression__ | ||
| Line 330: | Line 330: | ||
| </HTML> | </HTML> | ||
| + | |||
| + | |||
| + | ====== Conclusion ====== | ||
| + | |||
| + | Multiple Sclerosis is an inflammatory, autoimmune disease which disrupts the neurons’ ability to trigger action potentials. As of today, the pathophysiology of this disease is not fully understood, however, considerable advances have been made in understanding the factors behind this disease. It is evident that further research needs to be conducted to figure out the precise mechanism of the demyelination and remyelination process. The findings of this research will lead to more efficient treatment mechanisms and may even lead to a cure for Multiple Sclerosis. | ||
| + | |||
| + | |||
| + | <HTML> | ||
| + | <br> | ||
| + | </HTML> | ||
| Line 335: | Line 345: | ||
| Amato, M. P. & Portaccio, E. (2012). Management options in multiple sclerosis-associated fatigue. Expert Opinion on Pharmacotherapy, 13(2), 207-216 | Amato, M. P. & Portaccio, E. (2012). Management options in multiple sclerosis-associated fatigue. Expert Opinion on Pharmacotherapy, 13(2), 207-216 | ||
| + | |||
| + | Ascherio A, Munger KL (April 2007). "Environmental risk factors for multiple sclerosis. Part I: the role of infection". Annals of Neurology. 61 (4): 288–99. | ||
| Brosnan, C. F., & Raine, C. S. (1996). Mechanisms of immune injury in multiple sclerosis. Brain Pathology, 6(3), 243-257. | Brosnan, C. F., & Raine, C. S. (1996). Mechanisms of immune injury in multiple sclerosis. Brain Pathology, 6(3), 243-257. | ||
| + | |||
| + | Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet. 372 (9648): 1502–17 | ||
| de la Fuente AG et al. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol. 2015; 211(5):975-85. | de la Fuente AG et al. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol. 2015; 211(5):975-85. | ||
| Multiple Sclerosis Clinical Presentation. (2016). Retrieved September 18, 2016, from http://emedicine.medscape.com/article/1146199-clinical | Multiple Sclerosis Clinical Presentation. (2016). Retrieved September 18, 2016, from http://emedicine.medscape.com/article/1146199-clinical | ||
| + | |||
| + | Dyment DA, Ebers GC, Sadovnick AD (February 2004). "Genetics of multiple sclerosis".Lancet Neurol. 3 (92): 104–10 | ||
| Fowler, C. J., Panicker, J. N., Drake, N., Harris, C., Harrison, S. C. W., Kirby, M., Lucas, M., Macleod, N., Mangnall, J., North, A., et al. (2009). A UK consensus on the management of the bladder in multiple sclerosis. Postgraduate Medical Journal. 85, 552-559. | Fowler, C. J., Panicker, J. N., Drake, N., Harris, C., Harrison, S. C. W., Kirby, M., Lucas, M., Macleod, N., Mangnall, J., North, A., et al. (2009). A UK consensus on the management of the bladder in multiple sclerosis. Postgraduate Medical Journal. 85, 552-559. | ||
| + | |||
| + | Gilden DH (March 2005). "Infectious causes of multiple sclerosis". The Lancet Neurology. 4 (3): 195–202 | ||
| Hedley, L. (2012). Multiple sclerosis treatment options. The Pharmaceutical Journal. 288, 247-250. | Hedley, L. (2012). Multiple sclerosis treatment options. The Pharmaceutical Journal. 288, 247-250. | ||
