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Multiple sclerosis (MS) is a chronic inflammatory disease of the myelin sheath around nerve axons in the central nervous system, either because of attack on the myelin by the immune system or failure of the myelin-producing cells. It has had various names in the 150 years since its description, including sclerose en plaques, disseminated sclerosis and encephalomyelitis disseminate, reflecting its tendency to affect different places in the nervous system at different points in time and the plaque-like areas of scarring and atrophy that these attacks cause in the brain and spinal cord.

Quote:MS is the most common immune disorder of the nervous system, and is a significant cause of disability in Western nations. Its cause remains obscure, but there has been an enormous advance in understanding of its pathophysiology and options for its treatment[1].

MS probably existed in ancient times, but clinical descriptions cannot be identified in ancient medical texts in the way that cases of epilepsy and dementia can. This may be because the complex and variable symptoms and signs of the disorder often resulted in its being diagnosed as something else, as has happened not infrequently in more recent times; it is also possible that the disease’s predilection for the temperate zones and northern climes made it less common in the African, Near Eastern and Southern European locations in which the earliest medical texts tended to be written [2]. One of the earliest clinical descriptions of what is probably MS was written around 1200 in Iceland about Halldora, a young woman with episodic visual loss and paralysis that remitted after prayers to the saints. A Dutch nun, Saint Lidwina of Schiedam, had intermittent paroxysmal pain, visual loss and leg weakness after falling while skating on a frozen canal at age 16; she died at 53 in 1433 after multiple such attacks, and became the patron saint of the chronically ill and of figure skaters. Reports of waxing and waning neurological signs and symptoms with a predilection for the visual pathways and the spinal cord came predominantly from northern Europe, and have led to the suggestion of a "Viking gene" that is responsible for the disease [3].

The clinical features and distinctive pathology of sclerose en plaque were delineated by Charcot in 1868. These features had been observed before, and also described in the writings of at least one patient, but Charcot’s contribution, as with so many other neurological diseases, was to synthesize them and to differentiate them from the signs and symptoms of other disorders and establish criteria for diagnosis of the disease. Robert Carswell in England and Jean Cruveilher in France had described the signs and symptoms of the disease and found scarring and atrophy of the spinal cord in some patients during the 1830s, but did not recognize this as a distinct disease. The Swiss anatomist Georg Rindfleisch showed in 1863 that inflammatory lesions of the spinal cord were often distributed around blood vessels, but did not draw conclusions from this. Charcot demonstrated the cardinal symptoms that became part of a diagnostic triad that bears his name – nystagmus, intention tremor and scanning or telegraphic speech – and also found that patients had slowing of cognition and enfeeblement of memory, which was not generally agreed upon as a manifestation of MS for another century[4].

Several literary descriptions of MS are in retrospect evident in the 19th century. Augustus Frederick d’Este, grandson of King George III, kept a detailed diary from 1822 until 1846 that described transient monocular visual loss, leg weakness, hand clumsiness, dizziness, numbness, unsteadiness requiring the use of a wheelchair, urinary incontinence and impotence consistent with MS. A later diarist, Bruce Frederick Cummings, wrote under the pen name of  W.N.P. Barbellion an account of progressive neurologic deficit consistent with what is today called chronic progressive MS, that resulted in his death at age 31 in 1919 [5].

In the decades after Charcot’s description, salient features of MS were delineated by Walter Moxen in Britain and Edward Seguin in the United States: female predominance, generally non-inherited character and relapsing and remitting course. The causes of the disorder remained obscure, in part because the myelin sheath around nerve axons was not known until reported by Louis-Antoine Ranvier in 1878, and it was not until 1916 that James Dawson described the microscopic evidence of inflammation in myelin that is the hallmark of the MS plaque. Oligodendrocytes, the glial cells that produce myelin, were identified in 1928, and the role of the myelin sheath in rapid axonal transmission of nerve impulses (saltatory conduction) began to be understood at that time [6].

It was widely believed at that time that some unidentified toxin caused MS, and the occasional occurrence of  MS-like "paralytic accidents" after rabies vaccinations, suggested that viral infection might play a role. An animal model (experimental allergic encephalomyelitis) was developed in the 1930s by Thomas Rivers and colleagues at Rockefeller University, and it was shown that immune cells and not viruses were responsible for the inflammatory attacks [7]. Seven decades of subsequent research have identified multiple components of the immune system that are responsible for autoimmune diseases: T-cell lymphocytes, antibodies, complement and chemokines [8].

In subsequent decades a number of other theories were proposed as to the cause and mechanisms of MS, such as chronic circulatory insufficiency due to arterial or venous disease or depletion of the gut biome causing susceptibility to infection or altered immune function. Various treatments including cerebral vasodilators, surgical procedures to improve venous drainage, radiation therapy and probiotics have been attempted. The major therapeutic advances, however, have involved modulation of the immune system with corticosteroids, plasmapheresis,  interferon and its derivatives and the antineoplastic drug mitoxantrone. Recent attention has been focused on antibodies raised against attacking immune cells, neuroprotective agents and drugs that improve the ability of the damaged myelin sheath to conduct nerve impulses [9].


[Image: 640px-Symptoms_of_multiple_sclerosis.svg.png]
"Symptoms of multiple sclerosis" by Mikael Häggström (Wikimedia)
  • MS is classically defined by episodic neurologic deficit corresponding to lesions that are disseminated in time and space within the central nervous system.
  • Almost any type of symptom can occur, but certain types or complexes of symptoms predominate and the attacks must last more than 24 hours.
  • Another venerable clinical maxim is that MS causes symptoms without signs and signs without symptoms: patients will have neurological symptoms, sometimes quite intensely, that are not accompanied by abnormal findings on neurological examination, and in other cases neurological signs on examination will not be accompanied by patient complaints suggesting central nervous system dysfunction.
  • The progression of physical and cognitive deficits may occur cumulatively over time without identifiable remissions or relapses [10].

Sensory loss or disturbance (paresthesias) are often the earliest complaint, as is twitching of the facial muscles (myokimia). Eye symptoms, particularly diplopia, occur in about a third of patients, pain in about half of patients during their clinical courses and constitutional symptoms, especially dizziness and fatigue, are reported by 70 per cent of patients. Heat intolerance, depression and less frequently euphoria and subjectice difficulties with memory or attention are commonly reported. Charcot described a symptomatic triad of ataxia due to cerebellar involvement, nystagmus and tremor which bears his name. Facial weakness, more often facial pain due to trigeminal neuralgia and spinal cord symptoms involving weakness, bowel and bladder disturbance, sexual dysfunction or transverse myelitis are also common [11].

Optic neuritis is the first clinical event in 20 per cent of patients and 40 per cent eventually experience it. Fatigue is reported by as many as 75 per cent of patients, and is the leading cause of disability in 50 to 60 per cent. Spasticity is nearly universal, and the increased muscle tone and greater difficulty of performing movements and activities contributes to fatigue. Forty to 70 per cent of MS patients have cognitive difficulties, chiefly affecting memory but also involving visual perception and executive function, that also adversely affect quality of life and contribute to disability. About half of patients have significant pain, which is mainly neuropathic in character and related to the demyelinating lesions, but can also over time arise from spasticity, abnormal posture or impaired balance. Urinary symptoms can involve failure of the bladder to store urine properly, resulting in frequency, urgency or incontinence, or failure to empty normally, causing urinary retention and infection. Constipation is the most common intestinal complaint, due either to neurogenic bowel dysfunction from spinal lesions or to bowel immobility. Aphasia and other language disturbances or seizures are rare, reported by less than 5 per cent of patients [12].

The physical and neurological examination is often abnormal in MS and may change from examination to examination, not always in conjunction with clinical symptoms. The most common abnormalities are localized weakness, generally with spasticity of the involved limbs; focal sensory impairment, particularly of posterior column modalities (vibration and proprioception); slowing and decreased coördination of limb movements and an ataxic wide-based gait ("spastic ataxia"). Optic neuritis commonly involves unilateral visual loss or impairment, sometimes painful, but is usually retrobulbar in location and may cause only pallor of the optic disc on fundoscopic examination ("the patient sees nothing and the doctor sees nothing"). Eye movements are frequently abnormal, most commonly inability to move one eye laterally due to abducens nerve palsy or bilateral internuclear ophthalmoplegia from involvement of the medial longitudinal fasciculus in the brain stem, resulting in inability to move the eye on the side of the lesion to the midline (adduction) along with nystagmus in the other (abducting) eye [13].

MS is clinically classified on the basis of relapses and remissions or their absence. Relapsing-remitting MS (RRMS) is the classical form, and accounts for about 85 per cent of cases. Studies with serial MRI imaging indicate that asymptomatic demyelinating episodes can occur in between clinical relapses. About half of patients with RRMS convert to a secondary progressive form (SPMS) after 10-15 years of disease; attacks no longer remit and there is progressive accumulation of disability. Primary progressive MS (PPMS) is progressive without remissions from the start, and represents about 10 per cent of cases; 5 per cent of patients have a progressive course with periodic superimposed relapses (PRMS). There are also milder variants: the clinically isolated syndrome (CIS) , also called "possible MS" involves a single MS-like attack and some patients have mild and infrequent attacks with complete resolution of symptoms and little or no accumulation of deficit over 15 to 20 years of disease (Benign MS) [14].

The severity and progression of MS are measured by disability scales, chiefly the Kurtzke Disability Status Scale, developed in 1955 and now considerably expanded (EDSS). Grades from 0 to 4 are determined by functional system (FS) scores for pyramidal (motor), cerebellar, brain stem, sensory, bowel and bladder and visual status as well as other aspects of neurologic function, particularly cognition. These yield scores ranging in increments of 0.5 from a score of 0 for normal neurologic examination and cerebral function to a score of 10 for death from MS. Another simple measure of disability is the Ambulation Index, which is the length of time required to walk 25 feet [15].


MS is the most common autoimmune disorder involving the central nervous system, and affected 30 people per 100,000 with 2.5 new cases per 100,000 and 18,000 deaths in 2010. There are marked geographic and climate differences in prevalence, with 0.5 cases per 100,000 in Africa but 9 per 100,000 in the Americas and 80 per 100,000 in Europe generally, and 200 per 100,000 in northern European populations. Its onset is most commonly in the 20s and 30s, and at that age women predominate over men by about 2 to 1 and most cases are the classical RRMS. In cases with onset after age 50, incidence is about equal in women and men and PPMS is the most common form [16]. Individuals born in areas with high MS incidence who move to areas with low incidence before age 15 acquire the new region’s risk for MS, but if they migrate after age 15 they keep the MS risk of the area in which they were born. Many potential risk factors for MS have been scrutinized, generally with equivocal or results; there is an increased risk with smoking, and gout is less frequent among MS patients than would be expected while serum uric acid levels are lower than in individuals without MS [17].


Inheritance does not play a strong part in the acquisition of MS. The concordance rate between monozygotic twins is only 20 to 30 per cent, and the risk of developing the disorder is about 7 times greater for first-degree relatives like children and siblings than for the general population but the excess risk in families over a lifetime is only about 5 per cent. This is consistent with minimal genetic predisposition and greater effect from some environmental exposure, as is the occurrence of conjugal MS in husbands and wives who do not have any MS in their own biological families. Rather than gene mutations associated with the disease, it has been suggested that variants of genes (polymorphisms) may cause different degrees of gene expression in different people, and if genes regulating immune activity are involved, then some of those people may have exaggerated expression of a proinflammatory gene that results in untoward immune reactions and autoimmune disorders. A polymorphism may result in greater likelihood of developing MS or having a more severe or unremittent form of the disease if exposed to a trigger for the development of symptoms, while other polymorphisms might confer some degree of protection against the disorder. 

Polymorphisms of the HLA genes located on chromosome 6 (MHC or major histocompatibility complex) have been linked to susceptibility to autoimmune diseases including MS, type 1 diabetes and systemic lupus erythematosus. Increased MS risk has been associated with MHC alleles DR15 and DQ6, while other HLA alleles have had an apparent protective effect against developing MS (HLA-C554 and HLA-DRB1*11. About half of the modest genetic predisposition to MS is apparently due to these HLA-MHC genes, while the rest is due to 12 or more genes in other locations, polymorphisms of which may increase the risk of developing MS [18].


If genetic factors predispose certain individuals to an excessive immune reaction and the development of autoimmune disorders, or in some cases genetic protection against immune overreaction is absent, there must still be some event or agent that triggers the immune process. Viral infections have been suggested to activate self-reactive T-cells that may react against myelin, and chronic virus infection with periodic reactivation could produce remissions and relapses of disease. Several viruses have been proposed as MS triggers, initially measles and canine distemper and most recently Epstein-Barr virus (EBV). MS patients have a high incidence of serum antibodies against EBV and EBV antigens are often expressed in MS plaques, but most people with EBV infection do not develop MS and many patients with MS do not have evidence of EBV infection [19]. 

The geographic predilection of MS has raised the question of environmental causes in northern latitudes. If there is an environmental factor involved, it must exert its effect early as moving to a new location after age 15 causes people to incur the MS risk of their new domicile thereafter; in addition, some ethnic groups in regions farther from the Equator that have high MS incidences do not themselves often develop MS, such as Canadian Inuits, American Eskimos, the Sami or Lapps of Finland and the Maori of New Zealand. There is also some evidence in recent studies that the north-south differential in MS incidence is decreasing [20]. Vitamin D levels have been proposed as a causative environmental factor and vitamin D has a role in regulating immune response by decreasing the production of proinflammatory cytokines and increasing the production of anti-inflammatory cytokines. High circulating levels of vitamin D appear to be associated with a reduced risk of MS, and while vitamin D might be deficient in some northern areas that have less sunlight and higher MS incidence, studies suggest that Norway, where the traditional diet is very high in vitamin D, has a lower incidence of MS than its Scandinavian neighbors [21].

Hepatitis vaccination and venous insufficiency are recent suggestions for possible causative factors in MS that have not yet gained wide acceptance. Anecdotal reports that MS was more frequent after hepatitis vaccination prompted investigation by the Centers for Disease Control and Prevention (CDC), but an increased incidence of the disease among hepatitis-vaccinated individuals was not confirmed [22]. Several studies have suggested that venous stenosis and insufficient cerebral venous drainage can lead to venous stasis, iron deposition in the brain and the triggering of an immune reaction causing MS. Internal jugular vein-azygos vein angioplasty was reported to alleviate MS symptoms, but this study has not yet been replicated [23].


MS has historically been diagnosed by history and neurological findings. Current criteria specify that there have been two or more objectively evident attacks at different times, two separate episodes with clinical evidence from one and MRI abnormality ascribable to the other, one objectively-verifiable clinical attack with MRI evidence of two or more others in the past, a single episode of neurological deficit (clinically isolated syndrome) followed by a later episode or MRI abnormality or insidious progression of neurological deficit over a year accompanied by one brain lesion on MRI, two spinal cord lesions or abnormal cerebrospinal fluid studies [14]. 

MRI imaging is highly sensitive to the lesions of MS, being positive for 90 to 95 per cent of brain lesions and 75 per cent of spinal cord lesions, more in older than in younger patients. T2-weighted images show "bright objects" caused by edema associated with lesions, while T1-weighted images detect "black holes" from axonal death and resultant cerebral atrophy. Functional MRI and Magnetic Resonance spectroscopy may detect changes in patients with slight or absent changes on structural brain MRI or minimal clinical findings despite substantial MRI lesions. The current focus in MS neuroimaging is on correlation with therapeutic response [24].

Lumbar puncture was once routinely done and remains the only objective test for central nervous system inflammation; it is often helpful in patients with possible MS. Oligoclonal bands are present in 90 to 95 per cent of patients, and 70 to 90 per cent of those with MS will have intrathecal production of IgG [25]. Standard EEG is variably and nonspecifically abnormal in MS, but computer-assisted quantitative EEG shows differences between MS with benign prognosis and relapsing-remitting forms [26]. Evoked potentials to visual, auditory and somatosensory stimulation extracted from the EEG by signal averaging have been largely superceded by MRI, but may show separate lesions and predict MS course and effect of therapy [27].

Cerebral angiography is rarely used to differentiate MS and cerebral vasculitis. Ultrasound examination has been suggested for measurement of ventricular size in the evaluation of cognitive dysfunction in MS. Laboratory studies are appropriate to exclude differential possibilities such as Lyme disease, syphilis, thyroid disease, vitamin B12 deficiency and Wilson’s disease; Devic’s disease or neuromyelitis optica, which can more closely resemble MS, is associated with antibodies to the nerve membrane water channel aquaporin 4 [28].


For about a century there was no effective treatment for MS. In the last 25 years there have been substantial advances in its management, due in large part to biotechnology advances in the areas of neuroimaging, drug development, genetics and immunology. MS therapy now involves disease-modifying or immunomodulatory treatments to reduce the frequency and severity of relapses and slow progression of the disease, and symptomatic management of the effects of demyelination or neurological deficit. With one exception, disease-modifying drugs are approved only for the relapsing form of MS. Symptomatic management focuses on spasticity, bowel and bladder disturbances, effects of paralysis and immobility, alleviation of pain and amelioration if possible of cognitive and behavioral problems. There is evidence that prompt treatment of clinically isolated symptoms reduces the conversion of possible to probable or definite MS by about 40 per cent [29].

Acute relapses have historically been treated with corticosteroids, first ACTH and more recently methylprednisolone. This alleviates acute symptoms but may not change overall disease progression, and it is not clear that it works for optic neuritis. Plasmapheresis is considered probably effective as second-line treatment when steroids do not work or cannot be used [30].

Ten immunomodulatory drugs are now approved for relapsing MS in the United States. Three (fingolimod, teriflunomide and dimethyl fumarate) are taken orally, interferon-beta-1a is administered intramuscularly, pegylated interferon-beta-1a (mixed with PEG or polyethylene glycol for longer duration of action), interferon-beta-1b and glatirimer acetate are given subcutaneously and natalizumab and mitoxantrone require intravenous infusion [31].

 Interferon-beta-1b (Betaseron) was the first agent to be approved in 1993, and decreased the frequency of relapses by about a third, significantly reduced the acquisition of MS lesions and brought about a 10 per cent reduction in the incidence of disease progression. Side effects include asthenia, fatigue, depression, increased muscle tone, skin reactions at the injection site, leukopenia and increase liver enzymes, myasthenia and most commonly, flu-like symptoms. 

Intramuscular interferon-beta-1a (Avonex) decreased the annual exacerbation rate by 29 per cent, reduced disease progression from 35 per cent in the placebo group to 21 per cent in the treatment group and significantly decreased the number and volume of MRI enhancing lesions. The subcutaneous form (Rebif) reduced relapses by 27 (low dose) and 33 (high dose) percent, and was shown in other studies to reduce cumulative disability and the burden of MRI lesions with the higher dose. Flu-like symptoms were less than with interferon-beta-1b but injection site reactions, white blood cell abnormalities and liver disorders were more common. The subcutaneous preparation had fewer flu-like reactions, but skin reactions and abnormalities of liver function and white blood cells were more common. Both forms of interferon-beta-1a were associated with neutralizing antibodies which lessened drug effect, and this was more common with the subcutaneous form. Interferon-beta-1a admixed with PolyEthylene Glycol (PEGylated and called Plegridy) can be self-administered subcutaneously every 2 weeks, and reduced the relapse rate by 36 per cent, decreased disability progression by 38 per cent and lessened the appearance of new MRI lesions by 67 to 85 per cent as compared to placebo. Interferon-beta-1may be problematic in patients with uncontrolled depression, and consideration of glatirimer is recommended instead.

Glatirimer acetate (Copaxone) is a synthetic polypeptide that produced a 29 per cent reduction in relapse rate over 2 years and may have slightly reduced disability; it was therefore approved by the Food and Drug Administration for relapse prevention but not for slowing disability progression. A higher dose approved in 2014 may be more effective, and can be administered subcutaneously 3 times a week rather than once daily.

Natalizumab (Tysabri) is a monoclonal antibody, hence the "mab" in its name, that binds to the adhesion molecule alpha-4 integrin and prevents it from adhering to receptors and presumably from initiating an immune response. It is raised in mice and can therefore be immunogenic itself, so it is altered and "humanized" for monthly intravenous infusion. Natalizumab reduced relapses by 68 per cent and disease progression by 42 per cent over 2 years, but was also associated with fatal cases of the opportunistic viral infection progressive multifocal leukoencephalopathy and was therefore withdrawn in 2005. It was reintroduced in 2006 for patients with very active relapsing disease or no response to interferon or glatirimer. It may also work for primary and secondary progressive MS, but is available only through a restricted distribution system.

Fingolimod (Gilenya) is derived from miryocin, produced by a fungus related to several used in Chinese and Tibetan medicine. Fingolimod is an analogue of the cell membrane lipid sphingosine, and through sphingosine-1-phosphate receptors causes lymphocytes to remain in lymph nodes so they cannot initiate an immune attack; it may also stimulate the repair and replacement of glial cells, perhaps including the ones which synthesize myelin. It was the first MS drug that can be taken orally, and in daily administration significantly reduced relapses and delayed the acquisition of disability. Reduced lymphocyte count and resultant infection, macular edema, skin cancer and bradycardia and hypotension have occurred, the latter sufficiently severe that the first doses should be taken under medical observation and an ECG obtained before and after. The drug is now contraindicated in patients with cardiovascular disease.

Teriflunomide (Aubagio) inhibits the rapid division of cells, and may therefore retard the activation of T-cells to start an immune response. It produced a 31 per cent reduction in relapse rate and minimally decreased the progression of disability, and significantly reduced the development of definite MS in patients with clinically isolated syndromes. Decreased white blood cell count and increased blood pressure may occur along with flu-like symptoms and other nonspecific effects; liver toxicity, teratogenesis, peripheral neuropathy, acute renal failure, immunosuppression with infection and particularly activation of latent tuberculosis, skin hypersensitivity reactions, interstitial lung disease, hyperkalemia and hypophosphatemia. It is contraindicated in patients with liver disease, women of childbearing age who are not sterilized or using contraceptives and those taking its parent compound leflunomide (Arava) for arthritis.

Dimethyl fumarate (Tecfidera) was approved for oral treatment of relapsing MS because it decreased the proportion of patients who relapsed by half, decreased the annual rate of relapse by 53 per cent and caused a 38 per cent reduction in progression of disability over 2 years as compared to placebo. The appearance of MRI lesions was also significantly reduced compared to placebo. The drug activates the nuclear factor (erythroid-derived 2)-like 2 or Nrf2 pathway that regulates the synthesis of antioxidant proteins that protect against cell injury and inflammation, and may therefore have a neuroprotective effect. It is also an agonist of the nicotinic acid receptor, which may be helpful for oxidative cell stress and could account for the side effects of flushing, gastrointestinal upset, diarrhea and nausea. White blood cell count and liver function tests need to be monitored also. 

The most recent addition to the disease-modifying armamentarium is alemtuzumab (Lemtrada), developed for chemotherapy of leukemia and lymphoma and also used as an immunosuppressant in preparation for kidney, islet cell and bone marrow transplantation. It is a recombinant monoclonal antibody against the CD52 lymphocyte antigen, and cells to which it binds are targeted for destruction.  As a result, the risk of severe autoimmune reactions is significant, but the drug was significantly more effective than interferon-beta-1a or 1b in patients new to treatment or relapsing during treatment. In a later study, a quarter of the patients treated with alemtuzumab became free of disease activity (no relapses, no accumulation of disability, no new MRI lesions) while none of the interferon-treated patients did. 

Mitoxantrone (Novantrone) is approved for secondary progressive MS, relapsing MS that is worsening and for progressive relapsing disease. It is an immunosuppressive agent used for lymphocytic leukemia, lymphoma and breast cancer, and has been given "black box" warnings by the FDA on account of cardiac toxicity and risk of developing acute myelogenous leukemia. Some of the same adverse effects, along with hemorrhagic cystitis, are associated with cyclophosphamide (Cytoxan) therapy, but this immunosuppressive agent is effective in inducing remission of aggressive relapsing or secondary progressive MS, followed by maintenance therapy with glatirimer. No therapy is presently approved for primary progressive MS.

Pharmacological treatment, physical and occupational therapy, speech therapy and cognitive-behavioral psychotherapy have been shown to be effective for the management of symptoms and disability. The areas in which symptomatic therapy is appropriate include visual impairment from optic neuritis, fatigue, spaticity, bowel and bladder dysfunction, cognitive decline, depression and less frequently agitation, paroxysmal disturbances and particularly pain, tremor, heat intolerance and sexual dysfunction32. If not treated in one way or another, about a third of patients will have permanent physical disability after 20 to 25 years of disease. Five to 10 per cent will manifest apparently benign disease, with little or no disability after a long course, but these patients may show cognitive deterioration over time. Patients with primary progressive disease or spinal cord lesions from MS will have the worst prognosis, particularly males. Life expectancy is in general only modestly shortened, and death is caused by secondary infectious, pulmonary or renal complications in about two-thirds of patients. Although MS remains a significant long-term treatment and management problem, the accelerating pace of diagnostic and therapeutic development, due in large part to advances in genetic and drug development technologies, has improved its outlook over the past 25 years.


1. Compston A, Coles A (2008). Multiple sclerosis. Lancet, 372(9648): 1502-1517.

2. Maeder R (1979). Does the history of multiple sclerosis go back as far as the 14th century? Acta Neurol  Scand,  60 (3): 189–92. 

3. Holmøy T (2006). A Norse contribution to the history of neurological diseases. Eur. Neurol. 55 (1): 57–8. 

4. Murray TJ (2005). Multiple Sclerosis: The History of a Disease. New York, Demos Press.

5. Orrell RW (2005). Multiple Sclerosis: The history of a disease (review). J Roy Soc Med, 98(6): 289.

6. Piccolino M (2003). Nerves, alcohol and drugs, the Adrian-Kato controversy on nervous conduction: deep insights from a "wrong" experiment? Brain Res Rev, 43(3): 257-265.

7. Van Epps HL (2005). Thomas Rivers and the EAE model. J Exp Med, 202(1): 4.

8. Steinman L (2003). Optic neuritis, a new variant of experimental encephalomyelitis, a durable model for all seasons, now in its seventieth year. J Exp Med, 197(9): 1065-1071.

9. Sontheimer H (2015). Multiple sclerosis. In, Diseases of the Nervous System. Waltham MA; Academic Press. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

10. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtelotte WW (1983). New diagnostic criteria for multiple sclerosis: guideline for research protocols. Ann Neurol, 13(3): 227-231.Ann Neurol.  1983; 13(3):227-31.

11. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sanberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001). Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol, 50(1):121-127.

12. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sanberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol, 58(6): 840-846.

13. National Clinical Guideline Center (2014). Management of Multiple Sclerosis in Primary and Secondary Care (NICE Clinical Guidelines, No. 186). London: National Institute for Health and Care Excellence (UK).

14. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA. Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L. Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol, 69(2):292-302.

15. Kurtzke JF (1983). Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 33(11):1444-52.

16. Milo R, Kahana E (2010). Multiple sclerosis: Geoepidemiology, genetics and the environment. Autoimmun Rev, 9(5): A387-A394.

17. Ascherio A, Munger KL (2007). Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol, 61(6): 504-513

18. Baranzini SE (2011). Revealing the genetic basis of multiple sclerosis: are we there yet? Curr Opin Genet Devel, 21(3): 317-324.

19. Ascherio A, Munger KL (2007). Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol, 61(4): 288-299.

20. Salvetti M, Giovannoni G, Aloisi F (2009). Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol,  22(3):201-6.

21. Kampman MT, Brustad M (2008). Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology, 30(3):140-6.

22. Centers for Disease Control and Prevention (2010). FAQs about Hepatitis B Vaccine (Hep B) and Multiple Sclerosis. Bethesda, MD. US Department of Health and Human Services.

23. Lapaucis A, Lillie E, Dueck A, Straus S, Perrier L, Burton JM, Aviv R, Thorpe K, Feasby T, Spears J (2011). Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ,  183(16):E1203-12.

24. Sicotte NL (2011). Neuroimaging in multiple sclerosis: neurotherapeutic implications. Neurotherapeutics, 8(11): 54-62. therapeutics. 2011 Jan;8(1):54-62.

25. Dobson R, Ramagopalan S, Davis A, Giovannoni G (2013). Oligoclonal bands in multiple sclerosis and clinically isolated syndromes. Cerebrospinal Fluid Oligoclonal Bands in Multiple Sclerosis and Clinically Isolated Syndromes. A meta-analysis of prevalence, prognosis and effect of latitude. J Neurol Neurosurg Psychiat, 84(8): 909-914.

26. Vazquez-Marrufo M, Gonzalea-Rosa JJ, Vaquero E, Duque P, Borges M, Gomez C, Izquierdo G (2008). Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients. Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients. BMC Neurol, 8:44.

27. Margaritella N, Mendozzi L, Garegnani M, Nemni R, Colicino E, Gilardi E, Pugnetti L (2012). Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population. A hint for an early identification of benign MS? BMC Neurology, 12: 80.

28. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005). IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med, 202(4): 473-477.

29. Freedman MS (2013). Teriflunomide in relapsing multiple sclerosis: therapeutic utility. Ther Adv Chron Dis, 4(5): 192-205.

30. Cortese I, Chaudhry V, So YT, Cornblath DR, Rae-Grant A (2011). Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 76(3):294-300. Mt Sinai J Med. 2011 Mar-Apr;78(2):161-75. doi: 10.1002/msj.20239.

31. Derwenskus J (2011).  Current disease-modifying treatment of multiple sclerosis. Mount Sinai Med J, 78(2): 161-175.

32. Frohman T, Castro W, Shah A, Coutney A, Ortstadt J, Davis SL, Logan D, Abraham T, Abraham J, Remington T, Treadaway K, Graves D, Hart J, Stuve O, Lemack G, Greenberg B, Frohman EM (2011). Symptomatic treatment in multiple sclerosis. Ther Adv Neurol Disord, 4(2): 83-98.
Very superb and presentable information about MS.