Multiple Sclerosis Clinical Presentation
- Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA more...
Attacks or exacerbations of multiple sclerosis (MS) are characterized by symptoms that reflect central nervous system (CNS) involvement. The sine qua non of MS is that symptomatic episodes are “separated in time and space”—that is, episodes occur months or years apart and affect different anatomic locations. As an example, a patient may present with paresthesias of a hand that resolve, followed a few months later by weakness in a leg or visual disturbances (eg, diplopia). In addition, the duration of the attack should be longer than 24 hours.
Presentation of MS often varies among patients. Some patients have a predominance of cognitive changes, while others present with prominent ataxia, hemiparesis or paraparesis, depression, or visual symptoms. Additionally, it is important to recognize that the progression of physical and cognitive disability in MS may occur in the absence of clinical exacerbations.
Classic MS symptoms are as follows:
Sensory loss (ie, paresthesias) - Usually an early complaint
Spinal cord symptoms (motor) - Muscle cramping secondary to spasticity
Spinal cord symptoms (autonomic) - Bladder, bowel, and sexual dysfunction
Cerebellar symptoms - Charcot triad of dysarthria, ataxia, and tremor
Trigeminal neuralgia - Bilateral facial weakness or trigeminal neuralgia
Facial myokymia (irregular twitching of the facial muscles) - May also be a presenting symptom
Eye symptoms - Including diplopia on lateral gaze; these occur in 33% of patients
Constitutional symptoms - especially fatigue (which occurs in 70% of cases) and dizziness; fatigue must be differentiated from depression (which may, however, coexist), lack of sleep, and exertional exhaustion due to disability
Pain - Occurs in 30-50% of patients at some point in their illness
Subjective cognitive difficulties - With regard to attention span, concentration, memory, and judgment
Depression - A common symptom
Euphoria - Less common than depression
Bipolar disorder or frank dementia - May appear late in the disease course but is sometimes found at the time of initial diagnosis.
Symptoms associated with partial acute transverse myelitis
Patients with MS may present with many other manifestations, including the following:
Aphasia or dysphasia (occurs very rarely)
Seizures (5% of patients with MS)
Other paroxysmal symptoms (eg, ataxia, akinesia, paresthesias, pruritus)
Significant motor complaints without sensory deficits or dysautonomia
Paroxysmal symptoms may occur in bouts and are often triggered by movement or sensory stimuli.
ON is characterized by loss of vision (or loss of color vision) in the affected eye and pain on movement of the eye. Much less commonly, patients with ON may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an ON event or even several months following recovery.
Acute transverse myelitis
Partial, rather than total, acute transverse myelitis usually is a manifestation of MS. Acute partial loss of motor, sensory, autonomic, reflex, and sphincter function below the level of the lesion indicates acute transverse myelitis. One should strongly consider mechanical compression of the spinal cord in the differential diagnosis of transverse myelitis.
Fatigue is one of the most common symptom of MS, reported by at least 75% of patients with the disease. Fatigue is described as an overwhelming feeling of lassitude or lack of physical or mental energy that interferes with activities.
An estimated 50-60% of persons with MS describe fatigue as one of their most bothersome symptoms, and it is a major reason for unemployment among MS patients. One should rule out comorbid medical conditions, such as infections, anemia, vitamin deficiencies (eg, vitamin B12, folic acid, vitamin D deficiency) or thyroid disease, before attributing fatigue to MS.
Spasticity in MS is characterized by increased muscle tone and resistance to movement; it occurs most frequently in muscles that function to maintain upright posture. The muscle stiffness greatly increases the energy expended to perform activities of daily living (ADLs), which in turn contributes to fatigue.
The estimated prevalence of cognitive dysfunction in MS ranges from 40-70%. No correlation exists with the degree of physical disability, and cognitive dysfunction may occur early in the course of disease. This complication of MS can be a significant problem, affecting family and social relationships, as well as employment. Areas of cognition affected may include any of the following:
Comprehension and use of speech
Executive function (ability to correctly follow sequential steps)
As previously mentioned, pain can be a common occurrence in MS, with 30-50% of patients experiencing it at some time in the course of their illness. Pain typically is not associated with a less favorable prognosis, nor does it necessarily impair function; however, since it can have significant impact on quality of life, it needs to be treated appropriately.
Pain in MS can be classified as primary or secondary. Primary pain is related to the demyelinating process itself. This neuropathic pain is often characterized as having a burning, gnawing, or shooting quality. Secondary pain in MS is primarily musculoskeletal in nature and possibly results from poor posture, poor balance, or abnormal use of muscles or joints as a result of spasticity.
Urinary symptoms are common in MS, with most patients experiencing problems at some point in their disease. Bladder problems are a source of significant morbidity, affecting the person's family, social, and work responsibilities. Bladder dysfunction can be classified as failure to store, failure to empty, or both. Patients with impaired storage have a small, spastic bladder with hypercontractility of the detrusor muscle. Symptoms experienced may include urgency, frequency, incontinence, and nocturia. MS patients with advancing disability and impaired bladder function may experience recurrent urinary tract infections.
Constipation is the most frequent bowel complaint in patients with MS and is characterized as the infrequent or difficult passage of stools. Constipation may be the result of a neurogenic bowel or of immobility, which leads to slowed bowel activity. In addition, patients who have limited their fluid intake in an attempt to manage bladder symptoms and those with limited access to fluids due to immobility tend to have dry hard stools.
Persons with MS often experience an increase in symptoms of fatigue or weakness when exposed to high temperatures due to weather (especially hot, humid weather), exercise, hot showers or baths, or fever. Overheating, or heat intolerance, may result in blurring of vision (Uhthoff sign), usually in an eye previously affected by ON. These symptoms result from elevation of core body temperature, which further impairs conduction by demyelinated nerves, and they typically reverse rapidly when exposure to high temperature ends.
A thorough physical examination, including neurologic assessment, is critical to determine deficits in MS. All systems must be addressed, including cognition, mood, motor, sensory, and musculoskeletal, as well as the following:
Bulbar involvement typically refers to dysfunction of lower cranial nerves whose nuclei reside in the lower brainstem. Manifestations include dysphagia, which does not occur often in early MS and so may be attributed to a different disorder.
Patients with MS may demonstrate a variety of abnormal physical findings, and these findings may change from examination to examination, depending on the pattern of disease and whether the patient is having an exacerbation or relapse. Findings may include the following:
Focal sensory disturbances (with persistent decrease of proprioception and vibration)
Hyperreactive reflexes with clonus in the ankles and upgoing toes
Increased tone or stiffness in the extremities, with velocity-dependent passive range of motion
Additional signs may include poor coordination of upper and lower extremity movements, the Lhermitte sign, and wide-based gait with inability to tandem walk.
Secondary problems may include infections, urinary problems, skin breakdown, and musculoskeletal complaints. The skin should be examined in all nonambulatory patients, and the musculoskeletal system must be addressed as appropriate.
Optic neuritis, which involves the afferent visual pathway, typically causes acute to subacute unilateral loss of visual acuity, deficits in color and contrast sensitivity, visual field changes, and pain. Onset of ON typically occurs over minutes or hours, rarely days; however, loss of visual acuity may progress over days to weeks.
The loss of visual acuity in patients with ON may range from minimal to profound. In the Optic Neuritis Treatment Trial (ONTT), 35% of patients had visual acuities of 20/40 or better on entry, 30% of patients had visual acuities of between 20/50 and 20/200, and 35% of patients had visual acuities of 20/200 or worse. Only 3% of patients had no light perception (NLP). Given the rarity of NLP in ON, other potential etiologies for vision loss (eg, inflammatory, infiltrative, neoplastic) need to be considered in such patients.
Most cases of ON are retrobulbar. In these cases, "the patient sees nothing, and the doctor sees nothing" (ie, the fundus is normal). The disc may show mild hyperemia, however. Severe disc edema, marked hemorrhages, or exudate should prompt reconsideration of a diagnosis of demyelinating ON.
Optic disc pallor (involving a sector or being diffuse) often occurs months after anterior or posterior ON. Uncommon fundus findings include the following:
Disc and papillary hemorrhages
Compromise of the central arterial and venous circulations
The appearance of the disc does not correlate directly with the amount of inflammation, changes in visual field, or loss of visual acuity.
Patients with ON typically have loss of visual acuity in the ipsilateral eye. Contralateral and often asymptomatic visual field loss may also be detected. A relative afferent pupillary defect is present in unilateral cases and in bilateral-but-asymmetrical cases but may be absent in bilateral and symmetrical cases.
In the ONTT, nearly 100% of patients whose visual acuities were 20/50 or worse had a defect in their color sensitivity, and in those patients with visual acuities of 20/20 or better, 51-70% had altered color vision. Although visual acuity typically recovers after ON, patients may continue to complain of residual deficits in color, contrast sensitivity, brightness, and stereovision.
Patients with ON may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Movement or sound may induce them. Phosphenes may occur before or during an ON event or even several months following recovery.
Visual field changes (loss of visual field is usually in the ipsilateral eye) are common in patients with ON and typically reflect nerve fiber layer defects. The classic visual field defect of ON is the central scotoma, but any nerve fiber–type defect may occur.
Most patients with ON develop retrobulbar pain that becomes worse with extraocular movement. In the ONTT, mild to severe pain was present in 92.2% of patients. Pain was constant in 7.3% of patients, was constant and worse upon extraocular motility in 51.3% of patients, and was noted only with eye movement in 35.8% of patients.
Other reported visual changes in patients with ON include the following:
Uhthoff phenomenon - Exacerbation of symptoms induced by exercise, a hot meal, or a hot bath
Pulfrich effect - Latencies between the eyes are unequal, resulting in a sense of disorientation in moving traffic
In addition to ON, visual disorders that may occur in MS include diplopia, oscillopsia, and nystagmus (all of which involve the efferent visual pathway).
Patients with MS may present with diplopia from an internuclear ophthalmoplegia (INO). In an INO, an adduction deficit of the ipsilateral eye is present, with horizontal gaze nystagmus in the contralateral abducting eye. The lesion involves the medial longitudinal fasciculus (MLF).
The finding of bilateral INO is strongly suggestive of MS. Diplopia in MS may also result from an ocular motor cranial neuropathy, with a sixth nerve palsy representing the most common manifestation. Third and fourth cranial neuropathies are uncommon in MS. Combinations of deficits that may occur in MS include the following:
Horizontal or vertical gaze palsies
Wall-eyed bilateral INO (WEBINO) or wall-eyed monocular INO (WEMINO)
Paralytic pontine exotropia
The one-and-a-half syndrome (ie, unimpaired vertical gaze, ipsilateral eye fixed in horizontal gaze, and contralateral eye able to abduct in the horizontal plane only)
Oscillopsia can occur secondary to various types of nystagmus in MS. A new-onset, acquired pendular nystagmus is relatively common, but upbeat, downbeat, convergence-retraction, and other forms of nystagmus may also develop in MS, depending on the location of the demyelinating lesion.
Clinical Rating Scales
A patient may be rated according to several clinical disability scales, on the basis of findings on the history and physical examination. The most widely accepted of these is the 10-point Kurtzke Expanded Disability Status Scale (EDSS), which was developed originally in 1955 as the Disability Status Scale and has been revised over the years.
The EDSS assigns a severity score to the patient's clinical status that ranges from 0-10 in increments of 0.5. The scores from grades 0-4 are determined using functional systems (FS) scales that evaluate dysfunction in the following 8 neurologic systems:
Bladder and bowel
EDSS grades are as follows:
0 - Normal neurologic examination (all grade 0 in FS, cerebral grade 1 acceptable)
1.0 - No disability, minimal signs in 1 FS (ie, grade 1 excluding cerebral grade 1)
1.5 - No disability, minimal signs in more than 1 FS (more than 1 grade 1 excluding cerebral grade 1)
2.0 - Minimal disability in 1 FS (1 FS grade 2, others 0 or 1)
2.5 - Minimal disability in 2 FS (2 FS grade 2, others 0 or 1)
3.0 - Moderate disability in 1 FS (1 FS grade 3, others 0 or 1) or mild disability in 3 or 4 FS (3/4 FS grade 2, others 0 or 1) though fully ambulatory
3.5 - Fully ambulatory but with moderate disability in 1 FS (1 grade 3) and 1 or 2 FS grade 2, or 2 FS grade 3, or 5 FS grade 2 (others 0 or 1)
4.0 - Fully ambulatory without aid; self-sufficient; up and about some 12 hours a day despite relatively severe disability, consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk approximately 500 m without aid or resting
4.5 - Fully ambulatory without aid; up and about much of the day; able to work a full day; may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability, usually consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk approximately 300 m without aid or rest
5.0 - Ambulatory without aid or rest for approximately 200 m; disability severe enough to impair full daily activities (eg, to work full day without special provisions; usual FS equivalents are 1 grade 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for step 4.0)
5.5 - Ambulatory without aid or rest for approximately 100 m; disability severe enough to preclude full daily activities (usual FS equivalents are 1 grade 5 alone; others 0 or 1; or combinations of lesser grades usually exceeding those for step 4.0)
6.0 - Intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk approximately 100 m with or without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)
6.5 - Constant bilateral assistance (canes, crutches, or braces) required to walk approximately 20 m without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)
7.0 - Unable to walk beyond approximately 5 m even with aid; essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about approximately 12 hr/day (usual FS equivalents are combinations with more than 1 FS grade 4+; very rarely, pyramidal grade 5 alone)
7.5 - Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair (usual FS equivalents are combinations with more than 1 FS grade 4+)
8.0 - Essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed itself much of the day, retains many self-care functions; generally has effective use of arms (usual FS equivalents are combinations, generally grade 4+ in several systems)
8.5 - Essentially restricted to bed much of the day; has some effective use of arms; retains some self-care functions (usual FS equivalents are combinations, generally 4+ in several systems)
9.0 - Helpless bedridden patient; can communicate and eat (usual FS equivalents are combinations, mostly grade 4+)
9.5 - Totally helpless bedridden patient; unable to communicate effectively or eat/swallow (usual FS equivalents are combinations, almost all grade 4+)
10.0 - Death due to MS
Advantages of the EDSS are that it is widely used clinically, is easy to administer, and requires no special equipment. Its limitations are as follows:
It is heavily dependent on mobility
It is somewhat subjective in certain areas (eg, bowel and bladder function)
It is insensitive to small changes
It does not present an accurate picture of the patient's cognitive abilities and functional abilities in performing activities of daily living (ADLs)
It is nonlinear in terms of the time spent at various ranges of the scale
Despite its limitations, the EDSS is often used as a standardization measure for clinical trials.
Other useful scales include the Ambulation Index, which is based solely on the ability to walk 25 feet, and the Multiple Sclerosis Functional Composite (MSFC), which includes the Ambulation Index, the 9-hole peg test, and the PASAT attention test. The MSFC is reported as z scores, which have been difficult to translate into clinical significance. In addition, the Scripps Neurologic Rating Scale, developed by Sipe in 1984, has been used by some investigators. This scale has a finer incremental scale than the Kurtzke scale, but it is not widely accepted and does not consider cognitive involvement.
Criteria for Categorizing MS
MS is divided into the following categories, principally on the basis of clinical criteria, including the frequency of clinical relapses, time to disease progression, and lesion development on MRI[1, 2, 3, 4] :
Relapsing-remitting MS (RRMS)
Secondary progressive MS (SPMS)
Primary progressive MS (PPMS)
Progressive-relapsing MS (PRMS)
RRMS is characterized by recurrent attacks in which neurologic deficits appear in different parts of the nervous system and resolve completely or almost completely over a short period of time, leaving little residual deficit. Patients with a relapsing-remitting pattern account for approximately 85% of MS cases (see the images below).
Two subgroups sometimes included in RRMS are clinically isolated syndrome (CIS) and benign MS. CIS consists of a single episode of neurologic symptoms; it is sometimes labeled possible MS. In benign MS, patients have almost complete remission between relapses, and even 15-20 years after diagnosis they have little if any accumulation of physical disability. Making a diagnosis of benign MS too early during the course of the disease is discouraged, since MS can worsen, sometimes drastically, in patients with a history of mild manifestations at onset.
Global clinical deterioration in RRMS has traditionally been attributed to cumulative deficit due to incomplete recovery from repeated occurrences of individual relapses. However, evidence increasingly suggests an ongoing background neurologic deterioration that is independent of relapses.
Although MS was previously thought to be silent between relapses, magnetic resonance imaging (MRI) studies have demonstrated that inflammatory events are occurring in the brain at 10-20 times the predicted rate indicated by the mean relapse rate. This silent disease activity can occur in both white and gray matter and is associated with cerebral atrophy, which in most patients is evident in volumetric studies even at diagnosis.
Natural history data indicate that approximately 50% of patients with RRMS convert to a secondary progressive pattern within 10-15 years after disease onset. This pattern may or may not include relapses, but it is characterized by continued progression over years, with increasing disability. Treatment with disease-modifying agents is thought to slow the progression of RRMS. Unlike RRMS, SPMS without relapses does not seem to be responsive to currently available disease-modifying agents.
In PPMS, which accounts for approximately 10% of MS cases, function declines steadily without relapses. In PRMS, which accounts for fewer than 5% of patients with MS, occasional relapses are superimposed on progressive disease.
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec. 58(6):840-6. [Medline].
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar. 13(3):227-31. [Medline].
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr. 46(4):907-11. [Medline].
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001 Jul. 50(1):121-7. [Medline].
Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011 Jan 18. 76(3):294-300. [Medline]. [Full Text].
Sanford M, Lyseng-Williamson KA. Subcutaneous recombinant interferon-ß-1a (Rebif®): a review of its use in the treatment of relapsing multiple sclerosis. Drugs. 2011 Oct 1. 71(14):1865-91. [Medline].
Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals Inc. May 2010.
Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon ß-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 Jul. 13(7):657-65. [Medline].
Copaxone [package insert] [package insert]. North Wales, PA: Teva Pharmaceuticals USA. February 2009.
Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011 Oct 5. CD007621. [Medline].
Tysabri [package insert]. South San Francisco, CA: Biogen Idec Inc. 2011.
Novantrone [package insert]. Rockland, MA: Serono, Inc. May 2012.
Gilenya [package insert]. East Hanover, NJ: Novartis. September 2010.
Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genentech Corp. September, 2012. Available at [Full Text].
Jeffrey S. FDA approves third oral agent for MS. March 27, 2013. Medscape Medical News. Available at http://www.medscape.com/viewarticle/781450. Accessed: April 2, 2013.
US Food and Drug Administration. FDA approves new multiple sclerosis treatment: Tecfidera. March 27, 2013. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm. Accessed: April 2, 2013.
Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20. 367(12):1098-107. [Medline]. [Full Text].
Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep 20. 367(12):1087-97. [Medline]. [Full Text].
Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24. 380(9856):1819-28. [Medline].
Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24. 380(9856):1829-39. [Medline].
Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab more effective than interferon ß-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012 Apr 3. 78(14):1069-78. [Medline].
Jeffrey S. FDA Approves Interferon Autoinjector for MS. Available at http://www.medscape.com/viewarticle/777065. Accessed: February 20, 2013.
Windhagen A, Newcombe J, Dangond F, et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med. 1995 Dec 1. 182(6):1985-96. [Medline]. [Full Text].
Huan J, Culbertson N, Spencer L, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res. 2005 Jul 1. 81(1):45-52. [Medline].
Minagar A, Jy W, Jimenez JJ, et al. Elevated plasma endothelial microparticles in multiple sclerosis. Neurology. 2001 May 22. 56(10):1319-24. [Medline].
Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005 Aug 15. 202(4):473-7. [Medline]. [Full Text].
Nielsen NM, Westergaard T, Rostgaard K, et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol. 2005 Oct 15. 162(8):774-8. [Medline].
Nischwitz S, Muller-Myhsok B, Weber F. Risk conferring genes in multiple sclerosis. FEBS Lett. 2011 Dec 1. 585(23):3789-97. [Medline].
Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol. 2009 Jun. 22(3):201-6. [Medline].
Kampman MT, Brustad M. Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology. 2008. 30(3):140-6. [Medline].
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20. 296(23):2832-8. [Medline].
Kampman MT, Brustad M. Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology. 2008. 30(3):140-6. [Medline].
Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology. 2007 Jul 24. 69(4):381-8. [Medline].
Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009 Apr. 80(4):392-9. [Medline]. [Full Text].
Zivadinov R, Schirda C, Dwyer MG, et al. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study. Int Angiol. 2010 Apr. 29(2):158-75. [Medline].
Study To Evaluate Treating Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis Patients. Available at http://clinicaltrials.gov/ct2/show/NCT01089686. Accessed: 10/4/2010.
Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009 Dec. 50(6):1348-58.e1-3. [Medline].
Laupacis A, Lillie E, Dueck A, et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ. 2011 Nov 8. 183(16):E1203-12. [Medline]. [Full Text].
Centers for Disease Control and Prevention. FAQs about Hepatitis B Vaccine (Hep B) and Multiple Sclerosis. [Full Text].
National Multiple Sclerosis Society. Vaccination. Available at http://www.nationalmssociety.org/living-with-multiple-sclerosis/healthy-living/vaccinations/index.aspx. Accessed: November 17, 2011.
National Multiple Sclerosis Society. Who Gets MS?. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx. Accessed: 10/04/2010.
Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 2001 Apr. 22(2):117-39. [Medline].
Aguirre-Cruz L, Flores-Rivera J, De La Cruz-Aguilera DL, Rangel-Lopez E, Corona T. Multiple sclerosis in Caucasians and Latino Americans. Autoimmunity. 2011 Nov. 44(7):571-5. [Medline].
Matsuda PN, Shumway-Cook A, Bamer AM, Johnson SL, Amtmann D, Kraft GH. Falls in multiple sclerosis. PM R. 2011 Jul. 3(7):624-32; quiz 632. [Medline].
Roodhooft JM. Ocular problems in early stages of multiple sclerosis. Bull Soc Belge Ophtalmol. 2009. 65-8. [Medline].
Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010 Aug. 33(8):1061-7. [Medline].
Optic Neuritis Study Group. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol. 1991 Dec. 109(12):1673-8. [Medline].
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov. 33(11):1444-52. [Medline].
Lonergan R, Kinsella K, Duggan M, Jordan S, Hutchinson M, Tubridy N. Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?. Mult Scler. 2009 Dec. 15(12):1528-31. [Medline].
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29. 338(5):278-85. [Medline].
Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997 Nov. 120 ( Pt 11):2059-69. [Medline].
Bonhomme GR, Waldman AT, Balcer LJ, et al. Pediatric optic neuritis: brain MRI abnormalities and risk of multiple sclerosis. Neurology. 2009 Mar 10. 72(10):881-5. [Medline].
Filippi M. Enhanced magnetic resonance imaging in multiple sclerosis. Mult Scler. 2000 Oct. 6(5):320-6. [Medline].
Filippi M, Bozzali M, Horsfield MA, et al. A conventional and magnetization transfer MRI study of the cervical cord in patients with MS. Neurology. 2000 Jan 11. 54(1):207-13. [Medline].
Filippi M, Yousry TA, Alkadhi H, Stehling M, Horsfield MA, Voltz R. Spinal cord MRI in multiple sclerosis with multicoil arrays: a comparison between fast spin echo and fast FLAIR. J Neurol Neurosurg Psychiatry. 1996 Dec. 61(6):632-5. [Medline]. [Full Text].
Grossman RI, Barkhof F, Filippi M. Assessment of spinal cord damage in MS using MRI. J Neurol Sci. 2000 Jan 15. 172 Suppl 1:S36-9. [Medline].
Neema M, Goldberg-Zimring D, Guss ZD, et al. 3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis. Neuroimage. 2009 Jul 1. 46(3):633-41. [Medline]. [Full Text].
Poonawalla AH, Hou P, Nelson FA, Wolinsky JS, Narayana PA. Cervical Spinal Cord Lesions in Multiple Sclerosis: T1-weighted Inversion-Recovery MR Imaging with Phase-Sensitive Reconstruction. Radiology. 2008 Jan. 246(1):258-264. [Medline].
Vaneckova M, Seidl Z, Krasensky J, et al. Patients' stratification and correlation of brain magnetic resonance imaging parameters with disability progression in multiple sclerosis. Eur Neurol. 2009. 61(5):278-84. [Medline].
Wattjes MP, Barkhof F. High field MRI in the diagnosis of multiple sclerosis: high field-high yield?. Neuroradiology. 2009 May. 51(5):279-92. [Medline].
[Guideline] Traboulsee, A. et al. Revised Recommendations of the CMSC Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-up of Multiple Sclerosis. Consortim of Multiple Sclerosis Centers. Available at http://c.ymcdn.com/sites/www.mscare.org/resource/collection/9C5F19B9-3489-48B0-A54B-623A1ECEE07B/MRIprotocol2015.pdf. Accessed: August 13, 2015.
Agosta F, Absinta M, Sormani MP, et al. In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study. Brain. 2007 Aug. 130:2211-9. [Medline].
Fazekas F, Offenbacher H, Fuchs S, et al. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology. 1988 Dec. 38(12):1822-5. [Medline].
Colorado RA, Shukla K, Zhou Y, Wolinsky JS, Narayana PA. Multi-task functional MRI in multiple sclerosis patients without clinical disability. Neuroimage. 2012 Jan 2. 59(1):573-81. [Medline]. [Full Text].
Wang J, Xiao Y, Luo M, Zhang X, Luo H. Statins for multiple sclerosis. Cochrane Database Syst Rev. 2010 Dec 8. CD008386. [Medline].
Arnold DL, Matthews PM, Francis G, Antel J. Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease. Magn Reson Med. 1990 Apr. 14(1):154-9. [Medline].
Henning A, Schar M, Kollias SS, Boesiger P, Dydak U. Quantitative magnetic resonance spectroscopy in the entire human cervical spinal cord and beyond at 3T. Magn Reson Med. 2008 Jun. 59(6):1250-8. [Medline].
Marliani AF, Clementi V, Albini-Riccioli L, Agati R, Leonardi M. Quantitative proton magnetic resonance spectroscopy of the human cervical spinal cord at 3 Tesla. Magn Reson Med. 2007 Jan. 57(1):160-3. [Medline].
Berg D, Maurer M, Warmuth-Metz M, Rieckmann P, Becker G. The correlation between ventricular diameter measured by transcranial sonography and clinical disability and cognitive dysfunction in patients with multiple sclerosis. Arch Neurol. 2000 Sep. 57(9):1289-92. [Medline].
Walter U, Wagner S, Horowski S, Benecke R, Zettl UK. Transcranial brain sonography findings predict disease progression in multiple sclerosis. Neurology. 2009 Sep 29. 73(13):1010-7. [Medline].
Vazquez-Marrufo M, Gonzalez-Rosa JJ, Vaquero E, et al. Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients. BMC Neurol. 2008 Nov 24. 8:44. [Medline]. [Full Text].
Jeffrey S. TOPIC: Teriflunomide Delays Clinically Definite MS. Medscape Medical News. Available at http://www.medscape.com/viewarticle/803177. Accessed: May 8, 2013.
Rodriguez M, Karnes WE, Bartleson JD, Pineda AA. Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology. 1993 Jun. 43(6):1100-4. [Medline].
Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, et al. Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis. Eur J Neurol. 2016 Jan 19. [Medline].
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993 Apr. 43(4):655-61. [Medline].
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996 Mar. 39(3):285-94. [Medline].
Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998 Nov 7. 352(9139):1498-504. [Medline].
Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002 Nov 26. 59(10):1496-506. [Medline].
Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther. 2007 Sep. 29(9):2031-48. [Medline].
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995 Jul. 45(7):1268-76. [Medline].
Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler. 2000 Aug. 6(4):255-66. [Medline].
Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013 Jun. 73(6):705-13. [Medline].
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2. 354(9):899-910. [Medline].
Cadavid D, Jurgensen S, Lee S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PLoS One. 2013. 8(1):e53297. [Medline]. [Full Text].
Chun J, Brinkmann V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med. 2011 Sep. 12(64):213-28. [Medline].
Hughes S. Shorter washout reduces MS relapse switching off natalizumab. Medscape Medical News. October 7, 2013. [Full Text].
Hughes S. Shorter Washout Better for Natalizumab-to-Fingolimod Switch. Medscape Medical News. Available at http://www.medscape.com/viewarticle/822567. Accessed: April 1, 2014.
Cohen M, Maillart E, Tourbah A, De Sèze J, Vukusic S, Brassat D, et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol. 2014 Feb 24. [Medline].
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6. 365(14):1293-303. [Medline].
Semedo, D. Aubagio (Teriflunomide) Slows Brain Atrophy in Patients with Relapsing Multiple Sclerosis. Multiple Sclerosis News Today. Available at http://multiplesclerosisnewstoday.com/2015/10/08/aubagio-teriflunomide-slows-brain-atrophy-patients-relapsing-multiple-sclerosis/. October 8, 2015; Accessed: October 14, 2015.
A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing multiple sclerosis (TENERE). 4th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC)/Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). June 2, 2012 (ClinicalTrials.gov identifier: NCT00883337).
A multicenter double-blind parallel-group placebo-controlled study of the efficacy and safety of teriflunomide in patients with relapsing multiple sclerosis who are treated with interferon-beta. (ClinicalTrials.gov identifier: NCT01252355).
Fox EJ, Sullivan HC, Gazda SK, et al. A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis. Eur J Neurol. 2012 Feb. 19(2):307-11. [Medline].
Anderson P. Alemtuzumab Benefits Hard-to-Treat MS Patients. Medscape Medical News. Available at http://www.medscape.com/viewarticle/805173. Accessed: June 12, 2013.
Harrison DM, Gladstone DE, Hammond E, et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler. 2012 Feb. 18(2):202-9. [Medline].
Rojas JI, Romano M, Ciapponi A, Patrucco L, Cristiano E. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev. 2009 Jan 21. CD006643. [Medline].
Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan. 37(1):30-40. [Medline].
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4. 362(5):387-401. [Medline].
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4. 362(5):402-15. [Medline].
Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 2011 Jun. 10(6):520-9. [Medline].
Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurol. 2011 Nov. 10(11):1026-34. [Medline].
Multiple Sclerosis Association of America (MSAA). MS Research Update. Available at http://mymsaa.org/PDFs/MSAA_Research_Update_2013.pdf. Accessed: March 27, 2013.
Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011 Nov 19. 378(9805):1779-87. [Medline].
Anderson P. Myelin peptide skin patch safe, reduces MS activity. Medscape Medical News. July 29, 2013. [Full Text].
Walczak A, Siger M, Ciach A, Szczepanik M, Selmaj K. Transdermal application of myelin peptides in multiple sclerosis treatment. JAMA Neurol. 2013 Jul 1. 1-6. [Medline].
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998 Jul 30. 339(5):285-91. [Medline].
Tsui A, Lee MA. Multiple sclerosis and pregnancy. Curr Opin Obstet Gynecol. 2011 Dec. 23(6):435-9. [Medline].
Krupp LB, Christodoulou C, Melville P, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011 Apr 26. 76(17):1500-7. [Medline]. [Full Text].
Attarian HP, Brown KM, Duntley SP, Carter JD, Cross AH. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol. 2004 Apr. 61(4):525-8. [Medline].
MacAllister WS, Krupp LB. Multiple sclerosis-related fatigue. Phys Med Rehabil Clin N Am. 2005 May. 16(2):483-502. [Medline].
Solaro C, Uccelli MM. Management of pain in multiple sclerosis: a pharmacological approach. Nat Rev Neurol. 2011 Aug 16. 7(9):519-27. [Medline].
Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009 Feb 28. 373(9665):732-8. [Medline].
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics, Inc. 2010.
Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009 Jan 21. CD004193. [Medline].
US Food and Drug Administration. FDA approves Botox to treat specific form of urinary incontinence. August 25, 2011. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269509.htm. Accessed: November 28, 2011.
Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992 Feb 27. 326(9):581-8. [Medline].
Myhr KM. Vitamin D treatment in multiple sclerosis. J Neurol Sci. 2009 Nov 15. 286(1-2):104-8. [Medline].
Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. November 30, 2010. Available at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed: December 29, 2011.
Summerday NM, Brown SJ, Allington DR, Rivey MP. Vitamin D and multiple sclerosis: review of a possible association. J Pharm Pract. 2012 Feb. 25(1):75-84. [Medline].
Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2010 Dec 8. CD008422. [Medline].
DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol. 2003 Apr. 60(4):504-9. [Medline].
Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med. 2001 Feb 1. 344(5):319-26. [Medline].
Farez MF, Correale J. Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Arch Neurol. 2011 Oct. 68(10):1267-71. [Medline].
Azasan [package insert] [package insert]. Wilmington, NC: Salix pharmaceuticals Inc. August 2011.
Cyclophosphamide [package insert]. Deerfield, IL: Baxter Healthcare Corporation. June 2004.
Brooks M. New AAN guideline on psychiatric disorders in MS. Medscape Medical News. January 3, 2014. [Full Text].
Hughes S. New Test to Identify PML Risk With Natalizumab in MS. Medscape Medical News. Available at http://www.medscape.com/viewarticle/832504. Accessed: October 7, 2014.
Jeffrey S. No Cognitive Disadvantage in Pediatric- vs Adult-Onset MS. Medscape Medical News. Available at http://www.medscape.com/viewarticle/831536. Accessed: September 15, 2014.
Keller DM. Fingolimod Reduces Annual Brain Volume Loss in MS. Medscape Medical News. Jun 6 2014. [Full Text].
Minden SL, Feinstein A, Kalb RC, Miller D, Mohr DC, Patten SB, et al. Evidence-based guideline: Assessment and management of psychiatric disorders in individuals with MS: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 Dec 27. [Medline].
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol. 2015 Aug. 11 (8):471-82. [Medline].
[Guideline] Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence: A Consensus Paper. The Consortium of Multiple Sclerosis Centers. Available at http://www.mscare.org/?page=dmt. July 2014;
[Guideline] Filippi M, Rocca A, Arnold DL, Bakshi R, Barkhof F, De Stefano N, et al. Use of Imaging in Multiple Sclerosis. Gilhus NE, Barnes MP, Brainin M. European Handbook of Neurological Management. 2nd ed. Oxford (UK): Wiley-Blackwell; 2011. Vol 1: 35-51.
Wattjes MP, Rovira À, Miller D, Yousry TA, Sormani MP, de Stefano MP, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients. Nat Rev Neurol. 2015 Oct. 11 (10):597-606. [Medline].
Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015 Oct 8. 373 (15):1418-28. [Medline]. [Full Text].
Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Jun 22. 381 (9884):2167-75. [Medline].
|Clinical Presentation||Additional Data Needed for MS Diagnosis|
||None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,
but must be consistent with MS
||Dissemination in space demonstrated by MRI or
Await further clinical attack implicating a different site
||Dissemination in time demonstrated by
MRI or second clinical attack
||Dissemination in space demonstrated by
MRI or await a second clinical attack implicating a different CNS site
Dissemination in time, demonstrated by MRI or second clinical attack
|· Insidious neurologic progression suggestive of MS||One year of disease progression and dissemination in space, demonstrated by 2 of the following:
|Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.|