Multiple sclerosis (MS)

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1. Overview and Recommendations

1.1. Background

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the brain and spinal cord resulting in episodes of neurologic dysfunction that often recover (but the degree of recovery can vary and may have a gradually progressive course).
Lesions are disseminated in time and space (with episodes affecting separate sites in the central nervous system, occurring at least 30 days apart).
MS is an autoimmune disease likely due to a combination of genetic predisposition and environmental influence.
The onset is usually before age 50 years and is more common in women.

1.2. Evaluation

80% of patients will present initially with a clinically isolated syndrome before clinically definite multiple sclerosis (MS) is diagnosed.
Clinical presentations vary widely and may include the following signs and symptoms:
- spinal cord involvement (myelitis) with partial sensory or motor dysfunction, Lhermitte sign, or bowel and bladder dysfunction
- brainstem involvement, potentially leading to vision difficulties, impaired swallowing and speech, vertigo, and pseudobulbar palsy
- cerebrum involvement, which may result in cognitive impairment, depression, upper motor neuron signs, and unilateral motor or sensory deficits
- cerebellar involvement causing problems with balance, vertigo, and/or impaired coordination
Patients with suspected MS should be referred for a neurological consult (Strong recommendation).
Obtain magnetic resonance imaging (MRI) of the brain and spinal cord with and without contrast (although a diagnosis of MS should not be based on MRI findings alone) (Strong recommendation).
The diagnosis of MS should be made using established current criteria (such as revised 2010 international diagnostic criteria) after:
- assessing that episodes are consistent with an inflammatory process (Strong recommendation)
- excluding alternative diagnoses (Strong recommendation)
- establishing that lesions have developed at different times and are in different anatomical locations for diagnosis of relapsing-remitting MS (Strong recommendation)
- establishing progressive neurological deterioration over ≥ 1 year for diagnosis of primary progressive MS (Strong recommendation)

1.3. Management

For clinically isolated syndrome (a neurologic presentation suggestive of multiple sclerosis [MS]), treatments to reduce progression to clinically definite MS include:
- interferon beta-1b
- interferon beta-1a given either once weekly or 3 times weekly
- glatiramer acetate
- IV immunoglobulin (IVIG)
- teriflunomide
For treatment of acute relapse:
- consider glucocorticoids in any patient with an acute attack of MS due to short-term benefit on the speed of functional recovery (Strong recommendation)
- glucocorticoids dosing options include oral methylprednisolone 500 mg/day for 5 days and IV methylprednisolone 1g/day for 3-5 days (Strong recommendation)
- plasmapheresis should be considered for adjunctive treatment of exacerbations of relapsing-remitting MS (Strong recommendation)
For progressive MS, use of either interferon beta or glatiramer acetate is not recommended for patients with progressive, nonrelapsing forms of multiple sclerosis (Strong recommendation).
Disease-modifying therapies for relapsing-remitting MS:
- Immunomodulatory drugs should be initiated at the time of diagnosis.
- The choice of appropriate therapy depends on various factors including patient tolerability, risk stratification, disease activity, and adverse effect profile of each medication.
- Immunomodulatory options with evidence for efficacy include:
  - interferon beta (interferon beta-1a or interferon beta-1b) (Strong recommendation)
  - glatiramer acetate (Strong recommendation)
  - IV immune globulin (IVIG) (Weak recommendation)
  - monoclonal antibodies, such as alemtuzumab, daclizumab, natalizumab, and rituximab (but are associated with significant adverse events)
  - fingolimod
  - laquinimod
  - teriflunomide
  - dimethyl fumarate
  - intermittent long-term corticosteroids (high-dose methylprednisolone IV)
Treatment of selected specific impairments:
- For treatment of spasticity and muscle spasms, baclofen or gabapentin considered as first-line drugs (Weak recommendation).
- For ambulation and mobility impairments, consider dalfampridine, exercise therapy, or vestibular or multidisciplinary rehabilitation (Strong recommendation). For upper extremity tremor, consider botulinum toxin type A.
- For central neuropathic pain, consider gabapentin, pregabalin, amitriptyline, or duloxetine as first-line treatment (Strong recommendation). Second-line option is tramadol or opioids if used for short-term use (Strong recommendation). Consider cannabinoids for refractory pain (Strong recommendation).
- For fatigue, consider amantadine, aspirin, exercise, vestibular rehabilitation, mindfulness-based training, cognitive behavioral therapy, or fatigue management (Weak recommendation).
- For pseudobulbar dysfunction, consider dextromethorphan 20 mg/quinidine sulfate 10 mg.
- For urinary symptoms, consider oxybutynin or tolterodine and a bladder rehabilitation program (Strong recommendation). If refractory symptoms, consider bladder wall injection with botulinum toxin type A (Strong recommendation).
- For depression and anxiety, consider cognitive behavioral therapy and antidepressants. For memory impairment, consider cognitive training (Strong recommendation).

3. General Information

3.1. Description

inflammatory and neurodegenerative disease of brain and spinal cord resulting in episodes of neurologic dysfunction that often recover (but degree of recovery can vary and may have gradually progressive course)⁽³⁾
lesions are disseminated in time and space (episodes affecting separate sites in the central system, occurring at least 30 days apart)^(3, 4)

3.2. Definitions

clinically isolated syndrome (CIS)
- acute demyelinating episode affecting ≥ 1 site in central nervous system⁽³⁾
- 80% of patients who are ultimately diagnosed with multiple sclerosis present with CIS initially⁽³⁾
- 50%-80% of patients with CIS have lesions (on magnetic resonance imaging) showing prior disease activity⁽⁴⁾
- some patients with CIS may now be diagnosed as having MS at time of first presentation with appropriate lesions on magnetic resonance imaging (Ann Neurol 2011 Feb;69(2):292 full-text)
radiologically isolated syndrome
- incidental findings on magnetic resonance imaging (MRI) consistent with MS in clinically asymptomatic patients
- long-term prognosis unclear; patients may ultimately develop clinical symptoms and signs, and be diagnosed with definitive MS
- Reference - Ann Neurol 2011 Feb;69(2):292 full-text, editorial can be found in Ann Neurol 2011 Feb;69(2):234, commentary can be found in Ann Neurol 2011 Jul;70(1):182, Ann Neurol 2011 Sep;70(3):520

3.3. Types

clinically isolated syndrome
- first clinical presentation of disease that shows characteristics of inflammatory demyelination that could be MS, but does not yet meet criteria of dissemination in time
- clinically isolated syndrome in conjunction with brain lesions on magnetic resonance imaging (MRI) associated with high risk for meeting diagnostic criteria for MS
- Reference - Neurology 2014 Jul 15;83(3):278 full-text
relapsing-remitting MS^(1, 5, 6)
- about 85% of patients with MS are initially diagnosed with relapsing-remitting MS
- self-limited attacks of neurologic dysfunction with complete or partial recovery
- acute onset of attacks, with evolution over days to weeks
- patient is neurologically and symptomatically stable between attacks
- relapses become infrequent or stop after median 10-15 years in 50%-60% of patients
- DynaMed commentary -- remitting may be deceptive term because patients may continue to have subclinical magnetic resonance imaging activity while in clinical remission, and this may have effect on long-term outcome
secondary progressive multiple sclerosis^(2, 3, 5)
- begins as relapsing-remitting MS
- patients develop progressive course later in disease with or without continued relapses
- acute attack rate is usually reduced over time and disease course becomes steady deterioration in function
- 65% patients with relapsing-remitting enter secondary progressive phase
primary progressive multiple sclerosis
- steady decline in neurologic function from disease onset, without acute attacks^{(2, 3, 4, 5, 6)}
- 12.4% of patients had primary progressive MS in population study of 2,837 patients with definite MS in British Columbia, Canada (Neurology 2005 Dec 27;65(12):1919)
- onset typically in patients aged 50-60 years (later than relapsing-remitting multiple sclerosis [Lancet Neurol 2007 Oct;6(10):903, correction can be found in Lancet Neurol 2009 Aug;8(8):699])
phenotype modifiers defined in 2013 that can further classify relapsing-remitting and progressive MS (eliminates need for progressive relapsing subtype)
- to assess activity, which should be evaluated at least annually
  - active - clinical relapse and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually)
  - not active - patient has relapsing course but no relapses, gadolinium-enhancing activity, or new or unequivocally enlarging T2 lesions during assessment period
  - indeterminate - patients not assessed over a designated time frame
- to assess progression independent of relapses, which should be evaluated annually by history or objective measures
  - active and with progression
  - active but without progression
  - not active with progression
  - not active and without progression (stable disease)
- Reference - Neurology 2014 Jul 15;83(3):278 full-text
malignant multiple sclerosis - often used to describe MS with need for assistance with ambulation within 5 years of symptom onset (Neurology 2011 Jun 7;76(23):1996)
fulminant multiple sclerosis - severe rapidly progressive course with significant disability or death in relatively short time after disease onset (Neurol Sci 2011 Oct;32(5):953)

4. Epidemiology

4.1. Who is most affected

young adults⁽³⁾
female predominance 3 to 1⁽¹⁾

4.2. Incidence/Prevalence

worldwide incidence of multiple sclerosis 3.6 per 100,000 person-years in women and 2 per 100,000 person-years in men
- based on systematic review of studies from 1966 to 2007
- female:male incidence ratio has increased since 1955
- incidence higher at higher latitudes compared to equator, but difference has decreased since 1980 with increasing incidence at low latitudes
- Reference - Neurology 2008 Jul 8;71(2):129
incidence of pediatric acquired multiple sclerosis 0.51 per 100,000 person-years
- based on United States cohort of patients aged 0-18 years from 2004 to 2009
- incidence of other acute demyelinating syndromes (including optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis) 1.56 per 100,000 person-years
- Reference - Neurology 2011 Sep 20;77(12):1143, editorial can be found in Neurology 2011 Sep 20;77(12):1112

4.3. Likely risk factors

4.3.1. Genetic risk factors

about 20% cases of MS are familial⁽³⁾
concordance rate 20%-30% in monozygotic twins and 2%-3% in dizygotic twins⁽¹⁾

increased risk of multiple sclerosis observed among first-degree family members of persons with SLE
- based on population-based cohort study
- 23,658,577 persons from Taiwan National Health Insurance Research Database registered in 2010 evaluated
- 18,283 (0.08%) had SLE
- increased risk of multiple sclerosis observed among first-degree family members of persons with SLE (adjusted relative risk 2.58, 95% CI 1.16-5.72)
- Reference - JAMA Intern Med 2015 Sep 1;175(9):1518

genetic markers including DR15, DQ6, and DR4 (and corresponding genotypes) reported to be associated with increased risk of multiple sclerosis⁽³⁾
alleles of interleukin 7 receptor alpha chain (IL7RA), interleukin 2 receptor alpha gene (IL2RA), and in HLA locus associated with increased risk for MS
- based on 3 genome-wide studies with > 2,322 cases and 5,418 controls
- single-nucleotide polymorphism in IL7RA strongly associated with MS in 2 studies (p = 2.9 × 10^(-7) in both) and reported to be associated in 1 study
- single-nucleotide polymorphisms within IL2RA strongly associated with MS in 1 study (p = 2.96 × 10^(-7))
- multiple single-nucleotide polymorphisms in HLA-DRA locus strongly associated with MS in 1 study (p = 8.94 × 10^(-81))
- References
  - N Engl J Med 2007 Aug 30;357(9):851 full-text, editorial can be found in N Engl J Med 2007 Aug 30;357(9):927, commentary can be found in N Engl J Med 2007 Nov 22;357(21):2199, Lancet 2008 Jan 26;371(9609):283
  - Nat Genet 2007 Sep;39(9):1083
  - Nat Genet 2007 Sep;39(9):1108
early B-cell factor (EBF1) gene associated with increased risk of MS in Spanish white population
- based on case-control study
- 356 patients with MS patients and 540 ethnically matched controls were evaluated
- Reference - BMC Neurol 2005 Oct 28;5:19 full-text
interferon gamma allelic variant associated with MS susceptibility in men but not women
- based on case-control study
- 861 patients with MS and 843 controls in United States, Northern Ireland, and Belgium were evaluated
- Reference - Arch Neurol 2008 Mar;65(3):349
HLA-DRB1*15 allele associated with increased risk of pediatric onset MS in children with acquired demyelination
- based on cohort study
- 266 children with acquired demyelination syndrome and 196 healthy controls were followed for mean 3.2 years
- 24% of children with acquired demyelination syndrome developed MS
- presence of HLA-DRB1 alleles associated with significantly increased risk of MS (odds ratio 2.7)
- Reference - Neurology 2011 Mar 1;76(9):781 full-text, editorial can be found in Neurology 2011 Mar 1;76(9):768

4.3.2. Optic neuritis

history of optic neuritis associated with increasing risk of development of multiple sclerosis
- based on retrospective chart review
- 156 patients (median age at onset 31 years) presented with optic neuritis between 1935 and 1991 in Olmsted County, Minnesota
- in patients with history of optic neuritis, probability of progression to clinically definite multiple sclerosis (MS) based on life-table analysis
  - 39% at 10 years
  - 49% at 20 years
  - 54% at 30 years
  - 60% at 40 years
- Reference - Neurology 1995 Feb;45(2):244, commentary can be found in ACP J Club 1995 Jul-Aug;123(1):21
abnormal brain magnetic resonance imaging (MRI) associated with increased risk for MS in patients with optic neuritis
- based on 3 prospective cohort studies
- 389 patients with acute optic neuritis in Optic Neuritis Treatment Trial followed for up to 15 years
  - 15-year cumulative probability of MS 50%
    - 25% in patients with no lesions on baseline brain MRI
    - 72% in patients with ≥ 1 lesion on baseline brain MRI
  - Reference - Arch Neurol 2008 Jun;65(6):727 full-text
- prospective study of 388 patients followed for 10-13 years
  - 10-year risk of MS 38% overall
    - 22% for patients who had no lesions
    - 56% for patients who had ≥ 1 typical lesion on baseline MRI
  - Reference - Arch Ophthalmol 2003 Jul;121(7):944, editorial can be found in Arch Ophthalmol 2003 Jul;121(7):1039, commentary can be found in JAMA 2003 Jul 16;290(3):403
- prospective study of 388 patients with optic neuritis who did not have probable or definite MS at study entry
  - 5-year cumulative probability of clinically definite MS 30% overall
    - 16% in 202 patients with no MRI lesions
    - 51% in 89 patients with 3 or more MRI lesions
  - Reference - Neurology 1997 Nov;49(5):1404, commentary can be found in Neurology 1998 Oct;51(4):1236
patients with recurrent optic neuritis may develop neuromyelitis optica or MS
- based on retrospective chart review
- 72 patients with recurrent optic neuritis without intervening symptoms of disseminated demyelinating condition were evaluated
- conversion rates
  - 5-year conversion rates were 12.5% to neuromyelitis optica and 14.4% to multiple sclerosis
  - 10-year conversion rates were 12.5% to neuromyelitis optica and 29.8% to multiple sclerosis
- conversion rate to multiple sclerosis was 40% among 5 patients with ≥ 2 brain MRI lesions consistent with multiple sclerosis and 0 among 11 patients without such lesions (not significant)
- Reference - Arch Neurol 2004 Sep;61(9):1401 full-text, correction can be found at Arch Neurol 2009 Sep;66(9):1057
bilateral optic neuritis associated with development of MS in children
- based on 2 retrospective chart reviews
- 94 children < 16 years old who presented with idiopathic optic neuritis to Mayo Clinic between 1950 and 1988 were evaluated
  - detailed follow-up information available on 79 patients with median follow-up 19.4 years
  - probability of progression to definite MS based on life-table analysis
    - 13% at 10 years of follow-up
    - 19% at 20 years
    - 22% at 30 years
    - 26% at 40 years
  - bilateral sequential or recurrent optic neuritis increased risk of developing MS (p = 0.002)
  - Reference - Neurology 1997 Nov;49(5):1413
- 36 children aged 2.2-17.8 years (mean age 12.2 years) seen for optic neuritis
  - optic neuritis unilateral in 58% and bilateral in 42%
  - mean duration of follow-up 2.4 years
  - of 13 (36%) of children diagnosed with MS, bilateral optic neuritis in 58% and unilateral in 38% (p = 0.03 for bilateral optic neuritis and MS)
  - Reference - Neurology 2006 Jul 25;67(2):258
factors which may predict progression to MS among patients with optic neuritis
- multifocal visual evoked potential latency delay may predict progression to MS among patients with optic neuritis
  - based on prospective cohort study
  - 46 patients with optic neuritis without diagnosis of MS at baseline were followed for 1 year
  - among 29 patients with possible MS at baseline, patients with multifocal visual evoked potential latency delay had progression to MS within 1 year in 36.4% vs. 0% in patients with normal multifocal visual evoked potential latency (p = 0.03)
  - Reference - Arch Neurol 2006 Jun;63(6):847
- retinal vascular abnormalities and/or cells in vitreous or anterior chamber associated with development of multiple sclerosis in patients with acute optic neuritis
  - based on cohort study
  - 50 patients with acute optic neuritis were evaluated
  - abnormal vascular and inflammatory findings in 14 patients (28%)
    - fluorescein leakage in 10 (20%)
    - perivenous sheathing in 6 (12%)
    - cells in vitreous in 6 (12%)
    - cells in anterior chamber in 4 (8%)
  - at mean follow-up 3.5 years, development of MS in 57% of 14 patients with vascular and/or inflammatory findings vs.16% of 32 patients without vascular or inflammatory findings (p < 0.02)
  - Reference - Brain 1987 Apr;110 (Pt 2):405, commentary can be found in Brain 2010 Jun;133(Pt 6):1575 full-text
- elevated permeability of blood brain barrier in normal-appearing white matter on dynamic contrast-enhanced MRI may help predict progression from optic neuritis to MS within 2 years (level 2 [mid-level] evidence)
  - based on diagnostic cohort study without independent validation
  - 39 treatment-naive adults with optic neuritis had dynamic contrast-enhanced MRI within 28 days of symptom onset and were followed for up to 2 years
  - 23 patients started disease-modifying treatment within 6 weeks of baseline visit
  - 44% were diagnosed with MS by 2010 revised McDonald criteria (reference standard) within 2 years
  - permeability of blood brain barrier in normal-appearing white matter on MRI was increased in patients who progressed to MS vs. patients who did not progress (p = 0.004)
  - optimum cutoff for prediction of progression was permeability > 0.13 ml/100 g/minute
  - 1 patient lost to follow-up and excluded from analysis
  - performance of elevated permeability of blood brain barrier on MRI for predicting progression from optic neuritis to MS
    - in overall analysis
      - sensitivity 88%
      - specificity 71%
      - positive predictive value 71%
      - negative predictive value 88%
    - in analysis excluding 6 patients diagnosed with MS within 1 month of baseline
      - sensitivity 91%
      - specificity 71%
      - positive predictive value 63%
      - negative predictive value 94%
  - Reference - Brain 2015 Sep;138(Pt 9):2571 full-text

see also Optic neuritis

4.4. Possible risk factors

4.4.1. Smoking

smoking associated with increased risk of developing MS
- based on cohort study
- 22,312 persons in Hordaland, Norway in 1997 were evaluated
- 87 developed MS (0.39%)
- compared with never-smokers, tobacco smoking associated with increased risk for MS (rate ratio 1.81, 95% CI 1.1-2.9)
- Reference - Neurology 2003 Oct 28;61(8):1122

4.4.2. Obesity

obesity at age 18-20 years may increase risk of MS
- based on pooled analysis of 2 cohort studies
- 238,371 women from Nurses' Health Study and Nurses' Health Study II provided information on body size at ages 5, 10, and 20 years, weight at age 18 years, and weight and height at baseline
- 593 incident cases of MS reported over 40-year follow-up
- factors associated with increased risk of MS
  - body mass index ≥ 30 kg/m² at age 18 years (p < 0.001)
  - large body size at age 20 years (p = 0.009)
- no significant association between body mass later in adulthood and risk of MS
- Reference - Neurology 2009 Nov 10;73(19):1543 full-text

4.4.3. Reduced ultraviolet light exposure (vitamin D deficiency)

region of birth and low maternal exposure to ultraviolet radiation in first trimester associated with increased risk of MS in offspring
- based on cohort study
- 1,524 patients with MS born in Australia between 1920 and 1950 were analyzed
- increased risk of MS significantly associated with
  - lower ambient ultraviolet radiation in first trimester
  - region of birth (higher latitudes)
  - birth during November-December (vs. birth during May-June)
- month of birth not associated with risk of MS after adjustment for ambient ultraviolet radiation exposure during early pregnancy
- Reference - BMJ 2010 Apr 29;340:c1640 full-text
higher sun exposure at age 6-15 years associated with reduced risk of MS
- based on case-control study
- 136 patients with MS and 272 controls were evaluated
- higher sun exposure defined as average ≥ 2-3 hours/day in summer during weekends and holidays
- higher sun exposure when aged 6-15 years associated with decreased risk of MS compared with lower sun exposure (≤ 1-2 hours in sun on average) (adjusted odds ratio 0.31, 95%CI 0.16-0.59)
- Reference - BMJ 2003 Aug 9;327(7410):316 full-text

4.4.4. Risk factors with conflicting evidence

evidence for increased risk of multiple sclerosis with recombinant hepatitis B vaccine (MS) conflicting
- recombinant hepatitis B vaccine associated with increased risk of MS
  - based on case-control study
  - 163 patients with MS and 1,604 matched controls evaluated
  - compared to no vaccination, vaccination within 3 years of index date associated with increased risk of MS (odds ratio 3, 95% CI 1.5-6.3)
  - Reference - Neurology 2004 Sep 14;63(5):838
- no association between hepatitis B vaccination and development of MS
  - based on 3 case-control studies
  - 440 adults aged 18-49 years with MS or optic neuritis and 950 matched controls (Arch Neurol 2003 Apr;60(4):504)
  - 143 persons with MS and 1,122 matched controls in France (Arch Pediatr Adolesc Med 2007 Dec;161(12):1176), commentary can be found in Arch Pediatr Adolesc Med 2007 Dec;161(12):1214
  - 192 women with MS and 645 matched controls (N Engl J Med 2001 Feb 1;344(5):327 full-text), editorial can be found in N Engl J Med 2001 Feb 1;344(5):372, commentary can be found in N Engl J Med 2001 Jun 7;344(23):1793

conflicting evidence regarding association of chronic cerebrospinal venous insufficiency and risk of multiple sclerosis
- based on 3 case-control studies
- abnormal flow on transcranial and extracranial Doppler associated with increased risk of multiple sclerosis (MS)
  - based on case-control study
  - 65 patients with clinically defined MS and 235 controls not affected by MS were evaluated with combined transcranial and extracranial Doppler
  - controls included healthy patients and patients with other neurologic disorders
  - 65 patients with MS and abnormal transcranial Doppler studies and 48 control patients having venography for non-neurologic indications had unblinded venography
  - MS associated with abnormal venous outflow (odds ratio 43, 95% CI 29-65)
  - abnormal venography in patients with MS included
    - azygous vein stenosis in 86%
    - jugular vein stenosis (unilateral or bilateral) in 91%
  - no difference in venous hypertension between groups
  - Reference - J Neurol Neurosurg Psychiatry 2009 Apr;80(4):392 full-text
- rates of chronic cerebrospinal venous insufficiency do not appear higher in patients with MS than in healthy persons
  - based on case-control study
  - 177 adults (79 with multiple sclerosis, 55 siblings, and 43 unrelated healthy controls) were evaluated for cerebrospinal venous insufficiency by catheter venography and ultrasound
  - rates of chronic cerebrospinal venous insufficiency as assessed by catheter venography (no significant differences)
    - 2% with multiple sclerosis
    - 2% of siblings
    - 3% of unrelated healthy controls
  - rates of > 50% stenosis in any vein by catheter venography (no significant differences)
    - 74% with multiple sclerosis
    - 66% of siblings
    - 70% of unrelated healthy controls
  - no significant differences among groups in rates of chronic cerebrospinal venous insufficiency assessed by ultrasound
  - Reference - Lancet 2014 Jan 11;383(9912):138, editorial can be found in Lancet 2014 Jan 11;383(9912):106
- abnormal venous flow not associated with MS
  - based on case-control study
  - 21 patients with relapsing-remitting MS and 20 healthy controls had magnetic resonance imaging of carotid and vertebral arteries and internal jugular veins at C2-C3 level
  - no significant differences between groups in internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or presence of internal jugular blood reflux
  - internal jugular vein stenosis identified in 3 cases
  - Reference - Ann Neurol 2010 Aug;68(2):255

4.5. Factors not associated with increased risk

4.5.1. Immunizations (excluding hepatitis B)

no association between vaccination against influenza, tetanus, measles, or rubella, and development of MS or optic neuritis
- based on case-control study
- 440 adults aged 18-49 years with MS or optic neuritis and 950 matched controls were evaluated
- no association between vaccination against hepatitis B, influenza, tetanus, measles, or rubella and development of MS or optic neuritis
- Reference - Arch Neurol 2003 Apr;60(4):504

4.5.2. Oral contraceptives and pregnancy

neither oral contraceptive use nor parity associated with risk of MS
- based on cohort study
- 238,371 women in 2 cohorts in United States were evaluated
- 315 patients with definite or probable cases of MS identified during 18 years of follow-up in Nurses' Health Study and 8 years of follow-up in Nurses' Health Study II
- no association found between use of oral contraceptives or parity and risk of MS
- Reference - Neurology 2000 Sep 26;55(6):848

4.5.3. Other factors not associated with increased risk

protective effect associated with haplotypes HLA-C5 and HLA-DRB1*11⁽³⁾
traumatic injury not associated with increased risk of multiple sclerosis
- based on systematic review
- 16 observational studies (13 case-control studies and 3 cohort studies) evaluating association between traumatic injury and onset of multiple sclerosis reviewed
- traumatic injury not associated with increased risk of multiple sclerosis in analysis of
  - 8 case-control studies of moderate methodologic quality
  - 3 cohort studies of moderate to high methodologic quality
- Reference - Can J Neurol Sci 2013 Mar;40(2):168
apolipoprotein E (APOE) epsilon genotypes not associated with risk for MS
- based on meta-analysis
- 22 case-control studies with 3,299 patients with MS and 2,532 controls were analyzed
- no significant effect found for epsilon2 or epsilon4 status on MS risk
- Reference - Neurology 2006 May 9;66(9):1373

no apparent association between B12 deficiency and multiple sclerosis (Mult Scler 2003 Jun;9(3):239)

4.6. Associated conditions

4.6.1. Type 1 diabetes

multiple sclerosis associated with increased risk for type 1 diabetes
- based on 2 cohort studies
- 6,078 Danish patients diagnosed with diabetes before age 20 years and 11,862 Danish patients with multiple sclerosis in population registries were evaluated
  - compared with controls, patients with multiple sclerosis associated with increased risk for type 1 diabetes (relative risk 3.26, 95% CI 1.8-5.88)
  - Reference - Arch Neurol 2006 Jul;63(7):1001
- 1,090 patients with multiple sclerosis and their first-degree relatives were evaluated
  - prevalence of type 1 diabetes was
    - 0.5% in general population
    - 1% among parents and healthy siblings of patients with multiple sclerosis (p < 0.001 vs. general population)
    - 3% among patients with multiple sclerosis (p < 0.001 vs. general population)
  - Reference - Lancet 2002 Apr 27;359(9316):1461, editorial can be found in Lancet 2002 Apr 27;359(9316):1450, commentary can be found in Lancet 2002 Oct 19;360(9341):1253, Diabetes Care 2003 Nov;26(11):3192

4.6.2. Migraine

multiple sclerosis associated with increased risk of migraine
- based on systematic review of observational studies
- systematic review of 8 studies (7 case-control, 1 cohort study) evaluating association between multiple sclerosis and migraine in 1,864 patients with multiple sclerosis and 261,563 control patients without neurological condition
- compared to controls, patients with multiple sclerosis had increased risk of
  - migraine (odds ratio 2.6, 95% CI 1.12-6.04)
  - migraine without aura (odds ratio 2.29, 95% CI 1.14-4.58)
- Reference - PLoS One 2012;7(9):e45295 full-text

4.6.3. Restless legs syndrome

multiple sclerosis may be associated with restless legs syndrome
- based on cohort study
- 156 patients with multiple sclerosis (MS) (mean age 40.7 years) had structured questionnaire to diagnose restless legs syndrome (RLS)
- 32.7% (mean age 43.8 years) met criteria for RLS
- RLS was present in 60% of 15 patients with primary progressive form of MS vs. 30% of 142 patients with relapsing-remitting or secondary progressive MS (p = 0.06)
- Reference - Eur J Neurol 2007 May;14(5):534

4.6.4. Thyroid disease

MS associated with Graves disease, and might be associated with Hashimoto thyroiditis
- based on cohort study
- 491 patients with MS in Newfoundland and Labrador were analyzed
  - 15 patients had co-occurrence of Graves disease
  - 26 patients had co-occurrence of Hashimoto thyroiditis
- compared to general population, multiple sclerosis associated with
  - significant co-occurrence of Graves disease (p = 0.002)
  - nonsignificant co-occurrence of Hashimoto thyroiditis (p = 0.097)
- Reference - J Autoimmune Dis 2005 Nov 9;2:9 full-text

5. Etiology and Pathogenesis

5.1. Causes

autoimmune disease likely due to combination of genetic predisposition and environmental influence^(2, 3)

5.2. Pathogenesis

hypothesis for development of MS
- possible trigger of disease process is increased migration of autoreactive lymphocytes across blood-brain barrier, initiating immune response and inflammation in brain⁽³⁾
- T-lymphocyte subtype secretes interleukin-17, disrupting blood-brain barrier and allowing penetration of T-helper17 cells which can kill neurons⁽³⁾
- cells may enter central nervous system compartment via cerebrospinal fluid as well as from vessels (N Engl J Med 2011 Dec 8;365(23):2188 full-text), editorial can be found in N Engl J Med 2011 Dec 8;365(23):2231
- myelin-reactive T cells can lead to central nervous system inflammation and demyelination⁽²⁾
- B-cell response results in intrathecal synthesis of immunoglobulins⁽²⁾
axonal injury (due to demyelination) results in decreased nerve conduction and decreased function⁽²⁾
- remyelination occurs in lesions, but is likely transient
- progressive loss of axons results in irreversible disability
- early stages of disease course may be subclinical with infrequent clinical exacerbations
pathological findings in typical white matter plaque
- histologic features of acute MS lesions include⁽²⁾
  - indistinct margins
  - hypercellularity
  - lymphocytic perivascular infiltration
  - parenchymal edema
  - demyelination
  - loss of oligodendrocytes
  - widespread axonal damage
  - little or no astroglial scarring
- axonal transection due to inflammation in demyelinated lesions reported to be common
  - based on case series
  - 11 patients with MS had brain tissue sampled at autopsy
  - axonal transection found in all 47 MS lesions examined
  - Reference - N Engl J Med 1998 Jan 29;338(5):278 full-text
- cortical demyelination reported in 40% of patients with early stage multiple sclerosis
  - based on case series
  - 77 patients with definite MS or clinically isolated syndrome evaluated with brain biopsy and followed for median 3.5 years
  - 31 patients (40%) had cortical demyelination
  - cortical demyelination significantly associated with meningeal inflammation
  - Reference - N Engl J Med 2011 Dec 8;365(23):2188 full-text, editorial can be found in N Engl J Med 2011 Dec 8;365(23):2231

6. History and Physical

6.1. History

6.1.1. Clinical presentation

80% of patients present initially with a clinically isolated syndrome^(1, 3)
clinical presentations vary widely and can include the following signs and symptoms^(1, 3, 6)
- spinal cord involvement (myelitis) - potentially leading to
  - partial sensory or motor dysfunction below affected spinal level
  - Lhermitte phenomenon
  - bowel and bladder dysfunction
  - erectile dysfunction
  - "band-like" abdominal or chest sensation
- brainstem involvement - potentially leading to
  - double vision
  - oscillopsia (sensation of jerking in visual field)
  - internuclear ophthalmoplegia
    - impaired horizontal eye movement caused by lesion in medial longitudinal fasciculus, resulting in failure of adduction on attempted lateral gaze
    - multiple sclerosis is most frequent underlying cause
    - Reference - N Engl J Med 2013 Jan 17;368(3):e3 full-text
  - nystagmus
  - vertigo
  - impaired swallowing and speech
  - pseudobulbar palsy
- cerebrum involvement - potentially leading to
  - cognitive impairment
  - unilaterally impaired motor skills
  - unilaterally impaired sensation
  - depression
  - upper motor neuron signs
- cerebellar involvement - potentially leading to
  - problems with balance, vertigo, and/or impaired coordination
  - cerebellar outflow tremor
  - acute ataxic syndrome
- other signs and symptoms can include
  - tonic spasms
  - fatigue
  - pain
  - exercise intolerance
  - temperature sensitivity
  - optic neuritis
    - subacute loss of visual acuity; may range from central or centrocecal scotoma to blindness
    - usually unilateral and often painful
initial symptoms reported in cohort of 1,099 patients followed at multiple sclerosis (MS) clinic
- 45% had sensory symptoms
- 17% had optic neuritis
- 14% had insidious-onset motor symptoms (more common in patients > 40 years old at onset)
- 13% had limb ataxia and/or impaired balance
- 13% had diplopia and/or vertigo
- 6% had acute-onset motor symptoms
- Reference - Brain 1989 Feb;112 (Pt 1):133
migraine-like headache as presenting symptom in 5-year-old child with MS in case report (Pediatrics 2010 Aug;126(2):e459)

6.1.2. History of present illness (HPI)

in addition to the possible clinical presentations described above, most often patients with MS are < 50 years old and have history of all of⁽⁶⁾
- previous neurological symptoms
- symptoms that evolved over > 24 hours
- persisting symptoms over several days or weeks, followed by improvement
do not routinely suspect MS if main symptoms are fatigue, depression, or dizziness unless patient has history or evidence of focal neurological symptoms or signs⁽⁶⁾

6.1.3. Family history (FH)

age-adjusted risk of MS based on relationship to person with MS
- 0.2% for adopted first-degree relative (risk similar to general population)
- 3%-5% for first-degree relative (relative risk 15-25)
- 34% for monozygotic female twin (relative risk 170)
- 30.5% for both biologic parents with MS (conjugal MS) (relative risk 150)
- Reference - Lancet Neurol 2004 Feb;3(2):104

6.2. Physical

6.2.1. HEENT

eye findings can include^(1, 3)
- decreased visual acuity
- decreased color vision
- scotoma (holes in visual field)
- ophthalmoplegias (eye movement disorders)
- nystagmus
- relative afferent pupillary defect
  - tested by swinging light between eyes
  - pupil of diseased optic nerve or retina enlarges when illuminated while healthy pupil constricts
  - may be seen with optic neuritis, other optic neuropathies, asymmetric glaucoma, and some retinal problems
  - Reference - Ann Intern Med 2007 Apr 17;146(8):615
- acute uveitis (Ocul Immunol Inflamm 2004 Jun;12(2):137)
- pars planitis (Ocul Immunol Inflamm 2001 Jun;9(2):93)
- review of ocular manifestations of autoimmune diseases (including multiple sclerosis) can be found in Am Fam Physician 2002 Sep 15;66(6):991 full-text
other findings from brainstem lesions may include⁽³⁾
- dysarthria
- impaired swallowing

6.2.2. Neuro

neurologic phenomena that may occur in patients with MS include
- Lhermitte phenomena
  - Lhermitte sign - paresthesias radiating down extremities or trunk with neck flexion, suggesting intrinsic cervical spinal cord lesion typically affecting dorsal columns
  - reverse Lhermitte sign - Lhermitte symptoms associated with neck extension, suggesting compressive extra-axial cervical lesion
  - inverse Lhermitte sign - paresthesia radiating upward with neck flexion
  - Reference - Neurol Clin 2013 Feb;31(1):79
- Uhthoff phenomenon - transient worsening of vision or other neurologic symptoms with increased core temperature (such as during exercise, hot bath, fever)⁽³⁾
- useless hand of Oppenheim - sensation that hand or arm is unusable despite no visible weakness or ataxia, likely due to sensory deafferentation (Postgrad Med J 1993 Feb;69(808):149 PDF)
- Pulfrich phenomenon - visual phenomenon where patients may perceive moving objects as having an anomalous pathway (Surv Ophthalmol 1997 May-Jun;41(6):493)
upper motor neuron signs may include weakness, spasticity, hyperreflexia, and Babinski sign^(1, 3)
- Babinski sign might have limited inter-observer reliability and validity for identifying upper motor neuron weakness
  - based on cohort study
  - 10 physicians examined 10 persons (including 8 persons with unilateral upper motor neuron weakness)
  - Babinski sign had fair inter-reliability (kappa 0.3) and 56% agreement in persons with known weakness
  - slowness of foot tapping had substantial inter-reliability (kappa 0.73) and 85% agreement with known weakness
  - Reference - Neurology 2005 Oct 25;65(8):1165
hemisensory loss⁽³⁾
hemiparesis⁽³⁾
tremor (can be postural and/or action tremor)⁽³⁾
poor balance⁽³⁾
clumsiness (limb incoordination and gait ataxia)⁽³⁾
cognitive deficits⁽³⁾
- attention dysfunction
- problems with executive function
- dementia
emotional lability⁽³⁾

7. Diagnosis

7.1. Making the diagnosis

refer patients with suspected MS for a neurological consult⁽⁶⁾
- diagnosis of MS should be made using established current criteria (such as revised 2010 criteria) after
  - assessing that episodes are consistent with an inflammatory process
  - excluding alternative diagnoses
  - establishing that lesions have developed at different times and are in different anatomical locations for diagnosis of relapsing-remitting MS
  - establishing progressive neurological deterioration over ≥ 1 year for diagnosis of primary progressive MS
international diagnostic criteria for MS (2010 revisions to McDonald criteria) includes any of
- ≥ 2 attacks with objective clinical evidence of ≥ 2 lesions, or objective clinical evidence of 1 lesion with reasonable historical evidence of prior attack
  - attack is defined as patient-reported or objectively observed event with
    - presentation typical of acute inflammatory demyelinating central nervous system (CNS) event
    - duration ≥ 24 hours
    - absence of fever or infection
  - to make definite diagnosis of MS, at least 1 attack needs to be confirmed by any of
    - neurologic exam
    - abnormal visual evoked potential response in patient reporting prior visual disturbance
    - magnetic resonance imaging (MRI) consistent with demyelination in area corresponding to history of previous neurologic symptoms
- ≥ 2 attacks with objective clinical evidence of 1 lesion and dissemination in space demonstrated by ≥ 1 T2 lesions involving at least 2 of 4 typical CNS regions (periventricular, juxtacortical, infratentorial, or spinal cord)
  - gadolinium enhancement of lesions not required
  - if patient has brainstem or spinal cord syndromes, symptomatic lesions are not included for consideration of meeting criteria
- 1 attack with objective clinical evidence of ≥ 2 lesions and dissemination in time demonstrated by any of
  - asymptomatic gadolinium-enhancing and nonenhancing lesions occurring simultaneously at any time
  - new T2 and/or gadolinium-enhancing lesion on follow-up MRI (regardless of timing in comparison to baseline scan)
- 1 attack with objective clinical evidence of only 1 lesion (clinically isolated syndrome) and both dissemination in space and time as noted above
- primary progressive MS defined as 1 year of progressive disease (determined prospectively or retrospectively) plus any 2 of
  - evidence of dissemination in space in brain based on ≥ 1 T2 lesions in typical CNS regions (periventricular, juxtacortical, or infratentorial)
  - evidence of dissemination in space in spinal cord based on ≥ 2 T2 lesions in spinal cord (not counting symptomatic lesions in patient with brainstem or spinal cord syndrome)
  - ≥ 2 oligoclonal bands and/or elevated immunoglobulin G (IgG) index in cerebrospinal fluid (CSF)
- diagnosis of possible MS if suspicious but criteria are not completely met
- Reference - Ann Neurol 2011 Feb;69(2):292 full-text, editorial can be found in Ann Neurol 2011 Feb;69(2):234, commentary can be found in Ann Neurol 2011 Jul;70(1):182, Ann Neurol 2011 Sep;70(3):520
some patients with clinically isolated syndrome (CIS) may now be diagnosed as having MS at time of first presentation with appropriate lesions on MRI (Ann Neurol 2011 Feb;69(2):292 full-text)

7.2. Differential diagnosis

differential diagnosis in patients with suspected MS or white matter changes on magnetic resonance imaging (MRI) includes^(1, 4)
- age-related white matter changes
- other demyelinating diseases
  - acute disseminated encephalomyelitis (ADEM)
  - neuromyelitis optica (NMO) (Devic disease)
  - idiopathic transverse myelitis
- systemic inflammatory disease
  - Behcet syndrome
  - neurosarcoidosis
  - Sjogren syndrome
  - systemic lupus erythematosus
  - antiphospholipid antibody syndrome
  - other collagen vascular disorders
- metabolic disease
  - adult-onset metachromatic leukodystrophy
  - adrenoleukodystrophy
  - vitamin B12 deficiency
  - copper deficiency
  - zinc toxicity
  - vitamin E deficiency
- infections
  - Lyme disease
  - neurosyphilis
  - HIV infection
  - human T-lymphotrophic virus I/II (tropical spastic paraparesis)
- vascular disorders
  - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  - ischemic optic neuropathy (arteritic and nonarteritic) (see also Optic neuritis)
  - ischemic cerebrovascular events (including stroke and transient ischemic attack)
  - vasculitis (primary central nervous system or others)
  - Susac syndrome (small vessel arteriopathy)
  - dural arteriovenous fistula
  - cavernous hemangioma (2 case reports can be found in BMJ 1999 Jun 12;318(7198):1604 full-text), commentary can be found in BMJ 1999 Oct 2;319(7214):919
- neoplastic tumors (primary or metastatic)
  - central nervous system (CNS) lymphoma
  - gliomas
  - meningioma
  - paraneoplastic syndromes
- migraine
- somatoform disorders
- cervical spine disorders (spondylosis or stenosis)

7.3. Testing overview

no routine blood tests are specific for MS, but some tests may be useful to exclude alternative diagnoses before referring patients with suspected MS to a neurologist
obtain magnetic resonance imaging of brain and spinal cord with and without contrast
obtain lumbar puncture for cerebrospinal fluid studies if diagnosis remains uncertain or if alternative diagnosis is being considered
visual evoked potentials may be useful to identify patients at increased risk for developing clinically definite multiple sclerosis (AAN Guideline, Class II)

7.4. Blood tests

National Institute for Health Care Excellence (NICE) recommends excluding alternative diagnoses by performing blood tests before referring patients with suspected MS to neurologist, including⁽⁶⁾
- full blood count
- inflammatory markers (such as erythrocyte sedimentation rate, C-reactive protein)
- liver function tests
- renal function tests
- calcium
- glucose
- thyroid function tests
- vitamin B12
- HIV serology

7.5. Imaging studies

7.5.1. Magnetic resonance imaging (MRI)

7.5.2. Imaging criteria for diagnosis of MS

National Institute for Health and Care Excellence (NICE) recommends against diagnosing MS on basis of MRI findings alone⁽⁶⁾
2010 revision of McDonald criteria by International Panel on Diagnosis of MS
- 2010 MRI criteria for demonstration of dissemination in space
  - ≥ 1 T2 lesions involving at least 2 of 4 typical central nervous system (CNS) regions (periventricular, juxtacortical, infratentorial, or spinal cord)
  - gadolinium enhancement of lesions not required
  - if patient has brainstem or spinal cord syndromes, symptomatic lesions are not included for consideration of meeting criteria
- 2010 MRI criteria for demonstration of dissemination in time - either of
  - asymptomatic gadolinium-enhancing and nonenhancing lesions occurring simultaneously at any time
  - new T2 and/or gadolinium-enhancing lesion on follow-up MRI (regardless of timing in comparison to baseline scan)
- additional factors that may enhance detection of multiple sclerosis lesions, but need validation include
  - presence of ≥ 1 intracortical lesion using double inversion recovery imaging
  - MRI magnet strengths > 1.5 Tesla
  - MRI techniques (such as magnetic transfer imaging) that allow detection of damage outside focal lesions
  - detection of multiple lesions characteristic of multiple sclerosis in patient having MRI for other reason (radiologically isolated syndrome), which may be presymptomatic multiple sclerosis
- Reference - Ann Neurol 2011 Feb;69(2):292 full-text, editorial can be found in Ann Neurol 2011 Feb;69(2):234, commentary can be found in Ann Neurol 2011 Jul;70(1):182, Ann Neurol 2011 Sep;70(3):520

7.5.3. MRI techniques

advanced MRI techniques methods may help diagnose and monitor MS
- conventional MRI techniques (noncontrast and gadolinium-enhanced T1-weighted images and T2-weighted images) limited by weak association between patient's clinical status and findings such as grey-matter disease, atrophy, and diffuse damage throughout white matter
- nonconventional MRI techniques for brain imaging include
  - proton magnetic resonance spectroscopy (¹H-MRS) can detect metabolites which may be increased during myelin breakdown, remyelination, and inflammation
  - magnetization transfer MRI can be indicator of damage to myelin and axonal membranes
  - diffusion MRI can detect abnormalities in focal MS lesions and can reconstruct pathways of major white-matter bundles
  - functional MRI (fMRI) depends on blood oxygenation level-dependent (BOLD) contrast mechanism and can demonstrate brain activation
- other imaging of central nervous system includes
  - optic nerve imaging such as with ¹H-MRS
  - spinal cord imaging such as with ¹H-MRS and fMRI
- use of new contrast agents may include
  - Gadofluorine M which selectively accumulates in nerve fibers undergoing Wallerian degeneration
  - iron particles which can track macrophages
- Reference - Lancet Neurol 2008 Jul;7(7):615 full-text
multi-echo MRI sequences might detect more spinal lesions than T2-weighted sequences in patients with MS (level 2 [mid-level] evidence)
- based on diagnostic cohort without independent reference standard
- 83 spinal cord lesions from 29 patients with MS were assessed with MRI using multi-echo recombined gradient echo (MERGE) and T2-weighted fast spin-echo sequences
- 2 readers assessed MRI sequences
- reference standard was unblinded consensus review of all MRI sequences by 3 readers
- detection rates of MS spinal lesions for 2 readers
  - 81% and 94% with MERGE sequences
  - 70% and 64% with T2-weighted sequences
- number of false positives was higher for MERGE sequences than T2-weighted sequences in patients with MS and in 29 controls without MS
- Reference - AJR Am J Roentgenol 2012 Jul;199(1):157

7.5.4. MRI findings and assessment of disease severity

conventional MRI shows occult disease activity to be 5-10 times greater than that which may be predicted by clinical activity (number of clinical exacerbations)⁽²⁾
gray matter lesions occur frequently but may be poorly visualized on standard MRI protocols (AJNR Am J Neuroradiol 2005 Mar;26(3):572 full-text)
subclinical demyelinating lesions identified by MRI in asymptomatic patients associated with clinical conversion to MS in 33% within 5 years
- based on cohort study
- 70 patients (mean age 35 years) with subclinical demyelinating lesions identified during first brain MRI for medical problems other than MS were analyzed
- demyelinating lesions defined using Barkhof/Tintoré criteria
- clinical conversion to symptomatic MS in 23 (33%) patients during 5-year follow-up
  - 6 to optic neuritis
  - 6 to myelitis
  - 5 to brainstem symptoms
  - 4 to sensory symptoms
  - 1 to cerebellar symptoms
  - 1 to cognitive deterioration
- Reference - Arch Neurol 2009 Jul;66(7):841
spinal cord lesions on MRI might help detect MS in patients with clinically isolated syndrome without spinal symptoms who do not fulfill diagnostic criteria based on brain MRI alone (level 2 [mid-level] evidence)
- based on diagnostic cohort study without independent reference standard
- 121 patients with clinically isolated syndrome and either spinal cord or brain symptoms were assessed with MRI of brain and spinal cord for diagnosis of MS using 2010 revisions to McDonald criteria (reference standard)
- median follow-up 64 months
- 82 patients (68%) had spinal cord lesions on MRI
  - 36 patients diagnosed with MS based on brain MRI scan alone
  - 6 additional patients with nonspinal clinically isolated syndrome diagnosed with MS based on brain and/or spinal cord MRI scan
- Reference - Neurology 2013 Jan 1;80(1):69
composite magnetic resonance disease severity scale (MRDSS) may define severity of cerebral damage in MS (level 2 [mid-level] evidence)
- based on derivation cohort study without validation
- retrospective analysis of 103 patients with MS
- MRDSS composite of MRI lesion and atrophy measures
  - T2 hyperintense lesion volume
  - ratio of T1 hypointense lesion volume to T2
  - whole brain atrophy defined as normalized whole brain volume
- MRDSS was significantly associated with disability progression during mean 3.2 year follow-up after adjusting for baseline disability score
- Reference - Arch Neurol 2008 Nov;65(11):1449 full-text
- composite MRDSS may have greater sensitivity than individual MRI measures to detect disease progression over time
  - based on subgroup analysis of patients from cohort study above
  - 84 patients with follow-up MRI results were analyzed
  - compared to baseline, at mean 3.2 year follow-up
    - MRDSS scores, and 2 of 3 individual MRI measures indicated worsening of disease severity (p < 0.001)
    - MRDSS scores indicated worsening of disease severity in patients with relapsing-remitting and secondary progressive MS (p ≤ 0.05 for each), but only 2 of 3 individual MRI measures changed significantly in patients with relapsing-remitting MS and no individual MRI measures changed significantly in patients with secondary progressive MS
    - change in MRDSS was significantly different between relapsing-remitting and secondary progressive phenotypes, with no significant change in individual MRI components
  - Reference - J Neurol Sci 2012 Apr 15;315(1-2):49 full-text

7.5.5. Other imaging studies

measurements of retinal nerve fiber layer thickness obtained with optical coherence tomography may identify patients with MS (level 2 [mid-level] evidence)
- based on diagnostic case-control study
- 115 patients with multiple sclerosis and 115 healthy controls were evaluated with spectral-domain optical coherence tomography
- 60% of study cohort (69 patients and 69 controls) were separated out into a validation cohort
- in validation cohort, for identification of patients with MS
  - largest area under the receiver operating characteristic curve was 0.834 for the linear discriminant function
  - formula for linear discriminant function had
    - 83% sensitivity
    - 69% specificity
    - 2.62 positive likelihood ratio
    - 0.25 negative likelihood ratio
- Reference - Ophthalmology 2012 Aug;119(8):1705

point-of-care ocular ultrasound appears to have high specificity for optic disc swelling (level 2 [mid-level] evidence)
- based on small diagnostic cohort study without validation
- 14 patients at risk for conditions associated with optic disc edema were assessed by emergency physicians using point-of-care ultrasound
- 8 patients ultimately diagnosed with idiopathic intracranial hypertension, 5 with multiple sclerosis, and 1 with neuromyelitis optica
- 39% of 28 eyes had disc swelling on dilated funduscopic exam performed by expert
- optimum diagnostic thresholds for maximum optic disc height determined using area under receiver-operator characteristic curve analysis
- diagnostic performance of point-of-care ultrasound on per-eye basis
  - using diagnostic threshold > 1 mm maximum disc height had sensitivity 73% and specificity 100%
  - using diagnostic threshold > 0.6 mm had sensitivity 82% and specificity 76%
- Reference - Acad Emerg Med 2013 Sep;20(9):920

7.6. Cerebrospinal fluid (CSF) analysis

CSF analysis⁽¹⁾
- not required for diagnosis of relapsing-remitting MS
- only needed for diagnosis of primary progressive MS if magnetic resonance imaging (MRI) does not show dissemination in space
- may be useful when diagnosis remains uncertain or if alternative diagnosis is being considered
- negative CSF alone cannot be used to rule out diagnosis of MS, but if diagnostic suspicion low, normal CSF can reassure patients they likely do not have MS
oligoclonal immunoglobulin G (IgG) band testing may help identify MS in patients with neurological disorders (level 2 [mid-level] evidence)
- based on cohort study without independent validation
- 385 patients with various neurologic disorders were evaluated with new oligoclonal immunoglobulin G (IgG) band test
- for diagnosis of MS, IgG band testing had 96.2% sensitivity and 92.5%-99.5% specificity
- Reference - Arch Neurol 2005 Apr;62(4):574
see also Lumbar puncture

7.7. Evoked potential studies

American Academy of Neurology (AAN) recommendations for use of evoked potentials in patients with suspected multiple sclerosis (MS)
- based on systematic review with heterogeneity
- 9 trials with 892 adult patients evaluated patients with possible MS using evoked potentials and followed patients for diagnosis of clinically definite multiple sclerosis (CDMS)
- patients had broad spectrum of disease presentations including trials that excluded isolated optic neuritis and trial of patients with optic neuritis only
- visual evoked potentials probably useful to identify patients at increased risk for developing CDMS (AAN Guideline, Class II)
- somatosensory evoked potentials possibly useful to identify patients at increased risk for developing CDMS (AAN Practice Option, Class II)
- insufficient evidence to recommend brainstem auditory evoked potentials as useful study to identify patients at increased risk for developing CDMS (AAN Guideline, Class II)
- Reference - Neurology 2000 May 9;54(9):1720
compared to visual evoked potentials, brainstem and spinal cord potentials are less likely to be abnormal⁽¹⁾
multimodal evoked potentials results may predict clinical disability in patients with MS
- based on cohort study
- 50 patients with relapsing-remitting MS or clinically isolated syndrome had multimodal evoked potentials and were evaluated with neurologic exam, and assessment of Extended Disability Status Scale (EDSS)
- EDSS is scale from 0 to 10 for determination of disability from MS
  - scores of 1-4.5 are fully ambulatory patients
  - scores > 5 are patients with impaired ambulation with 10 being death from MS
- patients had evoked potentials (EPs) at baseline and at 6 month intervals
  - visual EPs
  - motor EPs to upper and lower extremities
  - somatosensory EPs (including median and tibial nerves)
- at each of 7 time points of measurement, EDSS values correlated with score that was summation of pathologic results of EPs (p = 0.001)
- summation score of pathologic results of EPs at baseline correlated with observed EDSS at 3 years (p < 0.001)
- Reference - Clin Neurophysiol 2012 Feb;123(2):406, editorial can be found in Clin Neurophysiol 2012 Feb;123(2):221

8. Treatment

8.1. Treatment overview

various counseling interventions may improve health outcomes in patients with MS
treatment of multiple sclerosis is based on pattern of clinical symptoms
- for clinically isolated syndrome (neurologic presentation suggestive of MS), treatments to reduce progression to clinically definite MS include
  - interferon beta-1b (level 1 [likely reliable] evidence)
  - interferon beta-1a given either once weekly or 3 times weekly (level 1 [likely reliable] evidence)
  - glatiramer acetate (level 2 [mid-level] evidence)
  - IV immunoglobulin (IVIG) (level 2 [mid-level] evidence)
  - teriflunomide (level 2 [mid-level] evidence)
- for treatment of acute relapse
  - consider glucocorticoids in any patient with acute attack of MS due to short-term benefit on speed of functional recovery (AAN Level A)
  - glucocorticoids dosing options include oral methylprednisolone 500 mg/day for 5 days and IV methylprednisolone 1g/day for 3-5 days
  - plasmapheresis should be considered for adjunctive treatment of exacerbations in relapsing multiple sclerosis (MS) (AAN Level B)
- for relapsing-remitting MS, use disease-modifying therapies
  - immunomodulatory drugs should be initiated at the time of diagnosis
  - choice of appropriate therapy depends on various factors including patient tolerability, risk stratification, disease activity, and adverse effect profile of each medication
  - immunomodulatory options with evidence for efficacy
    - interferon beta (interferon beta-1a or interferon beta-1b) demonstrated to reduce attack rate (AAN Level A) and may slow sustained disability progression (AAN Level B); not recommended by National Institute for Health and Care Excellence (NICE)
    - glatiramer acetate may reduce risk of exacerbation for patients with relapsing-remitting MS (AAN Level A; level 2 [mid-level] evidence); not recommended by NICE
    - IV immunoglobulin (IVIG) may prevent relapses in patients with relapsing-remitting multiple sclerosis (MS) (level 2 [mid-level] evidence)
    - monoclonal antibodies, such as alemtuzumab, daclizumab, natalizumab, and rituximab are effective but associated with significant adverse events
    - fingolimod reduces relapse rate in relapsing-remitting multiple sclerosis (level 1 [likely reliable] evidence) and reduces relapse rate compared to interferon beta-1a (level 1 [likely reliable] evidence)
    - laquinimod may reduce relapse rate and slow disability progression in patients with relapsing-remitting multiple sclerosis (level 2 [mid-level] evidence)
    - teriflunomide may decrease relapse in adults with multiple sclerosis, but might not reduce relapse in patients taking interferon beta (level 2 [mid-level] evidence)
    - dimethyl fumarate may decrease risk of relapse in patients with relapsing-remitting MS (level 2 [mid-level] evidence)
    - intermittent long-term corticosteroids (high-dose methylprednisolone IV) might reduce risk of disability progression at 5 years in patients with relapsing remitting multiple sclerosis (level 2 [mid-level] evidence)
- for progressive MS, use of either interferon beta or glatiramer acetate not recommended for patients with progressive, nonrelapsing forms of multiple sclerosis
treatment of selected specific impairments
- for treatment of spasticity and muscle spasms
  - baclofen or gabapentin considered as first-line drugs
  - tizanidine or dantrolene are second-line option
  - other options include botulinum toxin and cannabinoids
- for treatment impaired mobility
  - dalfampridine may improve walking speed in patients with MS (level 3 [lacking direct] evidence)
  - exercise therapy, multidisciplinary rehabilitation, and progressive resistance training of lower extremities may each have beneficial effect for patients with MS (level 2 [mid-level] evidence)
- for pain management
  - first-line treatments include pregabalin (EFNS Level A), amitriptyline (EFNS Level B), gabapentin (EFNS Level A), or duloxetine
  - consider tramadol as second-line treatment (EFNS Level B), and preferably only if acute rescue therapy is needed
  - use opioids as second- or third-line treatment if not chronically used (EFNS Level B)
- for fatigue consider amantadine, but limited evidence to determine efficacy for improving fatigue in multiple sclerosis (level 2 [mid-level] evidence)
- there is limited evidence to evaluate efficacy of anticholinergics for treating urinary symptoms in patients with multiple sclerosis
- for depression or anxiety
  - cognitive behavioral therapy may improve depression, adjustment, and coping in patients with MS (level 2 [mid-level] evidence)
  - consider antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SSNRIs), or tricyclic antidepressants
see also related summaries
- Disease-modifying therapies for multiple sclerosis
- Treatment of specific impairments in multiple sclerosis

8.2. Diet

8.2.1. Polyunsaturated fatty acids

no evidence to support used of omega-3 or omega-6 fatty acid compounds to treat MS⁽⁶⁾
polyunsaturated fatty acids may not improve clinical outcomes in patients with MS (level 2 [mid-level] evidence)
- based on Cochrane review of trials with methodological limitations
- systematic review of 6 low-quality randomized trials evaluating dietary interventions, besides vitamin D supplementation, in 794 adults with MS
- all trials evaluated polyunsaturated fatty acids (PUFAs)
- no trials compared PUFAs with placebo
- all trials had ≥ 1 limitation including unclear allocation concealment and unclear blinding
- comparing spread with linoleic acid (omega-6 fatty acid) to spread with oleic acid, no significant differences in
  - relapse in analysis of 2 trials with 132 adults
  - disease progression at 24 months in analysis of 2 trials with 144 adults
- comparing linoleic acid capsule vs. oleic acid capsule, no significant differences in disease progression and relapse at 24 months in 1 trial with 65 adults with chronic progressive MS
- comparing fish oil capsule with eicosapentaenoic acid plus docosahexanoic acid (both omega-3 fatty acids) vs. oleic acid for relapsing-remitting MS, no significant difference in
  - disease progression or relapse through 12 months in 1 trial with 27 adults
  - disease progression at 24 months in 1 trial with 292 adults
- Reference - Cochrane Database Syst Rev 2012 Dec 12;(12):CD004192

8.2.2. Vitamin D for treatment of MS

do not offer vitamin D supplementation if only purpose is to treat multiple sclerosis⁽⁶⁾

high-dose vitamin D supplementation does not appear to improve clinical outcomes or number of lesions in patients with multiple sclerosis (MS) (level 2 [mid-level] evidence)
- based on 3 small randomized trials
- high-dose vitamin D3 does not appear to increase serum calcium levels in patients with MS (level 3 [lacking direct] evidence)
  - based on small randomized trial with inadequate statistical power
  - 49 adults with MS randomized to vitamin D3 (up to 40,000 units/day) vs. unblinded control (vitamin D up to 4,000 units/day allowed) for 28 weeks
  - no significant differences in calcium-related measures
  - comparing high-dose vitamin D vs. control
    - mean annualized relapse rates at baseline 0.44 vs. 0.54
    - mean annualized relapse rates during trial 0.26 vs. 0.45 (not significant)
    - percent of patients with relapse 16% vs. 37% (not significant)
  - Reference - Neurology 2010 Jun 8;74(23):1852 full-text, editorial can be found in Neurology 2010 Jun 8;74(23):1846
- high-dose vitamin D3 does not appear to affect disability in patients with MS (level 2 [mid-level] evidence)
  - based on randomized trial with allocation concealment not stated
  - 62 patients aged 18-60 years with MS randomized to vitamin D3 300,000 units vs. placebo intramuscularly once monthly for 6 months
  - all patients received interferon beta-1a
  - 3 patients dropped out and not analyzed
  - no significant differences between groups in
    - changes in disability scores
    - number of gadolinium-enhancing lesions
  - Reference - Immunol Invest 2011;40(6):627
- high-dose vitamin D2 supplementation does not appear to improve imaging findings and may increase relapse rate in patients with relapsing-remitting multiple sclerosis (level 2 [mid-level] evidence)
  - based on small randomized trial
  - 23 adults with relapsing-remitting multiple sclerosis and relapse within prior 30 days to 2 years were randomized to high-dose vs. low-dose vitamin D2 for 6 months
    - high-dose vitamin D2 was 6,000 units twice daily, then adjusted to maintain serum 25-hydroxyvitamin D levels 130-175 nmol/L (52-70 ng/mL)
    - low-dose vitamin D2 was 1,000 units once daily, which was changed to vitamin D3 (1,000 units/day) by manufacturer, and adjusted to maintain serum 25-hydroxyvitamin D levels > 25 nmol/L (10 ng/mL)
  - comparing high-dose vs. low-dose vitamin D
    - median serum 25-hydroxyvitamin D levels 120 nmol/L (48 ng/mL) vs. 69 nmol/L (27.6 ng/mL) (p = 0.002)
    - cumulative number of new gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) 14 vs. 11 (not significant)
    - median change in total volume of T2 lesions on brain MRI -330 mm³ vs. -95 mm³ (not significant)
    - relapse in 4 patients (36.5%) vs. 0 patients (p = 0.04, NNH 2)
  - Reference - Neurology 2011 Oct 25;77(17):1611
- no additional trials of vitamin D in MS found in Cochrane review (Cochrane Database Syst Rev 2010 Dec 8;(12):CD008422)

see also Vitamin D intake and supplementation

8.3. Counseling

review information, support and social care needs regularly⁽⁶⁾
continue to offer information and support to people with MS or their family members or carers even if this has been declined previously⁽⁶⁾
telephone counseling may improve health outcomes in patients with MS (level 2 [mid-level] evidence)
- based on randomized trial without attention control
- 130 adults with MS randomized to telephone counseling vs. wait-list control
- telephone counseling included 1 single in-person motivational interview and 5 telephone counseling sessions focusing on exercise, fatigue management, communication and/or social support, anxiety and/or stress management, and reducing alcohol or other drug use
- counseling associated with greater improvement in
  - physical activity
  - spiritual growth
  - stress management
  - fatigue impact
  - mental health
- Reference - Arch Phys Med Rehabil 2008 Oct;89(10):1849
mindfulness-based intervention may improve quality of life in patients with MS (level 2 [mid-level] evidence)
- based on randomized trial without attention control
- 150 patients with MS randomized to mindfulness-based intervention vs. standard care for 8 weeks
- mindfulness-based intervention included
  - 2.5-hour classes once weekly plus one 7-hour session and daily homework
  - training based on nonjudgmental awareness of experiences and exercises including observation of sensory, affective, and cognitive domains of experiences
- mindfulness-based intervention associated with significant improvements in nonphysical dimensions of health-related quality of life, depression, and fatigue after treatment and at 6-month follow-up
- Reference - Neurology 2010 Sep 28;75(13):1141 full-text
interactive evidence-based patient information program may increase informed choice in patients with early MS (level 3 [lacking direct] evidence)
- based on nonclinical outcomes in randomized trial
- 192 patients aged 18-60 years with early relapsing-remitting MS or clinical isolated syndrome were randomized to 4-hour interactive evidence-based educational program vs. MS-specific stress management program (control) and followed for 12 months
- evidence-based program consisted of interactive 4-hour program presenting evidence on diagnostic testing, prognosis, and early MS disease-modifying drugs (DMDs), as well as a 57-page educational booklet
- informed choice defined as congruency between attitude about and use of disease modifying drugs combined with good risk knowledge
- informed choice assessed by Multi-Dimensional Measure of Informed Choice adapted to early MS
- comparing evidence-based patient information vs. control
  - informed choice at 6 months in 58.8% vs. 20.2% (p < 0.001, NNT 3)
  - good risk knowledge at 2 weeks in 65% vs. 26% (p < 0.05)
- no significant differences between groups or from baseline in
  - anxiety or depression at 6 months
  - attitude toward DMDs and DMD uptake at 12 months
- Reference - J Neurol Neurosurg Psychiatry 2014 Apr;85(4):411
information provision interventions have inconsistent evidence for effects on decision-making and quality of life in patients with MS
- based on Cochrane review
- systematic review of 10 randomized trials evaluating information provision interventions to promote informed choice and improve patient-relevant outcomes in 1,314 patients with MS
- heterogeneity in interventions and outcome measures precluded meta-analysis
- control group included usual care, standard information material, placebo, and interventions comparable in size to active intervention
- comparing information provision interventions to control, information provision interventions significantly improved
  - knowledge of MS in 4 of 4 trials
  - decision making in 1 of 4 trials
  - some measures of quality of life in 2 of 5 trials
- no adverse events in 6 trials reporting this outcome
- Reference - Cochrane Database Syst Rev 2014 Apr 21;(4):CD008757

8.4. Treatment of multiple sclerosis

for clinically isolated syndrome (neurologic presentation suggestive of multiple sclerosis [MS])
- interferon beta-1b reduces risk for developing clinically definite MS (level 1 [likely reliable] evidence)
- interferon beta-1a given either once weekly or 3 times weekly reduces progression to MS at 2 years in patients with first neurologic presentation (level 1 [likely reliable] evidence)
- glatiramer acetate might delay onset of clinically definite multiple sclerosis (MS) in patients with unifocal neurologic event and brain magnetic resonance imaging (MRI) lesions (level 2 [mid-level] evidence)
- IV immunoglobulin (IVIG) for first demyelinating event may prevent second event and may reduce incidence of patients meeting criteria for MS (level 2 [mid-level] evidence)
- teriflunomide 14 mg and 7 mg may each decrease conversion to clinically definite multiple sclerosis in patients with first suggestive clinical episode (level 2 [mid-level] evidence)
for acute relapse of MS
- glucocorticoids
  - consider glucocorticoids in any patient with acute attack of MS due to short-term benefit on speed of functional recovery (AAN Level A)
  - oral and IV corticosteroids associated with similar clinical and radiologic outcomes (level 2 [mid-level] evidence); dosing options include
    - oral methylprednisolone 500 mg/day for 5 days
    - IV methylprednisolone 1g/day for 3-5 days
- plasmapheresis should be considered for adjunctive treatment of exacerbations in relapsing multiple sclerosis (MS) (AAN Level B)
for progressive MS
- use of either interferon beta or glatiramer acetate not recommended for patients with progressive, nonrelapsing forms of multiple sclerosis
- interferon beta does not appear to reduce disease progression in patients with primary progressive MS, and treatment is associated with adverse effects (level 2 [mid-level] evidence)
- interferon beta may reduce relapse rate but not long-term disability progression in patients with secondary progressive MS (level 2 [mid-level] evidence)
- rituximab may delay disease progression in patients < 51 years old with primary progressive multiple sclerosis (MS) (level 2 [mid-level] evidence)
disease-modifying therapies for relapsing-remitting MS
- immunomodulatory drugs should be initiated at the time of diagnosis
- choice of appropriate therapy depends on various factors including patient tolerability, risk stratification, disease activity, and adverse effect profile of each medication
- interferon beta (interferon beta-1a or interferon beta-1b)
  - interferon beta demonstrated to reduce attack rate (AAN Level A) and may slow sustained disability progression (AAN Level B); not recommended by National Institute for Health and Care Excellence (NICE)
  - peginterferon beta1-a reduces relapse rate and progression of disability in patients with relapsing-remitting multiple sclerosis (level 1 [likely reliable] evidence)
  - interferon beta-1b for relapsing-remitting MS may be associated with reduced annual exacerbations and with lower mortality at 21 years (level 2 [mid-level] evidence)
- glatiramer acetate
  - may reduce risk of exacerbation for patients with relapsing-remitting MS (AAN Level A; level 2 [mid-level] evidence); not recommended by National Institute for Health and Care Excellence (NICE)
  - appears as effective as interferon beta, and associated with fewer flu-like symptoms and injection site reactions (level 2 [mid-level] evidence)
- IV immunoglobulin (IVIG) may prevent relapses in patients with relapsing-remitting MS (level 2 [mid-level] evidence)
- monoclonal antibodies are effective but associated with significant adverse events
  - alemtuzumab may be more effective than interferon beta-1a in patients with early, relapsing-remitting MS, but also associated with autoimmune adverse events (level 2 [mid-level] evidence)
  - daclizumab high-yield process (150 mg or 300 mg) reduces risk of relapse in adults with relapsing-remitting MS (level 1 [likely reliable] evidence)
  - natalizumab reduces relapse rate and progression of disability in patients with relapsing-remitting MS (level 1 [likely reliable] evidence), but use limited by association with progressive multifocal leukoencephalopathy
  - rituximab may reduce clinical relapses and magnetic resonance imaging (MRI) lesions in patients with MS (level 2 [mid-level] evidence)
- other immunomodulatory agents
  - fingolimod
    - fingolimod reduces relapse rate in relapsing-remitting MS (level 1 [likely reliable] evidence)
    - fingolimod reduces relapse rate compared to interferon beta-1a (level 1 [likely reliable] evidence)
  - laquinimod may reduce relapse rate and slow disability progression in patients with relapsing-remitting MS (level 2 [mid-level] evidence)
  - teriflunomide may decrease relapse in adults with MS, but might not reduce relapse in patients taking interferon beta (level 2 [mid-level] evidence)
  - dimethyl fumarate may decrease risk of relapse in patients with relapsing-remitting MS (level 2 [mid-level] evidence)
  - corticosteroids
    - intermittent long-term corticosteroids (high-dose methylprednisolone IV) might reduce risk of disability progression at 5 years in patients with relapsing-remitting multiple sclerosis (level 2 [mid-level] evidence)
    - addition of oral methylprednisolone for 3 consecutive days per month to interferon beta-1a may not delay disability progression in patients with relapsing-remitting MS (level 2 [mid-level] evidence)
- some disease-modifying antirheumatic drugs (DMARDs) and antineoplastic agents may have benefit for patients with MS
  - azathioprine may reduce relapse rate (AAN Level C) but no evidence on effect on disability progression (AAN Level U)
  - mitoxantrone
    - probably reduces attack rate in patients with relapsing MS (AAN Level B), though potential toxicity may outweigh clinical benefits in early stages of disease
    - may have beneficial effect on disease progression (AAN Level C)
  - methotrexate may favorably alter disease course in patients with progressive MS (AAN Level C)

see Disease-modifying therapies for multiple sclerosis for details

8.5. Treatment of specific impairments in multiple sclerosis

for specific impairments of multiple sclerosis, use coordinated multidisciplinary approach to care with a team of healthcare providers who have expertise in treating patients with multiple sclerosis (MS), including
- consultant neurologists
- MS nurses
- physical therapists and occupational therapists
- speech and language therapists
- psychologists
- dietitians
- social care and continence specialists
- primary care providers
for treatment of spasticity and muscle spasms
- limited evidence regarding efficacy of antispasticity agents in patients with MS, but consider
  - baclofen or gabapentin as first-line drug
  - tizanidine or dantrolene as second-line option
  - botulinum toxin may be beneficial for treatment of spasticity in adults (level 2 [mid-level] evidence)
  - cannabinoids
    - oral cannabis extract (OCE) may be offered to reduce patient-reported symptoms of spasticity and pain, except for neuropathic pain (AAN Level A)
    - tetrahydrocannabinol (THC) may be offered to reduce patient-reported symptoms of spasticity and pain, except for neuropathic pain (AAN Level B)
    - oromucosal cannabinoid spray (nabiximols) may be offered to reduce symptoms of spasticity or pain (AAN Level B)
- consider nonpharmacologic interventions that might improve spasticity in adults with MS, such as adjunctive physical therapy and intermittent theta burst stimulation (level 2 [mid-level] evidence)
for impaired mobility
- dalfampridine may improve walking speed in patients with MS (level 3 [lacking direct] evidence)
- exercise therapy may be beneficial for patients with MS not experiencing an exacerbation (level 2 [mid-level] evidence)
- multidisciplinary rehabilitation may improve levels of activity and participation in patients with MS (level 2 [mid-level] evidence)
- progressive resistance training of lower extremities may improve functional capacity in patients with MS (level 2 [mid-level] evidence)
for ataxia, tremor and impaired balance
- insufficient evidence to evaluate pharmacological and nonpharmacological therapy for ataxia or tremor in patients with MS (level 2 [mid-level] evidence)
- botulinum toxin type A associated with improvement in upper extremity tremor-related disability in patients with MS (level 2 [mid-level] evidence)
- physical therapy may be associated with clinical improvements in patients with cerebellar dysfunction due to MS (level 2 [mid-level] evidence)
for pain
- first-line treatments include pregabalin (EFNS Level A), amitriptyline (EFNS Level B), gabapentin (EFNS Level A), or duloxetine
- consider tramadol as second-line treatment (EFNS Level B), and preferably only if acute rescue therapy is needed
- use opioids as second- or third-line treatment if chronic treatment is not an issue (EFNS Level B)
- National Institute for Health and Care Excellence (NICE) also recommends consideration of capsaicin cream for patients with localized neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments
- consider cannabinoids if pain refractory to all other treatments (EFNS Level A)
  - cannabinoids appear effective for treatment of neuropathic and MS-related pain (level 2 [mid-level] evidence)
  - cannabis-derived oromucosal spray might improve MS-associated central neuropathic pain (level 2 [mid-level] evidence)
  - cannabis-derived oromucosal spray may improve central neuropathic pain in patients with MS, but associated with adverse effects (level 2 [mid-level] evidence)
- electro-acupuncture may improve pain and quality of life in patients with relapsing-remitting MS receiving immunomodulator therapy (level 2 [mid-level] evidence)
for fatigue
- pharmacologic interventions to consider include amantadine and aspirin (level 2 [mid-level] evidence)
- energy conservation management might reduce impact of fatigue and improve quality of life in short-term in patients with MS (level 2 [mid-level] evidence)
- exercise may improve fatigue in patients with MS (level 2 [mid-level] evidence)
- cognitive behavioral therapy may be more effective than relaxation therapy for reducing fatigue in patients with MS (level 2 [mid-level] evidence)
- group-based fatigue management program may reduce fatigue in patients with MS (level 2 [mid-level] evidence)
- pulsed electromagnetic therapy might improve fatigue in patients with MS (level 2 [mid-level] evidence)
for urinary symptoms
- limited evidence to evaluate efficacy of anticholinergics for treating urinary symptoms in patients with MS, but consider
  - antimuscarinic drugs (for example, oxybutynin, tolterodine) for symptoms of an overactive bladder (such as increased frequency, urgency, and incontinence)
  - bladder wall injection with botulinum toxin type A if antimuscarinic drugs ineffective or poorly tolerated
  - addition of cannabis-derived oromucosal spray to treatment regimen might improve urinary symptoms in patients with MS but not reduction in daily episodes of incontinence
  - individual bladder rehabilitation program may improve quality of life in patients with MS (level 2 [mid-level] evidence)
for sexual dysfunction, sildenafil citrate may be effective for erectile dysfunction with MS (level 2 [mid-level] evidence)
dextromethorphan/quinidine may reduce frequency and severity of pseudobulbar affect episodes in patients with MS (level 2 [mid-level] evidence)
for cognitive impairment
- cognitive training may improve some measures of memory function in patients with MS (level 2 [mid-level] evidence)
- ginkgo biloba does not improve memory performance in adults with MS (level 1 [likely reliable] evidence), and other pharmacological interventions such as donepezil, memantine, and rivastigmine may not be effective (level 2 [mid-level] evidence)
for depression or anxiety
- cognitive behavioral therapy may improve depression, adjustment, and coping in patients with MS (level 2 [mid-level] evidence)
- consider antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SSNRIs), or tricyclic antidepressants
- paroxetine might improve depression in patients with MS but may increase nausea and headache (level 2 [mid-level] evidence)
for oscillopsia, seizure, and other neurological symptoms
- National Institute for Clinical Excellence recommendations for oscillopsia
  - consider gabapentin as first-line treatment
  - consider memantine as second-line treatment
- no randomized trials identified to evaluate efficacy and safety of antiepileptic treatments in patients with multiple sclerosis and seizure

see Treatment of specific impairments in multiple sclerosis for details

8.6. Consultation and Referral

refer patients with possible diagnosis of MS to neurologist for further assessment, including
- patients with an episode of optic neuritis diagnosed by an ophthalmologist⁽⁶⁾
- patient with suspected MS who have magnetic resonance imaging (MRI) findings suggestive of MS (Ann Intern Med. 2014 Apr 1;160(7):ITC4-2-ITC4-18)
use coordinated multidisciplinary approach to care with a team of healthcare providers who have expertise in treating patients with MS, including⁽⁶⁾
- consultant neurologists
- MS nurses
- physical therapists and occupational therapists
- speech and language therapists
- psychologists
- dietitians
- social care and continence specialists
- general practitioners

8.7. Follow-up

monitor activity and progression
- assess for activity
  - relapsing MS - clinical assessment and brain imaging at least annually
  - progressive MS - clinical assessment annually, but no consensus on optimal frequency of imaging; annual spinal cord imaging not recommended unless there are spinal clinical findings
- assess for progression annually by history or objective measures of change
- Reference - Neurology 2014 Jul 15;83(3):278 full-text
National Institute for Health and Care Excellence (NICE) recommendations⁽⁶⁾
- advise patients with MS not to smoke and explain it may hasten disability progression
- complete comprehensive review of all aspects of care at least annually
  - review should include healthcare providers with expertise in MS and related complications
  - tailor review to patient's needs, including
    - MS symptoms - mobility and balance including falls, need for mobility aids including wheelchair assessment, use of arms and hands, muscle spasms and stiffness, tremor, bladder, sensory symptoms and pain, speech and swallowing, vision, cognitive symptoms, fatigue, depression, sleep, respiratory function
    - relapses in last year
    - general health - weight, smoking, alcohol and recreational drugs, exercise, access to routine health screening and contraception, care of other chronic conditions
    - social activity and participation
    - care and carers - personal care needs, social care needs, access to adaptations and equipment at home
- assess bone health on regular basis (following recommendations from NICE guideline on osteoporosis: assessing risk of fragility fracture [NICE 2012 Aug:CG146 PDF or at National Guideline Clearinghouse 2013 Feb 4:38410])
- if mobility severely reduced, assess
  - on regular basis and evaluate risk of contractures
  - areas at risk of pressure ulcers at every visit (following recommendations from NICE guideline on prevention and management of pressure ulcers [NICE 2014 Apr:CG179 PDF or at National Guideline Clearinghouse 2014 Sep 8:48026])
- discuss care provided by carers and care workers as part of care plan
- refer patients with MS to palliative care services for symptom control and for end of life care when appropriate
  - home-based palliative care services increase likelihood of dying at home in adults with advanced illness (level 1 [likely reliable] evidence)
    - based on Cochrane review
    - systematic review of 23 randomized or controlled clinical trials evaluating home-based palliative care services in 37,561 adults with advanced illness and 4,042 family caregivers
    - illnesses included advanced chronic obstructive pulmonary disease (COPD), heart failure, HIV, multiple sclerosis (MS), and multiple types of cancer
    - comparing home-based palliative care services to usual care, home-based palliative care services associated with
      - increased likelihood of dying at home in analysis of 7 studies with 1,222 patients
        
        odds ratio 2.21 (95% CI 1.31-3.71)
        
        NNT 3-15 with 34% dying at home in usual care group
      - reduced symptom burden for patients in 3 trials with 2,107 patients
    - Reference - Cochrane Database Syst Rev 2013 Jun 6;(6):CD007760 full-text
pregnancy issues⁽⁶⁾
- advise women with MS that
  - risk of relapse may decrease during pregnancy and transiently increase during 3-6 months post partum
  - pregnancy does not increase risk of progression of disease
- for patients with MS who are contemplating pregnancy, provide opportunity to discuss
  - fertility
  - risk of child developing MS
  - use of vitamin D before conception and during pregnancy
  - medication use in pregnancy
  - pain relief during delivery (including epidurals)
  - care of child
  - breastfeeding
vaccination
- National Institute for Health and Care Excellence (NICE) guideline recommendations⁽⁶⁾
  - live vaccinations may be contraindicated in patients with MS who are being treated with disease-modifying therapies
  - discuss possible benefits of flu vaccination and possible risk of relapse after flu vaccination if patient has relapsing-remitting MS
  - offer flu vaccinations to patients with MS in accordance with national guidelines
- influenza vaccination may be safe for patients with relapsing-remitting multiple sclerosis (MS) and may not be associated with increase in exacerbations or secondary progression (level 2 [mid-level] evidence)
  - based on randomized trial with allocation concealment not stated
  - 104 ambulatory patients with definite relapsing-remitting MS were randomized to influenza vaccine (49 patients) vs. placebo (55 patients) and followed for 6 months
  - overall MS exacerbation rate in sample (0.22-0.45/year) lower than expected from national data (0.6-1.3/year)
  - comparing influenza vaccine vs. placebo
    - mean time to relapse 91 days vs. 55 days
    - influenza in 7 patients vs. 3 patients (not significant)
  - no significant difference in attack rate (episodes within 28 days) or disease progression
  - Reference - Neurology 1997 Feb;48(2):312
- fingolimod may reduce vaccine-induced immunogenic response in adults with relapsing MS (level 3 [lacking direct] evidence)
  - based on nonclinical outcome from randomized trial
  - 138 adults aged 18-55 years with relapsing multiple sclerosis (MS) randomized to fingolimod 0.5 mg orally once daily vs. placebo for 12 weeks
  - all patients received seasonal influenza vaccine plus tetanus toxoid booster dose at 6 weeks
  - responder rate defined as seroconversion or ≥ 4-fold increase in antibody titer from prevaccinaton to postvaccination against tetanus toxoid or for ≥ 1 influenza virus strains contained in the influenza vaccine
  - comparing fingolimod vs. placebo, responder rate for
    - tetanus toxoid booster dose
      - at 3 weeks 40% vs. 61% (p < 0.05)
      - at 6 weeks 38% vs. 49% (not significant)
    - influenza vaccine
      - at 3 weeks 54% vs. 85% (p < 0.05)
      - at 6 weeks 43% vs. 75% (p < 0.05)
  - Reference - Neurology 2015 Mar 3;84(9):872

9. Complications and Prognosis

9.1. Complications

9.1.1. Psychiatric complications

compared to general population, patients with MS have
- elevated lifetime prevalence rates of
  - major depressive disorder
  - bipolar disorder
  - anxiety disorders
  - adjustment disorders
  - psychotic disorders
- increased risk of suicide (may be at least twice as common)
- increased prevalence of pseudobulbar affect
- Reference - American Academy of Neurology (AAN) evidence-based guideline on assessment and management of psychiatric disorders in individuals with MS (Neurology 2014 Jan 14;82(2):174 full-text)
MS associated with increased risk of major depression
- based on cohort study
- 115,071 persons aged ≥ 18 years old were followed for 1 year
- 322 persons had MS and 9,019 persons had major depression
- prevalence of major depression in persons with MS
  - 25.7% in persons aged 18-45 years
  - 8.4% in persons > 45 years old
- compared to persons without MS, persons with MS had increased risk for major depression (adjusted odds ratio 2.3, 95% CI 1.6- 3.3)
- Reference - Neurology 2003 Dec 9;61(11):1524
advanced severity of MS associated with increased risk of clinically significant depressive symptoms (level 2 [mid-level] evidence)
- based on cohort study
- 739 patients with MS surveyed for depressive symptoms and severity, duration, and course of multiple sclerosis
- 41.8% of patients had clinically significant depressive symptoms, and 29% had moderate to severe depression
- clinically significant depressive symptoms associated with
  - advanced severity of MS (odds ratio [OR] 6.04, 95% CI 3.29 -11.08)
  - intermediate severity of MS (OR 3.1, 95% CI 1.95 - 5.17)
  - shorter duration of MS (10 years less than mean duration) (OR 1.36, 95% CI 1.07 -1.73)
- no association found between clinically significant depressive symptoms and pattern of illness progression
- Reference - Am J Psychiatry 2002 Nov;159(11):1862
suicidal intent may be common in patients with MS
- based on cohort study
- 28.6% of community sample of 140 patients with MS reported suicidal intent at some point in their life
- strongest risk factors for suicidal intent were severity of major depression, alcohol abuse, and living alone
- Reference - Neurology 2002 Sep 10;59(5):674
pseudobulbar affect
- characterized by frequent and involuntary episodes of crying, laughing, or both that are unrelated or disproportionate to situation and to patient's mood at time of episode (Drugs 2011 Jun 18;71(9):1193)
- also known as emotional lability, emotionalism, and emotional incontinence (Drugs 2011 Jun 18;71(9):1193)
- case series of 4 patients with MS reported to have pathologic laughing and intractable hiccups can be found in Neurology 2006 Nov 14;67(9):1684

9.1.2. Cognitive impairment

relapse of MS may have short-term effects on cognitive function⁽⁶⁾
childhood and juvenile cases of MS associated with cognitive impairment
- based on cohort study
- 63 children or juvenile patients (mean age 15.3 years) with MS were matched to 57 healthy controls and had neuropsychological testing
- 2 patients had incomplete neuropsychological assessment due to poor compliance
- comparing 61 patients with MS vs. 57 controls
  - mean total intelligence quotient (IQ) 101.3 vs. 120.5 (p < 0.001)
  - IQ ≥ 90 in 65.5% vs. 96.5% (p < 0.001)
  - IQ < 70 in 5 patients (8%) vs. 0 patients (p < 0.001)
- cognitive impairment defined as failure on ≥ 3 tests observed in 19 patients (31%) with MS
- among patients with MS, IQ < 90 predicted cognitive impairment (odds ratio 18.2, 95% CI 4.6-71.7)
- Reference - Neurology 2008 May 13;70(20):1891, commentary can be found in Neurology 2009 Mar 31;72(13):1189
increased lesion volume in frontal and parietal white matter associated with worse cognitive performance in patients with MS
- based on cohort study
- 28 patients with MS were followed for 4-years
- increased lesion volume in frontal and parietal white matter associated with worse performance on tasks requiring sustained complex attention and working verbal memory (p < 0.001)
- Reference - Arch Neurol 2001 Jan;58(1):115 full-text

9.1.3. Seizures

3%-4% of patients with MS may experience seizures
- based on systematic review
- rate of epilepsy in 6 population-based studies with 1,843 patients with MS
  - 3.8% overall
  - 3.2% after excluding patients who had epilepsy before diagnosis of MS
- mean 4.11% prevalence of seizures in 7 hospital-based studies with 4,425 patients with MS
- types of seizures found in MS patients include
  - partial seizures, including
    - complex seizures
    - epilepsia partialis continua
  - generalized seizures
- no randomized trials identified evaluating treatment of seizures in patients with MS
- Reference - CNS Drugs 2009 Oct;23(10):805 full-text
0.89% of patients with MS may experience seizures
- based on retrospective cohort study
- data from 5,715 patients with MS at Mayo Clinic in Rochester, Minnesota, United States 1990-1998 was analyzed
- 51 patients (0.89%) had seizure activity including
  - generalized tonic-clonic seizure in 35 patients
  - simple or complex partial seizure in 11 patients
- 18 patients (35% of patients with seizures) had only 1 seizure episode
- Reference - Mayo Clin Proc 2001 Oct;76(10):983
review of seizures in multiple sclerosis can be found in Epilepsia 2008 Jun;49(6):948

9.1.4. Other complications

increased risk of infection⁽³⁾
sexual dysfunction⁽⁶⁾
pressure ulcers ⁽⁶⁾
paroxysmal hypothermia due to demyelination in pre-optic area of brain reported in case report of patient with MS (Neurology 2009 Jan 13;72(2):193)

9.2. Prognosis

9.2.1. Clinically isolated syndromes (CIS)

80% of patients who are ultimately diagnosed with multiple sclerosis present with a CIS initially⁽³⁾
- if magnetic resonance imaging (MRI) shows white matter abnormalities at clinically unaffected sites, chance of subsequent demyelination (and diagnosis of relapsing-remitting MS) is 50% at 2 years and 82% at 20 years
- rate of new episodes rarely exceeds 1.5 per year
some patients previously diagnosed with CIS may now be diagnosed as having MS at time of first presentation with appropriate lesions on magnetic resonance imaging (Ann Neurol 2011 Feb;69(2):292 full-text)
presence of antimyelin antibodies initially reported to be able to predict risk of conversion to clinically definite MS (CDMS) after first demyelinating event, but subsequent studies have failed to find an association
- based on 4 prognostic cohort studies
- study suggesting antimyelin antibodies predict risk of conversion to CDMS
  - antimyelin antibodies may predict early conversion to CDMS in patients with first demyelinating event
    - based on cohort study
    - 103 patients with first isolated acute neurologic event, typical disseminated white matter lesions on cerebral MRI, and cerebrospinal fluid analysis showing oligoclonal bands were tested at baseline for serum antibodies anti-MOG and anti-MBP and followed for mean 51 months (range 12-96 months)
    - neurologic exam for conversion to CDMS conducted every 3 months
    - 39 patients were seronegative to both antibodies, 9 seronegative patients (23%) had relapse at mean 45 months
    - 22 patients were seropositive to both antibodies, of whom 21 (95%) had relapse at mean 7.5 months
    - 42 patients were seropositive to only anti-MOG, of whom 35 (83%) had relapse at mean 14.6 months
    - Reference - N Engl J Med 2003 Jul 10;349(2):139, commentary can be found in N Engl J Med 2003 Dec 4;349(23):2269, Am Fam Physician 2004 Feb 1;69(3):666
- studies failing to find any association of antimyelin antibodies with risk of conversion to CDMS
  - serum antibodies against myelin oligodendrocyte glycoprotein (anti-MOG) and myelin basic protein (anti-MBP) not associated with progression to CDMS or diagnosis of MS
    - based on cohort study
    - 462 patients with first clinical event suggestive of MS and at least 2 clinically silent lesions on brain MRI were followed for 2 years and evaluated
    - no significant associations in overall analysis or subgroup analyses
    - Reference - N Engl J Med 2007 Jan 25;356(4):371, commentary can be found in N Engl J Med 2007 May 3;356(18):1888
  - serum anti-MOG and anti-MBP not significantly associated with rate of conversion to CDMS or time to conversion
    - based on cohort study
    - 114 patients with CIS evaluated and followed for mean 46.7 months
    - no significant association found between antibodies and rate of conversion to CDMS
    - Reference - N Engl J Med 2007 Jan 25;356(4):426 full-text
- antimyelin antibodies may predict earlier time to relapse but not CDMS
  - based on retrospective cohort study
  - 45 patients aged 16-55 years with first demyelinating event, intrathecal immunoglobulin G (IgG) and no other explanation for neurological symptoms evaluated and followed for mean 60.4 months (range 21-106 months)
  - no significant differences found comparing sera from 45 patients vs. 56 controls aged 21-25 years without neurological disease
    - 23 (51%) vs. 12 (21%) had anti-MOG IgM
    - 23 (51%) vs. 15 (27%) had anti-MBP IgM
    - 15 (33%) vs. 3 (5%) had both anti-MOG IgM and anti-MBP IgM
  - among 45 patients stratified by antibody status
    - no significant differences in relapse rates (53% to 75%)
    - no significant differences in rates of CDMS
    - time to relapse was shortest (median 5.5 months) in patients with both antibodies and longest (median 25 months) in patients with neither antibody (p < 0.006)
  - Reference - J Neurol Neurosurg Psychiatry 2006 Jun;77(6):739 full-text
MRI findings
- increase in lesion volume on brain MRI during first 5 years of follow-up associated with degree of long-term disability in patients with CIS
  - based on prognostic cohort study
  - 71 patients initially presenting with isolated syndromes suggestive of MS were followed for mean 14 years
  - clinically definite multiple sclerosis developed in 88% of 50 patients with abnormal results on initial MRI vs. 19% of 21 patients with normal initial MRI
  - disability score at 14 years moderately correlated with
    - lesion volume on MRI at 5 years
    - increase in lesion volume over first 5 years
  - Reference - N Engl J Med 2002 Jan 17;346(3):158 full-text, editorial can be found in N Engl J Med 2002 Jan 17;346(3):199
- spinal cord lesions on MRI associated with increased risk of conversion to clinically definite MS in patients with nonspinal clinically isolated syndrome
  - based on prospective cohort study
  - 121 patients with clinically isolated syndrome (CIS) and spinal cord or brain symptoms were assessed with MRI of brain and spinal cord for diagnosis of MS using 2010 revisions to McDonald criteria
  - at baseline, 52% had symptoms attributable to spinal cord and 48% had symptoms attributable to brain
  - clinically definite MS defined as second episode of new symptoms occurring after ≥ 1 month not attributable to other disease
  - 45.5% converted to clinically definite MS during median 64 months follow-up
  - compared to no spinal cord lesion, presence of spinal cord lesion associated with increased risk of conversion to clinically definite MS
    - in overall analysis (odds ratio [OR] 3.53, 95% CI 1.52-8.17)
    - in patients with nonspinal CIS (OR 6.48, 95% CI 2.34-17.95)
    - in patients with nonspinal CIS who did not fulfill McDonald brain MRI criteria (OR 14.4, 95% CI 2.6-80)
  - no significant association between spinal cord lesions and conversion to clinically definite MS in subgroup analysis of patients with spinal CIS
  - Reference - Neurology 2013 Jan 1;80(1):69
- corpus callosum lesion at presentation of CIS associated with increased risk of conversion to MS
  - based on prognostic cohort study
  - 158 patients with CIS who had MRI were followed for median 39 months
  - compared with absence of lesion, corpus callosum lesion associated with increased risk of conversion to MS after CIS (hazard ratio 2.7, 95% CI 1.6-4.5)
  - Reference - Neurology 2009 Dec 1;73(22):1837

in children with clinically isolated syndrome, monofocal presentation associated with increased risk of progression to MS at 4.5 years compared to polyfocal presentation
- based on cohort study
- 117 children < 16 years old with clinically isolated syndrome (CIS) in Netherlands were followed for mean 54 months (range 5-201 months)
  - 54 children (46%) had monofocal CIS presentation
  - 63 children (54%) had polyfocal CIS presentation
- second MS defining attack occurred in 43% with monofocal presentation vs. 21% with polyfocal presentation (p < 0.006)
- mean time to conversion to MS with monofocal presentation 17.7 months (range 2-75 months) vs. 24.7 months (range 2-79 months) with polyfocal presentation (no p value reported)
- Reference - Neurology 2008 Sep 23;71(13):967

9.2.2. Risk of relapse

9.2.3. Factors associated with increased risk of relapse

stressful life events associated with increased risk of exacerbations of MS
- based on systematic review
- systematic review of 14 observational studies (7 cohort studies with 567 persons and 7 case-control studies with 849 persons) evaluating association between stressful life events and exacerbations of multiple sclerosis
- 2 studies evaluated first exacerbations (leading to diagnosis of MS), and 12 studies evaluated exacerbations after diagnosis of MS
- stressful life events associated with increased risk of MS-related exacerbations (p < 0.0001)
- Reference - BMJ 2004 Mar 27;328(7442):731 full-text
human herpes virus-6 (HHV-6) active infection may increase risk of relapse in patients with relapsing-remitting MS
- based on 2 observational studies
- increasing anti-HHV-6 immunoglobulin G (IgG) titers associated with increasing risk of relapse in patients with relapsing-remitting MS
  - based on prospective cohort study
  - 145 patients with relapsing-remitting multiple sclerosis were followed for mean 45 months
  - increasing anti-HHV-6 immunoglobulin G (IgG) titers associated with increasing risk of relapse (p = 0.003 for trend)
  - Reference - Mult Scler 2012 Jun;18(6):799
- HHV-6 active infection may increase risk of exacerbations in patients with relapsing-remitting MS
  - based on case-control study
  - 105 patients with relapsing-remitting MS and 49 healthy blood donors were evaluated
  - 32 patients (31%) with relapsing-remitting MS were experiencing disease relapse
  - active HHV-6 infection identified in 17 patients (16%) with MS vs. none of controls (p = 0.003)
  - in patients with relapsing-remitting MS with HHV-6 active replication, viral load was higher during acute attack than during remission (p = 0.04)
  - Reference - Arch Neurol 2004 Oct;61(10):1523
varicella-zoster virus infection might increase risk of acute relapse in patients with multiple sclerosis
- based on case control study
- 15 patients with MS in acute relapse, 67 patients with MS in remission, and 120 controls were evaluated
- varicella-zoster virus (VZV) DNA identified in
  - 13 of 15 patients (87%) with MS in acute relapse
  - none of 67 patients with MS in remission
  - none of 120 controls
- Reference - Arch Neurol 2004 Apr;61(4):529
shorter disease duration and increased number of prior relapses associated with increased risk of relapse in patients with MS
- based on subset analysis of clinical trials
- 727 patients in placebo arms of MS clinical trials evaluated
- increased risk of relapse associated with
  - shorter disease duration (p = 0.015)
  - increased number of previous relapses (p ≤ 0.003 comparing 1, 2, or ≥ 3 relapses to no relapses over last 24 months)
- gadolinium enhancement status on magnetic resonance imaging (MRI) did not have additional predictive ability in subset of 306 patients
- Reference - Neurology 2005 Dec 13;65(11):1769

9.2.4. Factors associated with decreased risk of relapse

increased serum vitamin D levels associated with decreased relapse rate in pediatric-onset MS
- based on retrospective cohort study
- 110 patients with pediatric-onset MS evaluated
- every 10 ng/mL increase of adjusted serum 24-hydroxyvitamin D(3) levels associated with 34% decrease in relapse rate (incidence rate ratio 0.66, 95% CI 0.46-0.95)
- Reference - Ann Neurol 2010 May;67(5):618

higher serum vitamin D level associated with decreased risk of exacerbations of MS
- based on prospective cohort study
- 73 patients with relapsing-remitting MS followed for mean 7.1 years
- patients classified by serum vitamin D levels as low (< 50 nmol/L), medium (50-100 nmol/L), and high (> 100 nmol/L) and assessed for exacerbations
- 79% of patients had ≥ 1 exacerbation
- compared to patients with low vitamin D level, patients with medium and high vitamin D levels associated with decreased risk of exacerbations (p = 0.007 for trend)
- each doubling of serum vitamin D level associated with 27% decrease in risk of exacerbations (p = 0.008)
- Reference - Neurology 2012 Jul 17;79(3):261

9.2.5. Factors not associated with risk of relapse

vaccination does not appear to increase short-term risk for relapse in patients with MS
- based on cohort study with crossover design
- 643 patients were interviewed from population of 1,176 patients who had relapse of MS
- relapse defined as worsening of neurologic dysfunction lasting > 24 hours (excluding fatigue alone or fever-related symptoms)
- comparisons were based on case-crossover design comparing 2 months prior to relapse and the 4 preceding 2-month periods used as control periods
- similar analyses also done using 1-month and 3-month periods
- 135 patients had confirmed vaccination in 12 months preceding the index relapse
- only statistically significant difference between case and control periods was for combined tetanus vaccination and this suggested a protective effect
- Reference - N Engl J Med 2001 Feb 1;344(5):319, editorial can be found in N Engl J Med 2001 Feb 1;344(5):372

9.2.6. Conversion from relapsing-remitting MS to progressive MS

natural history of disease variable with different types of MS
- based on observational study
- 254 patients with definite MS followed prospectively for 1-5 years (mean 2.6 years)
- none of patients received immunosuppressive medication
- 30% progressive cases become stable
- 32% stable cases become progressive
- of relapsing cases, 20% become stable and 20% become chronic
- Reference - Arch Neurol 1989 Oct;46(10):1107
conversion from relapsing-remitting pattern to secondary progressive pattern may occur in about 2.5% of patients with MS/year
- based on cohort of 1,844 patients with definite or probable MS
- 1,562 patients had relapsing-remitting course initially
- 496 (32%) developed secondary progressive course
- conversion from initial relapsing-remitting phase to secondary progression occurs at estimated rate of 2.5% of patients/year
- Reference - Brain 2006 Mar;129(Pt 3):595 full-text, editorial can be found in Brain 2006 Mar;129(Pt 3):561, commentary can be found in Brain 2006 Dec;129(Pt 12):e56
current smoking may accelerate conversion from relapsing-remitting to progressive MS (level 2 [mid-level] evidence)
- based on cohort study
- 1,465 patients (mean age at baseline 42 years) with clinically definite MS (mean disease duration 9.4 years) followed for mean 3.29 years
  - 780 patients were never-smokers
  - 428 patients ex-smokers
  - 257 patients were current smokers
- compared to never-smokers, current smokers had accelerated progression to secondary progressive disease (HR 2.5, 95% CI 1.42-4.41)
- Reference - Arch Neurol 2009 Jul;66(7):858 full-text
patients without progression and no or limited disability after 10 years may still have significant risk for progression of MS
- based on cohort study
- 200 patients with Expanded Disability Status Scale (EDSS) score ≤ 3 at 10 years from onset of MS evaluated
- 45 of 196 patients (23%) converted to secondary progressive MS with relapsing-remitting course
- 169 (84.5%) followed up at 20 years
  - 88 (52%) continued to have no or limited disability (EDSS ≤ 3)
  - 36 (21%) progressed to needing a cane or worse (EDSS ≥ 6)
- Reference - Neurology 2007 Feb 13;68(7):496

9.2.7. Disability

male sex and younger age at disease onset each associated with early development of irreversible disability in patients with MS
- based on cohort study
- 1,844 patients with definite or probable MS were evaluated, including 1,562 patients with exacerbating-remitting initial course and 282 patients with progressive initial course
- disability defined using Kurtzke Disability Status Scale (DSS)
  - DSS 4 - limited walking without aid or rest for > 500 meters
  - DSS 6 - walking with unilateral aid without rest for no greater than 100 meters
  - DSS 7 - walking without rest for no greater than 10 meters, while leaning against a wall or holding onto furniture for support
- irreversible disability defined as reaching specific DSS level without improvements for at least 6 months
  - 56% patients had irreversible disability DSS 4 or worse at median age 44.3 years (44% did not reach endpoint)
  - 32% patients had irreversible disability DSS 6 or worse at median age 54.7 years (68% did not reach endpoint)
  - 21% patients had irreversible disability DSS 7 or worse at median age 63.1 years (79% did not reach endpoint)
- in multivariate analyses
  - male sex and younger age at disease onset were each associated with younger age at assignment of irreversible disability levels (p ≤ 0.01 for all levels of disability)
  - initial progressive course associated with associated with younger age at assignment of irreversible disability levels (p < 0.001 for all levels of disability)
- Reference - Brain 2006 Mar;129(Pt 3):595 full-text, editorial can be found in Brain 2006 Mar;129(Pt 3):561, commentary can be found in Brain 2006 Dec;129(Pt 12):e56
potential predictors of long-term physical disability include sphincter symptoms at onset, incomplete recovery from first attack, and short interval between first and second attack
- based on systematic review limited by clinical heterogeneity
- systematic review of 27 inception cohort studies with at least 40 patients with relapsing-remitting MS who were followed for at least 5 years
- meta-analysis not done due to heterogeneity of study designs
- poor prognosis associated with
  - bladder and/or bowel involvement at onset (hazard ratio [HR] 1.5-3.1)
  - incomplete recovery from first attack in 5 studies (HR 1.3-3.3)
  - shorter interval between first and second attack (HR 1.6-1.9)
- no clear association (either weak or inconsistent effect) found between prognosis, and gender and age at onset
- Reference - Arch Neurol 2006 Dec;63(12):1686, commentary can be found in Arch Neurol 2007 Sep;64(9):1359
in patients who develop MS after presentation with optic neuritis, mild disability common in first 10 years
- based on cohort study
- 127 patients in Optic Neuritis Treatment Trial who had first episode of optic neuritis, were followed for 10-12 years, and developed clinically definite MS were evaluated
- most patients had mild disability (65% had Expanded Disability Status Scale score < 3)
- degree of disability unrelated to presence of baseline MRI lesions
- 2 patients died from severe MS
- Reference - Arch Neurol 2004 Sep;61(9):1386, commentary can be found in Arch Neurol 2005 Mar;62(3):506

full recovery at 12 months in all children < 16 years old with acquired demyelinating syndrome who developed MS
- based on national cohort study
- 283 children < 16 years old with incident acquired demyelinating syndrome of the central nervous system (transverse myelitis, optic neuritis, or acute disseminated encephalomyelitis) evaluated for extent of recovery within 12 months and annually for up to 10 years
- among 59 children (21%) diagnosed with multiple sclerosis, all recovered full mobility, normal vision, and normal bowel and bladder control following incident attack (57 children recovered fully by 3 months, and all had normal neurologic exam by 12 months)
- Reference - Pediatrics 2015 Jul;136(1):e115

rate of progression in patients with progressive MS
- superimposed relapses may not accelerate progression of disability among patients with progressive MS
  - based on retrospective cohort study
  - 1,844 patients with definite or probable MS in a neurology referral center starting in 1976 were followed for mean duration of 11 years
  - 1,562 patients (85%) had relapsing-remitting onset
    - median time to limited walking ability was 11.4 years
    - median time to moderate limitation (ability to walk with unilateral support no more than 100 meters without rest) was 23.1 years
    - median time to severe limitation (ability to walk no more than 10 meters without rest while holding onto something for support) was 33.1 years
    - 496 (32%) of these patients developed secondary progressive type of MS
      - 197 patients (40%) in this subset had superimposed relapses
      - compared to no superimposed relapses, relapses associated with significantly longer time to reach severe limitation of walking ability
  - 282 (15%) had primary progressive onset
    - most of these patients had slight limitation on walking ability at onset
    - median time to moderate limitation was 7.1 years
    - median time to severe limitation was 13.4 years
    - 109 patients (39%) had superimposed relapses; relapses not associated with time course of irreversible disease progression
  - Reference - N Engl J Med 2000 Nov 16;343(20):1430 full-text, editorial can be found in N Engl J Med 2000 Nov 16;343(20):1486
- rate of progression of primary progressive MS variable
  - based on cohort study
  - 352 patients with primary progressive MS were evaluated
  - mean disease duration was 17.2 years and mean age at onset was 40 years
  - progression of disability to cane requirement occurred for
    - 25% at 7.3 years from onset
    - 75% at 25 years from onset
  - shorter time to cane requirement predicted shorter time to wheelchair requirement
  - sex, onset age, and onset symptoms did not predict rate of progression
  - Reference - Neurology 2005 Dec 27;65(12):1919
cognitive dysfunction common in patients with MS followed for 10 years
- based on cohort study
- 45 patients with MS and 65 matched healthy controls had neuropsychological tests at baseline, 4 years, and 10 years
- 8 patients with MS (18%) had cognitive dysfunction at baseline
- 25 patients with MS (56%) had cognitive dysfunction at 10 years
- degree of cognitive decline associated with
  - degree of physical disability (p = 0.001)
  - progressive disease course (p = 0.01)
  - increasing age (p = 0.01)
- Reference - Arch Neurol 2001 Oct;58(10):1602 full-text

9.2.8. Quality of life

patients with MS may have similar social functioning- and mental health-related quality of life as general population (level 2 [mid-level] evidence)
- based on cohort study
- 201 patients with definite MS in Olmsted County, Minnesota were analyzed
- 185 patients (92%) completed MS Quality of Life Health Survey
- 77% were mostly satisfied or delighted with their quality of life
- compared to general United States population, quality of life scores in patients with MS were
  - similar for social functioning, role emotional, mental health, and pain
  - worse for physical functioning, vitality, and general health
- Reference - Arch Neurol 2004 May;61(5):679, commentary can be found in Am Fam Physician 2004 Sep 1;70(5):935
pain is common in early stages of MS and is associated with decreased quality of life (level 2 [mid-level] evidence)
- based on cohort study
- 69 patients diagnosed with MS in past 6 months were evaluated and followed for 2 years
- clinically significant pain reported in
  - 63.2% at baseline
  - 51.5% at 1 year follow-up
  - 45.6% at 2 year follow-up
- pain significantly associated with low overall quality of life and depressive symptoms
- 44% of patients reported pain resulting in significant alteration of daily activities
- Reference - Clin J Pain 2009 Mar-Apr;25(3):211
parental MS associated with negative psychosocial impact on children and adolescents (level 2 [mid-level] evidence)
- based on systematic review limited by heterogeneity
- 20 studies evaluating psychosocial impact of parental MS on children and adolescents were reviewed
- no quantitative assessment of studies performed or reported
- qualitative analysis reported overall good evidence regarding association between presence of parental MS and negative psychosocial impact on children and adolescents
- Reference - Clin Rehabil 2010 Sep;24(9):789

9.2.9. Pregnancy and postpartum considerations for patients with MS

patients with MS may have increased risk of antenatal hospitalization, intrauterine growth restriction, and cesarean delivery (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 18.8 million deliveries from 2003 to 2006 Nationwide Inpatient Sample from Healthcare Cost and Utilization Project were reviewed
- 10,055 deliveries in women with MS evaluated
- compared to patients without MS, patients with MS had increased risk of
  - antenatal hospitalization (odds ratio [OR] 1.3, 95% CI 1.2-1.5)
  - intrauterine growth restriction (OR 1.7, 95% CI 1.2-2.4)
  - cesarean delivery (OR 1.3, 95% CI 1.1-1.4)
- no significant increase observed in pre-eclampsia or premature rupture of membranes
- Reference - Neurology 2009 Dec 1;73(22):1831, editorial can be found in Neurology 2009 Dec 1;73(22):1820
MS relapse rate appears to decrease during pregnancy but may increase during postpartum period
- based on cohort study
- 254 women with MS followed during 269 pregnancies for up to 12 months after delivery
- compared with mean rate of relapse prior to pregnancy (0.7 per woman/year), mean rate of relapse
  - decreased during first trimester (0.5 per woman/year, p = 0.03)
  - decreased during third trimester (0.2 per woman/year, p < 0.001)
  - increased during first 3 months post partum (1.2 per woman/year, p < 0.001)
- no significant difference in mean rate of relapse during second trimester compared with mean rate of relapse prior to pregnancy
- Reference - N Engl J Med 1998 Jul 30;339(5):285
exclusive breastfeeding may reduce risk of postpartum relapse in women with MS (level 2 [mid-level] evidence)
- based on cohort study
- 32 pregnant women with MS and 29 controls had structured interviews during each trimester and 2, 4, 6, 9, and 12 months post partum
- 52% of women with MS did not breastfeed or began regular supplemental feedings within 2 months (primary reason was to resume MS therapies in 60%)
- among women with MS, postpartum relapse in 87% of women who did not breastfeed or began regular supplemental feedings within 2 months vs. 36% of women who breastfed exclusively for ≥ 2 months post partum (adjusted hazard ratio 7.1, 95% CI 2.1-2.43)
- lactational amenorrhea associated with reduced risk of postpartum relapses (p = 0.01)
- Reference - Arch Neurol 2009 Aug;66(8):958
immediate postpartum period may be associated with increased incidence of MS
- based on case-control study
- 106 women with MS and 1,001 matched controls were evaluated
- compared to no pregnancy
  - 6-month period following pregnancy associated with increased risk of MS (OR 2.9, 95% CI 1.2-6.6)
  - both pregnancy and > 6 months from time of pregnancy not associated with increased risk of MS
- Reference - Arch Neurol 2005 Sep;62(9):1362

9.2.10. Pediatric-onset multiple sclerosis

childhood-onset MS more likely to have initial relapsing-remitting course than adult onset
- based on cohort study
- 394 patients with MS and disease onset at ≤ 16 years old (childhood onset) were compared to 1,775 patients with MS and disease onset at > 16 years old
- 110 (29%) of childhood-onset MS patients converted to secondary progression
- median time to secondary progression 28 years
- median age at secondary progression 41 years
- comparing childhood onset vs. adult onset MS
  - female:male ratio 2.8:1.8 (p < 0.001)
  - relapsing-remitting initial course in 98% vs. 84% (p < 0.001)
- in patients with childhood onset MS, estimated median times to reach secondary progression and irreversible disability were about 10 years longer than patients with adult onset MS but these points were reached at an age about 10 years younger (p < 0.001 for each)
- Reference - N Engl J Med 2007 Jun 21;356(25):2603 full-text

in children with clinically isolated syndrome, monofocal presentation associated with increased risk of progression to MS at 4.5 years compared to polyfocal presentation
- based on cohort study
- 117 children < 16 years old with clinically isolated syndrome (CIS) in Netherlands were followed for mean 54 months (range 5-201 months)
  - 54 children (46%) had monofocal CIS presentation
  - 63 children (54%) had polyfocal CIS presentation
- second MS defining attack occurred in 43% with monofocal presentation vs. 21% with polyfocal presentation (p < 0.006)
- mean time to conversion to MS with monofocal presentation 17.7 months (range 2-75 months) vs. 24.7 months (range 2-79 months) with polyfocal presentation (no p value reported)
- Reference - Neurology 2008 Sep 23;71(13):967

≥ 3 Barkhof criteria on magnetic resonance imaging associated with earlier conversion to MS in children
- based on cohort study
- 117 children < 16 years old with monofocal or polyfocal CIS presentation were evaluated with MRI and followed for mean 54 months (range 5-201 months)
- Barkhof criteria include
  - ≥ 9 T2 lesions
  - ≥ 1 infratentorial lesion
  - ≥ 1 juxtacortical lesion
  - ≥ 3 periventricular lesions
- compared with 0-2 Barkhof criteria, ≥ 3 Barkhof criteria associated with shorter time to second attack (mean 45 months vs. 123 months, p < 0.0001)
- Reference - Neurology 2008 Sep 23;71(13):967, editorial can be found in Neurology 2008 Sep 23;71(13):962
relapse may be more common in pediatric-onset MS than adult-onset MS
- based on cohort study
- 21 patients with pediatric-onset MS and 110 patients with adult-onset MS were followed for 3.7-4 years
- annualized relapse rate 1.13 for pediatric-onset MS vs. 0.4 for adult-onset MS (adjusted rate ratio 2.81, 95% CI 2.07 vs.3.81)
- Reference - Arch Neurol 2009 Jan;66(1):54

increased serum vitamin D levels associated with decreased relapse rate in pediatric-onset MS
- based on retrospective cohort study
- 110 patients with pediatric-onset MS evaluated
- every 10 ng/mL increase of adjusted serum 24-hydroxyvitamin D(3) levels associated with 34% decrease in relapse rate (incidence rate ratio 0.66, 95% CI 0.46-0.95)
- Reference - Ann Neurol 2010 May;67(5):618

İxtisaslara görə kateqoriyalar

Multiple sclerosis (MS)

1. Overview and Recommendations

1.1. Background

1.2. Evaluation

1.3. Management

2. Related Summaries

3. General Information

3.1. Description

3.2. Definitions

3.3. Types

4. Epidemiology

4.1. Who is most affected

4.2. Incidence/Prevalence

4.3. Likely risk factors

4.3.1. Genetic risk factors

4.3.2. Optic neuritis

4.4. Possible risk factors

4.4.1. Smoking

4.4.2. Obesity

4.4.3. Reduced ultraviolet light exposure (vitamin D deficiency)

4.4.4. Risk factors with conflicting evidence

4.5. Factors not associated with increased risk

4.5.1. Immunizations (excluding hepatitis B)

4.5.2. Oral contraceptives and pregnancy

4.5.3. Other factors not associated with increased risk

4.6. Associated conditions

4.6.1. Type 1 diabetes

4.6.2. Migraine

4.6.3. Restless legs syndrome

4.6.4. Thyroid disease

5. Etiology and Pathogenesis

5.1. Causes

5.2. Pathogenesis

6. History and Physical

6.1. History

6.1.1. Clinical presentation

6.1.2. History of present illness (HPI)

6.1.3. Family history (FH)

6.1.4. Social history (SH)

6.2. Physical

6.2.1. HEENT

6.2.2. Neuro

7. Diagnosis

7.1. Making the diagnosis

7.2. Differential diagnosis

7.3. Testing overview

7.4. Blood tests

7.5. Imaging studies

7.5.1. Magnetic resonance imaging (MRI)

7.5.2. Imaging criteria for diagnosis of MS

7.5.3. MRI techniques

7.5.4. MRI findings and assessment of disease severity

7.5.5. Other imaging studies

7.6. Cerebrospinal fluid (CSF) analysis

7.7. Evoked potential studies

8. Treatment

8.1. Treatment overview

8.2. Diet

8.2.1. Polyunsaturated fatty acids

8.2.2. Vitamin D for treatment of MS

8.3. Counseling

8.4. Treatment of multiple sclerosis

8.5. Treatment of specific impairments in multiple sclerosis

8.6. Consultation and Referral

8.7. Follow-up

9. Complications and Prognosis

9.1. Complications

9.1.1. Psychiatric complications

9.1.2. Cognitive impairment

9.1.3. Seizures

9.1.4. Other complications

9.2. Prognosis

9.2.1. Clinically isolated syndromes (CIS)

9.2.2. Risk of relapse

9.2.3. Factors associated with increased risk of relapse

9.2.4. Factors associated with decreased risk of relapse

9.2.5. Factors not associated with risk of relapse

9.2.6. Conversion from relapsing-remitting MS to progressive MS

9.2.7. Disability