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multiple sclerosis (MS); includes clinically isolated syndrome

Etiology: 1) hypotheses a) autoimmune disease directed against: - myelin-specific proteins - oligodendroglia b) chronic viral infection of the central nervous system - Epstein-Barr virus (EBV) [12] - risk of multiple sclerosis increases 32-fold after infection with EBV but remains unchanged after other viral infections [104] c) intestinal microbial flora might influence development of disease d) chronic cerebrospinal venous insufficiency is not a cause [37] 2) genetic & environmental factors contribute to susceptibility - sunlight & vitamin D independent risk factors [26] (both protective) - maternal vitamin D deficiency duing pregnancy associated with increased risk of multiple sclerosis in offsrping [66] - higher serum vitamin D in the neonatal period is associated with reduced risk for multiple sclerosis years later [70] - higher physical activity of women at baseline weakly associated with lower risk for multiple sclerosis (MS) [68] - may be due to women reducing physical activity in response to subclinical MS [68] - women with serum 25-hydroxyvitamin D levels < 12 ng/mL with 43% higher risk of multiple sclerosis within 9 years than those with levels > 20 ng/mL [75] - risk highest in smokers with HLA-DRB1*1 allele exposed to organic solvents [88] Epidemiology: 1) more common as distance from equator increases a) winter sunlight may be protective (esp as child) [9] b) vitamin D reduces risk [13] c) association is mainly driven by UVB exposure contributing to both MS susceptibility & severity [105] d) no association between MS & lattitude below 40 degrees [105] 2) outbreaks suggest transmission of agent that induces MS 3) susceptibility depends upon childhood residence - moving during childhood from a low to a high prevalence geographic region increases risk [3] 4) age of onset: 20-40 years 5) genetic factors a) high prevalence in whites (90-95% of patients) b) female:male ratio 3:1 c) ~ 15% of patients have a family history d) increased incidence among family members relationship risk general Caucasian population <0.2% sibling or parent with MS 1-3% dizygotic twin with MS 2-5% monozygotic twin with MS 17-40% Pathology: 1) inflammation & demyelination - inflammatory compromise of demyelinated axonal pathways - IL4I1 may diminish inflammation & enhance re-myelination in multiple sclerosis [77] 2) involvement of: a) optic nerve (optic neuritis) b) oculomotor nerve c) hemispheric white matter - cerebral cortex involvement is secondary & subtle [3] d) cerebellum e) brain stem 1] pyramidal tract 2] vestibular pathways f) spinal cord - sensory pathways (myelitis) 3) degenerative changes in both white matter & gray matter subsequent to demyelination [3] 4) activation of microglia & astrocytes within the substantia nigra may be associated with fatigue in MS [96] 5) demyelination of different areas of the CNS occur at different times [3] 6) reduced plasma amyloid beta & reduced Alzheimer disease risk [118] Genetics: 1) increased expression of syncytin-1 - HERV-W 7q21.2 provirus ancestral Env polyprotein 2) other implicated genes - CYFIP2, CRYAB, IL7R, IL22RA1, CD97, CD24 3) no genetic markers distinguish patients with MS from unaffected identical twins [23] Clinical manifestations: 1) presentation - 85% of patients present with an attack (symptomatic episode) - episodic facial paresis (case report) [109] - risk of 2nd attack in MRI-confirmed multiple sclerosis is 90% over next 10-15 years [3] - symptoms originating from different parts of the central nervous system occuring as discrete episodes separated by >= 30 days - late onset >= 50 years [115] - more likely to have progressive disease at onset - more likely to reach higher disability milestones 2) disease patterns - 85% have a relapsing/remitting course - symptoms usually begin focally or unilaterally, worsening over a few days - recovery occurs over weeks to months with recoveries becoming less complete with repeated relapses - symptoms eventually become bilateral, disseminated, & progressive, mean time 10-15 years [3] - 10-20% have a primary progressive course - without exacerbations or remissions - spinal cord often involved - 2/3 of patients with relapsing-remitting form eventually convert to secondary progressive form over a period of 10-15 years [3] - 10-30% have a benign course - optic neuritis & myelitis 3) common manifestations - sensory manifestations - numbness - patchy sensory loss - paresthesias: may be associated with neck flexion (Lhermitte's sign) - pain - weakness: - asymmetric weakness - most commonly in legs - upper motor neuron pattern - cerebellar ataxia - gait ataxia - decreased hand dexterity - intention tremor - abnormal reflexes - hyperreflexia - positive Babinski's sign - spasticity [3] - slurred speech, scanning speech, dysarthria - visual manifestations - monocular blurring of vision - diplopia - acute loss of vision (optic neuritis = papillitis) [3] - ocular manifestations - pale optic disks - internuclear ophthalmoplegia - nystagmus - pain with eye movements (optic neuritis) [3] - vertigo - urinary urgency & incontinence - urinary urgency & urge incontinence (detrusor overactivity) - overflow incontinence (urinary retention, neurogenic bladder) - case of bladder perforation after E coli UTI described [26] - constipation - impotence - depression, increased risk of suicide [3] - diurnal fatigue (mental & physical) - cool extremities - heat intolerance (Uhthoff phenomenon) - worsening of symptoms with activity or heat - fever - cognitive impairment [3] 4) less common manifestations - radicular pain - facial weakness - hearing loss - trigeminal neuralgia - euphoria - confusion - oscillating vision & eye movements - afferent pupillary defect - paroxysms - hyporeflexia - muscle atrophy - dementia - hearing loss 5) rare manifestations - severe apraxia - aphasia - choreoathetosis - seizures - perineal pain - hypersomnolence - hemianopsia - neglect 6) symptoms may be vague, preceding objective signs 7) clinically isolated syndromes of the cerebrum, optic nerve, or brainstem & cerebellum without sign/symptoms of spinal cord disease [35] 8) pregnancy - fertility is normal - disease activity generally declines during pregnancy, but often relapses within 2 months postpartum - overall course of the disease is unaffected by 1 or more pregnancies Laboratory: 1) confirmatory testing - cerebrospinal fluid (not necessary but helpful) [3]; important [111] - CSF protein electrophoresis - serum protein electrophoresis as a control - oligoclonal bands in CSF, but not in serum (oligoclonal bands in serum&CSF) - IgG index > 0.70 [CSF (IgG/albumin)/serum (IgG/albumin)] - cell count: < 40 WBC/mm3, predominantly lymphocytes - CSF protein < 100 mg/dL 2) exclusion testing - serum vitamin B12 - HTLV-1 titer - erythrocyte sedimentation rate (ESR) - rheumatoid factor - anti-nuclear antibodies (ANA) - anti-DNA antibodies - serologic tests for syphilis - angiotensin-converting enzyme - serology for Lyme disease - long chain fatty acids in serum - muscle biopsy - mitochondrial DNA analysis 3) serum 25-hydroxyvitamin D - higher serum 25-hydroxyvitamin D diminishes risk - serum 25-hydroxyvitamin D > 20 ng/mL during the 1st year of MS associated with slower 5 year progression [47,117] - less frequent relapses & fewer newer MRI lesions in patients with higher serum 25-hydroxyvitamin D levels [3] - serum 25-hydroxyvitamin D levels are inversely associated with MS activity on brain MRI [60] 4) myelin-oligodendrocyte glycoprotein IgG in serum/plasma [111] 5) aquaporin 4 receptor IgG in serum/plasma [111] 6) CRYAB antibody in CSF 7) 2-fold increase in methionine sulfoxide in CSF [78] 8) assessment of subclinical disease activity - neurofilament light chain in serum levels is significantly higher in patients with MRI-confirmed subclinical disease activity [79] - serum neurofilament light (NfL), a marker of axonal injury, predicts both relapse-associated worsening & disease progression independent of relapse [119] - serum GFAP is a better indicator of MS disease progression than serum neurofilament light chain [108] 9) see ARUP consult [32] Special laboratory: 1) visual evoked potentials 2) ophthalmoscopy: optic disk pallor consistent with optic neuritis 3) optic coherence tomography [111] 4) measurement of central conduction velocities after visual, auditory & somatosensory stimuli 5) neuropsychologic testing a) neuropsychologic impairments occur in 50% of patients with MS b) neuropsychologic impairment is independent of disease duration or physical impairment c) may be difficult for patient & clinician to recognize 6) transcranial sonography - substantia nigra changes may predict risk for progression Radiology: - magnetic resonance imaging with gadolinium enhancement a) diagnosis with MRI prior to treatment b) imaging of brain & spinal cord c) high intensity area on T2-weighted scans involving CNS white matter - FLAIR [109] (video) - not all T2 lesions are MS [69]* d) a confirmatory MRI must have 4 lesions involving white matter, or 3 if one is periventricular e) newer criteria invoke dissemination in space [25] 1] >= 2 T2 lesions in typical MS locations [25] - juxtacortical, periventricular, infratentorial spinal cord - one lesion must enhance with gadolinium, another must not enhance (1st MRI) 2] a new T2 lesion identified >= 30 days after a prior scan f) rule out lesion compressing spinal cord, brainstem g) lesions generally ovoid in shape & periventricular in distribution [3] h) enhancement with gadolinium suggests acute disease, non-enhancing lesions suggest older asymptomatic lesions [3] * diabetes mellitus, hypercholesterolemia, hypertension, migraine, & smoking may cause T2 hyperintensities on MRI as well as demyelinating disease [69] Diagnostic criteria: 1) objective abnormalities in the CNS, i.e. positive MRI 2) involvement of white matter long tracts: a) pyramidal tract b) cerebellar tracts c) medial longitudinal fasciculus d) optic nerve e) posterior columns 3) involvement of 2 or more areas of the CNS 4) dissemination in time & space a) 2 or more episodes of symptoms involving 2 different site in the CNS, each lasting at least 24 hours & occurring at least 1 month apart - no longer required b) symptomatic spinal cord or brainstem lesions count [81] c) stepwise progression over 6 months & at least 2 CSF IgG oligoclonal bands d) elevated CSF IgG index 5) age of onset 15-60 years 6) condition not attributable to another disease [3,45] * patients with clinically isolated syndrome (full criteria for MS not met) but with brain lesions on MRI have ~90% 10 year risk of developing MS [3] Differential diagnosis: 1) migraine (22%)* 2) fibromyalgia (15%)* 3) other demyelinating diseases a) acute disseminated encephalomyelitis (ADEM) b) Devic's disease (neuromyelitis optica) (6%)* - spinal cord lesions longitudinal rather than segmental in MS - lack of significant brain involvement - profound CSF leukocytosis c) idiopathic transverse myelitis d) optic neuritis [111] 4) somatoform disorders [3] - conversion disorder or other psychogenic disorder (11%)* 5) autoimmune disorders a) rheumatoid arthritis b) systemic lupus erythematosus c) Sjogren's syndrome d) Behcet syndrome [3] 6) infections a) Lyme disease (Borrelia burgdorferi) b) tertiary syphilis c) human T-cell lymphotropic virus-1 (HTLV-1) d) HIV myelopathy or HIV-related cerebritis 7) mitochondrial myopathy 8) sarcoidosis 9) adult-onset leukodystrophy a) adrenoleukodystrophy b) metachromatic leukodystrophy c) non-specific white matter changes [100] 10) metabolic disorders a) vitamin B12 deficiency b) vitamin E deficiency c) copper deficiency [3] 11) vascular disorders a) hypercoagulability b) microvascular ischemic disease c) CNS vasculitis d) Susac syndrome e) cerebral infarcts [100] 12) spinocerebellar degeneration 12) paraneoplastic syndrome [3] 14) brain neoplasms - primary CNS lymphoma - gliomas - brain metastases 15) structural lesions a) craniocervical junction tumor or malformation b) base of skull anomaly c) posterior fossa tumor or arteriovenous malformation (AVM) d) meningioma, glioma, primary CNS lymhoma e) spinal cord tumor f) cervical spondylosis herniated disc resulting in spinal cord compression 16) transverse myelitis - no CSF oligoclonal bands or CSF IgG index - no lesions on brain MRI - affects only one region of the spinal cord - optic nerve involvement excludes the diagnosis 17) medical disorders that cause transient neurologic dysfunction a) diabetes mellitus b) thyroid disease [3] 18) head trauma * % of misdiagnoses from [69] * migraine, microvascular ischemic disease & head trauma may also result in white matter MRI lesions [3] Management: 1) symptomatic a) diagnosis with MRI prior to treatment b) fever exacerbates symptoms of multiple sclerosis (Uhthoff phenomenon) - evaluate for infection if fever - treat fever with acetaminphen or NSAID prior to resorting to other medications c) fatigue - sleep hygiene, regular exercise, smoking cessation - amantadine - stimulants - modafinil (Provigil) [3] - armodafinil - amphetamine [3] - pemoline (Cylert) - reserve for failure of response to amantadine & modafinil [5] - not mentioned in MKSAP19 [3] - methylphenidate, modafinil, & amantadine no better than placebo [98] - observe for depression d) depression is common [3] - screen for depression - counseling, suicide prevention - antidepressants: - SSRI or SNRI for patients with fatigue [5] - TCA for patients with neuropathic pain [5] - antipsychotics [3] e) cognitive impairment - neuropsychologic testing - cognitive rehabilitation, counseling, cognitive therapy [3,61] - accomodation strategies - no proven therapy f) spasticity - treat if patient's ability to stand not dependent upon spasticity - physical therapy, stretching, massage therapy - medications for use in combination with physical therapy - baclofen - start 10 mg PO BID-TID; increase gradually - severe, intractable spasticity generally responds to intrathecal baclofen (implantable pump) [3] - tizanidine (alternative agent) [3] - cyclobenzaprine, carisoprodol [3] - benzodiazepine for nocturnal muscle spasm [5] - diazepam - clonazepam - Botox g) urinary urgency & incontinence - scheduled toileting (bladder retraining) for urge incontinence - anticholinergic agents for bladder spasticity (detrusor overactivity) - oxybutynin, tolterodine, solefenacin [3] - manual pelvic pressure & urinary catheterization for urinary retention - post-void residual > 100 mL with anticholinergic therapy suggests significant urinary retention & the need for urologic evaluation - urodynamic testing if mix of symptoms, uncertain etiology [3] h) constipation - dietary fiber - stool softener - suppositories - enemas - lactulose i) neuralgic pain - exercise, cognitive behavioral therapy, mind-body therapy - physical therapy, acupuncture - tricyclic antidepressant given QHS 1st line (low dose) [3,5] - nortriptyline - amitriptyline - gabapentin (Neurontin): start 100 mg TID [5] - pregabalin [3] - carbamazepine (Tegretol): start 200 mg PO TID - duloxetine [3] - topiramate [3] - capsaicin patch - tramadol [3] j) chronic aching pain j) dysmetria a) isoniazid b) clonazepam l) tremor - occupational therapy - postural tremor: propranolol - limb tremor: botulinum toxin [3] m) impaired mobility - physical therapy, occupational therapy - prosthetics: braces, cane, rollator, electrostimulatory walk devices [3] - dalfampridine (Ampyra) may improve walking [3] n) pseudobulbar affect: dextromethorphan/quinidine 2) exacerbations* - distinguish relapse from pseudorelapse due to worsening of neurological symptoms due to another cause, i.e.infection other physiologic stressor [3] - fever worsens symptoms of MS (pseudorelapse) [3] - supportive therapy for pseudorelapse - treat infection prior to administering methylprednisolone [3] - methylprednisolone - 1 g IV daily divided every 6 hours for 3-5 days for severe relapse [3] - oral methylprednisolone & IV methylprednisolone equally effective for moderately severe relapse [50,54] - methylprednisolone 1 g PO QD for 3 days [54] - no such equivalence of oral prednisone [3] - prednisone taper, avoid long-term glucocorticoid use - glucocorticoids most effective for optic neuritis [3] - ACTH IV or IM - plasmapheresis for severe exacerbations not responding to corticosteroids [3] 3) relapsing/remitting progressive disease - relapses with no or minimal effect on function may be observed & not treated [3] - disease-modifying therapy can reduce rate of relapse, slow disability progression (including progression to secondary progressive MS), & reduce accumulation of new demyelinating lesions seen on MRI [3] - self-injection with IFN-beta or glatiramer acetate 1st line [3] - Avonex (interferon-beta 1a) - betaseron (interferon-beta 1b) - early treatment may diminish later disability [17] - early treatment after acute demyelinating event delays 2nd event by 2.7 years [67] - may not reduce progression of disability [33] - vitamin D added to interferon-beta reduces demyelination on MRI [3] - avoid interferon-beta in patients with liver disease or depression [3] - glatiramer acetate (Copaxone) may delay progression of early MS [21] - combining interferon-beta with glatiramer acetate no better than either agent alone [3] - highly effective agents [99] - natalizumab (Tysabri) [3,8,42] (increased risk of PML) - alemtuzumab - more effective than interferon-beta 1a, but with more severe adverse effects [34] (NICE) - 40% lower rate of relapse vs IFN-beta but no effect on disability progression [72] - lower annual relapse rate than fingolimod (0.15 vs 0.34) but no greater benefits on cumulative rate of relapse, disability worsening, & disability improvement [72] - alemtuzumab & natalizumab with similar risks for relapse & disability worsening, but more patients appear to improve on natalizumab [72] - ofatumumab (Arzerra, Kesimpta) - ocrelizumab FDA-approved 2017 [87] - annual relapse rate higher in MS patients treated with rituximab vs ocrelizumab (0.20 vs 0.09) [107] - mitoxantrone - moderately effective agents [99] - sphingosine-1-phosphate-receptor modulators - fingolimod [3,22,44] - risk of severe exacerbation of MS after stopping fingolimod [94] - siponimod - ponesimod (Ponvory) - ozanimod - dimethyl fumarate (NGC:NICE) - off-label rituximab associated with fewer relapses over 2 years than dimethyl fumarate 3% vs 16% [106] - cladribine - modestly effective agents - teriflunomide - glatiramer acetate - interferon-beta 1a (AVonox) - betaseron (interferon-beta 1b - vitamin D added to interferon-beta reduces demyelination on MRI [3] - combining interferon-beta with glatiramer acetate no better than either agent alone [3] - others - laquinimod (investigational) [31] - copolymer-1 (COP-1) not mentioned in MKSAP17 [3] - calcitriol 2.5 ug/day (investigational) - high-dose statin may be of benefit [48] 4) primary progressive disease - ocrelizumab only FDA-approved agent for primary progressive disease - other agents not FDA-approved (2018) [3] - cyclophosphamide - methylprednisolone - azathiaprine - methotrexate 7.5 mg PO weekly - bortezomib superior to dexamethasone for refractory MS [51] - cladribine (investigational) - Procarin (experimental) 5) secondary progressive disease - disease-modifying therapy of relapsing-remitting MS reduces conversion to secondary progressive disease [3] - mitoxantrone, siponimod & cladribine only FDA-approved agents [3] - potential benefit on disease progression [28] - of limited use & potentially toxic - discontinuation of disease-modifying therapy if non-ambulatory for > 2 years & have no relapsing activity during that time period [3] 6) early possible multiple sclerosis (clinically isolated syndrome)* - disease-modifying therapy reduces conversion to relapsing-remitting MS by ~50% [3] - interferon-beta or glatiramer acetate [82] - betaseron may be of benefit [6,7] - avoid in patients with liver disease or depression [3] - teriflunomide 7-14 mg PO QD reduces risk of recurrence* 37-42% [52] - minocycline (investigational) [11] - may prevent progression to multiple sclerosis in patients with an isolated demyelinating event (optic neuritis) [73] - domperidone not useful [101] 7) disease-modifying therapy - cost effectiveness in question [29] - should be started soon after diagnosis [86] - reduces disease relapse & progression [3,86] - of benefit for clinically isolated syndrome [3] - discontinue if non-ambulatory for > 2 years without relapsing activity over same time period [3] 8) stem cell transplantation - investigational therapy for aggressive disease - progression-free 15-year survival 25% [27] - progression-free 5 year survival 46% [71] - mortality 3% within 100 days of procedure [71] - bortezomib in combination with dexamethasone +/- thalidomide for induction prior to high-dose chemotherapy with hematopoietic stem cell transplantation (NICE) 5) bulsulfan vs total body irradiation (high-intensity) or cyclophosphamide +/- antithymocyte globulin or fludarabine phosphate for conditioning [71] 6) treatment failure 6% vs 60% on drug therapy [85] 9) alternative medicine therapy - vitamin D +/- calcium may be of benefit [3,57] - vitamin D is recommended for all patients with MS [3] - cannabis extract, tetrahydrocannabinol, or cannabinoid spray may ease patient- reported spasticity & pain (excluding central neuropathic pain) [49] - likely not effective in improving objective measures of spasticity [49] - MKSAP19 suggests cannabis useful for treating refractory spasticity & pain [3] - may help reduce urinary frequency [49] - cannabinoids with small if any benefit [93] - high-dose biotin ineffective [97] 10) cognitive impairment - neuropsychologic testing, counseling, cognitive therapy [3,61] - accomodation strategies - no proven therapy 11) exercise & physical therapy - regular exercise may minimize disability [3] - stretching exercises can help reduce spasticity, & prevent painful muscle cramps [3] - supervised sessions in a vestibular rehabilitation program, with daily home exercises, improve balance, quality of life, & fatigue [83] 12) diet plays a role - high fat intake is associated with increased risk for multiple sclerosis relapse in children - association appears to be with saturated fat - high vegetable intake might be protective [76] - a Mediterranean diet is associated with better cognition [110] 13) health maintenance - immunizations recommended to minimize risk of infection - infections increase risk of relapse [3,46] - annual influenza vaccination recommended [3] - immunizations should be delayed for 4-6 weeks after an acute attack - live virus vaccines should not be administered to patientson immunosuppressive therapy [3] 14) patient education - treatments are expensive, hazardous - acute infections can trigger MS exacerbations - no therapies have proven benefits on the neurodegeneration that occurs with progressive multiple sclerosis [3] - venoplasty has no role in treatment of MS [37] - smoking cessation: - smoking increases risk of progression 3-fold [3,102] - National Multiple Sclerosis Foundation provides supplementary patient information 15) pregnancy & lactation - hormonal state of pregnancy itself is protective against disease activity [3] - generally safe to discontinue MS meds during pregnancy [3] - women with MS experience an increased risk of relapse after delivery [55] - pregnancy does not cause additional permanent disability in women with MS [3] - exclusive breastfeeding may reduce postpartum risk of MS relapse [55] - return of menstruation may mitigate the reduced risk of relapse - childbirth may have favorable long-term effect on course of multiple sclerosis [63] - have > 1 child & breast feeding > 15 months reduces risk for multiple sclerosis in mothers [74] * exacerbations with be precipitated by infection (3-fold risk) or stress (2-fold risk) [10] * clinically isolated syndrome = first clinical episode suggestive of multiple sclerosis [52] 16) Follow-up: - regular reassessment of patient's condition - interferon beta-1b may cause leukopenia & elevation of serum transaminases: follow-up once a month for 3 months, then once every 3 months - watch for symptoms of depression 17) Prognosis: - prior to disease onset, higher education & higher income are associated with lesser disease severity [114] - prior to disease onset, separation & divorce are associated with higher disease severity in relapse-onset disease [114] 18) Prevention: - supplemental vitamin D 1000-2000 IU daily to high-risk pregnant women & breast-feeding mothers with low serum 25-OH vitamin D levels (<20 ng/mL) & an immediate family member with MS [70] - a diet rich in fish & omega-3 polyunsaturated fatty acids may diminish risk of multiple sclerosis [84] - 1/2 hour of sunlight/day may cut risk of MS in 1/2 [103] - treatment of obesity or type-2 diabetes lowers risk of MS [116] - semaglutide lowers risk of MS by 76% - dulaglutide lowers risk of MS by 84% - liraglutide lowers risk of MS by 84% - empagliflozin lowers risk of MS by 77% - metformin lowers risk of MS by 61% [116] Comparative biology: - miconazole & clobetasol promote remyelination in mouse demyelinating disease - these 2 agents induced mouse oligodendrocyte-progenitor stem cells to turn into myelin-producing oligodendrocytes [53]

Interactions

disease interactions

Related

chronic cerebrospinal venous insufficiency (CCSVI) experimental autoimmune encephalomyelitis neuropsychologic testing oligoclonal banding in CSF (high-resolution CSF protein electrophoresis)

Specific

multiple sclerosis variants Schilder's disease; myelinoclastic diffuse sclerosis; balo concentric sclerosis

General

autoimmune disease demyelinating disease neurodegenerative disease

References

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Databases & Images

OMIM 126200 Entrez Gene 4397 image related to multiple sclerosis