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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
in the clinic
Multiple Sclerosis
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What characteristic symptoms or
physical findings should alert
clinicians to the diagnosis of MS?
 Optic neuritis: inflammation of the optic nerve
 Subacute visual changes + pain with eye movement
 Myelitis: focal inflammation within the spinal cord
 Sensory or motor symptoms below affected spinal level
 Other neurologic symptoms
 Eye movement abnormalities from brainstem involvement
 Chronic symptoms from widespread cortical
demyelination and global brain atrophy
 Cognitive dysfunction and mental and physical fatigue
 Worsening neurologic symptoms when body temp 
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What are the historical characteristics
associated with each subtype of MS?
 Clinically isolated syndrome (CIS)
 Full MS diagnostic criteria not met at 1st relapsing event
 Relapsing-remitting MS (RRMS): ~85% of pts with MS
 Repeated relapse episodes followed by recovery
 Secondary progressive MS (SPMS): 50-60% of pts with RRMS
 First few years: recovery of previous functioning common
 Over time: recovery diminishes, permanent disability occurs
 Primary progressive MS (PPMS): ~15% of pts with MS
 Progressive disability accumulation from onset of disease
 Disability accumulation can occur rapidly
 Radiologically-isolated syndrome (controversial)
 Incidental MRI findings meet diagnostic criteria for MS w/o
any history or symptoms suggestive of MS
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What are the McDonald criteria, and how can
they help clinicians diagnose MS?
 Official diagnostic criteria for MS
 Provide guidance on proper integration of clinical and
diagnostic evidence
 Criteria help differentiate MS from other conditions
 RRMS diagnosis
 Require clinical evidence of CNS demyelination
disseminated in space and time
 For PPMS diagnosis
 ≥1 yr neurologic disability progression + ≥2 of following:
 evidence of dissemination in space on brain MRI
 evidence of dissemination in space on spinal cord MRI
 cerebrospinal fluid findings consistent with MS
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What is the role of MRI in diagnosis?
 Primary diagnostic and prognostic tool in evaluation
 McDonald criteria often require confirmation based on MRI
 Dissemination in space: ≥2 lesions in ≥2 locations
 Dissemination in time:
 Asymptomatic contrast-enhancing lesion + asymptomatic
nonenhancing T2-bright lesion at baseline
or
 Development of a new white matter lesion or new contrast
enhancement on a follow-up scan
 Other MRI changes seen
 Demyelinating lesions in cortex
 Cortical and deep gray matter atrophy; white matter structure
atrophy
 Alterations in quantitative MRI measures in lesions and
normal-appearing white matter
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
 Typical MRI manifestations of MS
 Lesions in white matter regions appear hyperintense on T2weighted images; hypointense on T1-weighted images
 Lesions represent areas of demyelination and gliosis
 Lesions will show enhancement with administration of
gadolinium contrast if undergoing active inflammatory
process with breakdown of the blood-brain barrier
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What role does lumbar puncture play in
diagnosis?
 Spinal fluid can reveal signs of MS
 Unique oligoclonal bands in spinal fluid by isoelectric
focusing (in 90%-95% of patients with MS)
 Elevation of IgG index (in 50%-75%)
 Mild pleocytosis (in ≈50%)
 Negative CSF result alone doesn’t rule out MS
 But when clinical and radiologic suspicion is low, a normal
CSF result reassures patients they probably don’t have MS
 For RRMS diagnosis
 Criteria don’t require confirmation by CSF testing
 For PPMS diagnosis
 Test CSF if MRI features don’t meet criteria for dissemination
in space
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
When should clinicians consider obtaining
evoked potentials?
 When clinical exam and MRI don’t provide evidence of
dissemination in space
 Helps find evidence of subclinical demyelinating lesions
 Evoked potentials: electrophysiologic measurements of
the time it takes for nerves to respond to stimulation
 Reduced evoked potential conduction velocity on visualevoked potentials: detects prior demyelination
 Brainstem auditory-evoked potentials: provide evidence of
a lesion along the acoustic and brainstem pathways
 Somatosensory evoked potentials: provide evidence of
lesions in spinal sensory pathways
 Brainstem and spinal cord potentials less likely to be
abnormal than visual-evoked potentials in patients with MS
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
When should clinicians consider obtaining
optical coherence tomography?
 Optical coherence tomography measures the thickness
of nerve fiber layers in the retina
 Documents dissemination of disease activity in space
 In patients presenting with first attack of nonoptic neuritis
 Useful but not specific
 Retinal nerve fiber layer reductions seen
 Can be seen in patients with MS who have had optic
neuritis as well as those who have not had optic neuritis
 In patients with isolated optic neuritis
 In patients with neuromyelitis optica
 Can occur with compressive lesions of optic nerve
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What are the differential diagnoses?
 Other demyelinating diseases
 Acute disseminated encephalomyelitis
 Neuromyelitis optica (Devic disease)
 Idiopathic transverse myelitis
 Systemic inflammatory disease
 Systemic lupus erythematosus
 The Sjögren syndrome
 Sarcoidosis
 The Behçet syndrome
 Metabolic disorders
 Adult-onset leukodystrophy
 Vitamin B12 deficiency
 Copper deficiency
 Zinc toxicity
 Vitamin E deficiency
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
 Infections
 HIV, Lyme disease, syphilis
 Human T-lymphotropic virus
 Vascular disorders
 Sporadic and genetic stroke syndromes
 CNS vasculitis
 The Susac syndrome
 Dural arteriovenous fistula
 Migraine
 Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma)
or metastatic disease)
 Paraneoplastic syndromes
 Somatoform disorders
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
When should clinicians consider
consulting with a neurologist or
other specialist for diagnosis?
 Consult neurologist to confirm the diagnosis or facilitate
further testing
 If MRI findings suggest possible MS
 Obtain second opinions from MS specialty clinics
 If the diagnosis is unclear
 If treatment has failed
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
CLINICAL BOTTOM LINE: Diagnosis…
 Use the revised 2010 McDonald criteria
 Clinical Hx + physical exam findings + radiologic findings
 Show dissemination in disease activity over space & time
 Patients with RRMS have relapsing symptoms
 Patients with PPMS and SPMS experience progressive
disability accumulation
 Additional testing not required for Dx but can be helpful
 Lumbar puncture
 Evoked potentials
 Optical coherence tomography
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What is the overall approach to treatment
of patients with MS?
 Multidisciplinary and comprehensive approach can
significantly improve quality of life of patients with MS
 Prevent and manage relapses
 Use medication and nonmedical approaches for fatigue
 Treat spasticity and bladder dysfunction
 Assess cognitive functioning
 Consider ways to help patients maximize daily function
 Delay disease progression and reduce relapse rate with
medications
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What role does clinical subtype play in
guiding treatment decisions?
 Subtyping: critical 1st step before initiating drug therapy
 Many medications approved for CIS and RRMS
 Limited treatment options for SPMS and PPMS
 With progressive MS, clinical guidelines recommend
against using immunomodulatory drugs
 For most patients with RRMS, immunotherapy is indicated
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What medications are typically used?
 Interferon-β1a and β1b
 1st line Rx; reduce relapse rates by one third vs. placebo
 Glatiramer acetate
 1st line Rx; reduces relapse rates by one third vs. placebo
 Natalizumab
 Reduces relapse rates by about two thirds vs. placebo and
slows disability progression by approximately 40%
 Risk for potentially fatal infection (PML)
 Teriflunomide
 Reduces relapse rates by one third vs. placebo
 Reduces risk for disability & accumulation of lesions on MRI
 Class X (teratogenicity): contraception counseling essential
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
 Fingolimod
 Reduces relapse rates by about 50% vs. placebo and
reduces risk for disability & accumulation of lesions
 1st-dose bradycardia often occurs; don’t use with β-blockers
or if patient has known heart block
 Risk of retinal macular edema; eye exam required
 Varicella vaccination needed before treatment, if not immune
 Dimethyl Fumarate
 Reduces disability progression by about one-third vs
placebo and reduces new lesions on MRI scans
 FDA-approved for use in patients with RRMS
 Mitoxantrone
 Reduces relapse rates and is only drug ever shown to
reduce rate of disability accumulation in SPMS
 Use limited by risks for cardiac toxicity, secondary leukemia
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
When should clinicians consider
immunomodulatory therapy?
 Initiate at the time of diagnosis
 In the past: clinicians waited until a clinically definite
diagnosis established
 Now: Guidelines recommend initiating at the time of first
clinical symptoms for RRMS and CIS with risk factors for
later conversion
 Early treatment can reduce relapse rates and new lesion
formation and prevent disability accumulation
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What is the role of vitamin D?
 Vitamin D deficiency linked to pathophysiology of MS
 Immunoregulatory vitamin D receptors present on T cells
 Vitamin D interacts with the immunomodulatory effects of
estrogen and testosterone
 Reduced serum vitamin D levels are shown to predict
accumulation of new lesions
 High vitamin D levels linked with decreased relapse risk
 ? Ideal dosing and 25-hydroxyvitamin D serum levels
 Studies show benefit for serum levels of ≥50 nmol/L
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
How should clinicians choose therapy for
patients who are having an acute relapse?
 Relapse: new or worsening neurologic symptoms
lasting ≥24h without clear underlying triggers of pseudorelapse
 Standard treatment: high-dose corticosteroids
 IV infusion methylprednisolone, 1g/d for 3-5 days
 Alternate regimens: oral methylprednisolone, 1g/d for 5
days; oral prednisone, 1250 mg/d for 5 days
 Rescue treatment if relapse doesn’t respond to steroids
 Plasma exchange
 5 days of IM or SC adrenocorticotrophic hormone gel
 Pulse-dose IV cyclophosphamide
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
When should a patient with MS be
hospitalized?
 Severe relapse causes complete loss of mobility
 Severe relapse causes impaired bladder / bowel control
 Marked worsening during relapse warrants care that’s
beyond the capacity of the family
 Special monitoring needed during relapse treatment
 Such as blood glucose monitoring for steroid
administration in a patient with diabetes
 Administering rescue treatment
 Plasma exchange, pulse-dose cyclophosphamide therapy
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What treatments are used to alleviate
chronic symptoms?
 Use DMT to alleviate symptoms that remain chronic
Other symptomatic management:
 Spasticity
 Physical therapy, stretching, massage
 Baclofen, tizanidine, cyclobenzaprine, gabapentin,
benzodiazepines, carisoprodol, botulinum toxin
 Neuropathic pain
 Gabapentin, pregabalin, duloxetine, tricyclic antidepressants,
tramadol, carbamazepine, topiramate, capsaicin patch
 Fatigue
 Proper sleep hygiene, regular exercise
 Modafinil, armodafinil, amantadine, amphetamine stimulants
 Depression
 Individual or group counseling; Antidepressants
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
 Cognitive dysfunction
 Cognitive rehabilitation and accommodation strategies
 Mobility
 PT and OT, use of braces, canes, rolling walkers,
electrostimulatory walk-assist devices; Dalfampridine
 Urinary urgency / frequency
 Timed voids, avoidance of caffeine; Oxybutynin, tolterodine
 Urine retention
 Manual pelvic pressure, intermittent catheterization
 Heat Intolerance
 Avoidance of hot weather, hot tubs, etc., cooling equipment
 Pseudobulbar affect
 Dextromethorphan/quinidine
 Limb tremor
 Occupational therapy; Botulinum toxin
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
How should clinicians monitor patients
being treated for MS?
 Regularly assess safety and efficacy of DMT
 Focus safety assessments toward known AEs of treatment
 Catalog relapses
 Order regular MRI scanning
 Perform neurologic exam
 Consider changing treatment in patients with recurrent
relapses, new lesion formation, or disability accumulation
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What should clinicians do about
immunizations in patients with MS?
 Clinical practice guidelines recommend regular
immunizations for patients with MS
 Risk for MS relapses is significantly increased in the weeks
surrounding infectious episodes
 No evidence that MS worsens due to immunization with
any vaccines
 Fingolimod: special considerations
 Decreases the ability to combat viral infections
 Avoid using live viral vaccines while receiving the drug
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
CLINICAL BOTTOM LINE: Treatment…
 Prevent relapses: use DMTs and vitamin D supplementation
 DMTs only approved for CIS and RRMS
 Poor evidence for any benefit for SPMS or PPMS
 Use acute treatments at the time of relapses
 High-dose corticosteroids
 Plasma exchange
 Adrenocorticotrophic hormone gel
 Cyclophosphamide
 Manage symptoms on an individual basis
 Use pharmacologic and nonpharmacologic interventions
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.