Transcript Clinical Slide Set. Multiple Sclerosis

* For Best Viewing:
Open in Slide Show Mode
Click on
icon
or
From the View menu, select the
Slide Show option
* To help you as you prepare a talk, we have included the
relevant text from ITC in the notes pages of each slide
© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
Terms of Use
 The In the Clinic® slide sets are owned and copyrighted by the
American College of Physicians (ACP). All text, graphics,
trademarks, and other intellectual property incorporated into the
slide sets remain the sole and exclusive property of ACP. The slide
sets may be used only by the person who downloads or purchases
them and only for the purpose of presenting them during not-forprofit educational activities. Users may incorporate the entire slide
set or selected individual slides into their own teaching
presentations but may not alter the content of the slides in any way
or remove the ACP copyright notice. Users may make print copies
for use as hand-outs for the audience the user is personally
addressing but may not otherwise reproduce or distribute the slides
by any means or media, including but not limited to sending them as
e-mail attachments, posting them on Internet or Intranet sites,
publishing them in meeting proceedings, or making them available
for sale or distribution in any unauthorized form, without the
express written permission of the ACP. Unauthorized use of the In
the Clinic slide sets constitutes copyright infringement.
© 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.