Clinical Slide Set. Multiple Sclerosis - Annals of

© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.

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in the clinic

Multiple Sclerosis


What characteristic symptoms orphysical findings should alertclinicians 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


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


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


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


Typical MRI manifestations of MS

Lesions in white matter regions appear hyperintense on T2-weighted 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


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


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 visual-

evoked 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


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

When should clinicians consider obtaining optical coherence tomography?

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


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


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


When should clinicians considerconsulting with a neurologist orother 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


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


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


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


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


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


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

When should clinicians consider immunomodulatory therapy?


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


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 pseudo-relapse

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


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


What treatments are used to alleviate chronic symptoms? Use DMT to alleviate symptoms that remain chronicOther 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


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


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


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


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

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