Demyelinating Disease

Multiple Sclerosis

Gary Beaver DO

What Is Multiple Sclerosis (MS)?

• A disease in which the body’s immune system attacks the axonal sheathcalled myelin

• Affects the brain, spinal cord, andoptic nerves

• Primary cause may be autoimmune and/or viral

Worldwide Prevalence of MS

1. National Multiple Sclerosis Society. Just the Facts 2003-2004; 2. National Institute of Neurological Disorders and Stroke. 2004; 3. Data on file, Berlex, Inc.

Epidemiology of MS

• Approximately 400,000 affected in the United States1

• 2.5 million affected worldwide1

• Higher prevalence in women (2/3 female)1-3

• More common among those of Northern European descent1

• Age of onset usually 20 to 50 years1

• National annual cost of MS in the billions of dollars2

• Cost of disease modifying therapies per person/year (annualized cost at average wholesale price)3

– Betaseron® $18,972.75– Avonex® $17,598.75 – Rebif® $21,785.89– Copaxone® $17,251.35

Demyelinated Plaques

• Perivascular T-cell and macrophage infiltrates

• Intense gliosis (scar) formationin white matter more thangray matter

• “In early stages of disease,” predominantly myelin lossand inflammation

• Axonal loss

A Model of Immune Mechanisms in MS: Overview

Adapted from Donald Goodkin, MD and Craig Smith, MD

© 2003 Serono, Inc. All rights reserved.

Monocytes

Proposed Immunomechanisms for Damage in MS

IL = interleukin; IFN = interferon; TNF = tumor necrosis factor.

Vojdani A, et al. J Intern Med. 2003;254:363-374.

Activated T-helper cells

IL-2 IFNβ TNF

TNFα TNFβ

Apoptosis of cultured oligodendrocytes

TNF IFN

Injury to myelin & oligodendrocytes

White Matter Injury in MS

• Immune cells enter brain atblood vessel

• Damage to tissue as cells infiltrate

• Myelin is lost in the area

• Some axons irreversibly injured

• If inflammation resolves, some repair of myelin occurs slowly

Axonal Transection in Acute MS Lesions

• Pathologically– Axon loss due to wallerian degeneration follows

transection in areas of inflammation – This process is continuous and irreversible and

the major cause of unremitting disability– Chronic black hole formation on T1 precontrast

magnetic resonance imaging (MRI) scans and brain atrophy appear tobe the principal correlates of this process and have major consequences forcognitive function

MS Lesions: Axonal Demyelination & Transection

Adapted from Trapp et al. N Engl J Med 1998;338:278-285. © 1998 Massachusetts Medical Society. All rights reserved.

Brain Atrophy (Shrinkage) in Untreated MS

These images were acquired over the courseof 7 years from a single person with untreated

MS

Pathogenesis of MSWhat initiates this whole

process?

• Unknown mechanism for initiation of autoimmune dysfunction

• Theories:– Direct effect of infectious agent (many

implicated, none proven)– Molecular mimicry– Epitope spread

“What Is MS, Clinically?”• MS is usually a clinical (not pathological) diagnosis

– Dissemination of lesions in space and time• Spinal cord (myelopathy)• Brainstem • Optic nerves• Cerebrum

– Clinically definite or laboratory definite criteria

– Lack of other explanations to explain CNS symptoms

• MRI lesions

– McDonald criteria permit diagnosis on MRI alonewhen substantial burden of disease and evidenceof chronic activity

Who’s at Higher Risk?

• Young adults (20-45)– Less common in younger and older populations

• Women >men (2:1)

• Northern latitudes

• Genetic influence– Monozygotic twins (25-30%)

– Dizygotic twins and Nontwin siblings (3-5%)

– Parents or children (2%)

Hupperts R, et al. Neurology. 2001;57(2):290-295.Baranzini SE, et al. J Rehabil Res Dev. 2002;39(2):201-209.

Initial Symptoms

• Sensory 36%

• Visual loss 16%

• Weakness 13%

• Walking/balance 8%

• Double vision 7%

• Bladder 1%

• Other 5%

• Multiple 14%

MS: Typical Sensory Complaints

• Paresthesias/dysesthesias–Tingling, pins/needles,

vibrating, numbness

• L’Hermitte’s phenomenon–Neck flexion causes electrical sensations down

spine

MS: Typical Motor Complaints

• Weakness– Loss of power opening jars, holding pans– Difficulty washing/brushing/drying hair– Stumbling, difficulty on stairs

• Clumsiness– Difficulty typing, writing, or using tools– Running into door frames, walls– Acting drunken

• Tremor

MS: Typical Visual Complaints

• Blurred vision, usually in 1 eye– Film or shade over eye

– Retroorbital eye pain with eye movements

– Reduced color perception

• Double vision– Usually side-by-side and worse to 1 side

– May be vertical or oblique

– Often intermittent

– Can be perceived as blurred vision

MS: Typical Other Complaints• Fatigue: worse with exacerbations

• Vertigo: frequently with gait imbalance

• Cognitive: short-term memory and multitasking impairment

• Mood impairment – especially depression

• Bladder, bowel, and sexual dysfunction

MS: Sensitivity to Heat• Very often shows sensitivity to heat • External cause

–Bath/shower

–Hot weather

–Sun

• Internal cause–Fever

–Exercise

MS: Exacerbation

• Definition: new or recurrent MS neurological symptom orsign sustained for at least 24 hours

• Can last weeks or months• May not completely resolve• Triggers include viral infections

and postpartum• Average is 1 relapse a year in

early disease

Diagnostic Tools

• MRI

• Lumbar puncture

• Visual, brainstem auditory, and somatosensory evoked potentials

MRI Imaging in MS

Gdenhancement

T2 lesion

T1 “black hole”

Brain atrophy(shrinkage)

Spinal cord lesion

MS Mimics

• Vasculitis– Lupus, rheumatoid

arthritis, Sjogren’s

• Embolic stroke

• B12 deficiency

• Sarcoidosis

• HTLV

• HIV

• Lyme disease

• Neurosyphilis

• Lymphoma

• PML

MS: Laboratory• Electrophysiology

– Evoked potentials measure conduction times• VER, BAER, SSEP• Demonstrate demyelination not seen on MRI

• Spinal fluid– IgG index elevation

– Oligoclonal bands

– IgG synthesis rate

Classification and Prevalence of MS: Disease Courses

*if not on disease-modifying therapy.Adapted from Lublin FD, Reingold SC. Neurology. 1996;46:907-911; National Multiple Sclerosis Society. Just the Facts 2003-2004; Comi G. Curr Opin Neurol. 2000;13:235-240.

Dis

abili

tyD

isab

ility

TimeTime

Relapsing-Remitting

Relapsing-Remitting Followed by Secondary-Progressive

Progressive-Relapsing

Primary-Progressive

Prevalence

85% at diagnosis

50% within 10 years*80% to 90% within 25 years*

10%

5%

Relapsing-RemittingRelapsing-Remitting

Secondary-ProgressiveSecondary-Progressive

PreclinicalPreclinical

TimeTime

Natural History of MSMeasures of brain volumeMeasures of brain volumeRelapses and impairmentRelapses and impairmentMRI burden of diseaseMRI burden of diseaseMRI activityMRI activity

The exact relationship between MRI findings and clinical status of patients is not completely understood.Adapted from Trapp BD, et al. The Neuroscientist. 1999;5:48-57.

MS: Prognosis• Disease course

– 10-15% have no obvious clinical exacerbations– 50% have progressive worsening after 6 years– First 4 years have prognostic significance

• Favorable prognostic factors– Female, under 30, visual or sensory complaint– Long interattack interval (2 years) at onset

• Poor prognostic factors– Male, over 30, spinal cord or cerebellar signs– Frequent exacerbations (>1 a year)– Poor recovery from exacerbations

MS: Prognosis (cont.)

• Untreated natural history– 50% need cane or wheelchair by 15 years

• With treatment, this disability is delayed

– 10% never develop serious disability

– 67% work full-time at normal wage

– 30% of severe attacks (significant disability) will not recover completely

– 50% have some degree of cognitive impairment

Why Treat Early?

• Decrease relapse rate

• Decrease physical disability

• Decrease new brain lesions

• Decrease brain atrophy

Treatment of MS

• Acute exacerbations– Steroids

• Relapsing remitting prevention– Avonex

– Betaseron

– Copaxone

– Rebif

– Tysabri

– Novantrone can be used in aggressive relapsing-remitting MS

• Primary progressive prevention– No proven treatments

• Secondary progressive prevention – Betaseron– Novantrone– Rebif

Selectins

Chemo-Attraction

T cell

T cell

BloodBlood CNSCNS

Adhesion BasementMembrane

Release of proteases: E

ndot

heli

al L

inin

g

VLA4 VCAM-1

LFA-1 ICAM-1

fibronectin

MMPs

IFN: Primary Mechanism of Action

Glatiramer Acetate: Mechanism of Action

BDNF

BDNF

BloodBlood CNSCNS

Natalizumab: Mechanism of Action

VCAM-1

T cell

LFA-1

NVLA4 or 41 integrin

Natalizumab: VLA4 or 41 integrin antibody

End

othe

lial

Lin

ing

ICAM-1

Clinically Isolated Syndrome (CIS)

• CIS is the first acute clinical demyelinating event with evidence of prior subclinical demyelination on the brain or spinal cord MRI

• What CIS features are indicative of first MS attack?– a. Appropriate age

• Excludes too young and too old

– b. Characteristic syndrome• Optic neuritis: typically unilateral, retrobulbar, and painful in nature; some

recovery expected• Brainstem dysfunction: most commonly ocular motor syndromes (INO,

nystagmus), hemisensory and hemiparesis, or trigeminal neuralgia• Myelitis: partial sensory more common than partial motor; bladder and bowel

dysfunction is common; presence of Lhermitte’s sign; presence of band-like abdominal or chest pressure

– c. Other causes excluded

INO = intranuclear ophthalmoparesis.

The exact relationship between MRI findings and clinical status of patients is not completely understood.Frohman EM, et al. Neurology. 2003;61:602-611.

Clinically Isolated Syndrome (CIS)

• What CIS features are indicative of first MS attack? (cont’d)– d. Abnormal brain MRI with suggestive features

• The presence of 3 white matter lesions on T2 MRI is a very sensitive predictor (>80%) of subsequent development of CDMS in the next 7 to 10 years

• The presence of 2 gadolinium-enhancing lesions at baseline and the appearance of new T2 lesions or new gadolinium enhancement on follow-up scans are also highly predictive of subsequent CDMS

CDMS = clinically definite MS.

The exact relationship between MRI findings and clinical status of patients is not completely understood.Frohman EM, et al. Neurology. 2003;61:602-611.

Overview of Multiple Sclerosis

• MS may involve genetic, environmental, and immune factors1

• Myelin, axonal, and neuronal damage are concurrent and often subclinical and occur early in the disease course1

• Early inflammatory damage can be severe and may lead to long-term degeneration and clinical progression2

• Clinical, immunopathological, and imaging evidences support a role for early immune interventions in MS3

1. Trapp BD, et al. N Engl J Med. 1998;338:278-285; 2. De Stefano N, et al. Arch Neurol. 2001;58:65-70; 3. Comi G. Curr Opin Neurol. 2000;13:235-240.

Case #1

• 15 y/o female• March 02 pt with URI 1 week later

developed mild numbness of LLE resolved in 1-2 weeks.

• April 02 developed RUE “useless hand syndrome”

• MRI c-spine revealed WM lesion at C4 and C6 with 2 small WM lesions in cortex

Dx ADEM vs MS

• LP with 10 OCB, elevated IgG index

• Treated with IV Solumedrol 1gm q d for 5 days

• F/U mid May pt with normal clinical exam

• June 02 pt develops severe tetraplegia requires admission

Multiple Sclerosis

• MRI reveals extensive demyelination of cervical spine C2-C7 also multiple WM lesions b/l cortex largest in L post parietal region.

• IV Solumedrol 1gm q day started and pt continued to progress

Multiple Sclerosis

• Iv IgG .4gm/Kg for 5 days and pt began to stabilize.

• Treated with chemotherapy (Novantrone)

• Went to inpt rehab and made dramatic recovery.

• Treated with chemo for 6 months and started on Copaxone daily injections

Multiple Sclerosis

• Pt did well f/u MRI with no new lesions pt exam returned to normal other than reflex asymmetry.

• Successful varsity athlete, completed high school, and attended college.

Round #2

• 19 y/o

• Sept 06 developed numbness L midthoracic region into L leg

Round #2

• Treated with IV Solumedrol which caused the pt to become bradycardic and had to be stopped.

• Pt symptoms slowly resolved.

• Switched pt from Copaxone to Rebif.

Round #3

• Early Nov 06 pt developed diplopia and facial weakness.

• Exam revealed R gaze paresis, L INO, R facial weakness, and mild RUE weakness.

Round #3

• Treated with IV IgG .4gm/KG for 5 days with gradual improvement of symptoms

Round #4

• Late Nov 06 developed severe b/l LE (L>R) and LUE weakness.

• Sensory loss L side up to T4

Round #4

• Admitted to hospital received plasma exchange every other day for 14 days, IV Decadron, and Novantrone.

• Pt stabilized and begins to make slow improvement d/c’d home

Round #4

• Pt EF dropped from 71% to 53% making further Novantrone use risky.

• March 07 pt seen in clinic with normal neurologic exam on Rebif inj.

Round #5

Round #5

Round #5

Case #2

• 72 y/o male

• Progressive balance difficulties over the last few months

• Weakness and decreased dexterity of UE

Exam

• Nl mental status

• Normal cranial nerve exam

• 4/5 strength distal UE 5/5 all other muscle groups

• Mild decreased Vib/prop sense LE

• Mildly wide based gait

PML

Questions