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Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments. Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology The Ohio State University. Objectives. 1. Learn to diagnosis MS

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Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments

Aaron Boster M.D.

Assistant Professor of Neurology

Division of Immunology

The Ohio State University


Objectives

  • 1. Learn to diagnosis MS

  • 2. Learn to assess the risk of developing MS after a Clinically Isolated Syndrome

  • 3. Become more familiar with MS therapeutics and treatment algorithms


Questions:

  • 1. When faced with a clinically isolated syndrome, which tests can help delineate the risk to develop MS? 

  • 2. True or False: Starting MS therapies early improves long term outcome.

  • 3. True or False: MS patients have high risk pregnancies.


What Is MS?

Trapp, 1998

An chronic inflammatory demyelinating disorder of the CNS of uncertain etiology, likely autoimmune, associated with destruction of myelin sheaths and axons


MS Signs and Symptoms

  • Fatigue

  • Heat intolerance

  • Visual symptoms

  • Numbness, tingling, loss of sensation

  • Weakness

  • Imbalance

  • Urinary and sexual dysfunction

  • Cognitive deficits


Epidemiology

Peak age 15 to 45

Women : Men 2.5 : 1

Geographic variation

USA prevalence 0.1%

Approx ½ million MS patients in USA

Life expectancy essentially normal

Total lifetime cost > $2,200,000


Natural History of Multiple Sclerosis

Relapses and impairment

cMRI activity (T2, T1+Gd)

Axonal loss

Measures of brain volume

Secondary progressive

Preclinical

Relapsing-remitting

Adapted from Goodkin DE. UCSF MS Curriculum. January 1999.


Natural History of RRMS and PPMS

22 years from onset

5years

50% need a cane

50% bed bound

15% PPMS

85% RRMS

26 years from onset

50% SPMS and 50% need a cane

90% SPMS

11-15 years

30 years from onset

83% need cane

~ 34% bed bound

Weinshenker, 1989


Pathologically

Radiographically

CLINICALLY

Rx Response

Clinically

IsolatedSyndrome

Relapsing-

Remitting

Pre-Clinical

Secondary

Progressive

INFLAMMATORY ACTIVITY

Relapses

Atrophy

Active WML

Poor Rx effect

Rx effect

No New WMLs

PROGRESSION

NEURODEGENERATION

Time (Years)


CASE 1

30yo Science Teacher


CASE 1 30yo WF science teacher

1year ago, 3 week history of urinary urgency & frequency, one episode of fecal incontinence and bilateral foot numbness with frequent tripping

6 months ago, 2 week history of clumsy gait and poor balance, tremors of the right hand

1 month history of blurry vision with right gaze only


CASE 1 EXAM

Left intranuclear ophthalmoplegia

Hyper-reflexia of the bilateral legs

Bilateral upgoing toes (+ babinski)

Absent vibration, poor proprioception in feet

Mildly dysmetric finger-nose-finger and ataxic fine finger movements R>L

+ Romberg

Ataxic gait


CASE 1

  • Does she have MS?

  • How do we diagnose MS?


MS Diagnosis“Dissemination in space and time”


Diagnostic Criteria

  • Dawson criteria: 1916

  • Schumacher criteria: 1965

  • Poser criteria: 1983

  • McDonald criteria: 2001

  • Revised McDonald criteria: 2005

  • All criteria require dissemination in time and space


Summarized Diagnostic Criteria

August

November

1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS

2. Dissemination in Time:

Onset of neurological deficits separated by at least one month

3. Rule out other explanations!


New Diagnostic Criteria

DIS

August

November

DIT

  • Incorporate use of MRI

  • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time =

    Earlier MS Diagnosis


MRI - Dissemination in Space

3 of the following:

  • 9 T2 or 1 Gd+

  • 3 Periventricular

  • 1 Infratentorial

  • 1 Juxtacortical lesion


MRI - Dissemination in Time

Gd

Gd

> 3 months

T2

T2

> 1 month

> 1 month

CIS

Polman, 2005


DIAGNOSTIC WORK UP

  • History & Physical Exam

  • Brain and Spinal Cord MRI

  • Labs: rule out mimics of MS

    • Connective tissue diseases, infections, metabolic disorders

  • Cerebrospinal Fluid (when clinical and MRI evidence inconclusive)

  • Evoked Potentials:

    • Identify damage to visual, auditory, & touch perception systems

    • Less sensitive than MRI or cerebrospinal fluid


CSF Analysis

  • • Most helpful for suggesting an alternative Dx

  • -high protein, marked pleocytosis, PMNs

  • Elevated IgG Index >0.7

    • Increased CNS IgG synthesis, with normal serum IgG consistent with MS

  • Oligoclonal Bands

    • Presence of 2 distinct bands in CSF is consistent with MS


CSF OCB are not specific to MS!

  • Lupus 25%

  • Sarcoidosis 51%

  • Behcet’s dz 8%

Syphillis

CJD

Whipple’s disease

Lyme disease

Vaculitidies

Devic’s disease

Healthy siblings of MS patients

adapted from a lecture by Peter Riskind MD PhD 11/19/05


Metabolic: SCD (B12 def), Adrenomyeloneuropathy

Connective Tissue Diseases: Sjogren’s, SLE

Infectious: HIV, HTLV1, Lyme disease, Syphillis

Structural: Chiari malformation, spinal cord compression

Genetic: ataxias, paraplegias, mitochondrial

Neoplastic: CNS lyphoma, paraneoplastic

“MS variants”: ON, TM, ADEM, NMO

Other: Neurosarcoidosis, CNS vasculitis

Psychiatric

Differential Diagnosis


CASE 1

NEWLY DIAGNOSED RRMS

  • > 2 historical events with objective findings on examination

  • MRI consistent with MS

  • Normal “rule out labs”

  • CXR normal


Disease Modifying Therapies: 1993-2002

Glatiramer Acetate

(Copaxone®)

1997

IFN -1b

(Betaseron®)

1993

IFN -1a

(Rebif®)

2002

IFN -1a

(Avonex®)

1996

Type PolypeptideRecombinantRecombinantRecombinant

mixtureprotein proteinprotein

Indication Reduce freq. Reduce freq. Reduce freq.Slow prog.

of relapses of relapses of relapses in relapsing

in RRMS SlowDelay forms

disability indisability in Prevent 2nd

relapsing forms relapsing forms attack in CIS

Injection SC SCSC IM

Administration DailyEvery other day3x/week Weekly

Dosage 20 mg 250 g (8 MIU) 44 g 30 g


Reduction in Relapse Rate:

2 year data from Phase III Studies

70

60

50

40

32

% Reduction vs Placebo

29

28

30

18

20

10

0

Copxone

Avonex

Betaseron

Rebif


Glatiramer Acetate

Injection Site Reactions

Idiopathic Injection Reactions

Interferons

Flu-like symptoms

Liver dysfunction

Bone marrow

Endocrine abnormalities

Other:

Depression

Spasticity

Headaches

DMT Side Effects


Natalizumab

  • Humanized monoclonal Antibody against 41integrin

  • Selective adhesion-molecule inhibitor (SAM)

  • Prevents transendothelial migration of activated leukocytes from small venules into CNS


“68% relative reduction in the annualized

rate of relapse produced by natalizumab

was maintained at two years (P<0.001)”


Kleinschmidt-DeMasters, 2005


Second Line Agents

  • When a patient has failed or is otherwise unable to tolerate IFN and GA

    • Tysabri

    • IVIG


CASE 2

High School Football Star


CASE 2 - 16yo AAM, High school Football star

  • History: Woke blind in left eye, complains of pain with extra occular movements

  • Exam: Va OD 20/20, OS 20/200.

  • Left disk pallor, Left Afferent pupillary defect.

Optic Neuritis, a Clinical Isolated Syndrome


CASE 2

  • “Can I still play football?”

    “What is my son’s risk of developing Multiple Sclerosis?”

“Yes”

“We need an MRI and LP”


CASE 2


415 CIS pts with MRI & CSF and 50 month follow-up

+OBC doubled conversion risk to CDMS, independent of MRI findings


Optic Neuritis, CIS

  • MRI Brain & C spine

  • CSF: IgGI, OCB, W,R,G,P

  • IVMP 1gm daily x 5 days

WHAT ABOUT EARLY DMT?


CHAMPS, ETOMS, BENEFIT, PRECISE STUDIES

First ever attack

Second attack

placebo

Avonex, Rebif, Betaseron, or Copaxone

Time to Second Attack Delayed with Treatment


CASE 3

26yo IRS agent


CASE 3

  • 26yo LH WF with RRMS diagnosed 2yrs ago

  • 3 day history of difficulty writing, clumsy and numb left hand

  • No signs/symptoms of infection

  • No prior history of similar symptoms


CASE 3

ACUTE MS RELAPSE

  • IO & FE 4/5 on left hand

  • Hyper reflexia of left arm

  • Ataxic FFM & dysmetric FNF on left

  • Decreased LT on left face, arm, leg


CASE 3

Expanded Disability Status Scale

EDSS=0 last 3 visits


CASE 3

Acute MS Relapse

Expanded Disability Status Scale

Current EDSS=3


HOW TO IDENTIFY A RELAPSE?

  • CRITICAL,compare with previous examinations (history and examination), when ever possible

  • Relapses can be precipitated by infections and fever

    • Check U/A for occult UTI


TREATMENT OF RELAPSE

  • INPATIENT

    • Severe deficits

    • Risk of fall or other injury

    • Poor social support

  • OUTPATIENT

    • All other relapses


TREATMENT OF RELAPSE:

  • IV Solumedrol one gram daily for 5 days

  • Severe cases: up to 2 grams qd x 7d

  • Oral Prednisone for special circumstances

    • poor veins, insurance issues, travel, etc…


TREATMENT OF RELAPSE: PLASMAPHERESIS

  • Severe relapses not responding to steroids

  • 5 to 7 courses done on alternate days for 2 weeks

  • One course takes place over 3 to 4 hours


CASE 4

27yo Apartment Manager


CASE 4

Rapidly Worsening MS

  • 27yo F diagnosed with RRMS 5 years ago

  • DMT with Rebif since diagnosis

  • Suffered 3 MS relapses in past 15 months

    • each treated with Solumedrol

    • Incomplete recovery of cerebellar and pyramidal function

  • EDSS 1 year ago was 2.5, now 5.5


Rapidly Worsening MS

  • Documented worsening corresponding to >3 point EDSS increase in previous 12 months despite at least 6 months of IMT and at least 2 courses of IVMP

Treatment: Intense Immunosuppression


Rationale for Intense Immunosuppression in Rapidly Worsening MS

  • Inflammatory damage occurs during early RRMS

  • Permanent tissue damaged from recurrent bouts of inflammation, even during the silent periods of so-called remission

  • Accumulated disability is at least in part secondary to early active inflammatory disease

  • We can treat inflammation

  • During later disease stages, there

    is no / less inflammation and our

    treatments are not effective


GOOD IIS CANIDATE

  • Active progression over past several months or frequent severe relapses

    2. Age < 40

    3. Ambulatory

    4. Earlier disease course (RRMS or early SPMS)

    5. Incomplete recovery from relapses

    6. Frequent relapses leading to disability

    7. Persistence of multiple Gd+ MRI lesions

Boster, Lancet Neurology, 2008

0


POOR IIS CANIDATE

1. Age > 50

2. Long-standing, stable disability

-Predominantly motor or cerebellar deficits

-Non-ambulatory status

3. Significant spinal cord atrophy

4. Significant other medical problems

Boster, Lancet Neurology, 2008

0


Pulsed IVMP

  • May attempt to “stabilize” disease course

  • 1gram IVMP q15-30 days x 3-6 months

  • CRITICALto have close follow-up and document objective changes on exam


MITOXANTRONE

  • Chemotherapy drug used to treat a variety of cancers since 1987

  • FDA approved for progressive forms of MS or worsening RRMS

  • 12 mg/m2 q 3 months, many other regimens


CYCLOPHOSPHAMIDE

  • Chemotherapy agent

  • Also used in other autoimmune disease

  • Monthly IV infusion as an outpatient


Adverse RXN and Complications


Natalizumab

  • Not been studied in rapidly worsening MS

  • Extrapolate data from Phase II and AFFIRM trials

  • Risk of PML


CASE 5

45yo Automotive Executive


CASE 5

SPMS

  • 45yo RH M with 13yr history of MS

  • DMT with Glatiramer Acetate

  • Last MS relapse 7 years ago

  • Ambulation:

    • Cane 4 years ago

    • Walker 3 years ago

    • Wheelchair 1 year ago


Natural History of RRMS and SPMS

50% SPMS and 50% need a cane

85% RRMS

11-15 years

26 years from onset

90% SPMS

30 years from onset

83% need cane

~ 34% bed bound

Weinshenker, 1989


Treating SPMS

  • No treatment has been shown to be helpful UNLESS the patient still has superimposed relapses


Treating PPMS

  • PROMiSe trial post hoc analysis Glatiramer Acetate slowed progression of disease in men with earlier disease

  • IVIG

    • Delayed progression by 12 wks vs PCB (Pohlau, 2007)

    • Results need to be confirmed

  • Consider challenge with steroids or IIS if relatively rapid decline in ADLs


CASE 6

36yo Physician


CASE 6

  • 36yo WF with 4yr history of RRMS

  • Betaseron for past 3.5 years

  • Last MS relapse 1 year ago

  • EDSS 2, unchanged for past year

Wants to become

pregnant


Pre-pregnancy Counseling

MS not worsened

by pregnancy

Pregnancy not

worsened by MS

  • No differences in Prenatal Care

  • MS has no known effect on fertility

  • “High Risk” should be determined on

  • obstetrical status and disease activity

  • Little evidence to support increased risk

  • of relapse with anesthesia administration

  • Closely monitor for urinary tract infections


Pre-pregnancy Counseling

  • Only 10-15% of MS is familial


Pregnancy and Relapse Rate

Pregnancy

Pre-Pregnancy

Post Partum

PRIMS, n=254


Pre-Pregnancy Planning

Planned Pregnancy

  • Discontinue DMT 1-2

    menstrual cycles before

    planned conception

  • Brain MRI Scan

    Unplanned Pregnancy

  • First Trimester: Discontinue DMT

  • Second Trimester: Review safety data


Relapses During Pregnancy

Risk-Benefit Assessment:

severe motor, sensory or

cerebellar deficits that

affect ambulation

  • IV Solumedrol (Cat C)

  • Plasmapheresis

  • IVIG (Cat C)


DMT During Pregnancy

  • Insufficient data to

    support use of DMT

    during pregnancy

  • Interferons (Cat C, Abortifactant)

  • Glatiramer acetate (Cat B)

  • IVIG? (Cat C)


Post-Partum Management

Post-Partum DMT

  • Resume soon after delivery

    or after breastfeeding

    Breastfeeding

  • Not contraindicated

    • But DMT pass into breast-milk

  • May decrease relapse rate

    Post-Partum Relapses (~30%)

  • Treat with IVMP (PE or IVIG)

    • IVMP may impair wound healing

    • ? Prophylaxis with IVIG


Therapeutic Agents Under Investigation


Questions?


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