Each patient ought to feel somewhat the better after the physician's visit, irrespective of the nature of the illness. ~Warfield Theobald Longcope

Multiple Sclerosis: Diagnosis and Treatment

Monique Canonico DO

Assistant Clinical ProfessorJohn A. Burns School of Medicine

April 2015

Objectives

• 1. Learn the disease characteristics and demographics.

• 2. Discuss the pathophysiology.

• 3. Learn the clinical presentation.

• 4. Become familiar with MS therapeutics algorithms

It's not what you look at that matters, it's what you see.

-Henry David Thoreau

Epidemiology

• Peak age 15 to 45

• Women : Men 3 : 1

• Geographic variation

• USA prevalence 0.1%

• Approx. ½ million MS patients in USA

• Life expectancy essentially normal

-avg person US has 1/750 risk of MS (.1%)-risk in child or sibling of pt~ 4%-Monozygotic twins: 30%-over 159 genetic variations related to MS have been identified

GENETICS

What Is MS?• An chronic inflammatory demyelinating disorder of the

CNS of uncertain etiology, likely autoimmune, associated with destruction of myelin sheaths and axons

Trapp, 1998

-Described in late 1800s by Dr. Charcot-Perivascular inflammation and demyelination-Plaques occur anywhere in the CNS

-Most frequent: optic nerve, brainstem, cerebellum, spinal cord-Above lesions correlate with clinical sxs

-Axon sparing within the plaques

Pathological Hallmarks

-Disruption of blood-brain barrier-Unknown if demyelination precedes or follows inflammation-Acute inflammatory response of lymphocytes, plasma cells, macrophages

-Macrophages contain myelin breakdown product-Lymphocytes: antibody- and cell-mediated immunity (direct), secretion of lymphokines or cytokines (indirect)

Plaque evolution

Conduction block at site of lesionSlower conduction time along affected nerveIncreased subjective feeling of fatigue secondary to compensation for neurologic deficits

Results of Demyelination

Normal Conduction

Abnormal Conduction

Spinal MS

CASE 2

Kleinschmidt-DeMasters, 2005

Abnormal MRI Optic Nerve

Dawson’s Fingers

Abnormal MRI of Cerebellum

Symptoms are the body's mother tongue; signs are in a foreign language. ~John Brown

-Episodes of neurologic dysfunction followed by stabilization/remission-Relapses can be rapid or gradual onset-May persist or resolve over weeks to months-Relapsing-remitting pattern is most common in MS

Clinical Presentation

MS Signs and Symptoms

• Fatigue

• Heat intolerance

• Visual symptoms

• Numbness, tingling, loss of sensation

• Weakness

• Imbalance

• Urinary and sexual dysfunction

• Cognitive deficits

-Ascending numbness starting in feet-Bilateral hand numbness-Hemiparesthesia/dysesthesia-Generalized heat intolerance-Dorsal column signs

-Loss of vibration/proprioception-L’hermitte’s sign

Sensory Symptoms

-Unilateral or bilateral partial/complete internuclear ophthalmoplegia-CN VI paresis-Optic neuritis

-Central scotoma, headache, change in color perception, retro orbital pain with eye movement)

Visual Disturbances

-Weakness (mono-, para-, hemi- or quadriparesis)-Increased spasticity-Pathologic signs (Babinski, Chaddock, Hoffman)-Dysarthria

Motor Disturbance

-Urinary incontinence, incomplete emptying -Set up for UTI’s

-Cognitive dysfunction-Fatigue-Sexual dysfunction

Other Symptoms

Pain

• Trigeminal neuralgia in 2 percent

• L'hirmitte's sign in 9 percent

• Dysesthetic pain in 18 percent

• Back pain in 16 percent

• Visceral pain in 3 percent

• Painful tonic spasms in 11 percent

Anxiety and Depression

• Anxiety most prevalent

• 2/3 may have depression

• Euphoria

• Dysphoria

• Depression may severely impact the already present cognitive dysfunction that is associated with MS

Signs

• L’hirmitte’s Sign

• Uhtoff’s phenomenon

Neuro Exam

• Afferent pupillary defect

• Internuclear ophthalmoplegia

• Weakness

• Dysmetria

• Dysdiadochokinesia

• Increased reflexes

• Upgoing toe

Differential Diagnosis• Metabolic: SCD (B12 def),

Adrenomyeloneuropathy

• Connective Tissue Diseases: Sjogren’s, SLE

• Infectious: HIV, HTLV1, Lyme disease, Syphilis

• Structural: Chiari malformation, spinal cord compression

• Genetic: ataxias, paraplegias, mitochondrial

• Neoplastic: CNS lymphoma, paraneoplastic

• “MS variants”: ON, TM, ADEM, NMO

• Other: Neurosarcoidosis, CNS vasculitis

• Psychiatric

MS DIAGNOSIS “DISSEMINATION IN SPACE AND

TIME”

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

labs

• ANA

• ACE

• Lyme

• Anticardiolipin ab

• ESR

• HIV

• Syphilis IgG

• SSA, SSB

• Neuromyelitis optica antibody(AQP4 ab)

New Diagnostic Criteria

• Incorporate use of MRI

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

Earlier MS Diagnosis AugustAugust

NovemberNovember

DIS

DIT

Summarized Diagnostic Criteria

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!

AugustAugust

NovemberNovember

3 of the following:

• 9 T2 or 1 Gd+ • 3 Periventricular • 1 Infratentorial• 1 Juxtacortical lesion

MRI - Dissemination in Space

T2

MRI - Dissemination in Time

CIS> 1 month > 1 month

Gd

> 3 months

Polman, 2005

Gd

T2

CSF Analysis

• 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

• Most helpful for suggesting an alternative Dx-high protein, marked pleocytosis, PMNs

CSF OCB are not specific to MS!

• Lupus 25%• Sarcoidosis 51%• Behcet’s dz 8%

• Syphilis• CJD• Whipple’s disease• Lyme disease• Vasculitidies• Devic’s disease• Healthy siblings of

MS patients

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

TREATMENTACUTE

Steroids

IVIG

Plasma exchange

DISEASE MODIFYING

11 treatments

CAM

Recent evidence based guide lines published by the American Academy of Neurology

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 methylprednisolone one gram daily for 5 days

• Severe cases: up to 2 grams daily 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

Nonpharmacologic Management

• Exercise (avoid overheating)

• Physical / occupational therapy

• Nutrition (avoid extremes of weight)

• Avoid excess heat exposure or elevated core temperature

• Prompt tx of fever with antipyretics• Cool environment / cool bath

PHARMACOLOGICMGT

• MANY OPTIONS NOW

FDA-Approved Disease-Modifying AgentsAubagio (teriflunomide) Avonex (interferon beta-1a) Betaseron (interferon beta-1b) Copaxone (glatiramer acetate) Extavia (interferon beta-1b) Gilenya (fingolimod)   Novantrone (mitoxantrone) Rebif (interferon beta-1a) Tecfidera (dimethyl fumarate) Tysabri (natalizumab)Lemtrada (alemtuzumab)

The Big GunsTysabri (natulizumab)Gilenya (fingolimod)

Lemtrada (alemtuzumab)

Generic Copaxone is Here

• Data presented at the ACTRIMS/ECTRIMS mtg Sept 14

Randomized study comparing Copaxone with a generic version of glatimer acetate in 735 pts and vs placebo

-The GATE study found NO SUCH DIFFERENCES

-The numbers of enhancing MRI lesions were the same over 7-9 mos (the primary endpoint)

-Both groups showed superiority over placebo

-Adverse effects similar

Stem Cell Therapy

• Mesenchymal stem cell therapy for MS passed safety and feasibility in a Phase I study at the Mellen Center for MS

• This paves the way for larger studies

• The strategy is REPAIR of damaged tissues

• 24 patients (14 secondary progressive and 10 with relapsing remitting

• Tx was with autologous adult mesenchymal stem cells from the bone marrow

Neuropsychiatric Symptoms : MS

• Prozac/Paxil for depression

• Venlafaxine or mirtazapine for depression

• Can add methylphenidate if needed

• ECT is OK in MS (but carries risk of relapse)

• Anxiety is the most common MS symptomCognitive Behavioral Therapy is helpful

• Bipolar disease is twice as common in MS tx with valproate or Li or antipsychotics

AGENTAGENT MECHANISMMECHANISM ROUTEROUTE PHASEPHASE

RituximabRituximab Anti CD20Anti CD20 IV (2 x year)IV (2 x year) Phase IIPhase II

CampathCampath Anti CD52Anti CD52 IV (1 x year)IV (1 x year) Phase IIPhase II

DaclizumabDaclizumab Anti CD25Anti CD25 IV or SC (q mo)IV or SC (q mo) Phase IIPhase II

Anti IL-12Anti IL-12 Anti IL-12Anti IL-12 SC (qw or qow)SC (qw or qow) Phase IIPhase II

Statins Statins immunomodulatorimmunomodulator oraloral Phase IIPhase II

TeriflunomideTeriflunomide immunomodulatorimmunomodulator oraloral Phase IIIPhase III

Anti VLA-4Anti VLA-4 SAM inhibitorSAM inhibitor oraloral Phase IIIPhase III

FTY 720FTY 720 immunomodulatorimmunomodulator oraloral Phase IIIPhase III

Oral CladribineOral Cladribine immunosuppressanimmunosuppressantt

oraloral Phase IIIPhase III

MinocyclineMinocycline immunomodulatorimmunomodulator oraloral Phase IIPhase II

EstriolEstriol immunomodulatorimmunomodulator oraloral Phase IIPhase II

MBP 8292MBP 8292 immunomodulatorimmunomodulator IV (q month)IV (q month) Phase IIIPhase III

Therapeutic Agents Under InvestigationTherapeutic Agents Under Investigation

We cannot become what we need to be by remaining what we are.

-Max De Pree

CAM

• AAN guideline Feb 2014

• Knowledgeable advice should be given

• Counseling is part of the evaluation and mgt

• ( part of “Cognitive care” )• -CPT code 99201 (new)• -CPT code 99241 (est)

CAM and MS

• Gingko biloba- NOT helpful for cognition but probably helpful for fatigue

• Reflexology Possibly effective for MS paresthesia

• Vit D-may decrease exacerbations (5000 IU daily)

• Cigarette smoking increases progression in MS

• Cannibis-probably effective for pain and possibly effective foe spasticity

• Magnet therapy• Pulsed magnetic fields probably effective for

decreasing MS fatigue

Pulsed magnetic Field Therapymay help with MS fatigue

CAM in MS: SLeep

•No melatonin!•Theanine Serene (oral supplement)

PROGNOSIS

Time (Years)

Dis

ease

Par

amet

er

INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY

NEURODEGENERATIONNEURODEGENERATION

PROGRESSIONPROGRESSION

RelapsesRelapses

Active WMLActive WML

Time (Years)

Pre-Pre-ClinicalClinical

ClinicallyClinicallyIsolatedIsolated

SyndromeSyndrome

Relapsing-Relapsing-RemittingRemitting

SecondarySecondaryProgressiveProgressive

Rx effectRx effect Poor Rx effectPoor Rx effect

No New WMLs No New WMLs

CLINICALLYCLINICALLYRadiographicallyRadiographicallyPathologicallyPathologicallyRx ResponseRx Response

AtrophyAtrophy

PreclinicalPreclinical Relapsing-remittingRelapsing-remitting

Secondary progressiveSecondary progressive

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

Natural History of Multiple SclerosisRelapses and impairmentRelapses and impairment

cMRI activity (T2, T1+Gd)cMRI activity (T2, T1+Gd)

Axonal lossAxonal loss

Measures of brain volumeMeasures of brain volume

Weinshenker, 1989

15% PPMS15% PPMS

85% RRMS85% RRMS50% SPMS and

50% need a cane 90% SPMS11-15 years

26 years from onset

50% need a cane

5 years

Natural History of RRMS and PPMS

30 years from onset

83% need cane

~ 34% bed bound

22 years from onset

50% bed bound

Weinshenker, 1989

85% RRMS85% RRMS50% SPMS and

50% need a cane

90% SPMS

11-15 years

26 years from onset

Natural History of RRMS and SPMS

30 years from onset

83% need cane

~ 34% bed bound

Summary

• Demographics

• Presentation

• Differential

• Evaluation

• Treatment

Have PAtients call the Hawaii MS SOciety

808 532 0811