MS

Describe MS

• Epi

  • Age?

  • Ratio

  • Lat. Gradient?

  • Race?

  • RR %?

• Correlations:

  • What are the two correlations that increases risk of MS

• Genetics

  • Average Risk?

  • If somebody w/in first degree?

  • Twins?

  • Specific Gene Involved?

MS Epi:

• Peak Age: 20-30 ((24.5 years))

• 2:1 ratio women to men

• Latitudinal gradient 

  • Greater rates @ farther from equator 

• Race:

  • Highest: northern Europeans

  • Lowest: Asians, African Blacks

• 85% Initial RR (Relapsing-Remitting) 

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MS Correlations:

• Smoking:

  • Relative Risk of Smokers: 1.5

  • Risk of dev. SPMS = 3x higher in smokers

• Low Vit D

  • Mixed results in literature

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Genetics

• Average Risk: 1/750 (0.1%)

• If a first degree relative have MS: < 5%

• Twins

  • Monozygotic Twins:  31%

  • Dizygotic Twins:  5%

• Specific Gene Involved:

  • HLA-DR2 allele (Chromosome 6) 

    • Increases risk

Describe the Immunopathogenesis of MS

Inflammation → Demyelination → Axonal Loss

Myelin is stained red and axons green. Arrowheads indicate axons undergoing active demyelination. One demyelinated axon ends with an ovoid (arrow).

The irregular and discontinuous distribution of myelin around axons indicates areas of continuous demyelination.

Axonal transection commonly occurs in both chronic and acute plaques; it is more common than formerly appreciated, and varies in degree among patients.

What is the interpretation of these images?

T1-weighted scan w/ Gd contrast 

• shows areas of inflammation @ sites of Gd penetration 

  • blood vessel -> broken BBB -> CNS.

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T2-weighted (hyperintense) scans 

• visualize heterogeneous lesions 

  • represent cumulative burden of disease.

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T1-weighted hypointense images 

• visualize areas of substantial structural injury (axonal loss and gliosis)

• AKA “black holes.”

What are the four different MS Clinical Subtypes

Draw out the progression of MS

Describe the MS Diagnosis Criteria:

• History

• PE

• Labs

MS Diagnosis Criteria

• History:

  • (2 episodes time and space)

  • Relapsing-Remitting Course

• PE

  • APD

    • Afferent Pupillary Defect

  • INO

    • Inter-Nuclear Ophthalmoplegia

• Labs

  • CSF;

    • IgG index, 

    • OCB

  • Evoked Potentials

    • (VER, BAER, SSEP)

  • Blood

    • Rule out mimickers

  • MRI Brain/Spine w/ + w/o Gd

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MS Misdiagnosis Stats:

• 20%

• Most Common Alt. Disease

  • Migraine:  16%

  • Radiologically Isolated Syndrome (RIS):  9%

  • Spondylopathy:  7%

  • Neuropathy:  7%

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List the Clinical Features Suggestive of MS

• Disease Course

• Epi

• Key Symptoms

List the Clinical Features NOT Suggestive of  Multiple Sclerosis

• Epi

• Disease Course

• Symptoms

Clinical Features Suggestive of MS

• Disease Course:

  • Relapses and Remissions

  • Onset btw 15 - 50 y/o

• Epi:

  • Northern European ancestry 

  • Female

• Key symptoms:

  •  Optic neuritis

    • APD 

  • L’hermitte's sign

    • Shock-like sensation

  • Diplopia-INO

  • Fatigue

  • Uhthoff's phenomenon 

    • (Worsening of existing symptoms and fatigue)

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Clinical Features NOT Suggestive of  Multiple Sclerosis

• Epi

  • Onset: <10 + >50

• Disease Course

  • Steady progression

  • Deficit developing within minutes

• Symptoms:

  • Cortical Defects

    • aphasia, apraxia, alexia, neglect

  • Rigidity, sustained dystonia

  • Convulsions

  • Early dementia

list the different differentials for white matter lesions

Describe the relationship between age and white matter lesions

• 66-80% of MRI scans done on > 65 years of age → has periventricular white matter(PVWM) abnormalities

• Part of Normal Aging Process

Describe where MS White matter lesions occur

Location:

• Corpus callosum

• U-Fibers

  • white matter tracts that connect adjacent gyri (ridges) 

• Temporal Lobes

• Brainstem/Cerebellum

• SC

  • 90% involvement in MS

  • Rare in normal aging/small vessel disease

1. List the two labs that help in diagnosing MS

2. Of the two labs, what other differentials can exist besides MS

IgG Index Differential

• MS (80-90% sensitive/94% specific)

• Other Differentials

  • Aseptic meningitis

  • Lymphoma

  • Neurosyphilis

  • GBS

  • Cerebral Lupus

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Oligoclonal banding

• MS-83-94% specific

• Other Differentials

  • Encephalitis

  • Meningitis

  • Polyneuritis

  • Headache

  • SSPE

• Other CNS Inflammatory Disorders

  • Vasculitis

  • Neurosarcoid

  • CNS Lupus

  • GBS

  • Behcet’s

Describe the Evoked potentials in MS

• VER-80-85% abnormal in definite MS

  • Visual evoked potentials

• SSEP-65-80%

  • Somatosensory evoked potentials

• BAER-50-65%

  • Brainstem auditory evoked responses

1. List the MS Lab Workups

2. Lab Workups for Atypical Cases

MS Lab Workups

• Vasculitis Labs:  

  • [CRP, ESR, C3, C4, ACE]

• HIV, HTLV 1-2

• Vitamin D

• RPR, VDRL

  • Screening for Syphilis

• CADASIL: [Notch 3 mutation]

  • hereditary small‑vessel disease caused by a mutation in the NOTCH3 gene 

• Thyroid Panel

• Lupus Panel

• ANA, Rheum Factor

  • Autoimmune Screen

• Anticardiolipin Ab

  • Part of antiphospholipid syndrome work‑up.

• Lyme

• B12/Folate

• NMOSD Labs

  • neuromyelitis optica spectrum disorder 

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For Atypical cases:

• WBC Arasulfatase A 

  • (MLD)-Mayo Lab, yellow top

• Very Long Chain Fatty Acids (ALD, AMN)

  • Mayo Lab, green top

• Hexosaminidase A 

  • (Tay Sachs)

• Galactocerebrosidase C 

  • (Gal-C)

• Fasting blood lactate, Quantitative plasma AA, and Urine organic acid analysis (MELAS)

• Palmitoyl Protein Thioesterase 1 (adults), tripeptidyl peptidase 1, CLN3, and CLN5 (NCL) (Neuronal Ceroid Lipofuscinosis)

• NPC-1 (Niemann Pick)

  • Buccal or rectal mucosa biopsy for EM or skin biopsy 

    • fibroblast culture or peripheral blood smear 

    • (look for vacuolated monocytes)

• HIV

• Vasculitis W/U:

  • Behcet’s-Pathergy skin test or skin biopsy and/or derm/rheum referral

  • [CRP, ESR, C3, C4, ACE]

• Brain Biopsy

  • NCL shows fingerprint profiles and curvilinear and rectilinear bodies as well as diffuse white matter gliosis

  • Helpful in Systemic Histiocytosis or Whipple’s or Lymphoma

1. List Olek’s Rationale for using Tysabril

2. Limiting factor of using Tysabril

• 68% Relapse Rate Reduction

• 42% Slowing of Confirmed Disability

• 92% Reduction in MRI Gd Lesions

• 83% Reduction in MRI T2 Lesion

• 76% Reduction in MRI T1 Lesions

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Limiting Factor:

• PML: Progressive Multifocal Leukoencephalopathy]

1. List the CIS associated w/ MS

2. What do you do to determine if its CIS or Possible MS Attack in ER?

Clinically Isolated Syndromes (CIS) Associated w/ MS

• Optic Neuritis (ON)

  • Acute loss of vision

• Transverse Myelitis (TM) 

  • Spinal cord lesion

• Brainstem syndrome

  • Diplopia, face numbness or weakness, dysarthria

• Cerebellar syndrome 

  • Balance problems

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CIS or Possible MS Attack in ER Protocol

• Rule out infection

  • Treat w/ Abx if infection 

• Fundoscopy -> Spinal Tap + Blood

  • IgG index

  • OCB 

• Tx: Set-up Outpatient IV methylprednisolone 

  •  1000mg Daily x 5 days w/ no oral taper

  • Dose 1 may be given in ER AFTER LP

1. What is RIS?

2. Describe the relationship between RIS and MS

RIS:

• white matter anomalies characteristic of MS that are found on Brain/SC MRI

  • BUT Pt does not have characteristics of MS at that time

    • NO relapsing or progressive symptoms typical of inflammatory demyelination.

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RIS and MS

• 34% w/in 5 yrs to have an MS event

• 10% fulfilled the criteria for PPMS

• Significant Predictors of First Event:

  • Age + male + lesions @ Cervical/Thoracic Spine

1. Describe the relationship between MS and ONTT/CIS

2. Describe Interferon (IFN) Neutralizing Antibodies

   • What what are they?

   • Drugs Affected

3. List the biomarkers that rules out MS

ONTT ((Optic Neuritis Treatment Trial)):  

• 15 years -> 50% developed MS

• Baseline MRI

  • NO Lesions: 25% developed MS

  • >1 lesion: 72% developed MS

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CIS:

• % of developing MS

  • NO Lesions on Initial MRI: 19% MS in 14 years

  • >1 lesion on Initial MRI: 88% MS in 14 years

• % Developing EDSS (Expanded Disability Status Scale)

  • NO lesions on initial MRI: 6% EDSS (>6) in 20 yrs

  • >10 lesions on initial MRI: 45% EDSS (>6) in 20 yrs

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Interferon (IFN) Neutralizing Antibodies

• What are they?

  • antibodies pt develop against interferon‑β medications -> reduces effectiveness 

• Drugs Affected:

  • Avonex-5%

  • Rebif-25%

  • Betaseron-38%

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Biomarkers that rule out MS

• Aquaporin-4 

  • [Neuromyelitis Optica-NMO]

    • Serum:  91% specific and 73% sensitive

    • CSF:  60% predictive

• Myelin Oligodendrocyte Glycoprotein (MOG)

  • Marker for MOG‑associated disease (MOGAD) 

• JC Virus Antibodies

Describe the Ms Medications Decision Tree

• current therapy doing well

• New diagnosis RRMs

• Current therapy not doing well

Ms Medications Decision Tree

• current therapy doing well: No Changes

• New diagnosis RRMS

  • NO JC Ab: Tysabri

  • Jc Ab Pos: 

    • Tecfidera

    • Tysabri for 12 months -> Tecfidera

• Current therapy NOT doing well:

  • Switch to other DMT

  • Add Immunosuppressant

  • Switch to IVIG or IV Cytoxan

List the Potential Indicators of Suboptimal Response

• Clinical Indicators

• Functional Indicators

• Radiologic Indicators

Clinical Indicators

• Relapse frequency

  • ≥1 severe relapse or ≥2 relapses of any severity in 1 year

  • Relapse frequency not decreasing after pt on DMT for ≥6 to 12 months 

• Incomplete recovery at 6 months from one or more attacks

• Involvement of multiple neurologic systems or functional domains 

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Functional Indicators

• Progressive motor or cognitive impairment -> interferes w/ daily activities 

  • (after ruling out contributing factors)

• Increasing EDSS score or permanent residual disability

  • ***NOTE: Changes in EDSS scores <3.0 should not be used isolation to define treatment failure***

  • *** Increase in EDSS of ≥1  from prev score of 3.0–5.5 or 0.5 point increase from prev score of ≥6.0 = RRMS ->  SPMS or partial response to treatment in SPMS***

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Radiologic Indicators

• New or recurrent brain stem or spinal cord lesions

• Increasing lesion number/Size 

  • ***(eg, ≥3 enhancing lesions, or >3 new T2 lesions in 1 year, or ≥2 new T2 lesions on each repeated scan performed at no less than quarterly intervals)***

  • ***especially Significant if increase in >2 types of lesions or in the presence of EDSS worsening independent of attack***

List the MS Medications based on type

• PPMS

• SPMS

• SPMS w/ attacks

List the Treatments for Acute Attacks

List Tx for NMO

• PPMS

  • Ocrevus

• SPMS

  • No RRMS medications 

    • (Except Active SPMS-see below)

  • Trial of immunosuppression

    • MTX, Imuran, Cellcept, CTX, IV steroids

    • IVIG

    • PE (Plasma Exchange)

    • BMT (Bone Marrow Transplantation)

• SPMS with Attacks

  • Tecfidera

  • Tysabri

  • Mavenclad

  • Mayzent

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Acute Attacks Treatment

• Rule out Infection

• IV/Oral steroids or Achtar Gel

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NMO

• Rituxan

• Soliris (eculizumab)

• Enspryng (satralizumab)

• Uplizna (inebilizumab)

• Other immunosuppressants