demyelinating dz

Question 1

1. Be able to describe the basic subtypes of MS

Answer 1

Relapsing-Remitting (RRMS): Sporadic episodes of new or worsened symptoms (over 2-10 days), with variable improvement over 1- 6 months. Primary Progressive (PPMS): slow progression, without relapses. Secondary progressive MS: Start with relapsing course, but goes on to become progressiv. Relapsing-Progressive (RPMS): combo of relapses and progression from outset. Clinically isolated syndrome: first attack. Radiologically isolated syndrome: MS on MRI but without clinical attack.

Question 2

Which MS subtype is most common overall

Answer 2

relapsing remitting (85%).

Question 3

How many RRMS convert to SPMS?

Answer 3

50%

Question 4

tumefactive lesions

Answer 4

> 2cm, mimic tumors

Question 5

which MS subtype is most common in young adults? Middle age?

Answer 5

The majority of young adults are diagnosed with Relapsing-Remitting MS. Primary progressive is most common in middle age

Question 6

2. Be able to describe the basic epidemiology of MS (ie age, sex, ethnicity, geography)

Answer 6

A. Age: up to 3/4 present between ages 15-45. B. Sex: at least 2/3+ are women; increased prevalence over last several decades primarily seen in women. C. Highest incidence in Caucasians, tho recent data questions this. D. Geography: incidence increases with distance from equator; highest in UK, Iceland, Canada, Australia, USA

Question 7

MS pathology

Answer 7

demyelination, perivascular lymphocytic infiltrate, Axonal loss and formation of axon bulbs in both acute and chronic lesions, gray matter lesions, brain and/or spinal lesions,

Question 8

compare immunopathology btw MS patients

Answer 8

At least four types of immunopathology in white matter have now identified. Between patients, immunopathology is variable, while within a single patient, immunopathology does not vary. Gray matter lesions are classified based on location, NOT immunology

Question 9

Pathogenesis of MS

Answer 9

T cell activation in blood or lymph nodes by APC with antigen > T cells activate matrix metalloproteinases > BBB becomes leaky > T cells, B cells, macrophages, complement enter through BBB > B cells present antigen and secrete Abs > cytokine release in CNS causes further BBB breakdown > myelin and oligodendrocyte damage

Question 10

Discuss white matter immunopathology and MS subtypes

Answer 10

All Type IV are PPMS. Types I/II correlate with encephalomyelitis. Types III/IV correlate with oligodendrocyte dystrophy

Question 11

MS genetics

Answer 11

–Risk linked to HLA DR2; Link to IL-7 receptor, IL-2 receptor mutations; now >200 genes linked, most at odds ratios of about 1.1. Increased risk in family memebers

Question 12

MS and environmental causes

Answer 12

Risk factors include viruses (EBV), chlamydia, pneumoniae, smoking, Vitamin D deficiency (risk of developing dz and higher risk of relapse), obesity in young women, high salt diet (risk of worse MS)

Question 13

How is MS diagnosed

Answer 13

1. Multiple CNS lesions disseminated in space (2 separate locations in CNS) and time (RRMS – 2 or more clinical attacks 30+ days apart. PPMS - Minumum 12 months of progression of Sx) 2. Abnormal exam without other identified cause. 3. Primarily clinical diagnosis, but MRI/CSF can help define dissemination in time/space. 4. Dx afer single attack and single scan if certain MRI features seen

Question 14

MS early symptoms

Answer 14

Often unifocal at first, paresthesias (numbness and tingling), monocular loss of vision (optic or retrobulbar neuritis), gait problems, weakness, diplopia (double vision), Lhermitte’s (paresthesias down spine with neck flexion), urinary urgency/frequency, constipation
Often unifocal at first, paresthesias (numbness and tingling), monocular loss of vision (optic or retrobulbar neuritis), gait problems, weakness, diplopia (double vision), Lhermitte’s (paresthesias down spine with neck flexion), urinary urgency/frequency, constipation
Often unifocal at first, paresthesias (numbness and tingling), monocular loss of vision (optic or retrobulbar neuritis), gait problems, weakness, diplopia (double vision), Lhermitte’s (paresthesias down spine with neck flexion), urinary urgency/frequency, constipation

Question 15

MS late symptoms

Answer 15

Multifocal and more general: early symptoms plus fatigue, sexual dysfunction, depression, cognitive dysfunction, pain, dysphagia; rarely, seizures and hearing loss; problems related to immobility

Question 16

MS exam- corticospinal, sensory, visual

Answer 16

Often assymmetric, especially early. Mixed signs over time, as lesions accumulate. CORTICOSPINAL – weakness, spasticity, inc reflexes (upper motor neuron signs). SENSORY – loss/”added” sensation; cord level. VISUAL – acuity loss, eye movement abnormalities

Question 17

MS exam - cerebellar, mood, cognition, sexual

Answer 17

CEREBELLAR – ataxia, tremor, dysarthria (“Charcot’s triad”), balance, coordination. MOOD – depression, emotional lability. COGNITIVE IMPAIRMENT - ST memory, word-finding, visual-spatial function, hand-eye coordination. SEXUAL – impaired sensation

Question 18

Labs to diagnose MS

Answer 18

MRI, CSF analysis, Evoked potentials, optical coherence tomography, blood

Question 19

MS- MRI T1 results

Answer 19

a. T1 “holes”, bad long-term prognostic sign consistent with axonal damage, often felt consistent with more chronic lesions, but can be seen early. b. T1 with contrast-enhancing lesions = Blood-Brain-Barrier breakdown, and typically seen early in evolution of lesion, with enhancement only lasting 2-6 weeks. Enhancement means leakage of the dye is seen. Bad short-term prognostic sign

Question 20

MS- MRI T2 results

Answer 20

T2 hyperintense/bright lesion, seen with acute and chronic lesions, and includes FLAIR (fluid attenuated inversion recovery – makes CSF dark). There are many causes of bright dots on the T2 and FLAIR images, not just MS, so the pattern of lesions is RELATIVELY specific for MS. “Burden of Disease”, ie volume of lesions, seen even on first scan is predictive of disability over time.

Question 21

MS- MRI non contrast

Answer 21

atrophy: white and/or gray matter focal atrophy and brain parenchymal fraction global atrophy

Question 22

Long-term bad Prognostic Factors for MS

Answer 22

1) Atrophy, especially gray matter 2) High Burden of T1 holes 3) High Burden of T2 lesions 4) Posterior Fossa lesions 5) Spinal cord lesions

Question 23

nonspecific brain MRI changes

Answer 23

migraine, HTN and aging can all show up as microvascular ischemic dz

Question 24

MS- CSF analysis (protein, WBC, glucose, Igs, myelin basic protein)

Answer 24

Protein less than 110 mg/dl , WBC rarely more than 40/mm3, Glucose always normal, Immunoglobulins in CSF abnormal about 95% (elevated IgG index and/or oligoclonal bands >5), MBP elevation non specific

Question 25

IgG index

Answer 25

(IgG CSF / IgG serum)/ (Alb CSF/ Alb serum)

Question 26

What are evoked potentials used for in MS

Answer 26

PPMS diagnosis only. prolonged conduction times consistent with demyelination – visual, brainstem and somatosensory

Question 27

What method is used to measure disease progression of MS

Answer 27

Expanded Disability Status Scale : Zero is normal exam, 3 is moderate disability in at least one subscale, 6 is requires a cane to walk, 10 is death due to MS.

Question 28

MS prognosis

Answer 28

lifespan decreased 6-7 yrs. Unfavorable prognosis for males, older age at onset, African-americans

Question 29

MS therapy- behavioral

Answer 29

exercise, don’t smoke, vitamin D, treat co-morbidities such as HTN, DM, obesity

Question 30

MS therapy for acute attacks

Answer 30

will shorten attack, but no conclusive evidence this affects long-term progression of disability

1. High-dose corticosteroids: IV Solumedrol +/- Prednisone taper. Oral may work equivalently, so long as the dose is equal, but need to take MANY pills 2. Plasma exchange for severe demyelination unresponsive to steroids :works really only with Type II pathology, this may be first PATHOLOGY-SPECIFIC treatment in MSwill shorten attack, but no conclusive evidence this affects long-term progression of disability
2. High-dose corticosteroids: IV Solumedrol +/- Prednisone taper. Oral may work equivalently, so long as the dose is equal, but need to take MANY pills 2. Plasma exchange for severe demyelination unresponsive to steroids :works really only with Type II pathology, this may be first PATHOLOGY-SPECIFIC treatment in MS

Question 31

Immunomodulation in MS- first line drugs used and outcomes

Answer 31

•Interferon beta-1a (AVONEX, REBIF), Interferon beta-1b (BETASERON) and Glatiramer acetate (COPAXONE) are all approved for RRMS (home injections). Over 2-4 yrs, reduce new attacks by 1/3, slow progression of disability, decrease enhancing lesions and slow progression of T2 burden. Avonex may slow brain atrophy. All are poorly tolerated (ABC-R)

Question 32

Which immunomodulation drug in MS is more effective?

Answer 32

Tysabri (Natalizumab- Ab against a4-integrin)

Question 33

Tysabri MOA

Answer 33

a4-integrins are molecules on leukocytes that bind to VCAM-1 on the endothelial cells of the BBB, and facilitate adhesion and migration into the BBB. Tysabri blocks the a4-integrins from binding to VCAM-1, thus preventing leukocyte migration across the BBB

Question 34

Risks of using Tysabri

Answer 34

Risk of developing progressive multifocal leukoencephalopathy. Risks for development of PML include exposure to the JC virus, duration of use, prior exposure to chemotherapy (especially Mitoxantrone), and possibly small body mass and the so-called JCV Index or antibody titer, with higher Index associated with higher risk.

Question 35

Gilenya (fingolimod)

Answer 35

For RRMS. Phase II drug Is a superagonist of Spingosine-1- Phosphate -1 (S1P1) receptors seen in lymph nodes. Activation traps lymphocytes in lymph nodes. Superior to interferon B-1a (avonex)

Question 36

Aubagio (Teriflunomide)

Answer 36

Trials with good efficacy, acceptable safety, pregnancy category x. Phase II drug

Question 37

Tecfidera (Dimethyl fumarate, or BG12)

Answer 37

–Trials with excellent relapse effect, appears safe, ?better than GA. Phase 2 drug

Question 38

Lacquinimod

Answer 38

•Two Phase III completed , modest effect on relapses, 1/3 reduction in disability progression, safe

Question 39

Estriol

Answer 39

Combo with GA: At 1 year, significant reduction in relapses, and improvement in cognition vs GA alone

Question 40

Treatment of RRMS guidelines

Answer 40

Greatest risk of new disease activity is early, SO, Use more effective medications earlier/first

Question 41

Limitations of current therapy

Answer 41

Only partial, limited efficaacy in progressive MS, expensive, side effects, none restore funcion or replace neurons

Question 42

Treatment of SPMS

Answer 42

Only Betaseron is FDA-approved for SPMS, and only when still with relapses, but all meds are often used. First line therapy (not approved, but used) and mitoxantrone (FDA approved)

Question 43

Treatment of PPMS

Answer 43

nothing seems to work. Rituximab sometimes used