presentation by Kyle Smoot, MD
Oregon Clinic, West
Good Samaritan and St. Vincent's MS Center
November 9, 2009
Receives Honoraria from Serono and Pfizer
EPIDEMIOLOGY
leading cause of disability in young adults in US and Eur
400,000 pts in US
peaks age 25-35
female:male 2:1
women affected earlier than men
geographic distribution: more in northern N America and Europe
CASE FOR EBV AS ETIO
high DBV seropositivity in MS (99% vs 90-95% in general pop)
higher EBV seropositivity in kids with MD
higher seroprevalence rates with EBV
higher risk of developing MS with HX of infx mono
incr CD4 and CD8 immune response
CASE FOR VITAMIN D
D involved in suppression of pro-inflam cytokines, downreg of MHC class II
D has protective effect
reduction in relapse rate, serum levels assoc w/ MS related disability
8% relapse w/ vit D vs 30% w/o
dose in study: 14,000 IUs/day is usu dose, up to 40,000 (loading) then back down
no complications seen from these D doses
SYMPTOMS
optic neuritis, visual loss, pain with eye mvt, color distortion
brainstem lesions, binocular diplopia (INO), trigeminal neuralgia, vertigo (constant)
cortical/spinal cord lesions (bad in cord)
Lhermitte's sign and Uhthoff's symptom (worse with heat)
cognitive dysfx (late)
depression, constipation, fatigue
evidence of dissemination in space (multifocality)
and dissemination in time (recurrent attacks or progression)
bladder sx, retention, urging
CLINICAL COURSE
mc: relapsing remitting--exacerbations lasting 12+ hours and progressing gradually (90%)
primary progressive (mc in older pts and men) gradual worsening w/o attacks (no good tx)
secondary progressive starts relaps/remit then progressive (50 or 15%)
progressive-relapsing--steady decline with attacks
DIAGNOSIS
difficult to diagnose, no one test confirms, may follow pt for a while to dx
HX: the key part
PE:
afferent pupillary defect(swing test, dilettation instead of constrition)
intranuclear opthalmoplegia (look L and R, one eye doesn't adduct, classic esp in youth)
if double vision close one eye, if double goes away it's neuro
upper motor neuron signs: hyperreflexia, clonus
check for Babinski, may see spasticity, weakness
Imaging: MRI
white matter lesions on MRI, flarelike, near corpus callosum, adjacent to ventricles
multiple white matter lesions around ventricles or deeper in white matter
CSF: evoked potentials, IGG index and somekindaclonal bands, not specific
visual evoked potentials, look at checkerboard, mb very abn w/o optic neuritis
LABS: to rule out other DDX if HX indicates, he doesn't check these often
Lyme dz: he doesn't check if they're from PDX but checks with easterners, false + common
Syphillis: ask for risk factors, test if +
Lupus: ask if other systemic sx
Sarcoidosis: pulm involvement?
MCDONALD MS DIAGNOSTIC CRITERIA 2005 REVISED
change in sx, MRI, , find chart online
TX FOR SX OF RELAPSE
IV solumedrol 10000mg once a day for 3 days
usu follow w/ prednisone taper
plasmaphersis
for spasticity, depression, fatigue, constip, bladder and sex dysfx, cognitive impairment
baclofen and xanoflex for spasticity
amantadine for fatigue used in 30-40% of pts
provigil for fatigue used in narcolepsy
bladder and sex dysfx, use detrol
for cognitive impairment, ginkgo results not good, don't have good meds
TREATMENT FOR RELAPSING/REMITTING
Interferon Beta: avonex, betaseron, rebif
MOA: reduces TNF alpha, favors Th2, reduces passage or immune cells across BBB
Avonex 1a-IM weekly
Betaseron 1b-subcut alt days
Rebif 1b-subcu, 3x/wk
these around 15 years now
decr relapse by 30%, decrease MRI burden of T2 and enancing T1 lesions, decr disability
SE: muscle aching after injx, incr fatigue, chills, premed with naproxen or alleve
liver effects, check fx tests, no failure yet
may have to stop dt SEs
Neutralizing ABs: if you develop these the meds less effective, Betaseron mc, he doesn't use it
BEST therapy?
debatable
he's comparing all these drugs
four studies listed
Rebif pts more relapse free than Avonex, more injx site rxns
Betaseron better than Avonex in non-blinded study
Rebif vs Copaxone no big diff but less Gd+ lesions in Rebif group
Betaseron vs double dose vs Copaxone-->no sig diff
IFN not greater effect on T2, mb Gd enhancing activity
IFN not better for relapses, not more rapidly working
Copaxone not more tolerable
Glatirmaer Acetate (copaxone)
daily subcut injx
MOA: promote Th2 prolif & cytokines, competes with MBP for presentation on MHC class II, alters fx of macrophages
SE: no ache but yes flush
Imunosuppressant (Mitoxantrone/Novatrone
FDA approved, reduces relapses by 67%, prolongation to first relapse, delay in progression
SEs: cardiotoxicity, AML, amenorrhea
reserved for pts with rapidly advancing dz who've failed other therapies
Alpha4 Integrin antagonist (Natalizumab/Tysabri)
reduces relapses, slows progression
2 trials, impressive results, approved 2004
infusions given monthly
SE: infusion rxn, hep dysfx, Abs form in 6%, PML = progressive multifocal leukoencephalopathy in pts with immunocompromise, in those with JC polyomavirus (Abs present in 50-70% of adult pop, slowly prog demyelinating dz: dementia, motor dyxfx, vision loss, MRI: asymmetric, confluent white matter change, ill-defined and not enhancing
med suspended in 2005 dt 2 pts died of PML
also was used in Crohns and one of those pts got PML
pts who died were also taking avonex or methotrexate
reintroduced June 2006, TOUCH program
since 2006 24 more cases of PML
est risk: 1/1000
he doesn't have many pts on this, only uses if they're not doing well on other meds
COMPLEMENTARY THERAPIES FOR MS
diet: low sat fat, Swank diet
N-3 fatty acids: supp n-3 fatty acid reduces inflam cytokines
Add vit E to offset poss depletion with PUFAS
Vitamin D: 2000IU/day or 50,000IUs/week x3mo if low
he leaves other supps to pt (vit C, zinc, selenium can boost immune sys, he says you don't necc want to do that so he doesn't recommend high doses)
alphalipoic acid of some benefit:
prevents T cells from migrating across BBB, not combined with tysabri
low dose naltrexone (3-4.5 mg) used, seems to help metnal health not physical, need studies
cannabis for spasticity and urge incontinence
exercise: yoga for irritability and fatigue, teacher in Ca has program, tai chi
acupx: mostly for sx, fatigue, anxiety, mb spasticity, he uses it, helps some not others
EMERGING THERAPIES
ORAL MEDS
Cladribine: reduces CD4Tcells, infrequent dosing, at phase III
Teriflunomide inhibits B cells, in phase II, causes encephalitis
Fingolimod traps Tcells inperipheral lymph nodes, in phase II
Fumaric acid deviates T cells, causes flush, GI events, elevated LFTs, in phase II
Laquinimod promotes Th2, crosses BBB, getting ready for phase III
Monoclonal ABs: Rituximab/Rituxan used in B cell lymphoma, anti-CD20, Daclizumab/Zenapax, Alemtuzembab/Campath bindes CD52, once a year but causes probs, Ocrelizumab recruiting for phase II
QUESTIONS
Correlations of MS with mercury amalgams or heavy metal toxitiy? He doesn't look into that. "The thought from our side is there is no connection."
Helminthe therapy to push Th2 response? "It's a nice theory"
How to find studies quoted? He'll email references.
What is effect of placebo in trials? Small effect.
CIDP = chronic inflammatory demyelinating polyneuropathy presents with muscle weakness distally, loose reflexes
Young pt poss MS what odds of show up on MRI? "it just depends" more if classic optic neuritis, depends on exam, sx, if less weakness then less likely to be MS
Triggers of relapses? stress or none. he doesn't have them keep a journal but it sounds like a good idea. infx, a cold may trigger.
Prevalence of sexual dysfx? 30-40% have dysfx "we're not good about talking about it", ED in men, women can't orgasm, loss of sensation in genital region
Test vit D levels in all? yes. Find optimal levels in anyone? 10%. He says 30-50 is good level according to his lab, he shoots for 50, checks ea 3 mo. Just started doing this in last year.
Life expectancy? doesn't change, pneumonia and bed sores are issues. fewer people are going into secondary progressive with earlier treatment.
How tx GI issues? for constip uses stool softeners, magnesium. Rare for other issues to happen. Constip as presenting sx? not really.