Transcript Multiple Sclerosis - CMSA Madison Area Chapter

Multiple Sclerosis:
A Diagnosis and Treatment Update
Case Manager Society of America
Natasha Frost, MD
5/26/2016
Objectives
Define Multiple Sclerosis (MS)
Forms of MS
Diagnostic Criteria
MS Treatment
Disease modifying
Symptomatic
MS symptomatic issues important to therapy professions
Multiple Sclerosis
An immune-mediated disease of the central nervous system
A disease of myelin and axons
A disease of people and behaves differently in everyone
Huge spectrum of severity and disability from the same
disease
Balancing the Mediators of the Immune System
Proinflammatory and
Neurotoxic Factors
TH1 and TH17 cytokines
TNF
IL-1
osteopontin
leukotrienes
MMP
plasminogen activators
nitric oxide
reactive oxygen species
glutamate
antibody + complement
cell-mediated cytotoxicity
neurotrophins via p75NTR?
Destruction
Anti-inflammatory and
Neuroprotective Factors
TH2 cytokines
TGF-beta
soluble TNF receptor
soluble IL-1 receptor
IL-1 receptor antagonist
some prostaglandins
lipoxins
TIMP
antithrombin
BDNF
NGF
NT3
neurotrophic
NT4/5
factors
GDNF
LIF
The balance between the protective and destructive
response determines the net
effect of the inflammatory response
Kerschsteiner M et al. Ann Neurol 2003;53:292-304
Protection
Active Inflammatory Demyelination and Axonal Transection
It has been shown that
active inflammation results
in both demyelination and
axonal transection
Arrowheads = areas of active demyelination; Arrow = terminal axon ovoid; Human brain;
Red = immunostained for myelin basic protein; Green = immunostained for nonphosphorylated neurofilament;
Bar = 45 m.
Trapp BD et al. N Engl J Med. 1998;338:278-285.
Peterson JW et al. Neurol Clin. 2005;23:107-129.
Who gets MS and why?
Usually diagnosed between 20 and 50
Occasionally diagnosed in young children and older adults
More common in women than men (>2-3:1)
More common in smokers and children of smokers
Most common in those of Northern European ancestry
More common in Caucasians than Hispanics or African Americans;
rare among Asians
More common in temperate areas of the world
Environmental factor(s)?
Genetic factor?
Lower vitamin D exposure?
Combination?
What are the typical signs?
Classically
Optic neuritis
Transverse myelitis
Brainstem syndrome (diplopia)
Other
Numbness, weakness, vertigo etc.
More non specific but probably just as
common as classic presentation.
Differential Diagnosis of MS
(not all inclusive)
Infection - Lyme, syphilis, PML, HIV, HTLV1, Herpes
viruses
Inflammatory - CTD, vasculitis, sarcoid, Behcet’s,
Susac’s, celiac disease, NMO/Devic’s
Genetic/metabolic - B12, Copper, lysosomal, ALD,
mitochondrial, CADASIL, other genetic
Neoplastic - CNS lymphoma
Spine disease - vascular malformations, tumor,
degenerative/compressive spine disease
Psychiatric – psychosomatic, depression, etc..
Diagnosing MS
MS is a clinical diagnosis
Signs and symptoms
Paraclinical tests provide support
Magnetic resonance imaging
Spinal fluid
Evoked potentials
Diagnostic criteria:
Dissemination in time and space: evidence that damage has
occurred in at least two separate areas of the CNS at different
points in time
There must be no other explanation
Conventional MRI in MS Clinical Practice
FLAIR
T2
BOD*
T1 precontrast
T1 Gd
postcontrast
Disease Activity†
Black Holes†
The strongest
correlation with
progression of
disability
*Reprinted with permission from Miller DH et al. Magnetic Resonance in Multiple Sclerosis. Cambridge: Cambridge
University Press; 1997. †Reprinted with permission from Noseworthy JH et al. N Engl J Med. 2000;343:938-952. Copyright
© 2003 Massachusetts Medical Society. All rights reserved.
MRI in MS: typical features vs non specific
Peri-ventricular
Sub-cortical
Perpendicular
to ventricle
more specific for MS
Deep white
matter
Anterior/
posterior
horns
non-specific for MS
Clinical Patterns of MS
Relapsing-remitting
Secondary progressive
Primary progressive
Progressive relapsing
Time
Adapted from Lublin et al. Neurology.
1996;46:907-911.
Clinically Isolated Syndrome (CIS)
A first neurologic event suggestive of demyelination
Individuals with CIS are at high risk for developing clinically
definite MS if the neurologic event is accompanied by multiple,
clinically silent (asymptomatic) lesions on MRI typical of MS
Several MS medications are approved in CIS at risk for MS
Radiographically isolated syndrome
A MRI that looks “like MS”
No signs or symptoms of MS
Negative Prognostic Indicators
Frequent, multifocal attacks
Heavy MRI burden on initial scans
Pyramidal involvement
Ataxia
Cognitive difficulties
5 year accumulation of disability
Spinal progression (primary progressive MS)
?Males, older age at first symptoms, race
Relapse Management
Relapse = NEW symptom lasting at least 24 hours, and usually
accompanied by an objective change in neurologic findings.
Rarely “old symptom” that is worse.
“pseudo relapses” are common and should not be treated with steroids
Treatment with corticosteroids recommended if relapse
significantly interferes with functioning
3-5 day course of high-dose intravenous methylprednisolone with or
without oral taper
If very mild sensory symptoms or intermittent it can be allowed to just
run its course.
Other options – ACTH, IVIG or plasma exchange.
Rehabilitation can help restore function following a relapse
Disease modifying therapies (DMT)
Medication
Dose
Route
Frequency Side effects and monitoring
Inteferon betas
(Avonex, Betaseron,
Rebif, Extavia,
Plegridy)
varies
Self injection
IM or SQ
Every other day
to every 2
weeks
Flu like and injection site reactions
CBC, LFT, TSH monitoring
Glatiramer Acetate
(Copaxone)
20-40 mg
Self injection
SQ
Daily to 3 times
per week
Site reactions, lipoatrophy, and post injection reaction
Fingolimod
(Gilenya)
0.5 mg
Oral
Daily
Cardiac, macular edema, and infections
6 hour monitoring during first dose.
Labs and OCT afterwards
Teriflunomide
(Aubagio)
14 mg
Oral
Daily
Liver toxicity, hair loss, nausea,
Stays in system 2 years without chelation
Pregnancy Category X
Monthly LFTs for 6 months
Dimethyl fumarate
(Tecfidera)
240 mg
Oral
Twice a day
Flushing, GI side effects, rare infection
LFT and CBC monitoring
Natalizumab
(Tysabri)
300 mg
IV
Once a month
Rare infusion reaction and PML
Close clinical and imaging monitoring
Alemtuzumab
(Lemtrada)
12
mg/day
IV
Once a year, 5
day course x2
Other serious autoimmune (thyroid, TTP, kidney),
infection, malignancy, infusion reactions.
Monthly labs 4 years.
Mitoxantrone
(Novantrone)
12
mg/m2
IV
Every 3 months
Leukemia and cardiac toxicity, chemotherapy side effects
Frequent labs during treatment and life long follow up.
Why treat?
Goal is to reduce
Relapses
Disability progression
At 10 years w/o
50% need gait assistance
10% wheelchair
Progression of cognitive
difficulties
45-65% cross sectional.
Development of MRI lesions
Progression of brain atrophy
None are perfect
Early treatment important
7 years of imaging in a patient with relapsing
MS – courtesy of R. Fox
The Future of Treatment
Stem cells
Autologus versus donor
Intravenous versus intrathecal
Neuroprotection
Remyelinating agents
Medications for primary and secondary progressive MS
Ocrelizumab
Improved symptomatic management
Improved rehabilitation and devices
MS Symptomatic Treatment- so many things to talk about
and often too many medications
Symptoms
Fatigue, spasticity, pain, depression, cognitive dysfunction, balance,
neurogenic bladder/bowel, tremor, weakness, paresthesias,
numbness, gait disorder, falls, constipation, vision loss, and others.
MS is commonly blamed for all complaints. Especially those that
are not easily explained.
PT, OT, rehab and exercise are often the best place to start.
If these do not help we have many medications at our disposal but
caution as polypharmacy and medications side effects are very
common.
Depression in MS
Depression is common in MS
Lifetime prevalence 50% or more.
12 mo. prevalence 15-25%.
4.75x rate of antidepressant use as age matched controls and 3.21
those with OA.
Depression correlates with gender, marital status, insurance, fatigue
and DMT use.
Also, increased rate of suicide
IF they contact someone for depression it is usually PCP.
Responds to combination of therapy and medications (SSRIs etc…)
Worsens many other symptoms and makes them harder to treat.
(Kessing, International Clinical Pharmacology, 2008)(Cetin, MS, 2007)
Anxiety Disorder (25% prevalence in MS)
Etiology: reactive or biologic? Debated
Very common at time of diagnosis especially if some anxiety disorder
prior
Anxiety in partners of MS patients is equal to that of MS patients
Patient education, reassurance (e.g., at first diagnosis: “life isn’t over;
disease is mild in many patients, now many treatments”), and
psychotherapy are effective.
Counseling first and pharmacotherapy, if indicated: benzodiazepines
(note cognitive risk in MS) or SSRIs
Janssens ACJW. Acta Neurol Scand 2003;108:389
Cognitive problems in MS
Cognitive Disorder –
subtle changes are common (65+%)
severe dementia is uncommon
rare isolated first presentation
neuropsychological testing may be helpful
most studies to not indicate a benefit in MS from anti-Alzheimer’s
meds
behavioral strategies help
look for other fixable coexisting causes
Vitamin deficiencies
Thyroid problems
Depression
Medication side effects
Common and “fixable.”
Fatigue (lack of energy, lassitude)
Mild fatigue is almost universal in MS
Severe fatigue may be disabling in ≈ 5+% of MS patients
Fatigue may be associated with or due to depression, anxiety, sleep
disturbance, pain, heat sensitivity, diminished physical or mental
reserve, co-morbidities
First, assess/treat relevant medical (e.g., anemia, hypothyroidism) or
psychiatric co-morbidities
Second, non-pharmacologic therapy: exercise, behavioral therapy,
energy conservation (prioritize, naps, cooling), smoking cessation
Third, pharmacologic treatment: amantadine, modafinil/armodafinil,
methylphenidate, amphetamine
Krupp LB, Serafin DJ. Ch. 56 in JJA Cohe, RA Rudick. Multiple Sclerosis Therapeutics,
2012
Temperature sensitivity
Heat sensitivity is very common in MS
Sometimes cold reported as well (spasticity)
Brings back any old symptom when core temperature is up
Some studies suggest as little as ¼ degree
Not new damage, but decompensation under stress
Environment, exercise, illness, fever
Treat with
NSAIDs/Tylenol when ill
Cooling vests and other aides
Cold drinks, exercising in cool area/fan etc..
Cool down and wait it out
Gait Disorder
Figure out of MS related or other (such as joint disease)
Referral to therapy and increased activity
Treat spasticity
Evaluate for assistive devices
Cane, walker, chairs
AFO, walkaide/bioness
Money available for assistance NMSS/MSAA as not FDA approved
for MS.
Hip assist device
Medication for walking
Dalfampridine SR (Ampyra)
Dalfampridine SR (Ampyra)
Dalfampridine SR (Ampyra) – potassium channel blocker,
“axonal stabilizer”
Approved to improve walking speed in any form of MS
10 mg every 12 hours
Renal clearance (no kidney disease, increased dose increased
risk seizure)
In pivotal clinical trial
Improvement in timed 25 foot walk
Subset works and others does not
Subjectively other symptoms may improve but only has
approval for walking and often must prove effective
Ampyra
•
•
•
Average change in walking speed from baseline in double blind placebo controlled study.
More patients had a 10-30% improvement in timed 25 foot walk on Ampyra.
In both trials, 34-42% of patients responded versus 8-9% of placebo.
(Figure taken from Ampyra prescribing guide).
Spasticity
Therapy and home stretching
Aerobic activity program for any able limbs
Antispasticity medications
Lioresal (Baclofen)
Tizanidine (Zanaflex)
Sometimes benzodiazepines or others
Botox
Works best for single limb or targeted function
Baclofen pumps
Trial needed
Can be very effective for severe or more wide spread spasticity with
fewer systemic side effects.
Rarely infectious or malfunction complications
Neuropathic pain
Can be one of the hardest symptoms to treat
Again, make sure consistent with MS and nerve pain
Everything we use for this is used off label
Medications
Gabapentin, pregabalin, carbamazepine, phenytoin, lamotrigine,
duloxetine, tricyclic antidepressants etc.
NSAIDS
Narcotics
pain referral with procedures
Infusions, injections, morphine/baclofen pump
neurosurgery or radiation oncology referral
Radiofrequency ablation for trigeminal neuralgia or other
destruction of pain fibers.
Other overlooked symptoms
Balance
Fall prevention and home safety
Therapy, exercise, Tai Chi and Yoga
Coordination and ataxia
Therapy and adaptations
Tremor
Medications – beta blockers, topiramate, benzos etc.
Weighted utensils, pens, and other adaptations
Diplopia- prisms
Speech
Speech therapy and aspiration prevention
Very rarely feeding tubes
Other overlooked symptoms
Neurogenic bladder
Fluids and treating constipation
Evaluating caffeine intake
Urinary tract infections
Medications for overactive versus atonic bladder
Catheterization if needed
Neurogenic bowel
Fiber and fluids
Then, pro motility agents if needed
Sexual dysfunction (men and women)
Treat pain, mobility, and counseling
Medications for erectile dysfunction
Devices for erection or stimulation
This is the hardest for patients to bring up
Resources
National MS society (nmss.org)
WI chapter with support resources and patient
information.
Clinical trials by state (also clinicaltrials.gov)
Multiple Sclerosis Association of America
(MSAA.org)
UW MS Center
Myself, Dr. Luzzio, Dr. Fleming, and Jocelyn Wilke,
NP.
Appointments – 608-262-0546
[email protected]
Thank you and questions