Transcript ms goodies - Pennsylvania Neurological Associates

“Living Well With MS”
Problem-oriented MS treatment with
a positive spin
Charles S. Yanofsky, MD
www.susqneuro.com
The Best Revenge is Living Well
Tasks
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Pick your doctor
Build Support System
Plan for treatment
Find Help For your
symptoms
• Pay Attention to
General Health
• Read and ask
questions
“You” to neurologist
What are “you” going to Do??
Doctor
• Good working knowledge
about MS
– Neurologist
– Exp’c with MS patients
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Competence/qualifications
Compassion
? Word of mouth
You get along with
him/her. Mutual
understanding
• Let doctor sweat the
technical stuff and don’t
drive yourself crazy about
Don’t Squander your Doctor Visits
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Focus on 1-2 issues
Have your own agenda
Know what you want
Work Collaboratively
– Doctor is ally not adversary
• “I’m having a problem with such and such.
What can I do about it?”
How Am I Doing??
Supports
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Spouse/sign. Other
Family
Friends
Coworkers
Never lose sight of
what is important to
you.
– What gives you
pleasure/excites you.
Supports
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Who to tell
What to say
What are your expectations of others? Self?
Be sure you don’t ask for what they can’t
provide
To Tell or Not?
• Once you tell someone e.g. your boss you
can’t undo it.
• Consider this Carefully
• ¾ of pts who are disabled file on their own
• ¾ of unemployed MS’ers say they’d like to
work
• 60-70% disclose their MS to their
employers? But When??
Deciding on Therapy
• Suppressing the Disease - the four or five
alternatives.
• What your Doctor recommends
• Preferences?
– Stage/severity of disease
– Lifestyle effects
– Past experience
Interferons
• Low Dose
– Avonex – more convenient, less neutralizing
antibodies
• Hi Dose
– Betaseron, Rebif: Possibly more effective.
Increased effect on liver and neutralizing
antibodies
Interferons
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Betaseron, Avonex, Rebif
Cut attacks by about one third
Flu-like side effect
Liver effect
?Depression
Hold in pregnancy
Copaxone
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Novel Mechanism of action
Every day sq injection
Very well-tolerated
? As much MRI effect
Effect on important MRI black holes
? Effect on Disability
Good long term efficacy – longest experience.
Novantrone
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12 mg/M2/q 3 months
Chemotherapy agent
Cumulative dose 100 mg/M2
Monitor heart EF
New Agents Being Looked At
• Rituxan (Rituximab) binds to b-lymphocyte
CD-20 surface (non-Hodgkins)
• Inosine (Incr uric acid, decr inflamm)
• Zenapax (daclizumab): binds to activated
lymphocyte IL-2 (Kidney transplants)
• Lipitor/Zocor
Symptom Management
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Fatigue
Pain
Gait disturbance
Visual problems
Spasticity
Urology/Sexual
Depression
Cognitive problems
Relationships
General Health
• Diet and Weight
• Exercise
• What’s Important to
you?
Divide and Conquer
Problems, Problems, More Problems!!
Problems have solutions
• Optimism
• Collaboration between
patient and physician
Experience Proves:
Optimism wins out over
pessimism
Optimism vs. Pessimism
• Optimistic Persons do better clinically
– are they optimistic because they feel better or
do they feel better because they are optimistic??
• Optimists are willing to explore possibilities
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Keep trying
Don’t reject therapies that may help
Work with their professionals
bring up issues pertinent to quality of life
Optimism: Rationale
• It works better
• More effective treatments than before
• New effective treatments on Horizon
Demise of Tysabri
• Forces us to look at Options
• Novantrone
• NRABC
Be not Afraid
• New Breakthroughs
• New Strategies
MS Issues
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Neuromuscular function
Gait
Vision
Nutrition
Bladder Function
Sexual Function
MS Issues (cont’d)
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Pain/Paresthesia
Energy
Spousal/ Social/Relationships
Psychiatric
Cognition
Spiritual Needs
Sex
• Complex Issue
• Psychiatric aspects
– Anxiety
– Performance
– Relational
• Physical Issues
– Motor dysfunction
– Sensory Loss
– Ass’d with bladder/ spinal cord
Sex (Sol’s)
• Drugs
– Newer agents
– Stopping certain drugs
• Relational (counseling)
• Techniques
– Methods to get around specific problems
• Openness!!
Psychiatric
• Reaction to chronic disease
• Reaction to other person’s reaction
– spouse
– employer
– other
• Direct effect of MS on brain
• Effect of other meds especially interferons
psychiatric
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Talk it out
support groups
avoid whipping yourself
help with medication
Developing outlets
– pleasures
– hobbies
– “purpose”
Spiritual Needs
• Developing a personal context
• Creating a “network” of acquaintances or
one empathic person
• Refuse to be defined by your illness
• Taking charge
Cognition: More common than
previously realized
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Attention
Concentration
Short-term memory
Information Processing
Executive Function/Organization
Perception
Speech
50 up to 67% of patients
Cognition
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Decreased speed of transmission
Slowness of processing
Problem with multitasking
Everpresent fatigue
Cognition: What’s going on??
• Connections between patches of brain
cortex are frayed.
• Fatigue may play a role
• Speed of communication between patches
or brain
“Lesion Burden”
More lesions = Greater Effect
Less lesion burden
Cognition - solutions
• Problems with thought
don’t make you less of
a person
• Just like a limp or
problem with vision
you have to get around
it
• Efficient working
when you’re at your
best
Cognition: Sol’s 2
• Aids:
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Notes
Organizers
Alarms
Keyboards
Personal Assistants
Cell phone
External brain
Cognition- sol’s 3 :Let people
know...
• You are not goofing off
• You still care about your work
• Slowness of decision making does not make
you indecisive
• If you are distractible it is not because you
don’t care
Medical Solutions
• Drugs for fatigue
• Alzheimer type drugs seem to be effective
– Aricept
• Stimulants and drugs for fatigue
– Provigil, Caffeine, amantadine
• Anxiety is the enemy of recall
• Immunomodulators/suppressants? Long
term prognosis? IF supported by MRI
NM/ Fatigue
• Causes more Weakness
• ?Due to prolonged inflammation
– ?similar to prolonged viral illness (cold)
• Something in the blood causes fatigue
• Damage to nerve fibers is not as important
• ? Does more fatigue mean more
inflammation
• Does fatigue affect prognosis?
NM/Fatigue/Sol’ns
• Drugs:
– Amantadine
– Activating
antidepressants
• Prozac, Wellbutrin
– Stimulants
• Ritalin, Cylert,
– 4-Aminopyridine
– Bupropion (Wellbutrin)
NM/Fatigue/Sol’ns
• Exercise
– Preemptive - Goal to
increase Stamina
• Budgeting Energy
– Energy-Saving
Strategies
Energy:
• Chronic effect of inflammation
• ?Viral Illness?
Energy (Solutions)
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Exercise (Incr. Stamina)
Amantadine
Activating Antidepressants
Stimulants
anti-inflammatories
4-AP
Neuromuscular Function/prob’s
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Weakness
Fatigue
Spasticity
Incoordination
– tremor
– Ataxia
– Dyscontrol
NM Fxn/ Weakness/sol’ns
• Attack: Treat Inflammation
– Steroids, longer acting agents
• Physical Therapies
– Increase strength, endurance
– Movement Strategies
– Assistive Devices
• Occup. Therapy: increase function
NM/Spasticity/Why?
• Nervous system: Control through
INHIBITION
• Brain connection to spinal cord inhibits
reflexes
• Connections are broken
• Reflexes are dis-inhibited (liberated from
higher control
• Reflexes are increased
• Spasticity=Resistance to Motion: Tightness
NM/Spasticity/Sol’ns
• Physical/occup Therapies
• Be sure there are no exacerbating
bladder/bowel problems
• “Limbering” loosening up
• Drugs:
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Baclofen
Tizanidine (Zanaflex)
Valium
Dantrium
MS interrupts pathways
“Attack” = inflammation
Series of MRI scans in one patient
LHermitte Phenomenon
Spinal Cord
INO
Inflamed Optic Nerve
Inflammation
• MS “attack” = Area of inflammation
• One or more Areas in the Nervous system is
inflamed
Problem: Reducing inflammation
• Acute attack
• Preventing attack
Acute Attack
• Steroids
– Solu-Medrol intravenous
– Decdron, Prednisone others
Preventing attack/progression
• Interferons
– Betaseron
– Avonex
– Rebif
• Copaxone
• Novantrone
• Immune-suppressing drugs
– Methotrexate, Imuran, Cell-Cept (mycophenolate),
Baclofen
Baclofen Pump
NM/incoord./problem
• Disconnection of:
– Cerebellum
– Other motor areas
• Tremor
– Postural: trunk and head
– in arms and legs
• Disorganization of Movement
NM/Incoor/Sol’s
• Physical Therapy
– Mov’t Strategies and Synergies
– Assistive Devices
• Drugs
– Tremor
– Coordination
– anti-spastic
NM/Tremor/Surgery
• Thalamotomy/Pallidotomy
• Tremor pacing device
Activa tremor implant
tremor device
• placed in the VIM of thalamus
Gait/Problems
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Weakness
lowers affected more than uppers
Control
Loss of Balance
Ataxia
Gait/Weakness
• Therapy
• Exercise for muscle strengthening
• Stretches and Drugs for Spasticity
Gait/Balance
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Usually temporary
Balance Exercises
cane /walker
vestibular medications
attention to incoordination
Vision
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Loss of Vision in one eye (optic Neuritis)
Double Vision
Problems in coordinating moving eyes
Complex visual perceptive problems
Vision
• Fortunately most problems are temporary
Nutrition
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Regular well-balanced diet recommended
Low saturated fats
Vitamin Supplement
Avoid Obesity
Bladder
• Spastic Bladder
• Flaccid Bladder
• “Dyssynergia”
Bladder/Spastic
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Bladder is small and tight
urgency, frequency
many voids with small volumes
Goes with spasticity in legs
Ditropan (XL), Detrol
Bladder Control
Bladder/flaccid
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Late in disease and less frequent
Bladder is large and empties poorly
Chronic change
Intermittent Catheter usually recommeded
Bladder dyssynergia
• Sphincter and bladder contract together
• Trouble pushing urine out against a closed
sphincter
• Training and medication that affects
contraction of both elements
Bladder
• Spastic
– Oxytrol patch, Ditropan, Detrol
• Outlet obstruction
– Flomax, Cardura, Hytrin
• Decrease Output
– Desmopressin
• Botox in bladder wall
• Urecholine: For flaccid bladder/urine retention
Paresthesias
• Discomfort to severe pain
• “Painful tonic spasms”
• Anticonvulsants
– Tegretol, Dilantin, Neurontin
• Antidepressants
Recent Advances
New Treatments
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Immunomodulators
Antibody Therapies
Pumps
New Drugs
Devices
Rebif study
• Positive results were reported from a large
clinical trial in Europe, Canada and
Australia of interferon beta-1a (Rebif®) in
relapsing-remitting MS. The drug reduced
relapse rate, slowed progression of
disability and reduced MRI-detected brain
lesions. Reduced chance of time to first
exacerbation compared with Avonex.
Betaseron in progressive MS
• A large European clinical trial of interferon
beta-1b (Betaseron®) in over 700 people
with secondary-progressive MS was
stopped early because the study showed the
drug can slow the progression of disability.
The U.S. FDA is reviewing study findings
for possible approval of Betaseron for this
new use
Monoclonal Antibodies
• Researchers across the U.S. continued or
began separate clinical trials of two
monoclonal antibodies (LeukArrest, by
ICOS Corp. and Tysabri (Antegren) by
Athena Neurosciences) aimed at reducing
the severity and duration of MS attacks by
blocking the entry of destructive immune
cells into the brain and spinal cord.
Antegren (Tysabri)
• Elan drug teamed up with Biogen Idec
• monoclonal antibody
• attaches to alpha 4 Integrin
– protein on lymphocyte
– protein is lymphocyte attachment to blood
vessels
Tysabri
• 2 cases of PML – fatal disease
– Both patients using Avonex
• Is drug dead?
• Will this tell us something more about MS?
LeukArrest (monoclonal Ab)
Prevents White cells from invading brain
Red areas = myelin breakdown
Oral interferon
• Researchers at the University of Texas
Health Science Center began a small-scale
clinical trial of an oral form of interferon
alpha for relapsing-remitting disease, based
on positive findings in rodents with MS-like
disease
TCR (t-Cell receptor) peptide
(Connetics)
• vaccine against t-cells
Growth Factors
• Insulin-like growth factor
• Increase myelin
• When and where to implant
Stem Cell Transplants
• May be more effective for diseases that kill
neurons or brain cells
• One day may be effective for treating
certain persons with MS
Herpes 6
• Roseola in toddlers
– erythema subitum
– rash
– neurologic symptoms
– mononucleosis like in adults
• can invade CNS
HHV-6
• Demyelinating when invades CNS
• Detected high levels in MS CNS
(Challoner)
• Detected in bloodstream in MS patients
• Also seen in chronic fatigue
HHV-6 Treatment
• Similar to Cytomegalovirus
• Ganciclorir and Foscarnet
– Gan can affect WBC’s
– Fos can affect Kidneys anemia, lytes
• ?How long to treat?
HHV-6 tests
• Peripheral blood test
• “Shell vial Culture”
• HerpesVirus Diagnostics Inc
– c/o Federal Express, 11101 W. Plank Court,
Wauwatosa, WI 55226
• $270.00
Disability
• If you have little disability over a long time you
are more likely to have mild MS
• Followed patients mild v. not mild for 10 years.
Milder patients progressed less. EDSS of 2 or less
93% chance of little disability. Small study
• Didn’t everybody know that?
• Unfortunately you can’t predict how things will be
early in the disease.
• Pittock et al Annals of Neurology (2004;56:303306).
Genetic Risk of MS
• Risk of MS is 1 per 750 in the United States
• Risk increases to 2-5 per 1000 if first degree
relative has the disease
– 1/40 for parent
• Risk 30-50% for identical twin
• “Multiplex” families with >1 members important
• Implication: MS is genetic with environmental
influence. “Polygenic”
Black v White
• Black: MS about half as common
• Rare in Africa
• Worse disease: More frequent progress to
cane 16 v. 22 years Kurtzke 6 on average
• Neurology 63[11]:2039-45 Dec 14, ‘04
• Black NH residents much more cognitively
and physically impaired and on fewer meds,
younger
Hygeine hypothesis
• Exposure to a younger sib decrease risk of
MS
• Sunlight effect
• MS patients are more sheltered?
– Less exposure to pathogens in early life
• JAMA 1005;293:463-469
Infectious Agents tied to MS
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Canine dystemper virus
Chlamidia pneumoniae
Epstein-Barr (mononucleosis virus)
HHV-6
HTLV l
Measles
PML? (JC virus, SV40 papovaviruses)
? Lyme
Sarcoid
Neuromyelitis Optica IgG
• May be different disease with different
immune determinant
• NMO-IgG to the Mayo Clinic
• The Lancet 2004, Dec 11; 364[9451]:210612 Lennon et al
Hep B vaccine and MS
• MS patients compared to controls had a
threefold increased chance of having gotten
the Hep B vaccine in the past three years.
• 11 of 164 MS patients received at least one
Hep B shot within 3 years compared with
36 of 1604 control patients.
• What does it mean? Nothing.
• 2nd study found no relationship
Statins
• EAE in mice can be partly reversed with statin
• MS patients WBC response becomes more normal
after treatement with statin
• Human MS trials underway
• Small study with Zocor 30 patients encouraging
• Recommendation: If your cholesterol is high, use
statins. Otherwise the jury is still out.
Sun Exposure
• MS more common in higher latitudes
• Tasmania study van der Mei et al More sun
exposure more skin damage associated with
less MS British Medical Journal
(2003;327:316).
• UVR radiation more common in tropics
• ? Effect of vitamin D which has some
immunomodulatory effect
Clinical Trials
• Avonex Plus
– Mtx, azathiatprine, Tysabri
• Copaxone plus
• Betaseron plus
• Rituxan (Rituximab) binds to b-lymphocyte CD20 surface
• Inosine
• Zenapax (daclizumab): binds to activated
lymphocyte IL-2
• ABT-874 immunosuppressor
• Lipitor