“Living Well With MS”

Problem-oriented MS treatment with a positive spin

Charles S. Yanofsky, MDwww.susqneuro.com

The Best Revenge is Living Well

Tasks

• 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 neurologistWhat are “you” going to Do??

Doctor

• Good working knowledge about MS– Neurologist– Exp’c with MS patients

• 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 it.

Don’t Squander your Doctor Visits

• 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

• Spouse/sign. Other• Family• Friends• Coworkers• Never lose sight of

what is important to you.– What gives you

pleasure/excites you.

Supports

• 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

• Betaseron, Avonex, Rebif

• Cut attacks by about one third

• Flu-like side effect

• Liver effect

• ?Depression

• Hold in pregnancy

Copaxone

• 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

• 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

• 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– 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

• Neuromuscular function

• Gait

• Vision

• Nutrition

• Bladder Function

• Sexual Function

MS Issues (cont’d)

• 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

• 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

• Attention• Concentration• Short-term memory• Information Processing• Executive Function/Organization• Perception• Speech• 50 up to 67% of patients

Cognition

• 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

• pacing

Cognition: Sol’s 2

• Aids:– 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)

• Exercise (Incr. Stamina)

• Amantadine

• Activating Antidepressants

• Stimulants

• anti-inflammatories

• 4-AP

Neuromuscular Function/prob’s

• 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:– Baclofen– Tizanidine (Zanaflex)– Valium– Dantrium– Botox

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

• 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

• Usually temporary

• Balance Exercises

• cane /walker

• vestibular medications

• attention to incoordination

Vision

• 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

• Regular well-balanced diet recommended

• Low saturated fats

• Vitamin Supplement

• Avoid Obesity

Bladder

• Spastic Bladder

• Flaccid Bladder

• “Dyssynergia”

Bladder/Spastic

• Bladder is small and tight

• urgency, frequency

• many voids with small volumes

• Goes with spasticity in legs

• Ditropan (XL), Detrol

Bladder Control

Bladder/flaccid

• 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

• 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;56:303-

306).

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

• 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]:2106-12 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 CD-20

surface• Inosine • Zenapax (daclizumab): binds to activated lymphocyte

IL-2• ABT-874 immunosuppressor• Lipitor