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PARKINSON DISEASE UPDATE

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Title: PARKINSON DISEASE UPDATE


1
PARKINSON DISEASE UPDATE
  • HARVEY A. DRAPKIN, D.O., FACN

2
1817 DESCRIBED BY JAMES PARKINSON
  • SIX CARDINAL FEATURES
  • REST TREMOR
  • RIGIDITY
  • FLEXED POSTURE
  • BRADYKINESIA HYPOKINESIA
  • LOSS OF POSTURAL REFLEXES
  • FREEZING PHENOMENON
  • TO DIAGNOSE TWO OF ABOVE, WITH AT LEAST ONE
    BEING REST TREMOR OR BRADYKINESIA

3
CORE BIOCHEMICAL PATHOLOGY
  • IS DECREASED DOPAMINE NEUROTRANSMISSION IN THE
    BASAL GANGLIA. MOST PARKINSON SYNDROMES HAVE
    DEGENERATION OF THE NIGROSTRIATAL DOPAMINE SYSTEM
    WITH MARKED LOSS OF STRIATAL DOPAMINE. IN SOME
    STRIATAL DEGENERATION WITH LOSS OF DOPAMINE
    RECEPTORS OCCURS.

4
DRUG INDUCED PARKINSON
  • RESULTS FROM
  • BLOCKAGE OF DOPAMINE RECEPTORS OR
  • DEPLETION OF DOPAMINE STORAGE, DECREASED
    DOPAMINERGIC ACTIVITY IN THE STRIATUM LEADS TO
    DISINHIBITION OF THE SUBTHALMIC NUCLEUS AND THE
    MEDIAL GLOBUS PALLIDUS, THE PROMINENT EFFERENT
    NUCLEUS OF THE BASAL GANGLIA. UNDERSTANDING HAS
    LED TO DOPAMINE REPLACEMENT, SURGICAL TREATMENT

5
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7
INITIAL SYMPTOMS OF PARKINSON DISEASE
  • 60 OF SUBSTANTIA NIGRA DOPAMINERGIC NEURONS
    ALREADY LOST AT ONSET
  • DOPAMINE CONTENT OF STRIATUM IS ONLY 20 OF
    NORMAL
  • MOTOR SYMPTOMS ARE PROMINENT , i.e. TREMOR,
    STIFFNESS SLOWNESS, LOSS OF DEXTERITY, GAIT
    DISTURBANCE, AND MUSCLE ACHES, PAINS AND CRAMPS.
  • S.N. PATHOLOGY BLACK BROWN TAN

8
NON-MOTOR SYMPTOMS OF PARKINSON DISEASE
  • BEHAVIORAL DEPRESSION, ANXIETY, DECREASED
    MOTIVATION, PERSONALITY CHANGES, LESS INCLINATION
    TO SPEAK, BRADYPHRENIA
  • SENSORY NON-SPECIFIC PAINS, AKATHISIA, RESTLESS
    LEGS AND OTHER SLEEP PROBLEMS
  • AUTONOMIC CONSTIPATION, BLADDER DYSFUNCTION,
    IMPOTENCE, LOW BLOOD PRESSURE

9
PATHOGENESIS OF PARKINSON DISEASE
  • ACTUAL CAUSE UNKNOWN FACTORS IMPLICATED
    INCLUDE
  • GENETIC, ENVIRONMENTAL TOXINS, AND ENDOGENOUS
    TOXINS, FROM CELLULAR OXIDATIVE REACTIONS. TWO
    MAJOR PATHOGENETIC HYPOTHESES
  • MISFOLDING OF PROTEINS, etc.
  • MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

10
DIFFERENTIAL DIAGNOSIS OF PARKINSON DISEASE
  • ESSENTIAL TREMOR OCCASIONALLY CONFUSED WITH
    PARKINSON DISEASE. HOWEVER, 20 OF ET PATIENTS
    DEVELOP PD
  • SECONDARY PARKINSONISM, i.e. DRUGS, NPH,
    INFECTIONS, etc.
  • PARKINSON PLUS SYNDROMES, i.e. CBD, LBD, AD,
    MSA, PSP
  • HEREDODEGENERATIVE HD, WILSON,
    HALLERVORDEN-SPATZ

11
TREATMENT OF PARKINSON DISEASE
  • MEDICAL
  • DOPAMINERGIC AGENTS
  • ANTI-CHOLINERGICS etc.
  • SURGICAL
  • ABLATIVE
  • RESTORATIVE
  • D.B.S.
  • PHYSICAL THERAPIES
  • P.T.
  • O.T.
  • SPEECH
  • OMT, BIOFEEDBACK
  • EXERCISE Rx, TAI-CHI
  • PSYCHOTHERAPIES
  • COUNSELLING
  • SOCIAL WORK
  • MEDS., etc.

12
WHEN TO START TREATMENT FOR PARKINSON DISEASE
  • WHEN DISEASE MANIFESTATIONS INTERFERE WITH SOCIAL
    AND VOCATIONAL ACTIVITIES, WORSENING OR GAIT OR
    BALANCE OR OTHER ACTIVITIES OF DAILY LIVING.
  • PARTNERSHIP WITH PATIENT!

13
WHY DELAY THERAPY?
  • MINIMAL EFFECT ON ADL
  • PATIENT PREFERENCE
  • DRUG SIDE EFFECTS
  • LEVODOPA SPARING STRATEGY TO FORESTALL LONG
    TERM COMPLICATIONS OF THE DRUG

14
WHAT ABOUT NEUROPROTECTIVE AGENTS?
  • ATTEMPT TO SLOW OR IMPEDE DISEASE PROGRESSION AND
    CELL DEATH. HARD TO EVALUATE AS SOME AGENTS ALSO
    CONFER A SYMPTOMATIC BENEFIT.
  • IDENTIFICATION OF PRE-CLINICAL DISEASE STATE AND
    BIOMARKER IS A PRIORITY OF CURRENT RESEARCH.
  • PET AND SPECT?

15
SOME NEUROPROTECTIVE AGENTS MANY ONGOING
STUDIES
  • SERMS PROTECT AGAINST DOPA-ERGIC NEURONAL
    DEGENERATION
  • VITAMIN E (TS) ENRICHES SUBST NIGRA
    MITOCHONDRIA, DECREASED OXIDATIVE STRESS
  • COENZYME Q10 ATTENUATES MPTP EFFECTS ON
    DOPAMINE NEURONS
  • SELEGILINE PRESERVES MITOCHONDRIAL CO-Q10
    LEVELS
  • MINOCYCLINE INTERFERES WITH ACTIVATION OF
    APOPTOTIC PATHWAYS

16
MORE NEUROPROTECTIVE AGENTS
  • AMANTADINE NMDA RECEPTOR ANTAGONIST
  • DOPAMINE AGONISTS ANTI-OXIDANT, PROTECT
    DOPAMINE NEURONS, etc.
  • CALM-PD STUDY PRAMIPEXOLE VS. L-DOPA SPECT
  • REAL-PET STUDY ROPINIROLE VS. L-DOPA FD-PET
  • EARLY PD - CO-Q-10, MAOBIS. DOPAMINE AGONISTS AS
    SYMPTOMATIC TREATMENT

17
TREATMENT OF EARLY PARKINSON DISEASE
  • CONSIDER CO-Q-10, VITAMIN E (TS) MAY HELP LEG
    CRAMPS?
  • SELEGILINE OR RASAGILINE (2ND GENERATION MAOBI)
    AMPHETAMINE EFFECT?
  • AMANTADINE RAPID ONSET OF ACTION, AVOID IN
    COGNITIVE PROBLEMS
  • ANTI-CHOLINERGICS ESPECIALLY GOOD FOR TREMOR
    NOT SO FOR ELDERLY
  • DOPAMINE AGONISTS PRAMIPEXOLE AND ROPINIROLE.
    LONG ACTING

18
WHAT ABOUT LEVODOPA/CARBIDOPA?
  • STILL THE BEST, ESPECIALLY SHORT TERM
  • LONG TERM USE MOTOR FLUCTUATIONS, DYSKINESIAS
  • INVERSELY PROPORTIONAL TO AGE
  • BUT NEARLY ALL PATIENTS EVENTUALLY REQUIRE IT
  • COMTAN EXTENDS HALF-LIFE OF LEVODOPA, EARLY
    USE??

19
WHEN TO START LEVODOPA/CARBIDOPA
  • FOR EARLY SYMPTOMATIC TREATMENT AND FOR RAPID
    RESPONSE, i.e. TO AID PATIENT TO CONTINUE WORKING
    ESPECIALLY FOR RIGIDITY BRADYKINESIA
  • WHEN OTHER MEDS FAIL OR BECOME LESS EFFECTIVE
  • AS ADD-ON TREATMENT TO DOPAMINE AGONISTS, etc.
  • FOR DE NOVO ELDERLY PATIENT. DOPAMINE AGONISTS
    SIDE EFFECTS?

20
SOME STRATEGIES TO ENHANCE L-DOPA EFFECT
  • SELTZER WATER//Parcopa//something new
  • BREAK CRS IN HALF
  • LIMIT DIETARY PROTEIN DURING THE DAY
  • USE CR FORM AT BEDTIME
  • START OFF THE DAY WITH BOTH REGULAR AND CR MEDS
  • ADD COMTAN TO PROLONG EFFECT AND INCREASE
    ON-TIME

21
OTHER THERAPEUTIC OPTIONS - SURGERY
  • ABLATIVE THALAMOTOMY, PALLIDOTOMY
    IRREVERSIBLE
  • RESTORATIVE EMBRYONIC DOPAMINERGIC TISSUE
    TRANSPLANTATION SOME GRAFTED NEURONS
    DIFFERENTIATED AND RE-INNERVATED
  • DEEP BRAIN STIMULATION THALAMIC, PALLIDAL,
    SUBTHALAMIC MORE TREATMENT FLEXIBILITY

22
MOTOR COMPLICATIONS OF PARKINSON DISEASE
  • MAJOR THERAPEUTIC PROBLEM OVER TIME
  • MOST STUDIES SHOW 50 COMPLICATIONS AT 5 YEARS
  • ASSOCIATED WITH
  • DISEASE PROGRESSION
  • PULSATILE NON-PHYSIOLOGIC STIMULATION OF DOPAMINE
    RECEPTORS FROM LEVODOPA

23
MOTOR COMPLICATIONS INCLUDE
  • INVOLUNTARY CHOREIC OR ATHETOID MOVEMENTS
  • MOTOR FLUCTUATIONS INCLUDING WEARING-OFF
  • ACUTE DYSTONIAS
  • ON-OFF PATTERN WITH RAPID FLUCTUATIONS
  • PEAK-DOSE
  • DIPHASIC DYSKINESIAS
  • FOG

24
TREATMENT STRATEGIES FOR MOTOR FLUCTUATIONS
  • PERSISTENT DYSKINESIAS LOWER L-DOPA DOSE, ADD
    AMANTADINE, TRY SINEMET CR
  • PREVENTIVE STRATEGY IS TO START DOPAMINE AGONIST
    MAOBI PRIOR TO L-DOPA
  • WEARING-OFF - CR PREPS, ADD COMTI
  • EARLY AM FOOT DYSTONIA CR AT HS, AND/OR BOTOX

25
MORE TREATMENTS FOR MOTOR FLUCTUATIONS
  • ON-OFF PATTERN WITH RAPID FLUCTUATIONS THESE
    PATIENTS HAVE NARROW THERAPEUTIC WINDOW FOR
    L-DOPA. CONSIDER CR PREPS, COMTI, MAOBI,
    APOMORPHINE, DOPAMINE AGONISTS, LIQ, L-DOPA
  • PEAK DOSE AND DIPHASIC DYSKINESIAS TREAT AS
    PERSISTENT DYSKINESIA
  • FREEZING (OFF ON) PREVENT OFF LOWER DOSE
    FOR ON

26
FOG (FREEZING OF GAIT) IN PARKINSON DISEASE
  • HIGHLY DEBILITATING
  • SHORT-LASTING INHIBITION OF MOVEMENT EXECUTION OR
    SWITCH, OFF FOG IS PART OF ADVANCED PD
  • ON FOG ALSO RELATED TO DURATION OF L-DOPA
    TREATMENT
  • PPFG IS ANOTHER CONDITION IN WHICH FOG IS THE
    PREDOMINANT SYMPTOM
  • PROGRESSES TO WHEELCHAIR IN 5 YEARS

27
FOG PROPOSED MECHANISMS
  • MALFUNCTION OF BASAL GANGLIA AND THEIR
    CONNECTIONS TO MOTOR PROGRAM STORAGE AREA OF
    SPINAL CORD. RESULTS IN CORTICAL OVERDRIVE
    TRANSFORMING AUTOMATIC GAIT INTO A VOLUNTARY
    ACTION. HOWEVER, FOG CAN ALSO BE RELATED TO
    VASCULAR DISEASE AND CEREBRAL ISCHEMIC INSULTS

28
FOG TREATMENT OPTIONS
  • COGNITIVE STRATEGIES SUBSTITUTE A CONSCIOUS
    MOTOR PROGRAM
  • SELEGILINE AND RASAGILINE
  • L-DOPS
  • BOTOX
  • EXTRACRANIAL PULSED ELECTROMAGNETIC FIELDS
  • CSF DRAINAGE
  • DBS OF STN

29
WHAT ABOUT DEEP BRAIN STIMULATION?
  • OFTEN HELPFUL IN TREATMENT OF MOTOR FLUCTUATIONS
  • MOST COMMON TYPE IS DEEP BRAIN STIMULUS OF STN.
    ACTS LIKE ELECTRONIC LEVODOPA. REDUCES TREMOR,
    RIGIDITY AND BRADYKINESIA, ALLOWS REDUCTION OF
    L-DOPA DOSE, BUT ANTI PD-EFFECT NO BETTER THAN
    L-DOPA.

30
MORE ON DEEP BRAIN STIMULATION
  • DEEP BRAIN STIMULATION IS ACTUALLY BETTER FOR
    TREMOR ALONE THAN L-DOPA
  • CONTRAINDICATIONS INCLUDE LACK OF RESPONSE TO
    L-DOPA AND COGNITIVE PROBLEMS
  • ADVERSE EFFECTS OF DBS HEMORRHAGE, INFECTION,
    WIRE BREAKAGE, SPEECH IMPAIRMENT, DYSTONIA

31
MORE ON NON-MOTOR SYMPTOMS
  • ANXIETY DEPRESSION HIGH PREVALENCE BUT
    UNDERDIAGNOSED AND UNDERTREATED
  • USE ANXIETY DEPRESSION SCALES
  • SCREEN PERIODICALLY, i.e. DOWN OR HOPELESS OR
    LITTLE INTEREST
  • MEDS AND LAB SCREENING MAY DETECT TREATABLE
    CONDITION

32
TREATMENTS FOR ANXIETY-DEPRESSION
  • BZPS USE JUDICIOUSLY IF AT ALL. SHORT TERM?
  • BUSPIRONE SLOW ONSET OF ACTION. HIGH DOSES MAY
    WORSEN SYMPTOMS
  • SSRI EFFECTIVE, AMANTADINE LOWERS RISK OF ED.
    5H-T SYNDROME RARE
  • TCAS MAY HELP DROOLING BLADDER SYMPTOMS.
    BUPROPRION, MIRTAZAPINE, NEFAZODONE, VENLAFAXINE
    ALSO USED

33
ADDITIONAL TREATMENTS FOR ANXIETY-DEPRESSION
  • COGNITIVE BEHAVIORAL OFTEN BETTER OUTCOME IF
    COMBINED WITH MEDICATIONS
  • SERIAL ECT BUT MAY AFFECT MEMORY AND COGNITION
  • REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION
  • STRUCTURED PHYSICAL THERAPY PROGRAM

34
HALLUCINATIONS AND PSYCHOSIS
  • MOST HALLUCINATIONS ARE VISUAL DUE TO DISTURBED
    SENSORY PERCEPTION
  • RELATED TO CHRONIC DOPAMINERGIC TREATMENT
  • EARLY ON THINK LBD
  • TWO CATEGORIES MINOR AND ELABORATE
  • OCCUR IN LOW LIGHT AND SLEEP WAKE TRANSITION

35
HALLUCINATIONS AND PSYCHOSIS
  • OCCURRENCE WITH CLOUDED SENSORIUM OR DELIRIUM.
    USUALLY RELATED TO PHARMACOTOXIC, INFECTIOUS,
    METABOLIC OR ENDOCRINE CAUSES
  • TREAT UNDERLYING CONDITION
  • DELUSIONAL STATES OCCUR WITH CLEAR SENSORIUM WITH
    LOSS OF INSIGHT
  • MORE LIKELY IN DEMENTED PARKINSON PATIENTS

36
TREATMENT OF HALLUCINATIONS/PSYCHOSIS
  • SEARCH FOR CORRECTABLE (PIME) ETIOLOGIES
  • COGNITIVE BEHAVIORAL THERAPY
  • GRADUAL REDUCTION OF PARKINSON MEDS
  • QUETIAPINE OR CLOZAPINE WITH OR WITHOUT ECT
  • CHOLINESTERASE INHIBITORS

37
SLEEP DISORDERS IN PARKINSON DISEASE
  • INTRINSIC PART OF PARKINSON DISEASE DOPAMINE
    INVOLVED
  • PREVALENCE 75 TO 98 OF PARKINSON PATIENTS
  • INCLUDE
  • DIMS (DISORDERS OF INITIATING AND MAINTAINING
    SLEEP)
  • PARASOMNIAS
  • D.O.E.S. OR EDS

38
D.I.M.S.
  • PATIENTS HAVE DIFFICULTY FALLING ASLEEP, POOR
    SLEEP QUALITY, FREQUENT AWAKENINGS AND EARLY
    AROUSAL
  • COMMON IN ELDERLY AND MORE SO IN PARKINSON
    DISEASE
  • SLEEP STAGES III IV AND REM ARE DECREASED
  • MOTOR COMPLICATIONS OF PARKINSON DISEASE, PLMS,
    RLS, AND OSA MAY OCCUR

39
PARASOMNIAS SLEEP RELATED BEHAVIORAL EVENTS
  • INCLUDE NOCTURNAL VOCALIZATIONS, SOMNAMBULISM,
    NIGHT TERRORS AND VIVID NIGHTMARES AND RBD
  • REM SLEEP BEHAVIOR DISORDER ACTING OUT DURING
    REM SLEEP DUE TO LOSS OF MUSCLE ATONIA
  • RBD RELATED TO DOPAMINE DENERVATION, MAY
    PREDICT PARKINSON DISEASE

40
EDS - EXCESSIVE DAYTIME SLEEPINESS
  • 15 TO 20 TIMES AS COMMON IN PARKINSON AS HEALTHY
    ELDERLY (1)
  • REASONS INCLUDE PARKINSON DISEASE MOTOR
    DISABILITY AND DISEASE PROCESS, EFFECT OF
    DOPAMINERGIC MEDS, AND OTHER CONDITIONS, i.e.
    DEPRESSION
  • EPWORTH SLEEPINESS SCALE HELPS RULE OUT OSA,
    NARCOLEPSY AND IDIOPATHIC HYPERSOMNIA

41
SOS - SUDDEN ONSET SLEEP
  • EXTREME MANIFESTATION OF EXCESSIVE DAYTIME
    SLEEPINESS VS. SINGULAR ENTITY
  • DOPAMINERGIC DRUGS ARE MAJOR CONTRIBUTORS
  • MODIFIED ESS HELPS TO IDENTIFY PROBLEMATIC EDS,
    i.e. DRIVING, WORKING
  • PSG HELPS RULE OUT PRIMARY SLEEP DISORDER

42
TREATMENT OF EXCESSIVE DAYTIME SLEEPINESS
  • EDUCATE PATIENT REGARDING SLEEP HYGIENE, RISKS OF
    SOS
  • REDUCE OR ELIMINATE SEDATING DRUGS
  • USE LOWEST DOSE OF DOPAMINERGIC AGENTS
  • EVALUATE AND TREAT MED-PSYCH CONDITIONS
  • TRY CAFFEINE AND OTHER STIMULANTS
  • DBS??

43
SO, WHATS NEW IN PD TREATMENT?
  • DOPAMINE AGONISTS
  • APOMORPHINE RESCUE TREATMENT FOR OFF
  • ROTIGOTINE PATCH MONOTHERAPY EARLY ADJUNCT
    TREATMENT FOR OFF
  • SUMANIROLE ALSO NEUROPROTECTIVE
  • ROPINIROLE CR
  • MAOBIS
  • ZYDIS SELEGILINE (ONCE DAILY)
  • RASAGILINE NO AMPHETAMINE EFFECT

44
WHAT ELSE IS NEW IN PD TREATMENT?
  • ISTRADEPHYLLINE SEL. ADENOSINE A2A RECEPTOR
    ANTAGONIST ANTI PD EFFECT WITHOUT DYSKINESIAS.
  • NS2330 TRIPLE MONAMINE REUPTAKE INHIBITOR, i.e.
    DOPAMINE, 5HT, NE, TO HELP MOTOR , COGNITION AND
    DEPRESSION

45
AND FURTHERMORE
  • SARIZOTAN SHTIA RECEPTOR AGONIST AND WEAK
    DOPAMINE ANTAGONIST. ADD ON THERAPY, REDUCES
    DYSKINESIAS
  • TALAMPANEL GLUTAMATE ANTAGONIST. MAY REDUCE
    DYSKINESIAS
  • NEUROPROTECTIVE AGENTS
  • NEUROTROPHIC FACTORS
  • CELL TRANSPLANTATION
  • GENE THERAPY

46
SELECTED REFERENCES
  1. Fahn, S., Przedborski, S. Parkinsonism in
    Merritts Neurology. Eleventh Edition. Chapter
    115. 2005.
  2. Blumenfeld, H. Basal Ganglia in Neuroanatomy
    Through Clinical Cases. Chapter 16. 2002.
  3. Hauser, R., Pahwah, R. Current Treatment
    Challenges and Emerging Therapies in Parkinsons
    Disease Suppl. To Neurologic Clinics. Oct. 2004.
    Vol. 22 No. 35.
  4. Schapira, A.H.V., Olanow, C.W. Neuroprotection in
    Parkinson Disease JAMA, Jan. 21, 2004. Vol. 291
    No. 3.
  5. Morelli, M. Adenosine A2a Antagonists Potential
    Preventive and Palliative Treatment for
    Parkinson(s) Disease. Exp. Neurol 184 (2003)
    20-23.
  6. Sawada, ., Shimohama, S. Estrogens and Parkinson
    Disease. Endocrine Vol. 21. No. 1, 77-79, June
    2003.
  7. Fariss, M.W., Zhang, J-G. Vitamin E Therapy in
    Parkinsons Disease. Toxicology 189 (2003)
    129-146.

47
SELECTED REFERENCES
  1. Sharma, S. et al. Neuroprotective Actions of
    Coenzyme Q 10 in Parkinsons Disease. Methods in
    Enzymology. Vol. 382 (2004).
  2. Thomsa, M., LE, Weidong, Jankovic, J.
    Minocycline and Other Tetracycline Derivatives A
    Neuroprotective Strategy in Parkinsons Disease
    and Huntingtons Disease. Clinical
    Neuropharmacology Vol. 26, No.1, pp. 18-23.
  3. Henchcliffie, C. A Step Toward Restorative
    Therapy in Parkinsons Disease Abstract and
    Commentary. Neurology Alert. Vol. 24 No.2 Oct.
    2005.
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