PARKINSON DISEASE UPDATE

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PARKINSON DISEASE UPDATE

• HARVEY A. DRAPKIN, D.O., FACN

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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

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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.

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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

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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

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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

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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

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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

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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.

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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!

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WHY DELAY THERAPY?

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

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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?

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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

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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

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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

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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??

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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??

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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

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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

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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

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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.

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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.