PARKINSON DISEASE UPDATE

HARVEY A. DRAPKIN, D.O., FACN

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

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.

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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LOSS OF DEXTERITY. AND MUSCLE ACHES. PAINS AND CRAMPS. PATHOLOGY: BLACK BROWN TAN .e. • S. i. STIFFNESS & SLOWNESS.N. TREMOR.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 . GAIT DISTURBANCE.

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

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

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

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

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

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

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? .WHAT ABOUT NEUROPROTECTIVE AGENTS? • ATTEMPT TO SLOW OR IMPEDE DISEASE PROGRESSION AND CELL DEATH.

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 COQ10 LEVELS • MINOCYCLINE – INTERFERES WITH ACTIVATION OF APOPTOTIC PATHWAYS .

L-DOPA – SPECT • REAL-PET STUDY – ROPINIROLE VS. • CALM-PD STUDY – PRAMIPEXOLE VS. PROTECT DOPAMINE NEURONS. L-DOPA – FDPET • EARLY PD .MORE NEUROPROTECTIVE AGENTS • AMANTADINE – NMDA RECEPTOR ANTAGONIST • DOPAMINE AGONISTS – ANTI-OXIDANT.CO-Q-10. MAOBI’S. DOPAMINE AGONISTS AS SYMPTOMATIC TREATMENT . etc.

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.TREATMENT OF EARLY PARKINSON DISEASE • CONSIDER: CO-Q-10. LONG ACTING .

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.WHAT ABOUT LEVODOPA/CARBIDOPA? • STILL THE BEST. EARLY USE?? .

e. • FOR DE NOVO ELDERLY PATIENT.WHEN TO START LEVODOPA/CARBIDOPA • FOR EARLY SYMPTOMATIC TREATMENT AND FOR RAPID RESPONSE. i. 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. DOPAMINE AGONISTS SIDE EFFECTS? . etc.

SOME STRATEGIES TO ENHANCE L-DOPA EFFECT • SELTZER WATER//Parcopa//something new • BREAK CR’S 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” .

PALLIDOTOMY – IRREVERSIBLE • RESTORATIVE – EMBRYONIC DOPAMINERGIC TISSUE TRANSPLANTATION – SOME GRAFTED NEURONS DIFFERENTIATED AND REINNERVATED • DEEP BRAIN STIMULATION – THALAMIC. SUBTHALAMIC – MORE TREATMENT FLEXIBILITY .OTHER THERAPEUTIC OPTIONS .SURGERY • ABLATIVE – THALAMOTOMY. PALLIDAL.

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 .

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 .

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

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

“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 .FOG (FREEZING OF GAIT) IN PARKINSON DISEASE • HIGHLY DEBILITATING • SHORT-LASTING INHIBITION OF MOVEMENT EXECUTION OR SWITCH.

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

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 .

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

DYSTONIA .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. SPEECH IMPAIRMENT. WIRE BREAKAGE.

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

AMANTADINE LOWERS RISK OF ED. NEFAZODONE. 5H-T SYNDROME RARE • TCA’S – MAY HELP DROOLING & BLADDER SYMPTOMS. SHORT TERM? • BUSPIRONE – SLOW ONSET OF ACTION. BUPROPRION. MIRTAZAPINE. HIGH DOSES MAY WORSEN SYMPTOMS • SSRI – EFFECTIVE. VENLAFAXINE ALSO USED .TREATMENTS FOR ANXIETY-DEPRESSION • BZP’S – USE JUDICIOUSLY IF AT ALL.

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 .

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 .

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

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 .

O. OR EDS .E.S.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.

S. RLS.M. POOR SLEEP QUALITY.D. AND OSA MAY OCCUR . PLMS.I. • PATIENTS HAVE DIFFICULTY FALLING ASLEEP. 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.

PARASOMNIAS – SLEEP RELATED BEHAVIORAL EVENTS • INCLUDE NOCTURNAL VOCALIZATIONS. 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. SOMNAMBULISM. MAY “PREDICT” PARKINSON DISEASE .

DEPRESSION • EPWORTH SLEEPINESS SCALE HELPS RULE OUT OSA. i.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.e. NARCOLEPSY AND IDIOPATHIC HYPERSOMNIA . AND OTHER CONDITIONS.

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

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?? .TREATMENT OF EXCESSIVE DAYTIME SLEEPINESS • EDUCATE PATIENT REGARDING SLEEP HYGIENE.

WHAT’S NEW IN PD TREATMENT? DOPAMINE AGONISTS: • APOMORPHINE – RESCUE TREATMENT FOR “OFF” • ROTIGOTINE PATCH – MONOTHERAPY EARLY.SO. ADJUNCT TREATMENT FOR “OFF” • SUMANIROLE – ALSO NEUROPROTECTIVE • ROPINIROLE CR MAOBI’S • ZYDIS SELEGILINE (ONCE DAILY) • RASAGILINE – NO AMPHETAMINE EFFECT .

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

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

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

J. 18-23.1. S. C. A Neuroprotective Strategy in Parkinson’s Disease and Huntington’s Disease. LE. Clinical Neuropharmacology Vol.SELECTED REFERENCES 8. Thomsa. Neuroprotective Actions of Coenzyme Q 10 in Parkinson’s Disease. 24 No. Minocycline and Other Tetracycline Derivatives.. . 10. Methods in Enzymology. M. 2005. Jankovic. Vol. 26. Neurology Alert. Sharma. 382 (2004). et al. 9. A Step Toward Restorative Therapy in Parkinson’s Disease Abstract and Commentary. Vol. No. Henchcliffie. Weidong. pp.2 Oct.

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