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

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

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

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

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

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.

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!

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

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?

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

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, MAOBI’S. DOPAMINE AGONISTS AS SYMPTOMATIC TREATMENT

TREATMENT OF EARLY PARKINSON DISEASE CONSIDER: CO-Q-10, VITAMIN E (TS) – MAY HELP LEG CRAMPS? SELEGILINE OR RASAGILINE (2 ND 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

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??

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?

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”

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

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

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

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”

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

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

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. ACTS LIKE “ELECTRONIC LEVODOPA”. REDUCES TREMOR, RIGIDITY AND BRADYKINESIA, ALLOWS REDUCTION OF L-DOPA DOSE, BUT ANTI PD-EFFECT NO BETTER THAN L-DOPA.

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

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

TREATMENTS FOR ANXIETY-DEPRESSION BZP’S – 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 TCA’S – MAY HELP DROOLING & BLADDER SYMPTOMS. BUPROPRION, MIRTAZAPINE, NEFAZODONE, VENLAFAXINE ALSO USED

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. 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

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

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

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

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

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

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

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??

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

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

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

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

SELECTED REFERENCES 8.Sharma, S. et al. Neuroprotective Actions of Coenzyme Q 10 in Parkinson’s Disease. Methods in Enzymology. Vol. 382 (2004). 9.Thomsa, M., LE, Weidong, Jankovic, J. Minocycline and Other Tetracycline Derivatives; A Neuroprotective Strategy in Parkinson’s Disease and Huntington’s Disease. Clinical Neuropharmacology Vol. 26, No.1, pp Henchcliffie, C. A Step Toward Restorative Therapy in Parkinson’s Disease Abstract and Commentary. Neurology Alert. Vol. 24 No.2 Oct