Download PARKINSON DISEASE UPDATE

PARKINSON DISEASE
UPDATE
HARVEY A. DRAPKIN, D.O., FACN
1817 – DESCRIBED BY JAMES
PARKINSON
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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
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–
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?
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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 COQ10 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 – FDPET
• 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 (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
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
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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 REINNERVATED
• 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 LDOPA DOSE, ADD AMANTADINE, TRY
SINEMET CR
• PREVENTIVE STRATEGY IS TO START
DOPAMINE AGONIST & MAOBI PRIOR TO LDOPA
• “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 LDOPA. 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 ANXIETYDEPRESSION
• 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.
2.
3.
4.
5.
6.
7.
Fahn, S., Przedborski, S. Parkinsonism in Merritt’s Neurology.
Eleventh Edition. Chapter 115. 2005.
Blumenfeld, H. Basal Ganglia in Neuroanatomy Through Clinical
Cases. Chapter 16. 2002.
Hauser, R., Pahwah, R. Current Treatment Challenges and
Emerging Therapies in Parkinsons Disease Suppl. To Neurologic
Clinics. Oct. 2004. Vol. 22 No. 35.
Schapira, A.H.V., Olanow, C.W. Neuroprotection in Parkinson
Disease JAMA, Jan. 21, 2004. Vol. 291 No. 3.
Morelli, M. Adenosine A2a Antagonists; Potential Preventive and
Palliative Treatment for Parkinson(s) Disease. Exp. Neurol 184
(2003) 20-23.
Sawada, ., Shimohama, S. Estrogens and Parkinson Disease.
Endocrine Vol. 21. No. 1, 77-79, June 2003.
Fariss, M.W., Zhang, J-G. Vitamin E Therapy in Parkinson’s
Disease. Toxicology 189 (2003) 129-146.
SELECTED REFERENCES
8.
9.
10.
Sharma, S. et al. Neuroprotective Actions of Coenzyme Q 10 in
Parkinson’s Disease. Methods in Enzymology. Vol. 382 (2004).
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. 18-23.
Henchcliffie, C. A Step Toward Restorative Therapy in Parkinson’s
Disease Abstract and Commentary. Neurology Alert. Vol. 24 No.2
Oct. 2005.