Update on Management of Parkinsons Disease

Dr. Alim Akhtar Bhuiyan Consultant & Co-ordinator

Neurology Department

Parkinsons Disease A real concern

Prevalence of Parkinsons disease:
In US , approximately 1 million people are suffering from Parkinsons disease. There is no exact epidemiological data regarding PD is available in our Country. But approximate Prevalence is 0.37%. Parkinsons disease is age related and life expectancy of people is growing day by day. So the prevalence will be much higher in near future.

2.3

CORE BIOCHEMICAL PATHOLOGY

DECREASED DOPAMINE NEURO -TRANSMISSION 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 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).

PATHOGENESIS OF PARKINSON DISEASE

ACTUAL CAUSE UNKNOWNFACTORS 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

What goes wrong in Parkinsons disease?

Parkinsons disease symptoms result from loss of dopaminergic neurons in the brain which cause depletion of Dopamine in the brain.

Inability to co-ordinate muscular activity Death of specific brain cells in the substantia nigra

LOSS OF DOPAMINE
Effects on other systems

2.3

Parkinsonism and Classification of Symptoms

Parkinsonism is a collective term that is used to describe a number of conditions that cause distinctive motor signs. Parkinsonism is typically classified into the following 3 categories: 1) Primary parkinsonism (Idiopathic) 2) Secondary parkinsonism-Drug related, stroke ,encephalitis 3) Parkinsonism-plus (MSA)

CARDINAL FEATURES
REST TREMOR RIGIDITY BRADYKINESIA HYPOKINESIA LOSS OF POSTURAL REFLEXES TO DIAGNOSE: TWO OF ABOVE, WITH AT LEAST ONE BEING REST TREMOR OR BRADYKINESIA

INITIAL SYMPTOMS OF PARKINSON DISEASE

60% -70% 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.

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 IMPOTENCE, LOW BLOOD PRESSURE DYSFUNCTION,

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, HALLERVORDENSPATZ

Overview of Parkinsons Disease Therapies

In general, patients with Parkinsons disease are managed in 3 ways: Pharmacologic treatments Surgical intervention Non-pharmacologic Treatments
Other Complementary therapies include the following:
Patient education

Counseling Speech therapy Physical therapy Occupational therapy

WHY DELAY THERAPY?

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

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.

SOME NEUROPROTECTIVE AGENTS MANY ONGOING STUDIES

VITAMIN E (TS) ENRICHES SUBST NIGRA MITOCHONDRIA, DECREASED OXIDATIVE STRESS COENZYME Q10 ATTENUATES MPTP EFFECTS ON DOPAMINE NEURONS

SELEGILINE PRESERVES MITOCHONDRIAL CO-Q10 LEVELS

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

TREATMENT OF EARLY PARKINSON DISEASE

CONSIDER: CO-Q-10, VITAMIN E (TS) MAY HELP LEG CRAMPS?

SELEGILINE OR RASAGILINE AMPHETAMINE EFFECT? (2ND GENERATION MAOBI)

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

Treatment Algorithm

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 SPECIALLY FOR RIGIDITY & BRADYKINESIA WHEN OTHER MEDICATIONS 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

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 ONTIME

OTHER THERAPEUTIC OPTIONS SURGERY

ABLATIVE THALAMOTOMY, PALLIDOTOMY IRREVERSIBLE DEEP BRAIN STIMULATION THALAMIC, SUBTHALAMIC MORE TREATMENT FLEXIBILITY PALLIDAL,

RESTORATIVE EMBRYONIC DOPAMINERGIC TISSUE TRANSPLANTATION SOME GRAFTED NEURONS DIFFERENTIATED AND RE-INNERVATED NOT VERY USEFUL.

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 DOPAMINE RECEPTORS FROM LEVODOPA

OF

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 AMANTADINE, TRY SINEMET CR

L-DOPA

DOSE,

ADD

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: 1) CR PREPS, 2)COMTI, 3) MAOBI, 4) DOPAMINE AGONISTS, 5) APOMORPHINE, 6) LIQ. L-DOPA
PEAK DOSE AND DIPHASIC DYSKINESIAS TREAT AS PERSISTENT DYSKINESIA FREEZING (OFF & ON) PREVENT OFF LOWER DOSE FOR ON

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 UNDERDIAGNOSED AND UNDERTREATED
USE ANXIETY & DEPRESSION SCALES

PREVALENCE

BUT

SCREEN PERIODICALLY, i.e. DOWN OR HOPELESS OR LITTLE INTEREST

MEDS AND CONDITION LAB SCREENING MAY DETECT TREATABLE

TREATMENTS FOR ANXIETYDEPRESSION

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. 5HT SYNDROME RARE

TCAS 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

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

Early disease

Moderate disease Dyskinesia threshold

Advanced disease

Plasma levodopa concentrations

Dyskinesia threshold
Dyskinesia threshold

Therapeutic window

Efficacy threshold

Efficacy threshold

Efficacy threshold

On

Off

On

Off

On

Off

Time

Stalevo: Mechanism of Action

With dual inhibition, significantly more Levodopa reaches the brain, with a 30-50% reduction in plasma variability
Gordin et al. 2006

Levodopa
3500

After 4 weeks levodopa/DDCI/entacapone treatment

Levodopa plasma levels (ng/ml)

3000 2500 2000 1500 1000 500 0 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Repeated daily dosing of levodopa/DDCI/entacapone extends the bioavailable levodopa while reducing peaktrough variations

18.0

UPDRS III scores

12.0

Levodopa with DDCI and entacapone Traditional levodopa plus placebo

6.0

0.0

-6.0 Baseline (N=484)

1 (N=410)

2 3 (N=101) (N=90) Years

4 (N=44)

5 (N=37)

Delayed start analysis of 3 long-term studies Over 5 years, early initiation of Levodopa with a DDCI and Entacapone resulted in a significant benefit compared with a delayed start in treatment

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