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.

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.

PATHOGENESIS OF PARKINSON DISEASE ACTUAL CAUSE UNKNOWNFACTORS IMPLICATED INCLUDE:

ENDOGENOUS TOXINS, FROM CELLULAR OXIDATIVE REACTIONS.
OXIDATIVE STRESS

GENETIC, ENVIRONMENTAL TOXINS, AND

MITOCHONDRIAL

DYSFUNCTION

AND

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

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.

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 (SDS,OPCA,SND) , CBGD , PSP

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

NON-MOTOR SYMPTOMS OF PARKINSON DISEASE

BEHAVIORAL DEPRESSION, ANXIETY, DECREASED MOTIVATION,

PERSONALITY CHANGES, LESS INCLINATION TO SPEAK, BRADYPHRENIA ; PSYCHOSIS/HALLUCINATION

SENSORY NON-SPECIFIC PAINS, AKATHISIA, RESTLESS LEGS AND

OTHER SLEEP PROBLEMS

AUTONOMIC CONSTIPATION, BLADDER DYSFUNCTION, IMPOTENCE,

LOW BLOOD PRESSURE

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 SUBSTANTIA NIGRA MITOCHONDRIA,

DECREASED OXIDATIVE STRESS

COENZYME Q10 ATTENUATES MPTP EFFECTS ON DOPAMINE NEURONS MAOB-I (SELEGILINE /RASAGELINE) PRESERVES MITOCHONDRIAL
COENZYME-Q LEVELS

MORE NEUROPROTECTIVE AGENTS

AMANTADINE NMDA RECEPTOR ANTAGONIST DOPAMINE

AGONISTS ANTI-OXIDANT, PROTECT DOPAMINE NEURONS, etc.

EARLY PD - CO-Q-10, MAOBIS. DOPAMINE

AGONISTS AS SYMPTOMATIC TREATMENT

WHAT ABOUT LEVODOPA / CARBIDOPA?

STILL THE BEST, ESPECIALLY SHORT TERM LONG TERM USE MOTOR FLUCTUATIONS, DYSKINESIAS
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 ON-TIME

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 Dyskinesia

DIPHASIC DYSKINESIAS
FOG

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

TREATMENTS FOR ANXIETYDEPRESSION

BZPS USE JUDICIOUSLY IF AT ALL. SHORT TERM?
BUSPIRONE SLOW ONSET OF ACTION.
WORSEN SYMPTOMS HIGH DOSES MAY

SSRI EFFECTIVE, AMANTADINE LOWERS RISK OF ED.

SYNDROME RARE

5H-T

TCAS MAY HELP DROOLING & BLADDER SYMPTOMS.

BUPROPRION, MIRTAZAPINE, NEFAZODONE, VENLAFAXINE ALSO USED

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

Treatment Algorithm

OTHER THERAPEUTIC OPTIONS SURGERY

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

RESTORATIVE EMBRYONIC DOPAMINERGIC TISSUE TRANSPLANTATION

SOME GRAFTED NEURONS DIFFERENTIATED AND RE-INNERVATED NOT VERY USEFUL.

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 PDEFFECT 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