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2.3
Inability to co-ordinate muscular activity Death of specific brain cells in the substantia nigra
LOSS OF DOPAMINE
Effects on other systems
2.3
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
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.
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,
ATTEMPT TO SLOW OR IMPEDE DISEASE PROGRESSION AND CELL DEATH. HARD TO EVALUATE AS SOME AGENTS ALSO CONFER A SYMPTOMATIC BENEFIT.
VITAMIN E (TS) ENRICHES SUBST NIGRA MITOCHONDRIA, DECREASED OXIDATIVE STRESS COENZYME Q10 ATTENUATES MPTP EFFECTS ON DOPAMINE NEURONS
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
RESTORATIVE EMBRYONIC DOPAMINERGIC TISSUE TRANSPLANTATION SOME GRAFTED NEURONS DIFFERENTIATED AND RE-INNERVATED NOT VERY USEFUL.
ASSOCIATED WITH DISEASE PROGRESSION PULSATILE NON-PHYSIOLOGIC STIMULATION DOPAMINE RECEPTORS FROM LEVODOPA
OF
DIPHASIC DYSKINESIAS
FOG
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 ON
NON-MOTOR SYMPTOMS
ANXIETY & DEPRESSION HIGH UNDERDIAGNOSED AND UNDERTREATED
USE ANXIETY & DEPRESSION SCALES
PREVALENCE
BUT
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
Early disease
Advanced disease
Dyskinesia threshold
Dyskinesia threshold
Therapeutic window
Efficacy threshold
Efficacy threshold
Efficacy threshold
On
Off
On
Off
On
Off
Time
With dual inhibition, significantly more Levodopa reaches the brain, with a 30-50% reduction in plasma variability
Gordin et al. 2006
Levodopa
3500
Repeated daily dosing of levodopa/DDCI/entacapone extends the bioavailable levodopa while reducing peaktrough variations
18.0
12.0
6.0
0.0
1 (N=410)
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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