1. Parkinson’s Disease (PD)

2. Parkinson’s Disease
Degenerative brain disease of elderly people, characterized by progressive motor difficulty. It causes significant disability and shortens life expectancy.

3. Parkinson’s Disease Epidemiology Age is the most important risk factor
Increasing prevalence with longevity
Affects 0.3% of population
And 1% of people above 60 years of age
Affects around 1 million people in N. America
World-wide distribution
Largely under-diagnosed, so under-estimated

4. Mortality in PD Reduced life expectancy
Mean survival after onset ~ 15 years
longer in non-demented PD cases
longer with L-dopa use
The most common causes of death:
pulmonary infection/aspiration, urinary tract infection, pulmonary embolism and complications of falls and fractures
It is estimated that mean survival after onset of parkinsonism today is approximately 15 years. Survival is longer in those patients who at the first clinical assessment were non-demented. Survival has significantly improved since the widespread use of levodopa, provided the drug is started before the patient reaches UPDRS stage 2.5. The survival in Parkinson’s disease is longer than it is in multiple system atrophy or progressive supranuclear palsy. The most common causes of death are pulmonary infection/aspiration, pulmonary embolism, urinary tract infection, and complications of falls and fractures.

5. Survival in Parkinsonism Prior to Levodopa
This shows 215 parkinson patients who had onset and first clinic visit before January 1, 1974, when levodopa was least accessible to most of these patients. The observed survival is significantly reduced compared to expected survival in the general population of the same year of birth and same sex, with p<
Since the widespread use of levodopa, 565 parkinson patients had onset and were first seen after December 31, 1973 when levodopa was readily available in the study area, and covered by medical insurance. The survival is reduced compared to expected (p=0.029). The difference between the observed and expected survival in these patients is much smaller than in patients who had restricted access to levodopa.

6. Parkinson’s Disease Diagnosis Clinical criteria- The Triad:
Resting tremor
Cogwheel rigidity
Akinesia
Asymmetry of tremor and rigidity

7. Parkinson’s Disease Presenting Symptoms Tremor Fatigue Slowness
Gait difficulty
Frequent falls
Pain

8. Parkinson’s Disease Other clinical features: Stooped posture
Shuffling and festinating gait
Poor arm swing
Expressionless face
Monotonous slurred speech
Small hand-writing
Poor balance

9. Parkinson’s Disease Differential Diagnosis of Parkinsonism
Drug induced Parkinsonism
Depression
Normal Pressure Hydrocephalus
Vascular Lacunar States

10. Parkinson’s Disease
Other degenerative diseases with Parkinsonian features.
Progressive Supranuclear Palsy (PSP)
Multi-System Atrophy (MSA)
Lewy Body Dementia
Wilson’s Disease

11. Parkinson’s Disease Diagnostic Tests: Brain imaging: CT and MRI
Positron-emission Tomography (PET scan)

13. Pathology of Parkinson’s Disease

17. Pathophysiology of Parkinson’s Disease

18. Main Biochemical Abnormality
Marked striatal DA depletion
“Striatal dopamine deficiency syndrome”
At death, DA loss > 90%
<50% DA loss is asymptomatic
~70% DA loss for symptom manifestations
Severity of DA loss best correlates with bradykinesia in PD
Marked depletion of dopamine in the striatum was first detected in 1960 in Parkinson’s disease patients. Compared to other neurological diseases, the abnormality was so specific that sometimes Parkinson’s disease is biochemically defined as striatal dopamine deficiency syndrome. At the time of death, more than 90% loss of dopamine has been noted in most Parkinson’s disease patients. The threshold for the emergence of parkinsonian features has not been fully established. Autopsy review of subjects with no parkinsonian symptoms had less than 50% dopamine loss in the striatum while a 70% dopamine loss in the striatum results in parkinsonian manifestations. The severity of dopamine loss best correlates with the severity of bradykinesia in Parkinson’s disease.

19. Parkinson’s Disease Treatment-Replenishing of Dopamine: L-Dopa
L-Dopa+Carbidopa (Decarboxylase Inhibitor)
COMT Inhibitors

20. Diagram of LD Metabolism
Levodopa is actively transported across the gut barrier and the blood-brain barrier via the large neutral amino acid carrier. It is believed to be subsequently taken up by the presynaptic nigral neuron, where it is converted into dopamine and can then be released in a physiologic fashion into the synaptic cleft.
When levodopa is administered along with other dietary amino acids, competition will exist for transport across both the gut and the blood-brain barriers. This is the primary reason why administration with food is generally not advised, since levodopa will not be fully absorbed when administered in this fashion.
In the peripheral circulation, levodopa is rapidly decarboxylated into dopamine, where it is then quickly degraded. Dopamine itself does not cross the blood-brain barrier, and can stimulate the area postrema, causing significant nausea and vomiting. In the early days of levodopa therapy, many patients had considerable difficulty tolerating levodopa because of its emesis-producing characteristics. A few years after levodopa was brought into clinical practice, a decarboxylase inhibitor was developed which prevents peripheral degradation of dopamine, thereby enabling a much larger percentage of levodopa to actually cross the blood-brain barrier into the central compartment. There are a number of decarboxylase inhibitors available around the world, the two most common being carbidopa in the United States and benserazide in Europe and elsewhere. With a decarboxylase inhibitor, the drug is rapidly absorbed into the brain, usually 30 to 45 minutes after oral ingestion, and once in the central nervous system the drug has a half-life of about 60 to 90 minutes.

21. Parkinson’s Disease L-Dopa Treatment: Most efficacious treatment.
Helps all the symptoms of PD
Improves functionality
Extends life expectancy
Generally well tolerated

23. Survival in Parkinsonism Prior to Levodopa
This shows 215 parkinson patients who had onset and first clinic visit before January 1, 1974, when levodopa was least accessible to most of these patients. The observed survival is significantly reduced compared to expected survival in the general population of the same year of birth and same sex, with p<
Since the widespread use of levodopa, 565 parkinson patients had onset and were first seen after December 31, 1973 when levodopa was readily available in the study area, and covered by medical insurance. The survival is reduced compared to expected (p=0.029). The difference between the observed and expected survival in these patients is much smaller than in patients who had restricted access to levodopa.

24. Parkinson’s Disease Acute side-effects of L-Dopa treatment:
Gastro-intestinal
Psychosis
Hypotension
Arrhythmias

25. Parkinson’s Disease Chronic side-effects of L-Dopa treatment
Failure of efficacy and shortened time
On-Off Phenomena
Dystonia
? Enhances progression of disease

26. Parkinson’s Disease Treatment- Increasing the release of Dopamine:
Amantadine
Adjunct or very early treatment
Side-effect: Psychosis
May reduce Dystonia

27. Parkinson’s Disease Treatment- Preventing Dopamine Breakdown:
MAO-inhibitor
Selegeline

28. Parkinson’s Disease Treatment-Dopamine receptor agonists
Ergot-Derived:
Bromocriptine
Pergolide
Non-Ergot Derived
Ropinirole (Requipe)
Pramipexole (Sifrol)

29. Parkinson’s Disease Dopamine Agonists:
Effective, especially early in the disease
Allow the reduction of L-Dopa dose
Less Dyskinesia
Prevent the long term side-effects of L-Dopa

30. Parkinson’s Disease Treatment- Anticholinergics:
Trihexyphenidyl
Biperiden (Long acting)
More effective in the control of tremor
Anti-cholinergic side effects
May produce psychosis

31. Parkinson’s Disease Treatment Strategies:
Start with Dopamine agonists or enzyme inhibitors
Add the lowest dose of L-Dopa with disease progression
Add adjunctive medications to reduce dose of L-Dopa
Add Anti-cholinergics if tremor in prominent

32. When to Begin Therapy
Definitive neuroprotective therapy not yet available
Timing of symptomatic therapy is individual
degree of functional impairment
lifestyle of patient
When definitive neuroprotective therapy is available, immediate intervention with these agents will become the standard of treatment in early Parkinson’s disease. Since no neuroprotective therapies are available, initiating therapy in Parkinson’s disease must be individualized. Evaluation of the degree of functional impairment and the individual lifestyle of the patient are important when making decisions about the proper timing of initiation of therapy. Similar clinical presentations may lead be different management styles based on variables such as the patient’s attitude towards medications, the patient’s employment, or perhaps the patient’s need to continue to be a caregiver for a spouse. Adequate patient education and partnering between patients and physician will promote empowerment from the patients and enhance clinical decision making.

33. Parkinson’s Disease Surgical Treatment (Ablative): Thalamotomy
Pallidotomy
Sub-thalamotomy
Deep Brain Stimulation (DBS):
Thalamic (for tremor)
Internal Globus Pallidum.
Subthalamic nucleus.