1. PARKINSON’S DISEASE
Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

2. James Parkinson was an English surgeon, apothecary, geologist, paleontologist, and political activist.
Born: April 11, 1755, Shoreditch, London, United Kingdom
Died: December 21, 1824, Shoreditch, London, United Kingdom
Spouse: Mary Dale (1783–1824)
Education: Barts and The London School of Medicine and Dentistry
James Parkinson

3. James Parkinson Four generations of family were surgeon-in London
He was initially medical apprentice with his father
Became medical student at London Hospital (1776)
Awarded diploma of the company of surgeons (1784)
Founding member Medico-Chirurgical Society (1812)
Founding member of Huntarian Society (1819)
Gold Medalist of Royal College of Surgeons (1822)

4. Descriptive Epidemiology of Parkinson Syndrome
Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years.
The incidence has been estimated to be cases per 100,000 population per year.
Most studies yielding a prevalence of approximately 120 cases per 100,000 population. 
Parkinson disease is about 1.5 times more common in men than in women.
The incidence of parkinson syndrome and Parkinson’s disease rises with age, and has been reported at between five and twenty-four cases per hundred thousand. The best available incidence studies--those from the Rochester, Minnesota, database--suggest the incidence of parkinson syndrome in the U.S.A. is 20.5 per 100,000 population. Because the population is slowly aging, and the recognition of parkinsonism is improving, it is expected that the incidence will slowly rise.
Door-to-door prevalence surveys of the general population have revealed that 35-42% of the cases of parkinson syndrome in the general population remain undiagnosed. Most of those would be early cases, those with akinetic-rigid form of parkinsonism, or those who have been mistaken as having had a neurological disease such as essential tremor. The reported prevalence rates range from per 100,000 population. In the U.S. and Canada it is estimated that the prevalence is 300 per 100,000 population. This should be regarded as a conservative estimate.
A review of 934 patients found the onset of parkinson syndrome was at age 61.6, while the onset of Parkinson’s disease was at age 62.4 years. Parkinsonism is very rare before age 30 and only 4-10% of the cases have onset before the age of 40 years.

5. 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
Normal substantia nigra
Severe depigmentation due to loss of nigral neurons in PD. A B
Substantia Nigra

6. Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson's disease. The brown colour is positive immunohistochemistry staining for alpha-synuclein.

7. Parkinson’s Disease Risk Factors
Definite: Old age
Highly likely: MZ co-twin with early-onset PD
Probable: Positive family history
Possible: Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head trauma, etc.
Possible protective effect: Smoking
Every study indicates that age is a definite risk factor. However, the pattern of substantia nigra neuronal loss is different in normal aging than in Parkinson’s disease. Subregional striatal dopamine loss in normal aging is distinct from that in Parkinson’s disease patients.
Genetics is a highly likely risk factor, at least in early-onset Parkinson’s disease, as shown in monozygotic co-twins. Several studies have reported that a positive family history of Parkinson’s disease is more common in the probands with Parkinson’s disease than with controls, but because of patient recall bias, or because their family members are more sensitized to the presence of Parkinson’s disease than the controls would be, the significance of these data are unclear. In the event these observations are accurate, this finding may reflect a common genetic background, or it may be common environmental exposure, or a combination of the two.
There are several possible factors which are associated with increased risk. These include exposure to herbicides, pesticides, heavy metals, proximity to industry, rural residence, consumption of well water, repeated head injury, etc. Gender, race, and presence of essential tremor do not modify the risk of Parkinson’s disease.

8. Cause of PD Unknown in most cases
Genes
AD inheritance very rare; mutation unknown
Mutation of Alpha synuclein gene (chromosome 4q) identified in one large Italian (Contursi) and 5 Greek autosomal dominant families
Mutation of parkin gene in autosomal-recessive juvenile parkinsonism
Environment
Majority of cases believed caused by environmental factors but none identified so far
Genes plus environment?

9. Early Signs and Symptoms
Cardinal Characteristics
Resting tremor
Bradykinesia
Rigidity
Postural instability
Other
Micrographia
Masked face
Slowing of ADLs
Stooped, shuffling gait
Decreased arm swing when walking
In contrast to tremor and bradykinesia, rigidity is rarely a patient-reported symptom. Assessment of rigidity involves passive movement of the neck, upper limbs, and lower limbs, to assess for an increase in tone throughout the range of motion. In mild cases, rigidity may be increased by “activation” of the contralateral limb by opening and closing the hand, or other repetitive tasks. Rigidity should be distinguished from spasticity because this increase in tone is more prominent with initiation of movement and is greater in one direction than the other.
Although usually not an early sign or symptom of idiopathic Parkinson’s disease, postural instability emerges with disease progression. On examination, the examiner should stand behind the patient and ask the patient to maintain their balance when pulled backwards. The examiner should pull back briskly to assess the patient’s ability to recover, being careful to prevent the patient from falling.

10. Additional Signs and Symptoms
Difficulty arising from a chair
Difficulty turning in bed
Hypophonic speech
Sialorrhea
Loss of the sense of smell
Foot dystonia
There are numerous other signs and symptoms of Parkinson’s Disease that are often brought to the physician’s attention by the patient or family members. Micrographia is a common early sign, characterized by a slowness or smallness to the handwriting. Mask facies is another bradykinetic symptom characteristic of Parkinson’s disease. Slowing of activities of daily living occurs, including such activities as dressing, bathing, turning in bed, getting in and out of a chair, or in and out of a car. Gait is often characterized by some shuffling or dragging of a leg, and the posture may be stooped with flexion of the knees, hips, trunk, and neck.
Bulbar symptoms include bradykinetic or hypophonic speech, which may require the patient to repeat himself frequently. Drooling is common. Choking may occur. Although nonspecific, the loss of the sense of smell, or anosmia, has been well-documented in Parkinson’s disease. Some patients will present with a foot dystonia in which the foot will turn in and there will be involuntary curling of the toes, especially in the morning.

11. Non-motor symptoms Sleep disturbances
Rapid eye movement (REM) behavior disorder (RBD)
Loss of normal atonia during REM sleep)
Decreased sense of smell
Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking

12. Criteria for Diagnosis
At least two of three:
Resting tremor
Bradykinesia
Rigidity
Absence of a secondary cause—drugs, metabolic, etc.
Definitive diagnosis can only be made by autopsy
The diagnosis of Parkinson’s disease requires at least two of the three cardinal features of rest tremor, bradykinesia, or rigidity. Since postural instability is usually a later sign of Parkinson’s disease, that cardinal feature is often not included as a criteria for diagnosis.
Furthermore, the diagnosis of idiopathic Parkinson’s disease necessitates ruling out secondary causes of parkinsonism. Certainly drug induced parkinsonism, metabolic etiologies, and other secondary causes must be eliminated. Unfortunately, there are currently no lab tests or neuroimaging studies to confirm a diagnosis of idiopathic Parkinson’s disease. Rather, a definitive diagnosis of Parkinson’s Disease can only be made by autopsy, with neuropathologic findings of substantia nigra depigmentation, neuronal loss, and the presence of Lewy bodies in the substantia nigra.

13. Neurodegenerative disorders with Parkinsonism (I)
Progressive supranuclear palsy
Supranuclear  ophthalmoplegia
Parkinsonism
Pseudobulbar palsy
Behavioral and cognitive impairment
Imbalance and walking difficulty
Frequent falls
Corticobasal degeneration
Parkinsonism
Limb apraxia/limb alien limb
Apraxia(ideomotor apraxia and limb-kinetic apraxia)
Aphasia
Dystonia/unilateral, coarse tremor

14. Progressive Supranuclear Palsy
Photographs of oculomotor abnormalities of patient. A, Upward gaze. B, Right gaze. C, Forward gaze. D, Left gaze. E, Downward gaze. F, Frenzel goggles.

15. Neurodegenerative disorders with Parkinsonism (II)
Multiple system atrophy
Shy-Drager syndrome
Autonomic insufficiency—orthostasis, impotence
Striatonigral degeneration
Tremor less prominent
Olivopontocerebellar atrophy
Cerebellar signs
Other neurodegenerative disorders that present with parkinsonism are the various types of multiple system atrophy. As the name implies, these are disorders in which multiple neuronal systems have degenerated. In patients with Shy Drager syndrome, the main characteristic differentiating it from Parkinson’s disease is a autonomic disturbance, such as orthostatic hypotension, impotence, and bowel and bladder incontinence. Although the parkinsonian features respond poorly to anti-PD medications, low-blood pressure symptoms respond to midodrine and fludrocortisone.
Striatonigral degeneration is clinically similar to idiopathic PD, but tremor is not a prominent feature, and has a limited response to antidopaminergic medications.
Patients with olivopontocerebellar atrophy, or OPCA, have cerebellar signs that differentiate it from idiopathic Parkinson’s disease. There are currently no treatment options for these patients, although one recent study reports some benefit from amantadine.

16. Neurodegenerative Disorders with Parkinsonism (III)
Diffuse Lewy body disease
Early onset of dementia
Delusions and hallucinations
Agitation
Alzheimer’s disease
Dementia is the primary clinical syndrome
Rest tremor is rare
Finally, patients with parkinsonism that have an early onset of dementia, or where dementia is the primary clinical finding, likely have either diffuse Lewy body disease or Alzheimer’s disease. All patients with idiopathic Parkinson’s disease have Lewy bodies in the substantia nigra and many, if not all, will have them in the cortex and other areas of the brain. Patients with a diagnosis of diffuse Lewy body disease have significant cortical Lewy bodies, and this cortical neurodegeneration is believed to produce the symptoms of dementia, delusions, hallucinations, agitation, and delirium.
Alzheimer’s disease is almost always characterized by dementia, and this is the primary clinical abnormality, but parkinsonian features such as bradykinesia, rigidity and postural instability may occur. Resting tremor is usually rare in the Alzheimer’s disease population.
In general, all these neurodegenerative disorders respond quite poorly to dopaminergic medication, although early in the course of the disease any of these can have motor benefits from dopaminergic agents.

17. Vascular Parkinsonism
Abrupt onset, usually unilateral
Step-wise or no progression
Other signs—hemiparesis, aphasia, hyperreflexia
Infarcts on neuroimaging helpful in confirming diagnosis
Patients who have multiple cerebral infarctions affecting the basal ganglia, substantia nigra, or their pathways may develop parkinsonian features. “Vascular” parkinsonism usually has an abrupt onset, is usually unilateral rather than bilateral, and progression, if any, is usually in a stepwise fashion. Other signs on exam include hemiparesis, aphasia, and hyperreflexia. Although seeing abnormalities on a CT or MRI scan may be helpful in confirming the diagnosis, small vessel ischemic changes, or lacunar or cortical infarction may occur in other atypical forms of parkinsonism, as well as in patients with idiopathic Parkinson’s disease.

18. Hydrocephalus-induced Parkinsonism (NPH)
Normal pressure hydrocephalus—idiopathic
Clinical triad:
Parkinsonism
Gait disorder
Urinary/fecal incontinence
Dementia
Patients with normal-pressure, communicating, or obstructive hydrocephalus can have parkinsonian symptoms. The clinical triad that patients develop is a parkinsonian gait disorder, incontinence, and dementia. The diagnosis is usually made by CT or MRI scan showing the hydrocephalus. In some instances, nuclear medicine cisternography, looking for abnormalities in CSF flow, is helpful. Hydrocephalus-induced parkinsonism may improve if the underlying cause of hydrocephalus is determined and treated. Additionally, patients with normal pressure hydrocephalus may benefit from ventriculoperitoneal shunting. Often, lumbar puncture with removal of cc of CSF on three consecutive days may produce a self-limiting improvement in gait, and is a useful “diagnostic” test prior to V-P shunting. However, some cases in which no improvement is seen after serial lumbar puncture may improve after ventriculoperitoneal shunting.
Normal pressure hydrocephalus

19. Management Anticholinergics Dopaminergic agents COMT inhibitors
Levodopa
Dopamine agonists
COMT inhibitors
MAO-B inhibitors
Amantadine
Dopaminergic therapy with levodopa or dopamine agonists is the cornerstone of symptomatic management of Parkinson’s disease. As can be seen in the next slide, levodopa replaces dopamine presynaptically, while dopamine agonists act directly on receptors post-synaptically. Levodopa is administered with a peripheral decarboxylase inhibitor, either benserazide or carbidopa. The newest class of drugs, the COMT inhibitors, also increase the bioavailability of levodopa, by inhibiting peripheral or central catechol O-methyl transferase. Other agents are anticholinergics, the MAO-B inhibitor selegiline, and the antiviral amantadine.

20. Management Treatment for nonmotor symptoms
Symptomatic drug therapy
Good control of motor signs of PD for 4-6 years
Levodopa/carbidopa: The gold standard treatment
MAO–B inhibitors: Can be considered for initial treatment
Dopa agonists: Monotherapy in early disease and adjunctive therapy in moderate to advanced disease
Anticholinergic agents (e.g., trihexyphenidyl, benztropine): Second-line drugs for tremor only
Treatment for nonmotor symptoms
Sildenafil citrate (Viagra): For erectile dysfunction
Polyethylene glycol: For constipation
Modafinil: For excessive daytime somnolence
Methylphenidate: For fatigue (potential for abuse and addiction)

21. Anticholinergics Dopaminergic depletion cholinergic overactivity
Effective mainly for tremor and rigidity
Common agents (Start low, go slow):
Trihexyphenidyl: mg/day
Benztropine: 1-8 mg/day
Side effects:
Dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention
Although belladonna alkaloids were initially used for the treatment of Parkinson’s disease in the later part of the 19th century, it was not until the 1950s that anticholinergics were routinely used for treatment. Although the exact mechanism of action is unknown, it is believed that dopamine depletion leads to an overactivity of acetylcholine in the striatum, and that reduction of this relative overactivity is responsible for improvement in parkinsonian symptoms. Anticholinergics may also inhibit dopamine reuptake in the striatum. Clinical studies have shown that cholinergics are mainly effective for tremor and rigidity and do not help with other parkinsonian symptoms. The commonly used anticholinergics include trihexyphenidyl, benztropine, and ethopropazine. The anticholinergics should be started at very low doses, and then gradually increased. Anticholinergics are usually not recommended in older patients because of higher propensity to cause adverse effects. Common side effects of anticholinergics include dry mouth, sedation, delirium, confusion, hallucinations, constipation, and urinary retention.

22. Early treatment of Parkinson's disease
Early treatment of Parkinson's disease. Prescription dated 1877 from the College of Physicians of Philadelphia Library. In treating Parkinson's disease, Charcot used belladonna alkaloids (agents with potent anticholinergic properties)

23. Levodopa/Carbidopa Most effective drug for parkinsonian symptoms
First developed in the late 1960s; rapidly became the drug of choice for PD
Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers
Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide)
Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations, confusion, paranoia hallucinations.
Levodopa was first introduced as a therapeutic agent for Parkinson’s disease in the late 1960s, and rapidly became the drug of choice for treatment. Despite the development of many more treatment options, it remains the mainstay of therapy for most patients. It is by far the most clinically effective drug for the symptoms of Parkinson’s disease, being capable of alleviating virtually all of the cardinal symptoms including bradykinesia. Since bradykinesia is among the most disabling features of this disorder, the effectiveness of levodopa for this problem cannot be over-emphasized. We have also learned that when this drug is started early in the course of Parkinson’s disease it can produce a smooth and dramatic clinical response leading to virtually normalization of symptoms. This smooth response typically lasts for several years before problems with therapy develop.
Nausea and vomiting are probably the most common side effects, with occurrence of nausea in as many as 20% of patients when first started on levodopa. In most cases, this nausea is due to insufficient blockade of peripheral decarboxylase, and therefore the administration of supplemental carbidopa can be very effective at controlling this kind of nausea. Carbidopa is now available for prescription in the United States under the trade name Lodosyn.
Other patients may develop postural hypotension when levodopa is added and this may reflect the mild autonomic insufficiency which patients with Parkinson’s disease develop. Dyskinesias and motor fluctuations are late effects seen with increased loss of dopaminergic neurons.

24. Levodopa/Carbidopa Formulations
Type
Onset
Duration
Immediate Release
10/100, 25/100, 25/250
20-40 min
2-4 hr
Controlled Release
25/100, 50/200
30-60 min
3-6 hr
“Liquid levodopa”
(dissolved tablets)
10-20 min
0.5-1 hr

25. Selegiline Irreversible MAO-B inhibitor
Clinically active by inhibiting dopamine metabolism in brain
May be neuroprotective
Dosage: 5 mg at breakfast and lunch
Side effects: insomnia, hallucinations, nausea (rarely), OH
Potential interactions with tricyclics and SSRI antidepressants
MAO-B acts to degrade dopamine after its release. Selegiline is the prototype MAO-B inhibitor for the treatment of Parkinson’s disease. The question of selegiline’s putative neuroprotection has been controversial since its development.
Selegiline is dosed at 5 mg twice daily, at breakfast and lunch.
Selegiline side effects include hallucinations, orthostatic hypertension, insomnia and, on occasion, nausea. There is also potential for a serious reaction with certain antidepressants, known as the serotonin syndrome, in which patients may develop extremely high blood pressure and other associated symptoms.

26. COMT Inhibitors
Newest class of antiparkinsonian drugs: tolcapone, entacapone
Potentiate LD: prevent peripheral degradation by inhibiting catechol O-methyl transferase
Reduces LD dose necessary for a given clinical effect
Helpful for both early and fluctuating Parkinson’s disease
May be particularly useful for patients with “brittle” PD, who fluctuate between off and on states frequently throughout the day
The COMT inhibitors are the newest class of antiparkinsonian drugs. COMT stands for catechol O-methyltransferase, which is the second major enzyme involved in the peripheral degradation of levodopa. COMT acts on levodopa to create an inactive metabolite, CO methyldopa. This particular metabolite competes with levodopa itself for active transport across the blood-brain barrier and therefore reduces levodopa absorption. Drugs that block formation of this metabolite therefore potentiate the effect of levodopa and lengthen its half-life. The COMT inhibitors have been positioned as particularly useful for patients with brittle Parkinson’s disease who experience rapid and frequent motor fluctuations. The current examples of COMT inhibitors available world wide include tolcapone and entacapone.

27. Dopamine Agonists
Dopamine agonists have proved antiparkinsonian activity.  
Addition DA allows 20%-30% reduction of levodopa and improvement in the disabling complications.
DA have been successfully used as monotherapy.
Apomorphine is a combined D1 and D2agonist but has to be administered subcutaneously
There are two subclasses of dopamine agonists: ergoline and non-ergoline agonists.
Both subclasses target dopamine D2-type receptors.
The ergoline agonists include:
Bromocriptine
Pergolide
Cabergoline
Non-ergoline agonists are:
Ropinirole
Pramipexole

28. Peak Dose Dyskinesia or Dystonia
Chorea is more common than dystonia
May be worse on more affected side
May not be as disabling as akinesia/rigidity
Dose adjustments, add-ons:
Reduce LD dose, increase dose frequency
Convert to LD-CR
Reduce LD, add DA, COMT inhibitor, or MAO-B inhibitor
Peak dose dyskinesias or dystonia are the most common form of motor fluctuation, and are often worse on the more parkinsonian side. The involuntary movements are often not as disabling as akinesia and rigidity, and most patients prefer to have dyskinesias rather than immobility. To treat these symptoms it is useful to reduce levodopa dosing concentrations at peak dose while trying to increase levodopa dosing concentrations at trough dose, according to the levodopa dosing curve. This may be done by switching from immediate-release levodopa to a controlled release form, or by reducing levodopa and adding a dopamine agonist, a COMT inhibitor or an MAO-B inhibitor.

29. Wearing Off
Regular and predictable decline in response 2-4 hours after LD dose
Most common motor fluctuation
Dose adjustments, add-ons:
Change to LD-CR, or increase LD frequency
Reduce LD, add DA or COMT inhibitor
The most common motor fluctuation is a regular and predictable wearing off two to four hours after an immediate-release levodopa dose. This is most easily treated by increasing levodopa dosing frequency or changing to the controlled-release preparation. Furthermore it may also be effective to reduce the total dose of levodopa and add a dopamine agonist or COMT inhibitor.

30. On-off Response
Sudden and unpredictable off periods unrelated to dosing schedule
One of the hardest features to manage
Dose adjustments, add-ons:
Reduce LD, add DA
On/off responses are sudden, unpredictable off periods are usually unrelated to dosing schedule, and are quite difficult to manage. In general it is best to reduce levodopa dosing and add a dopamine agonist.

31. Surgical Treatments for Parkinson’s Disease
Ablative
thalamotomy
pallidotomy
Electrical stimulation
VIM thalamus, globus pallidus internus, sub-thalamic nucleus
Transplant
autologous adrenal, human fetal, xenotransplants, genetically engineered transplants
Surgical treatments can be roughly divided into three separate categories. The first is ablative, in which stereotactic lesions are made in very specific anatomical locations within the brain. The second is deep brain stimulation, where an electrode is placed within specific areas of the brain and a high-frequency pulsatile voltage is used to mimic the effects of ablation. The third is cell transplantation where extraneous cells are placed into the striatum of the brain in an attempt to mimic the function of substantia nigra cells which perish in Parkinson’s disease.

32. Improvements with Pallidotomy
Pallidotomy has positive effect on dyskinesia and a moderate effect on tremor.
Bradykinesia was not affected.
Posteroventral pallidotomy may be useful in patients with PD who have severe motor fluctuations and may allow an increase in levodopa dose to alleviate bradykinesia in "off" states. Specific Features:
Dyskinesia %
Wearing off dystonia %
Tremor %
Rigidity %
Bradykinesia %
Gait %
All aspects of Parkinson’s disease do not respond to the same extent after a pallidotomy. The most dramatic improvement is seen in the levodopa-induced dyskinesias, followed by both wearing off and levodopa dystonia. There is also moderate-to-good improvement in tremor and rigidity with mild-to-moderate improvement in bradykinesia and gait.

33. Deep Brain Stimulation (DBS)
High frequency, pulsatile, bipolar electrical stimulation
Surgical procedure of choice for Parkinson disease
Does not involve destruction of brain tissue
Reversible
Can be adjusted as the disease progresses or adverse events occur
Bilateral procedures can be performed without a significant increase in adverse events
Deep brain stimulation is a newer technology. A high frequency pulsatile current is discharged from an electrode which is implanted in certain areas within the brain. Although exclusively internalized, the device is actually activated or deactivated with the use of an external magnet. The electrode reaches the surface of the brain and is connected via wire retroauricularly to the magnetic switch, which is typically placed under the clavicle. The exact physiology of deep brain stimulation on a cellular level is unknown; however, it mimics the effects of lesioning, possibly by “jamming” normal cellular communication.

34. THANK
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