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

2. 11 April 1755 Shoreditch, London, England Died
James Parkinson
Born
11 April 1755 Shoreditch, London, England
Died
21 December 1824 (aged 69) Langthorne, North Yorkshire, England
Cause of death
Stroke
Nationality
British
Ethnicity
White British
Occupation
Surgeon
Known for
First description of Parkinson's disease
Spouse(s)
Mary Dale

3. Four generations of family were surgeon-apothecaries in London
James Parkinson
Four generations of family were surgeon-apothecaries 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. Classification of Parkinson Syndromes in a Community
Idiopathic PD ~ 85% of all PS cases
Neuroleptic-induced parkinsonism (DIP) 7% - 9%
MSA (SDS, SND, OPCD) ~ 2.5%
PSP ~ 1.5%
Vascular parkinson syndrome ~ 3%
PS due to MPTP, CO, Mn, recurrent head trauma is extremely rare
No new cases of postencephalitic parkinsonism since l960s
Idiopathic Parkinson’s disease is the most common variant of parkinsonism, accounting for over 80% of all parkinson syndromes seen in the general population. Neuroleptic-induced parkinsonism, also known as drug-induced parkinsonism, is now the second most common variant in the general population, and accounts for 7-9% of parkinsonian patients. Multiple system atrophy, which includes Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar degeneration, accounts for approximately 2.5%, while progressive supranuclear palsy and vascular parkinson syndrome are seen at approximately 1.5% and 3% of all parkinson patients. Rare causes of parkinson syndrome are MPTP-induced parkinsonism, carbon monoxide poisoning, manganese poisoning, recurrent head trauma, etc. It is of note that no new cases of postencephalitic parkinsonism have been reported since the 1960s.

5. Descriptive Epidemiology of Parkinson Syndrome
Incidence
5-24/ 105 worldwide (USA: 20.5/105)
Incidence of PS/PD rising slowly with aging population
Prevalence
57-371/105 worldwide (USA/Canada 300/105)
35%-42% of cases undiagnosed at any time
Onset
mean PS 61.6 years; PD 62.4 years
rare before age 30; 4-10% cases before age 40
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.

6. Pathology of Parkinson’s DiseaseB
On the left top is a picture of a normal midbrain with abundant pigmentation of the substantia nigra. Below that is the midbrain from a Parkinson’s disease patient with the substantia nigra depigmented. The second set at the top is the microscopic section of normal substantia nigra. Below that is the section from substantia nigra of a Parkinson’s patient. It shows profound loss of pigmented neurons and gliosis. On the extreme right is a pigmented neuron containing a Lewy body inclusion. The Lewy body is characterized by dense pink center and light pink periphery. Together, the loss of substantia nigra dopaminergic neurons and the presence of Lewy body inclusions are regarded as the hallmark of idiopathic Parkinson’s disease pathology. C D
Normal substantia nigra
Severe depigmentation due to loss of nigral neurons in PD.
Loss of pigmented neurons in the PD brain
Lewy body

7. 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.

8. Normal Basal Ganglia Functional Anatomy
This cartoon outlines the complex circuitry between the cortex, striatum, subthalamic nucleus and thalamus. The arrows point the direction of different tracts and the colors indicated on the right show the neurotransmitters involved at each level. The positive sign near the end of the tract indicates that the impulses are excitatory, while the negative sign indicates inhibitory impulses. For reference, keep in mind the width of these tracks. Of special interest are the dopaminergic pathways and the excitatory glutamatergic pathways.

9. Functional Anatomy of Parkinson’s Disease
This slide shows the changes in the basal ganglia cortical circuitry after substantia nigra compacta damage. The main features are the reduced dopaminergic impulses from substantia nigra to the striatum, enhanced excitation of the subthalamic nucleus and the globus pallidus internus, and increased inhibition of the thalamus. Thus surgical lesion or electrode implantation to facilitate a depolarizing conduction block of subthalamic nucleus and globus pallidus internus would produce symptomatic benefit in Parkinson’s disease.

10. 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.

11. Cause of PD
mutation of parkin gene in autosomal-recessive juvenile parkinsonism
Environment
Majority of cases believed caused by environmental factor (s) but none identified so far
Genes plus environment?
Unknown in most cases; not accelerated aging
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

12. Environmental Toxin Model: MPTP
Reproduces all the major motor features of PD
MAO-B
MPTP MPP+
(In astrocytes)
Dopaminergic neuron mitochondria
Inhibits NADH--CoQ1 (Complex I) of mitochondrial respiratory chain
ATP production falls
Cell death
Several environmental toxins have been known to produce parkinson syndrome, notably manganese poisoning, cyanide poisoning, and carbon monoxide poisoning, but the most specific toxin for the substantial nigra is MPTP. It produces parkinsonism in humans as well as animals. In humans, the parkinsonism has all the cardinal features of idiopathic Parkinson’s disease—tremor, bradykinesia and rigidity. MPTP is converted to MPP+ in astrocytes by the enzyme monoamine oxidase B. The MPP+ thus formed is then taken up by dopaminergic neuron mitochondria where it inhibits complex I of the mitochondrial respiratory chain, resulting in the fall of ATP production and eventual cell death. MPTP is so far the best experimental model for the production of parkinsonism in animals.

13. Schematic representation of the mechanisms involved in toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). BBB, blood—brain barrier;MPDP+, 1-methyl-4-phenyl-2,3-dihydropyridinium; MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, its four-electron oxidation product 1-methyl-4-phenylpyridinium; MAO, monoamine oxidase.

14. 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.

15. 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.

16. 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.

17. Clues Suggesting Atypical Parkinsonism
Early onset of, or rapidly progressing, dementia
Rapidly progressive course
Supranuclear gaze palsy
Upper motor neuron signs
Cerebellar signs—dysmetria, ataxia
Urinary incontinence
Early symptomatic postural hypotension
There are a number of factors useful in separating an atypical form of parkinsonism from idiopathic Parkinson’s disease. Patients with early-onset or rapidly progressive dementia, are more likely to have diffuse Lewy body disease or Alzheimer’s disease. In addition, a history of a rapidly progressive course should trigger the clinician to look for other parkinsonian syndromes. The presence of supranuclear gaze palsy, especially a downgaze palsy, suggests Progressive Supranuclear Palsy, a parkinsonism-plus syndrome.
Evidence of upper motor neuron involvement, such as Babinski’s sign or mild hyperreflexia, suggests pyramidal pathway involvement, while patients exhibiting cerebellar signs such as dysmetria, ataxia, nystagmus, titubation, or gait ataxia need to be evaluated further for cerebellar diseases. Patients with early onset of urinary incontinence should be evaluated for normal pressure hydrocephalus or other possible symptomatic or secondary causes of parkinsonism.
Early symptomatic postural hypotension is rare in PD, and suggests the possibility of multiple system atrophy.

18. Neurodegenerative disorders with Parkinsonism (I)
Progressive supranuclear palsy
Supranuclear downgaze palsy, square wave jerks
Upright posture/frequent falls
Pseudobulbar emotionality
Furrowed brow/stare
Corticobasal degeneration
Unilateral, coarse tremor
Limb apraxia/limb dystonia/alien limb
Idiopathic Parkinson’s disease is a neurodegenerative disorder that specifically results from degeneration of the nigrostriatal pathways. However, other neurodegenerative disorders can present with parkinsonian-type features. After idiopathic Parkinson’s disease, progressive supranuclear palsy (PSP) is the most common parkinsonian neurodegenerative disorder. The hallmark signs of supranuclear downgaze palsy and square-wave jerks are often late stage symptoms, but should always be looked for in patients with parkinsonism. Unlike the stooped posture of a Parkinson’s disease patient, PSP patients are often quite upright. Furthermore, when these patients sit in a chair, rather than carefully sitting to protect themselves like PD patients, PSP patients will almost fall into the seat, sometimes striking their heads on the wall with their feet leaving the ground. PSP patients also exhibit pseudobulbar emotionality, or laughing or crying somewhat inappropriately and often uncontrollably. Finally, the classic PSP type facial expression is one of a furrowed brow and a significant stare with a lack of eye blinks and a lack of the ability to move the eyes. Again, this is often a later sign of PSP. Early in the course of PSP, patients may respond fairly well to dopaminergic medications, but the response usually wanes.
Corticobasal degeneration, also known as corticobasal ganglionic degeneration, is a neurodegenerative parkinsonian disorder often associated with a very coarse unilateral tremor. The pathognomonic clinical sign of corticobasal degeneration is a limb apraxia, usually of one upper limb. The arm is often held in a dystonic posture, and the arm may move seemingly on its own and under poor control by the patient, the “alien limb” sign. This condition does not respond to anti-PD medications, but the dystonic posture may benefit from botulinum toxin injections.

19. 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.

20. 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.

21. Differential Diagnosis of PD:
Secondary Parkinsonism
Drug-induced
Toxin-induced
Metabolic
Structural lesions (vascular parkinsonism, etc.)
Normal pressure Hydrocephalus
Infections
Causes of secondary parkinsonism include drugs, toxins, metabolic disorders, infection, structural lesions, and hydrocephalus. In all of these instances careful historical review and appropriate laboratory testing is useful in confirming the diagnosis.

22. Toxin-induced Parkinsonism
MPTP
Carbon monoxide
Manganese
Cyanide
Although neuro-epidemiologists have postulated a significant role for environmental toxins as a cause for idiopathic Parkinson’s disease, no factor has been identified. However, other toxin-induced parkinsonian disorders are known. MPTP, a derivative of meperidine, is a contaminant in the manufacture of certain illicit drugs. MPTP crosses the blood-brain barrier and is converted to MPP+, a neurotoxin specifically taken up by dopaminergic nerve terminals. This leads to degeneration of dopamine neurons and thus parkinsonism.
Carbon monoxide poisoning, if not fatal, may result in parkinsonism due to basal ganglia destruction. Occupational manganese exposure from mining will produce basal ganglia impairment and a parkinsonian syndrome, as will cyanide exposure.

23. 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.

24. Hydrocephalus-induced Parkinsonism (NPH)
Can be communicating or obstructive
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.

25. Treatment Options Preventive treatment
No definitive treatment available
Symptomatic treatment
Pharmacological
Surgical
Non-motor management
Restorative—experimental only
Transplantation
Neurotrophic factors
The treatment options available for Parkinson’s disease can be divided into symptomatic treatment, treatments for non-motor complications, preventive therapy, and restorative therapy.
At the present time, there is no definite preventive treatment available for Parkinson’s disease. There is, however, a wide range of symptomatic treatment options, including both pharmacologic and surgical methods. The non-motor management of Parkinson’s disease includes treatment of depression, orthostatic hypotension, excessive drowsiness, psychosis, and other symptoms. Finally, restorative therapies such as fetal or porcine cell transplantation are in experimental use, and neurotrophic factors such as GDNF, and small molecules such as neuroimmunophilins, are being explored.

26. Drug Classes in PD Dopaminergic agents Levodopa Dopamine agonists
COMT inhibitors
MAO-B inhibitors
Anticholinergics
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.

27. Sites of Action of PD Drugs
selegiline
Substantia Nigra
Dopamine agonists
bromocriptine
pergolide
pramipexole
ropinirole
Amantadine*
levodopa
GABA DA
BBB
carbidopa
benserazide
tolcapone
entacapone
The asterisk for amantadine indicates it has other sites of action, as well.
See slide 6 for details.
ACh
baclofen
Striatum
trihexiphenidyl

28. Anticholinergics Dopaminergic depletion cholinergic overactivity
Initially used in the 1950s
Effective mainly for tremor and rigidity
Common agents (Start low, go slow):
Trihexyphenidyl: 2-15 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.

29. Levodopa 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
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.

30. 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 tricyclic 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.

31. Levodopa/Carbidopa Formulations
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

32. DAs: Common Adverse Effects
Nausea, vomiting
Dizziness, postural hypotension
Headache
Dizziness
Drowsiness & somnolence
Dyskinesias
Confusion, hallucinations, paranoia
Erythromelalgia; pulmonary & retroperitoneal fibrosis; pleural effusion & pleural thickening; Raynaud’s phenomena. May be more common with ergotoline DAs
Common adverse effects of dopamine agonists include nausea, vomiting, orthostatic hypotension, headaches, dizziness, drowsiness, dyskinesias, confusion, hallucinations and paranoia. More rare adverse effects include diplopia, abnormal vision, rash, weight gain or loss, erythema, dry mouth, constipation, and diarrhea. Erythromelalgia, pulmonary and retroperitoneal fibrosis, plural effusion and plural thickening, and Raynaud’s phenomenon are rare adverse effects which are believed to be more common with ergotoline dopamine agonists. However, some of these same adverse effects have also been reported in a patient using the non-ergot dopamine agonist ropinirole.

33. Levodopa-Induced Dyskinesias
Manifestation of excessive dopaminergic stimulation
Typically late effect, and with higher doses
Narrowing of therapeutic window
Rare in LD-naive patients on DA monotherapy
Most common is “peak dose” dyskinesia
disappears with dose reduction
Choreiform, ballistic and dystonic movements
Most patients prefer some dyskinesias over the alternative of akinesia and rigidity
Levodopa-induced dyskinesias are a very important complication of chronic therapy of levodopa. Generally speaking, these are seen later in the disease and at higher doses of levodopa. It is very interesting that dyskinetic movements are very rare in patients who are unexposed to levodopa, who are taking monotherapy with either long-acting dopamine agonists or other antiparkinsonian drugs such as anticholinergics or amantadine. This suggests that dyskinesias are really a manifestation of excessive dopaminergic stimulation.
The most common form of dyskinesia is the so called peak-dose dyskinesia, which occurs when plasma and CNS levels of levodopa are at their highest. This particular type of dyskinesia can be easily treated by simply reducing the size of each individual dose of levodopa. Unfortunately, with advancing Parkinson’s disease the therapeutic window between improvement and dyskinesias narrows such that whenever an “on” state occurs, dyskinesias may be present to a lesser or greater degree.
These movements are usually characterized by a mixture of choreiform, ballistic and dystonic movements.
Most patients with advanced Parkinson’s disease, however, prefer to have some dyskinesias and enjoy an “on” state, as opposed to suffering severe akinesia, and rigidity of the “off” states.

34. COMT Inhibitors
Newest class of antiparkinsonian drugs: tolcapone, entacapone
MOA similar to dopa decarboxylase inhibitors
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.

35. Entacapone Dosage: 200 mg w/each levodopa dose
Parkinson’s Study Group 1997: Increased on time by 5%, more in pts w/least on time
Rinne et al., 1998: Increased on time by ~10%; decreased levodopa
Diarrhea, dopaminergic SEs
Entacapone has recently been approved for marketing in the United States. It has a shorter half-life than tolcapone, and is dosed with each individual levodopa dose. Its effectiveness as adjunctive therapy has been demonstrated in clinical trials, which also demonstrated a levodopa dose reduction of approximately 100 mg/day. It produces typical dopaminergic side effects.

36. Dopamine Receptor Subtypes
D1, D2 subcortical
D3, D4, D5 cortical
Differentiated biochemically & pharmacologically into two families:
D1 family: D1, D5
D2 family: D2, D3, D4
There are several types of dopaminergic receptors. The D1 and D2 receptor families are distinguished by differences in their guanine nucleotide binding proteins and subsequent action on adenyl cyclase, by the ability to bind specific agonists and antagonists, and by their regional distribution in the brain. The D1 family of the dopamine receptors are further subdivided as D1 and D5 receptor subtypes, and the D2 family is subdivided into D2, D3, and D4. It is believed that a combined D1/D2 receptor effect is the most effective for relief of parkinsonian symptoms. Levodopa stimulates both D1 and D2 receptors.

37. DAs: Receptor Effects D1 D2 D3 D4 D5 Ergot Bromocriptine ++ +
Cabergoline
+++ ?
Lisuride
Pergolide
Non-Ergot
Pramipexole
++++
Ropinirole
Neurology 1998; 50(suppl 3)

38. Off-period Dystonia Appears when LD level is low, especially early AM
w/ or w/o parkinsonism
Dose adjustments, add-ons:
more frequent LD dosing to avoid low plasma levels
add DA, COMT inhibitor, MAO-B inhibitor
Off-period dystonia or wearing-off foot dystonia is most prominent early in the morning after a night’s sleep. To treat these conditions it may be useful to increase the dosing frequency of levodopa or to convert to a controlled-release preparation. In addition, it may also be helpful to add a dopamine agonist, COMT inhibitor or MAO-B inhibitor.

39. Apomorphine D1/D2 agonist
Parenteral delivery (s/c., i/v., sublingual, intranasal, rectal)
Rapid “off” period rescue
2-5 mg s.c.; pen injection systems
Treatment of unpredictable, frequent motor fluctuations
continuous s/c. infusion via mini-pump
SE: nausea, vomiting, hypotension
trimethobenzamide 250 mg TDS.
domperidone 20 mg TDS; not available in U.S.
Apomorphine is a potent mixed D1/D2 agonist. Because of its extensive first-pass metabolism when administered orally, parenteral administration is employed, either through subcutaneous, intranasal, intravenous, sublingual, or rectal routes. Its very rapid onset of effect—ten to fifteen minutes in most patients—makes it especially useful for “off” period rescue. (Sublingual administration delays onset somewhat.) Pen injection systems available in Europe make it possible for patients to self-administer, an especially helpful system for patients with unpredictable off periods. Duration of effect of a single dose is approximately one hour. Continuous subcutaneous infusion via a mini-pump is also possible. Nausea, vomiting and hypotension are significant in most patients, but can be well controlled by domperidone administration 20 mg three times per day, beginning hours before the first dose. Domperidone is not available in the United States. Some experience suggests that trimethobenzamide 250 mg TID may be an alternative to domperidone.

40. Managing Early Complications: Altered Mental States
Confusion, sedation, dizziness, hallucinations, delusions
Reduce or eliminate CNS-active drugs of lesser priority
anticholinergics – sedatives
amantadine – muscle relaxants
hypnotics – urinary spasmodics
Reduce dosage of DA, COMT inhibitor, or LD
When patients develop confusion, sedation, dizziness, hallucinations, or delusions, the simplest intervention is to reduce or to eliminate sedating medications or antiparkinsonian medications of lesser priority. Commonly used sedating medications include hypnotics, sedatives, muscle relaxants, and urinary antispasmodics. Low-potency antiparkinsonian medications that may contribute significantly to confusion include anticholinergics, amantadine, and selegiline. When this option is not adequate, dosage reduction of levodopa, dopamine agonist, or COMT inhibitor may be necessary. Drug-related psychotic symptoms in early illness are often associated with atypical parkinsonian syndromes.

41. Initial Therapy: What is the Chief Complaint?
Predominant Symptom Clinical Options
No functional impairment Delay therapy
Mild symptoms Amantadine, selegiline
Discrete symptoms Tremor—anticholinergic
Depression— antidepressant
Anxiety—anxiolytic
Functionally disabling Levodopa, dopamine symptoms agonist, COMT inhibitor
It is important to evaluate the patient’s chief complaint as a guide to initial management in early Parkinson’s disease. A patient with mild symptoms but no real functional impairment may not require any pharmacologic intervention. Patient education regarding the natural course of the illness with a follow-up visit in 4 to 6 months may be adequate. Patients with mild symptoms may also improve with amantadine or selegiline. Certain patients may have especially discrete symptoms, such as isolated tremor, depression, or anxiety. These patients may particularly benefit from an anticholinergic agent for tremor alone, or an antidepressant or anxiolytic agent for their behavioral symptoms. If the patient reports functionally disabling symptoms, stronger antiparkinsonian medications such as levodopa, a dopamine agonist, or a COMT inhibitor will be necessary. It should be noted that a COMT inhibitor must be used with levodopa, or it will be ineffective.

42. Managing Early Complications: Wearing Off/Mild Dyskinesia
For pts on DA monotherapy:
elevate dosage of agonist
add LD, w/ or w/o COMT inhibitor
For pts on LD:
add DA, COMT inhibitor, or MAO inhibitor
reduce LD dosage
use combination of immediate and CR
When patients experience wearing off of medication effect or mild dyskinesia, there are a number of options for managing this difficulty. For patients on levodopa alone, the physician may recommend the addition of a dopamine agonist, a COMT inhibitor, and/or an MAO inhibitor. Each of these adjunctive medications will permit the reduction of levodopa dosage. Another alternative is to utilize combinations of immediate- and controlled-release levodopa.
For patients who are taking a dopamine agonist alone, the physician may choose to elevate the dosage of the agonist to the high therapeutic range. If this is not adequate they may then choose to add levodopa with or without a COMT inhibitor.

43. Late Complications Motor
response fluctuations, dyskinesias, dystonia, freezing, falls
Behavioral/neuropsychological
depression, sleep disorders, psychosis
Autonomic
orthostatic hypotension; hyperhidrosis, constipation, impotence, urinary incontinence or retention
The management of late stage Parkinson’s disease involves treatment of motor fluctuations, dyskinesias, dystonia, freezing and falls. In addition, besides these motor fluctuations there are behavioral and neuropsychological concerns, such as depression, sleep disorders and psychosis. Autonomic problems include orthostatic hypotension, hyperhidrosis, constipation, impotence, urinary incontinence or urinary retention.

44. Peak Dose Dyskinesia or Dystonia
Chorea 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.

45. 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.

46. 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.

47. Other Motor Complications
Diphasic dyskinesia
dyskinesia at beginning and end of dose
Dose adjustments, add-ons: add DA
Drug failure
late afternoon, probably related to poor gastric emptying or absorption
liquid preparations; increase gastric motility; decrease dietary protein
apomorphine rescue
Other motor complications include biphasic dyskinesia, or dyskinesias at the beginning end of dose of levodopa dosing. These are thought to be a result of rapid changes in plasma concentrations of levodopa, and are mediated through changes of the postsynaptic receptor. Dosage adjustments are quite similar to those discussed previously, but in general the addition and emphasis of a dopamine agonist is the most successful way to treat this type of complication. In this way one may avoid rapid levodopa changes and the levodopa kinetic-related motor difficulty.
A failure of levodopa dose response usually occurs in the late afternoon and is believed to be related to poor gastric emptying or poor gastric absorption of levodopa. If this occurs, the use of “liquid levodopa” may allow for rapid absorption of the drug, and sometimes a more predictable response. This is simply prepared by dissolving five carbidopa/levodopa 25/100 tablets in 500 cc of water with vitamin C added to stabilize the mixture. In addition, the use of liquid Madopar is suggested. Other treatments to increase gastric motility include the addition of cisapride 10 mg three times a day and a reduction in dietary protein to reduce levodopa complications at the large neutral amino acid carrier. If manipulation of levodopa absorption does not improve drug failure, the use of an apomorphine rescue is also helpful.

48. Freezing and Falls Freezing
motoric block; at initiation of gait, turning, narrow spaces
use auditory, visual, proprioceptive cues
Falls
physical therapy evaluation
cane, scooter, wheelchair may be necessary
Freezing and falls are perhaps the most frustrating motor complications in advanced Parkinson’s disease in terms of treatment. These motor blocks can occur at gait initiation, turning, or walking through narrow spaces such as doorways or halls, and do not respond to medication. It is often useful to use auditory, visual or proprioceptive cues to somehow begin gait initiation. Some patients will sing or use a marching cadence that they may speak or simply think to begin gait initiation. At times proprioceptive use can include a step back before stepping forward, or the use of a trained dog to provide this sensory information. Lastly, using visual cues such as lines on the floor, a caretaker’s foot placed in front of the frozen limb, or a flashlight beam will also be helpful. Falling may be improved with physical therapy, the use of a cane, wheelchair or motorized scooter.

49. Cognitive Assessment Memory difficulties: 11-29% of PD patients
Benign forgetfulness
Delirium
Alzheimer’s disease
Other dementias
Evaluation
Brain imaging
Lumbar puncture
EEG
Blood work for thyroid profile, vitamin B12, serology, chemistry panel
In addition to the motor complications seen so frequently in Parkinson’s disease there are other, non-motor, complications that need to be addressed. Perhaps the most frustrating condition for a caregiver is the cognitive impairment that occurs in this condition. Memory problems are reported in 11-29% of Parkinson’s disease patients, and range from benign forgetfulness to delirium and other dementias that can occur from Lewy body disease, Alzheimer’s disease, multi-infarct dementia or normal pressure hydrocephalus. Evaluation should include brain imaging, lumbar puncture, EEG, and blood work for a thyroid profile, vitamin B12, serology and chemistry panel.

50. Orthostatic Hypotension
Light-headedness, dizziness, fatigue, shoulder or neck pain, blood pressure drops when standing
Taper anti-hypertensive agents
Taper non-PD drugs
Increase salt intake
Compression stockings
Fludrocortisone ( mg/d)
Midodrine ( mg/d)
The most common autonomic symptoms seen in outpatient clinics are lightheadedness from orthostatic hypotension. If patients report dizziness, fatigue, shoulder or neck pain, and have a blood pressure drop when changing from sitting to standing position, it is necessary to address this situation. Most commonly, reduction of antihypertensive agents is the first step, followed by tapering non-Parkinson’s disease medications if necessary. Increased salt intake is often effective alone, but the use of compression stockings and glucocortisone have also been traditional methods of managing these symptoms. More recently the introduction of midodrine, an alpha agonist, has allowed the treatment of this condition with less difficulty with lower extremity edema than salt intake or glucocortisone. Suggested dosing is from mg daily.

51. 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.

52. Improvements with Pallidotomy
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.

53. Deep Brain Stimulation (DBS)
High frequency, pulsatile, bipolar electrical stimulation
Stereotactically placed into target nucleus
Can be activated and deactivated with an external magnet
Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation
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.

54. Cell Transplants Autologous adrenal transplants No efficacy
Allogenic human fetal transplants
Initial encouraging clinical results
Xenogenic fetal transplant (porcine and bovine)
Preliminary results pending
Genetically engineered cells
Research ongoing
A variety of cell transplantation techniques have been attempted and are currently ongoing for further studies for the treatment of Parkinson’s disease. Autologous adrenal transplants of dopaminergic producing cells from the adrenal gland of the same individual have not proven to be efficacious and have been largely abandoned. Allogenic human fetal transplants have showed encouraging results and study of these continue. Xenogenic fetal transplants from porcine and bovine brains studies are beginning, but results are still pending. Finally, genetically engineered stem cell technology research is ongoing; however, no cells have been actually transplanted to date into a human with Parkinson’s disease.

55. Human Fetal Transplants
Efficacy
Encouraging preliminary results in young (<60) PD pts
Patients greater than 50 years did not improve
PET studies consistent with cell functioning
Autopsies (2) show cell survival
Problems
4-10 embryos < 10 weeks gestation needed
Immunosuppression requirements unknown
Numerous technical problems
Potential for dyskinesias, even without any PD medications