From Introduction to Treatment
Dpt. Aamir Memon
→ Parkinson disease is a progressive brain disorder characterized by the loss of
neurons in an area of the midbrain known as the substantia nigra.
→ These neurons use dopamine as a neurotransmitter and project their axons to the
thalamus and the caudate and putamen areas of the basal ganglia.
→ Parkinsonism refers to any disease that alters dopaminergic pathways connecting
the substantia nigra to the basal ganglia.
→ The striatal system is involved in voluntary muscle movement; it consists of the
substantia nigra, caudate, putamen, globus pallidus, subthalamus, and thalamus.
→ Dopamine is the principal neurotransmitter in the nigrostriatal tract connecting the
substantia nigra with the caudate and putamen.
→ Parkinsonism is a clinical syndrome of rigidity, bradykinesia, resting tremor,
and postural instability (loss of postural reflexes).
→ Estimated prevalence: 500,000–1 million patients in United States
o Incidence: 40,000–60,000 new cases per year in USA.
o Affects up to 0.3% of general population, but 1–3% of those >65 y/o.
→ PD is largely a disease of older adults: only 5–10% of patients have symptoms
before 40 y/o (young-onset PD).
→ Occurs between 45 and 65 years of age:
o Distribution is equal in men and women.
o Most cases are sporadic, but some cases are familial.
→ Average age of onset is 60 years.
→ Most cases are due to Parkinson's disease, an idiopathic disorder with a prevalence
of about 1-2 per 1000.
→ In the first half of the last century, parkinsonism was a common sequela of von
Many theories on cell death but no firm conclusions:
→ Apoptosis, mitochondrial dysfunction, oxidative stress, excitotoxicity, deficient
neurotrophic support, immune mechanisms are linked to the pathogenesis of PD
→ In Parkinson's disease, there is selective degeneration of monoamine-containing
cell populations in the brainstem and basal ganglia, particularly of pigmented
dopaminergic neurons of the substantia nigra and locus ceruleus with decreased
→ In addition, scattered/affected neurons in basal ganglia, brainstem, spinal cord, and
sympathetic ganglia contain large homogenous eosinophilic, cytoplasmic inclusion
bodies (Lewy bodies) which possess neurofilament, ubiquitin, and crystalline
→ Alterations in mitochondrial complex I activity appear to play an important role in
the pathogenesis of Parkinson's disease
→ The reasons why dopaminergic neurons appear selectively vulnerable to complex I
inhibition are not clear;some evidence suggests that dopamine can promote
→ Addition of exogenous dopamine is toxic to neurons in culture which undergoes
auto-oxidation to generate reactive oxygen species.
→ Thus, dopamine within dopaminergic neurons may provide a source of reactive
oxygen species, which, when coupled with reduced complex I function, may
promote cell death.
Parkinson’s disease (PD)
o MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
o Acquired immunodeficiency syndrome
o Subacute sclerosing panencephalitis
o Postencephalitic parkinsonism
o Creutzfeldt-Jakob disease
o Chronic hepatocerebral degeneration
o Wilson’s disease
Multiple system atrophy
o Striatonigral degeneration
o Shy- Drager syndrome
o Olivopontocerebellar atrophy
Progressive supranuclear palsy
Corticobasal ganglionic degeneration
Progressive pallidal atrophy
Dementia with Lewy bodies
Lubag (X-linked dystonia-parkinsonism)
Autosomal dominant (AD) and autosomal recessive (AR) patterns of inheritance
have been identified.
1. Park 1: chromosome 4q21-23:
o Alanine-53-threonine mutation in the α-synuclein gene.
o Autosomal dominant (AD).
o Earlier disease onset (mean, age 45 years).
o Faster progression.
o Some with fluent aphasia.
2. Park 2: chromososme 6q25.2-27:
o The parkin gene.
o Autosomal recessive (AR).
o Relatively young-onset parkinsonism.
o Early dystonia.
o Symmetric involvement.
o Good levodopa response.
o Absence of Lewy bodies at autopsy.
3. Park 3: chromosome 2p13:
o Autosomal dominant (AD) but with 40% penetrance.
o All from northern Germany and southern Denmark.
o Nigral degeneration and Lewy bodies at autopsy.
o Dementia may be more common
4. Park 4: chromosome 4p14-16.3:
o Autosomal dominant (AD).
o From a family known as the Iowa kindred.
o Also younger age of onset (mean, 34 years).
o Rapid clinical course.
o Early-onset dementia.
o Equivocal response to levodopa.
o Some family members with only postural tremor resembling essential tremor.
o Autopsy shows Lewy bodies in the nigra and hippocampus.
5. Park 5: mutation in ubiquitin carboxy-terminal hydrolase L1 on chromosome 4:
o Autosomal dominant (AD).
o Young-onset progressive parkinsonism.
6. Park 6: chromosome 1p35-36:
o Autosomal recessive (AR).
o Early-onset parkinsonism.
o Slow progression.
o Marked response to levodopa.
o Gene not yet identified.
7. Park 7: chromosome 1p3:
o Early Autosomal recessive (AR) parkinsonism.
o Slow progression.
o With levodopa responsiveness.
o Mostly from the Netherlands.
Cardinal features of parkinsonism
o Resting tremor
o Flexed posture (of the neck, trunk, and limbs)
o Disorders of postural reflexes
→ Resting tremor: causes "pill rolling" between thumb and index fingers and
o Parkinsonian tremor is characteristically slow, of medium to coarse
amplitude (3-7 Hz); present at rest; increased by emotion, fatigue, stress,
and anxiety; absent in sleep; and decreased by volitional activity.
o It typically affects the distal appendicular muscles, leading to:
Flexion-extension movements of the metacarpophalangeal and
interphalangeal joints of the fingers and thumb
Adduction-abduction movements of the thumbs (pill rolling)
Pronation-supination movements of the wrists.
It often begins unilaterally in the hand and may be present initially
only in the thumb or a single finger.
o The tremor then typically spreads to the ipsilateral lower extremity
(hemiparkinsonism) before involving the opposite half of the body.
o In addition to resting tremor, an action tremor (7-12 Hz) may be seen.
o Tremor of the protruded tongue is not uncommon, whereas tremors of the
head, lips, and jaw are less frequent.
→ Bradykinesia (decreased movements).
o Bradykinesia is the most disabling manifestation of parkinsonism
o It’s characterized by delay in the initiation and execution of willed
movements and a general reduction of associated automatic movements.
o Bradykinesia explains (at least partially) the facial hypomimia, reduced
blinking, impaired ocular convergence, monotonous and low-volume
speech (bradylalia, eventually leading to anarthria), drooling of saliva,
micrographia, and slow shuffling gait with reduced associated movements
that occur in parkinsonism.
→ Muscle rigidity: causes slowness of voluntary muscle movement (bradykinesia)
and cogwheel rigidity
o Rigidity is characterized by a plastic resistance to passive movements that
affects both agonist and antagonist muscles (e.g., flexors and extensors,
pronators, and supinators) to a similar extent and that is constant throughout
the entire range of movement.
o Rigidity affects more axial and proximal limb muscles and can be detected
early in the disease process.
o The phenomenon of cogwheel rigidity is characterized by periodic
modifications of muscle tone due to the superimposed tremor that can be
seen and felt when passively moving the extremity.
o The akinetic-rigid syndrome is characteristic of PD and due to abnormal
dopaminergic input to the striatum.
→ Disorders of postural fixation
o May affect the head, trunk, limbs, or the entire body, resulting in:
Forward displacement of the head,
Forward or backward instability of the trunk,
Difficulty in maintaining an erect posture when being slightly
pushed, and easy falling.
→ Freezing phenomena are also common in PD
o Consist of transient periods, usually lasting seconds, in which the motor act
is halted, being stuck in place.
o In freezing, the voluntary motor act being attempted is halted because
agonists and antagonist muscles are spontaneously and isometrically
o Freezing phenomena include start-hesitation (freezing when gait is
initiated), turn-hesitation (freezing when turning), destination-hesitation
(freezing when approaching a target), freezing when an obstacle is
encountered, spontaneous sudden transient freezing, palilalia or freezing of
speech (i.e., repetition of the first syllable of the word trying to be verbally
expressed), apraxia of eye opening (levator inhibition), and freezing of
limbs (e.g., during writing or teeth-brushing).
o With start-hesitation, the feet take short sticking, shuffling steps before the
patient can begin walking; with progression the feet become glued to
o Freezing occurs in idiopathic parkinsonism, symptomatic parkinsonism,
PSP, multisystems atrophy, and may be idiopathic without other features
except loss of postural reflexes and mild bradykinesia
→ May demonstrate:
o A simian posture (forward flexion of the trunk, flexion of the elbows, and
partial flexion of the knees),
o The parkinsonian hand (mild dorsiflexion of the wrist, flexion of the
metacarpophalangeal joints, extension and adduction of the fingers, and
slight ulnar deviation)
o The dystonic foot posture (extension of the great toe, flexion of the toes,
arching of the sole, and inversion of the foot).
o Other features include sleep abnormalities, and pain, as well as a variety of
sensory complaints, constipation, hesitance and frequency of micturition,
seborrhea, hyperhidrosis, exaggerated nasopalpebral reflex (glabellar tap or
Myerson's sign), blepharospasm, blepharoclonus, and oculogyric crisis.
o Abnormalities of speech are common and include hypokinetic dysarthria,
hypophonia, bradyphrenia (slow to think or respond to questions),
tachyphemia (repetition of a word or phrase with increasing rapidity and
decreasing volume), palilalia, inappropriate silent periods, and tip-of-the-
tongue• phenomenon (a type of anomia in parkinsonism that is a semantic
rather than a phonetic retrieval deficit).
→ May have behavioral signs and are often dependent, fearful, indecisive, and
o Depression occurs in 30% of patients, whereas dementia occurs in 40% and
increases with age (below age 60, 8%; greater than age 80, 69%).
→ Sudden onset of sleep (SOS) with no prior warning symptoms of drowsiness
o The strongest predictors of SOS are:
Longer disease duration
Presence of various sleep disturbances.
o Taking non-ergoline dopamine antagonists is more strongly associated with
SOS in patients below 70 years of age and in those with disease duration
less than 7 years.
→ Camptocormia (bent spine syndrome) is characterized by an abnormal posture
of the trunk with marked flexion of the thoraco-lumbar spine, which increases
during walking and abates in the recumbent position.
o Originally thought to be a psychogenic disorder, camptocormia is
recognized as a feature of parkinsonian and dystonic disorders.
→ Neurons contain intracytoplasmic, eosinophilic bodies called Lewy bodies
→ In patients with Parkinson-like symptoms, diagnosis is often made based on
history and physical examination.
→ A positive response to levodopa is strongly indicative of Parkinson.
→ There are other disorders that may cause parkinsonism besides Parkinson disease
(sometimes called “Parkinson plus”).
These disorders may be difficult to separate clinically from Parkinson disease.
A lack of response to medication for Parkinson, early dementia, and other
neurologic signs may all suggest such conditions.
Up to 30% of patients with parkinsonism ultimately have a cause other than
Consider the following:
→ Medications may cause secondary parkinsonism by blocking the D2 receptor in
the basal ganglia.
o Common agents responsible for this effect include typical neuroleptics such
as haloperidol and the anti-emetic metoclopramide.
o Up to 5% of patients on long-term valproic acid will develop parkinsonism
with a cognitive decline that may be reversible.
→ Progressive supranuclear palsy (PSP) is a degenerative disorder in which patients
have a toppling gait, impaired voluntary up-and-down eye movements, and
o PSP should be considered in a parkinsonian patient who presents with
falling as an early symptom.
→ Multiple system atrophy (MSA) refers to a group of degenerative disorders in
which there are abnormalities in multiple neurologic systems, including the basal
ganglia, corticospinal tract, autonomic nervous system, and cerebellum.
o The Shy-Drager syndrome is a subtype of MSA with impotence, postural
hypotension, and parkinsonism.
o Striatonigral degeneration features parkinsonism and later signs of
pyramidal dysfunction, hyperreflexia, extensor toes, and postural
o Olivopontocerebellar atrophy has prominent brainstem and cerebellar
degeneration with associated parkinsonism.
→ Diffuse Lewy body disease may cause parkinsonism, accompanied by an early
cognitive decline, prominent visual hallucinations, a fluctuating course, and
sensitivity to major antipsychotics.
o Pathologically, Lewy bodies are seen in cortical areas in addition to the
→ Normal pressure hydrocephalus (NPH) involves the triad of gait disorder,
cognitive decline, and incontinence.
o Patients may appear parkinsonian but the gait is usually apraxic rather than
parkinsonian (patients seem unable to “figure out” how to walk but can still
bicycle with their legs effectively when lying in bed on their back).
o NPH may be a delayed manifestation following a head injury, subarachnoid
hemorrhage, meningitis, or may occur spontaneously.
o On computed tomography (CT) or magnetic resonance imaging, large
ventricles are seen without significant atrophy.
o Gait is “magnetic,” with difficulty picking up the feet despite good strength
→ Parkinsonism may be secondary to toxins such as chronic manganese or carbon
Treatment (Early Stage):
→ Treatment of Parkinson disease has become a specialized endeavor, with the
continuing development of new medications and treatments.
→ Patients with early Parkinson may not require treatment with medication until they
experience difficulty functioning.
→ Selective monoamine oxidase inhibitors, selegiline and rasagiline,
may be neuroprotective.
→ These have been used as first-line agents in early Parkinson disease.
→ Once difficulty arising from a chair, walking, or using the limbs becomes a
problem, medication aimed at improving these functions is indicated.
Levodopa is the most effective anti-parkinsonian medication, and is the
cornerstone of therapy for most patients.
o Despite this, many physicians delay the use of levodopa until later in the
course with the hope that the long-term side effects of this medication can
be reduced or delayed.
o The effect may be dramatic when administered early in disease. Used alone,
large doses are needed for effect, and the peripheral effect causes nausea
and orthostatic hypotension.
o When combined with a dopa-decarboxylase inhibitor (carbidopa), the
peripheral effects are minimized, and the dose may be reduced as more of
the dopa reaches the brain to be converted to dopamine.
o Combination medication is available as a short-acting or long-acting
o The short-acting medication is available as 10/100, 25/100, and 25/250,
with the first number referring to the milligrams of carbidopa and the
second number referring to the milligrams of levodopa.
o A long-acting (CR) form is available as 25/100 or 50/200 mg, but does not
confer a significant added benefit.
o Levodopa/carbidopa 25/100, 3 to 4 times a day is the usual starting dose.
The most common side effect of levodopa therapy is nausea.
o Early motor fluctuations, dyskinesia, and on-off phenomena are common
problems encountered with levodopa/carbidopa as parkinsonism
o Dystonia, agitation, hallucinations, and sleep disorders also may occur,
particularly in patients with dementia.
o Providing levodopa/carbidopa 30 minutes before meals and limiting protein
intake during the day may improve absorption and efficacy of
Advantages of Levodopa:
o Most efficacious antiparkinsonian drug
o Immediate therapeutic benefits (within 1 week)
o Easily titrated
o Reduces mortality
o Lower cost
Disadvantages of Levodopa:
o No effect on disease course,
o No effect on nondopaminergic symptoms, such as dysautonomia, cognitive
disturbances, and postural instability, motor fluctuations and dyskinesia develop
over time (especially in younger patients, those with more severe disease and
those requiring higher doses).
Dopamine agonists are advocated by some authorities as early monotherapy in an
attempt to spare the use of levodopa early in the disease.
o Pergolide, bromocryptine, ropinerole, pramipexole, and rasagiline are
available dopamine agonists.
o Because pergolide, pramipexole, and ropinerole are longer-acting agents,
they may help smooth out motor fluctuations seen with levodopa therapy,
and have fewer choreiform-like dyskinesias than levodopa.
o However, they may cause nausea, hypotension, hallucinations, and
confusion, as well as excessive somnolence.
o Gradual titration to the desired dose is the most effective strategy.
o They may be used as monotherapy or in combination with other anti-
o Ergot derived dopamine agonists (pergolide, bromocryptine, cabergoline)
have recently been shown to cause valvular heart disease in up to 5% of
o In addition, dopamine agonists may cause impulsive behaviors, such as
gambling and hypersexuality, particularly at higher doses.
o Patients taking dopamine agonists should be warned not to drive if
excessive somnolence is a significant complaint. It is not known if lowering
the dose of dopamine agonist will help this.
Drug Ergot derived D1 D2 D3/D4 Half-life (hrs)
Bromocriptine Yes — ++ + 3
Pergolide Yes + ++ ++ 27
Pramipexole No — ++ +++ 12
Ropinirole No — ++ + 4
Cabergoline Yes — ++ + 65
+, least receptor affinity.
+++, greatest receptor affinity.
Catecholamine-O-methyltransferase (COMT) inhibitors (entacapone and
o Extend the pharmacologic half-life of levodopa
o May decrease the amount of “off” time.
Selegiline is a selective monoamine-B oxidase inhibitor that increases the
availability of dopamine at the synaptic terminal.
o A recent Cochrane review indicated that monoamine B inhibitors have an
unproven role in early Parkinson disease.
Anticholinergic medications were used in the past, but are no longer commonly
prescribed due to their side effect profile.
o option for young patients (<60 y/o) whose predominant symptoms are
resting tremor and hypersalivation
o available agents—trihexyphenidyl and benztropine;
o adverse effects often limit use—memory impairment, confusion,
Amantidine, an NMDA antagonist, was initially demonstrated to have a modest
o This agent is now used to reduce dyskinesias when that side effect of
Small doses of an anti-epileptic medication zonisamide appear to be effective in
reducing “off-time” in patients with Parkinson disease (grade B).
Rasagiline, a selective monoamine-B oxidase inhibitor, was recently approved for
use in Parkinson disease.
o This can be used both as an initial agent early in Parkinson disease, or as an
add-on agent for “on-off” problems later in the disease.
o In the usual dosing of 0.5 to 1.0 mg per day, there do not appear to be
problems with reactions to tyramine-containing foods.
There is an increased incidence of melanoma in patients with Parkinson disease. It
is unclear if this is related to its treatment or to the disease itself.
Treatment (Late Stage):
→ After approximately 5 years of treatment with levodopa, probably because of loss
of buffering action by remaining dopaminergic neurons, patients develop a variety
of difficult-to-treat side effects of levodopa.
→ Such problems include the following:
Wearing-off of levodopa may be improved by giving the levodopa more
frequently, using longer-acting dopa preparations, adding dopamine agonists to
levodopa, adding COMT inhibitors such as tolcapone or entacapone, or adding
rasagiline (grade A).
o Fatal hepatotoxicity has occasionally occurred with tolcapone.
Use smaller and more frequent levodopa doses, or lower the levodopa dose
and add dopamine agonists.
Amantidine may also be helpful in this setting.
“On-off” fluctuations refer to dramatic, unpredictable shifts from under-treated to
These are difficult to treat.
Adding dopamine agonists, using COMT inhibitors, using rasagiline, and
occasionally using injectable apomorphine may be helpful.
Confusion, sleep disorder, and psychosis may be helped by decreasing the
medication, particularly limiting anticholinergics, amantidine, and other
medications with sedating or anticholinergic effects.
Adding clozapine (grade B) or quietipine (grade C) may be used in
Olanzepine should not be routinely used due to side effects in parkinsonian
patients (grade B).
Clozapine may cause a fatal agranulocytosis and must be closely
antiparkinsonian drugs in order of their potential to produce delirium
(anticholinergics > amantadine > selegiline > dopamine agonists > catechol
methyltransferase inhibitor > levodopa)
Impulse control disorders have recently been identified in patients with
Parkinson disease (gambling, hypersexuality, excessive shopping, etc.).
o These may be associated with the use of dopamine agonists or be related to
the disease entity.
Deep-brain stimulation of the subthalamic nucleus has been studied in recent
o These studies showed measurable improvements in activities of daily
living, emotional well-being, and mobility, but with a higher risk of serious
adverse events including fatal intracerebral hemorrhage (grade B).
Lesion vs. deep brain stimulation
o Thalamotomy— most effective for parkinsonian and essential tremor
o Pallidotomy—improves bradykinesia, tremor, rigidity, dyskinesia in PD
o No technology or adjustments required
o No indwelling device
o Inability to do bilateral lesions without increased risk of dementia
o Swallowing dysfunction, etc.
o Side effects could be permanent
Deep brain stimulation surgery (globus pallidus internus or subthalamic
o Minimal to no cell destruction,
o Ability to perform deep brain stimulation on both sides
o Adjust the stimulation settings as the disease progresses
o More expensive
o Requires technical expertise
o Could be prone to hardware malfunctions (kinks, lead fractures) or infections
The ideal surgical candidate:
o Clear PD diagnosis with unequivocal and sustained levodopa response
o Relatively young
o Emotionally and physically stable.
Many patients with Parkinson disease develop dementia.