1.

Definition

Parkinsons disease (PD) was first described by Dr. James Parkinson in 1817 as a shaking
palsy. It is a chronic, progressive neurodegenerative disease characterized by both motor and
nonmotor features.

2. Anatomy and Physiology of Basal Ganglia

a. Basal ganglia.

The basal ganglia consist of the caudate nucleus (CN), putamen, globus pallidus (= pallidum;
GPe = external segment, GPi = internal segment; putamen + pallidum = lentiform nucleus),
claustrum, substantia nigra (SN; SNc = pars compacta, SNr = pars reticularis), and the
subthalamic nucleus (STN). CN + putamen = (dorsal) striatum; nucleus accumbens + portions of
olfactory tubercle + anterior portion of putamen + CN = limbic (ventral) striatum. Substantia
nigra (SN): The SNr (ventral portion of SN) contains small amounts of dopamine and iron,
giving it a reddish color, while the SNc (dorsal portion) contains large quantities of dopamine
and melanin, making it black (whence the name, substantia nigra).

b. Connections.

The basal ganglia are part of a number of parallel and largely distinct (segregated) neural
pathways (circuits). Each circuit originates in a cortical area that is specialized for a specific
function (skeletal motor, oculomotor, associative-cognitive, or emotional-motivational control),
passes through several relay stations in the basal ganglia, and travels by way of the thalamus
back to the cerebral cortex. Cortical projection fibers enter the basal ganglia at the striatum (input
station) and exit from the GPi and SNr (output station).

Input from the thalamus and brain stem also arrives at the striatum. Within the basal ganglia,
there are two circuits subserving motor function, the so-called direct and indirect pathways. The
direct pathway runs from the putamen to the GPi and SNr, while the indirect pathway takes the
following trajectory: putamen ! GPe ! STN ! GPi ! SNr. The GPi and SNr project to the thalamus
and brain stem.

c. Neurotransmitters.

Glutamate mediates excitatory impulses from the cortex, amygdala, and hippocampus to the
striatum. Synapses from STN fibers onto cells of the GPi and SNr are also glutamatergic. Both
the excitatory and the inhibitory projections of the SNc to the basal ganglia are dopaminergic. In
the striatum, dopamine acts on neurons bearing D1 andD2 receptors, of which there are various
subtypes (D1 group: d1, d5; D2 group:d2,d3,d4).D1 receptors predominate in the direct
pathway, D2 receptors in the indirect pathway. Cholinergic interneurons in the striatum form a
relay station within the basal ganglia (transmitter: acetylcholine). Medium spiny-type neurons
(MSN) in the striatum have inhibitory projections to the GPe, GPi, and SNr (transmitters:
GABA, substance P/SP, enkephalin/Enk). Other inhibitory GABAergic projections run from the
GPi to the STN, from the GPi to the thalamus (ventrolateral and ventroanterior nucleus), and
fromthe SNto the thalamus. The thalamocortical projections are excitatory.

d. Motor function.

The direct pathway is activated by cortical and dopaminergic projections to the striatum. The
projection from the striatum in turn inhibits the GPi, diminishing its inhibitory output to the
thalamic nuclei (i.e., causing net thalamic activation). Thalamocortical drive thus facilitates
movement initiated in the cerebral cortex (voluntary movement). In the indirect pathway, the
striatum, under the influence of afferent cortical and dopaminergic projections, exerts an
inhibitory effect on the GPe and STN. The result is a diminished excitatory influence of the STN
on the GPi and SNr, ultimately leading to facilitation of cortically initiated voluntary movement
and inhibition of involuntary movement.

Besides having nonmotor functions that are not clearly understood, the basal nuclei play a
complex role in controlling movement. In particular, they are important in (1) inhibiting muscle
tone throughout the body (proper muscle tone is normally maintained by a balance of excitatory
and inhibitory inputs to the neurons that innervate skeletal muscles); (2) selecting and
maintaining purposeful motor activity while suppressing useless or unwanted patterns of
movement; and (3) helping monitor and coordinate slow, sustained contractions, especially those
related to posture and support. Th e basal nuclei do not directly influence the eff erent motor
neurons that bring about muscle contraction but act instead by modifying ongoing activity in
motor pathways.

3. Epidemiology

PD is one of the most common neurodegenerative disorders. The Parkinsons Disease

Foundation reports that approximately 1 million Americans currently have the disease.5 The
incidence of PD in the U.S. is approximately 20 cases per 100,000 people per year (60,000 per
year), with the mean age of onset close to 60 years. The prevalence of PD is reported to be
approximately 1% in people 60 years of age and older and increases to 1% to 3% in the 80-plus
age group

4. Pathogenesis

This condition is associated with a gradual destruction of neurons that release the
neurotransmitter dopamine in the basal nuclei. Because the basal nuclei lack enough dopamine to
exert their normal roles, three types of motor disturbances characterize PD: (1) increased muscle
tone, or rigidity; (2) involuntary, useless, or unwanted movements, such as resting tremors (for
example, hands rhythmically shaking, making it difficult or impossible to hold a cup of coff ee);
and (3) slowness in initiating and carrying out diff erent motor behaviors. People with PD find it
difficult to stop ongoing activities. If sitting down, they tend to remain seated, and if they get up,
they do so very slowly.
5. Pathophysiology

The cause of Parkinson disease is unknown. Its structural pathological correlate is a loss of
neurons in the caudal and anterolateral parts of the SNc, with reactive gliosis and formation of
Lewy bodies (eosinophilic intracytoplasmic inclusions in neurons) and Lewy neurites
(abnormally phosphorylated neurofilaments) containing synuclein. Loss of pigment in the
substantia nigra can be seen macroscopically. The most prominent neurochemical abnormality is
a deficiency of dopamine in the striatum, whose extent is directly correlated with the severity of
PD. The physiological effect of the lack of (mostly inhibitory) dopamine neurotransmission in
the striatum is a relative increase in striatal activity, in turn causing functional disinhibition of the
subthalamic nucleus via the indirect pathway.

Meanwhile, in the direct pathway, decreased striatal inhibition of the GPi enhances the inhibitory
influence of the GPi on the thalamus, leading to reduced activity in the thalamocortical

projection. These changes in neural activity manifest themselves in the clinically observable
akinesia, rigidity, and postural instability.
6. Clinical Manifestations
I. Cardinal Manifestations
a. Bradykinesia, hypokinesia, and akinesia.

Motor disturbances include slow initiation of movement (akinesia), sluggishness of movement

(bradykinesia) and diminished spontaneous movement (hypokinesia); these terms are often used
nearly interchangeably, as these disturbances all tend to occur together. Spontaneous fluctuations
of mobility are not uncommon. The motor disturbances are often more pronounced on one side
of the body, especially in the early stages of disease. They affect the craniofacial musculature to
produce a masklike facies (hypomimia), defective mouth closure, reduced blinking, dysphagia,
salivation (drooling), and speech that is diminished in volume (hypophonia), hoarse, poorly
enunciated, and monotonous in pitch (dysarthrophonia). The patient may find it hard to initiate
speech, or may repeat syllables; there may be an involuntary acceleration of speech toward the
end of a sentence (festination). Postural changes include stooped posture, a mildly flexed and
adducted posture of the arms, and postural instability. Gait disturbances appear in the early
stages of disease and typically consist of a small-stepped gait, shuffling, and limping, with
reduced arm swing. Difficulty initiating gait comes about in the later stages of disease, along
with episodes of freezing complete arrest of gait when the patient is confronted by doorway
or a narrow path between pieces of furniture. It becomes difficult for the patient to stand up from
a seated position, or to turn over in bed. Impairment of fine motor control impairs activities of
daily living such as fastening buttons, writing (micrographia), eating with knife and fork,
shaving, and hair-combing. It becomes difficult to perform two activities simultaneously, such as
walking and talking.

b. Tremor.

Only about half of all PD patients have tremor early in the course of the disease; the rest usually
develop it as the disease progresses. It is typically most pronounced in the hands (pill-rolling
tremor) and is seen mainly when the affected limbs are at rest, improving or disappearing with
voluntary movement. Its frequency is ca. 5 Hz, it is often asymmetrical, and it can be
exacerbated by even mild stress (mental calculations, etc.).
c. Rigidity.

Elevated muscle tone is felt by the patient as muscle tension or spasm and by the examiner as
increased resistance to passive movement across the joints. Examination may reveal cogwheel
rigidity, i.e., repeated, ratchetlike oscillations of resistance to passive movement across the wrist,
elbow, or other joints, which may be brought out by alternating passive flexion and extension.

d. Postural instability (loss of balance).

Propulsion and retropulsion arise in the early stages of Parkinson disease because of generalized
impairment of the postural reflexes that maintain the bipedal stance. Related phenomena include
involuntary acceleration of the gait (festination), difficulty in stopping walking, gait instability,
and frequent falls.
II. Accompanying Manifestations
a. Behavioral Changes
Depression.

The range of depressive manifestations includes worry, anxiety, avoidance of social contact,
general unhappiness, listlessness, querulousness, brooding, somatoform disturbances, and
(rarely) suicidal ideation.

Anxiety.

Tension, worry, mental agitation, lack of concentration, and dizziness are relatively common
complaints.

Dementia.

Impairment of memory and concentration in early PD-associated dementia may be difficult to

distinguish from depressive manifestations. The side effects of pharmacotherapy (p. 212) must
be kept in mind before treatment is initiated for patients suffering from disorientation, confusion,
suspiciousness, and other emotional changes.

Hallucinations.

A state of excessive suspiciousness, vivid dreams, and increasing anxiety may evolve into one of
severe confusion with visual hallucinations. Frank psychosis (e. g., paranoid delusions, ideas of
reference, or delusional jealousy) may be due to other causes than PD, particularly an adverse
effect of antiparkinsonian medication.

b. Autonomic Dysfunction
Blood pressure changes.

Hypotension is a common side effect of antiparkinsonian medications (levodopa, dopamine

agonists). Marked orthostatic hypotension, if present, suggests the possible diagnosis of
multisystem atrophy.
 Constipation

This may be caused by autonomic dysfunction, as a manifestation of the disease, or as a side

effect of medication (anticholinergic agents).

Bladder disorders.

Polyuria, urinary urgency, and urinary incontinence occur mainly at night and in patients with
severe akinesia (who have difficulty getting to the toilet). PD only rarely causes severe bladder
dysfunction.

Sleep disorders.

PD commonly causes disturbances of the sleepwake cycle, including difficulty falling asleep,
nocturnal breathing problems similar to sleep apnea syndrome, and shortening of the sleep cycle.
Sleep may also be interrupted by nocturnal akinesia, which makes it difficult for the patient to
turn over in bed.

Sexual dysfunction.

Spontaneous complaints of diminished libido or impotence are rare. Increased libido is a known
side effect of levodopa and dopamine agonists.

Leg edema

This is often as the result of physical inactivity.

c. Sensory Manifestations
Pain

Pain in the arm or shoulder, sometimes accompanied by fatigue and weakness, may be present
for years before the cardinal manifestations arise and enable a diagnosis of PD. Back pain and
nuchal cramps are frequent secondary effects of parkinsonian rigidity and abnormal posture.
Dystonia may also come to attention because of the pain it produces.
The symptoms and signs of Parkinsons disease reflect a highly selective pattern of degeneration
in the brain. The worst damage occurs in the dopamine-producing neurones of the substantia
nigra, and this accounts for many of the abnormalities of movement, referred to as
parkinsonism. These neurons project to the corpus striatum via the nigrostriatal pathway. The
consequence of loss of neurones in the substantia nigra is dopamine deficiency in the corpus
striatum. This may be unilateral, asymmetrical or symmetrical.

The noradrenaline- and 5HT-producing neurones in the brainstem are also affected, and this may
explain the high incidence of depression in Parkinsons disease. The neurones that deliver
acetylcholine to the cerebral cortex are affected as well; this, together with involvement of the
cortial neurones themselves, contributes to cognitive symptoms. In all these locations the
neurones degenerate in a characteristic way, forming clumps of protein called Lewy bodies.

7. Diagnosis

The diagnosis of Parkinson disease (PD; sometimes termed idiopathic Parkinson disease, to
distinguish it from symptomatic forms of parkinsonism, and from other primary forms) is mainly
based on the typical neurological findings, their evolution over the course of the disease, and
their responsiveness to levodopa (Ldopa). Longitudinal observation may be necessary before a
definitive diagnosis of PD can be given. PD is characterized by a number of disturbances of
motor function (cardinal manifestations) and by other accompanying manifestations of different
kinds and variable severity.

8. Treatment

The goal of treatment is improvement of the motor, autonomic, and cognitive symptoms of the
disease. The treatment generally consists of medication along with physical, occupational, and
speech therapy. Neurosurgical procedures are mostly reserved for intractable cases (see below).
Pharmacotherapy is palliative, not curative. It is begun when the patient has trouble carrying out
the activities of daily living and is prescribed, not according to a uniform pattern, but in relation
to the needs of the individual patient.
 Dopaminergic agents.

Levodopa is actively absorbed in the small intestine and rapidly distributed throughout the body
(especially to skeletal muscle). Amino acids compete with the levodopa transport system at the
bloodbrain barrier. A decarboxylase inhibitor that does not penetrate the bloodbrain barrier
(benserazide or carbidopa) is administered together with levodopa to prevent its rapid breakdown
in the peripheral circulation. Once it reaches the brain, levodopa is decarboxylated to dopamine,
which is used for neurotransmission in the striatum. After it has been released from the
presynaptic terminals of dopaminergic neurons in the striatum and exerted its effect on the
postsynaptic terminals, it is broken down by two separate enzyme systems (deamination by
monoamine oxidase type B, MAO-B; methylation by catechol- O-methyltransferase, COMT).
Levodopa effectively reduces akinesia and rigidity, but has only a mild effect against tremor. Its
long-term use is often complicated by motor fluctuations, dyskinesia, and psychiatric
disturbances.

Dopamine agonists (DAs) mimic the function of dopamine, binding to dopamine receptors. Their
interaction with D1 and D2 receptors is thought to improve motor function, while their
interaction with D3 receptors is thought to improve cognition, motivation, and emotion. Long-
term use of DAs is less likely to cause unwanted motor side effects than long-term use of
levodopa. Commonly used DAs include bromocriptine (mainly a D2 agonist), lisuride (mainly a
D2 agonist), and pergolide (a D1, D2, and D3 agonist). Apomorphine, an effective D1 and D2
agonist, can be given by subcutaneous injection, but its effect lasts only about 1 hour. Other,
recently introduced dopamine agonists are ropinirol and pramipexol (D2 and D3), cabergoline
(D2), and dihydroergocryptine (mainly D2). Selegiline inhibits MAO-B selectively and
irreversibly ( reduced dopamine catabolism increase in striatal dopamine concentration).
Entacapone increases the bioavailability of levodopa via peripheral inhibition of COMT.
 Nondopaminergic agents.

Anticholinergic agents

(biperidene, bornaprine, metixene, trihexyphenidyl) act on striatal cholinergic interneurons.

Budipine can relieve tremor (risk of ventricular tachycardia ECG monitoring). Glutamate
antagonists (amantadine, memantine) counteract increased glutamatergic activity at the N-
methyl-D-aspartate (NMDA) glutamate receptor in the indirect pathway.
 Transplant Surgery

Current research on intrastriatal transplantation of stem cells (derived from fetal tissue, from
umbilical cord blood, or from bone marrow) seems promising.

Stereotactic Neurosurgical Procedures, Deep Brain Stimulation

These procedures can be used when PD becomes refractory to medical treatment. Pallidotomy
(placement of a destructive lesion in the GPi) derives its rationale from the observed
hyperactivity of this structure in PD. Deep brain stimulation requires bilateral placement of
stimulating electrodes in the GPi or STN. Highfrequency stimulation by means of a
subcutaneously implanted impulse generator can improve rigor, tremor, akinesia, and dyskinesia.

Genetics of PD

A genetic predisposition for the development of PD has been postulated. Mutations in the genes
for synuclein (AD), parkin (AR), and ubiquitin C-terminal hydrolase L1 (UCHL1; AD) have
been found in pedigrees affected by the rare autosomal dominant (AD) and autosomal recessive
(AR) familial forms of PD.