Introduction
Parkinson’s disease affects more than 1 million Americans and has a prevalence rate of 1% in indi-viduals over age 55 years. The direct annual cost in the United States is over $10 million. Both sexes are equally involved, and the incidence climbs exponentially with increasing age to 7% above age 70 years. Idiopathic Parkinson’s disease usually begins above age 55, while patients with genetic causes of Parkinson’s disease starting as early as age 30 to 45 years. Parkinson’s disease has a dra-matic impact on quality of life and produces a marked reduction in life expectancy.
The hallmarks of Parkinson’s disease and parkinsonism are bradykinesia (diminished speed and spontaneity of voluntary movements), resting tremor, cogwheel rigidity, gait changes, and late postural instability, all due to reduced levels of dopaminergic transmission from structural or functional disruption of nigrostriatal pathways.
Parkinson’s disease refers to the primary idio-pathic form and represents 2/3 of all parkinson-ism. Parkinsonism is the secondary form and refers to the above clinical and biochemical fea-tures that develop from specific causes such as repeated head trauma (boxing), infections of the upper midbrain, medications that affect dopamine transmission, or CNS diseases that damage the nigrostriatal pathway and other brain areas.
Pathophysiology
Idiopathic Parkinson’s disease results from the slowly progressive death of CNS dopaminergic neurons and some adrenergic and serotonergic neurons. Death of the melanin-containing pig-mented dopaminergic neurons in the pars com-pacta of the substantia nigra is responsible for the motor signs of this disease. Evidence suggests that the death of dopaminergic neurons begins a decade before symptom onset. When the neuronal loss reaches about 70% of total neurons, symp-toms begin. The cause of dopaminergic neuronal death is unknown, but current theories include exposure to environment neurotoxins, abnormal mitochondrial function, abnormal oxidative metabolism, and generation of misfolded α-synu-clein protein, which is toxic.
Grossly, there is loss of pigmentation in the substantia nigra and other dopaminergic nuclei such as the locus ceruleus (Figure 12-2). Micro-scopically, there is loss of small pigmented neurons in the substantia nigra and eosinophilic, cytoplas-mic inclusion bodies surrounded by a clear halo (Lewy bodies) in remaining neurons, which con-tain aggregations of neurofilaments and α-synu-clein protein attached to ubiquitin.
Substantia nigra dopaminergic neurons project to the ipsilateral striatum (caudate nucleus and putamen). Dopamine release from substantia nigra neurons stimulates D1 receptors and inhibits D2 receptors, resulting in the striatum sending impulses to the motor cortex (called the basal gan-glia–thalamocortical motor circuit) in a direct excitatory pathway via thalamic nuclei. Concomi-tant inhibitory impulses to the motor cortex in a polysynaptic indirect pathway via globus pallidus externa, subthalamic nucleus, and thalamic nuclei are also sent. Loss of dopaminergic nigral cells leads to striatal dopamine depletion and overall decreased motor cortex excitation. The loss of excitatory stimulation decreases excitatory activity of the direct pathway to the motor cortex and increases inhibitory activity of the indirect path-way to the motor cortex. Not yet completely understood, the increased inhibitory input to the motor cortex causes bradykinesia.
Using the surround inhibition model of the basal ganglia, the loss of substantia nigra input to the striatum would cause loss of inhibition of com-peting motor movements (Figure 12-1). For exam-ple, when a normal individual flexes an arm, the bicep fires (desired movement) and the tricep is inhibited (surround inhibition). In the patient with Parkinson’s disease, flexion of the arm fires both the bicep (desired movement) and tricep (loss of surround inhibition), resulting in bradykinesia.
The tremor of Parkinson’s disease is felt to be sec-ondary to interruption of the CNS oscillatory pathway in the globus pallidus and thalamus.
Five percent of Parkinson’s disease is due to autosomal dominant mutation in the parkin gene and occasionally in the α-synuclein gene. The role ofα-synuclein in the pathogenesis of Parkinson’s disease is receiving attention since α-synuclein is normally abundant in neurons and presynaptic terminals, as well as in Lewy bodies. The parkin gene product appears to be involved in identifying 126 FUNDAMENTALS OF NEUROLOGIC DISEASE
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proteins such as α-synuclein for degradation via the ubiquitin pathway.
Major Clinical Features
The diagnosis of Parkinson’s disease is usually made by the presence of asymmetrical bradykine-sia, cogwheel rigidity, resting tremor, and good response to levodopa. Rigidity consists of a con-stant resistance to passive muscle stretching in both flexors and extensors throughout range of motion due to stretching force induction of some antagonistic motor units to fire. In Parkinson’s dis-ease, rapid flexion and extension or rotation of the wrist or elbow often elicits a ratchetlike feeling (cogwheel rigidity).
Table 12-2 lists the common clinical features of Parkinson’s disease in the early, middle, and advanced stages. The disabling feature is bradyki-nesia. One patient described early bradykinesia as walking in a swimming pool with water up to the neck and advanced bradykinesia as walking in a swimming pool filled with molasses. Thus,
patients spend enormous amounts of energy per-forming routine activities of daily living.
In a simplistic fashion, everything “slows down”
in the patient with Parkinson’s disease. Limb and chewing movements are slow; gait is slow, shuf-fling, difficult to initiate, and often with a stooped posture; standing balance is impaired from slow corrective steps to maintain balance, so falling is common; spontaneous facial expression is mini-mal (masked facies); gut peristalsis is slow so con-stipation is common; and mental activities are slower than normal so there are both less sponta-neous speech and delayed answers to questions spoken in a soft, dysarthric voice. In 40% a demen-tia develops in the later disease stages.
Major Laboratory Findings
Routine blood and CSF studies are normal. Neu-roimaging is seldom helpful in diagnosing Parkin-son’s disease or distinguishing it from other causes of parkinsonism. In Parkinson’s disease, PET stud-ies with radioactive fluorodopa demonstrate
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Figure 12-2 Gross brain specimen in patient with Parkinson’s disease, showing loss of pigmentation in the sub-stantia nigra (arrows) and locus ceruleus.
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reduced uptake greater in the putamen than in the caudate.
Principles of Management and Prognosis Since no treatments can halt disease progression of Parkinson’s disease, management aims at mini-mizing the symptoms and maximini-mizing patient functioning and safety. Presently there is contro-versy whether drugs such as monoamine oxidase inhibitors (e.g., selegiline) can slow the rate of early disease progression.
The mainstay of early treatment is providing additional dopamine or dopamine agonists to the striatum. Dopamine cannot cross the blood–brain barrier and causes considerable systemic nausea and hypotension by stimulating peripheral dopamine pathways. Levodopa was found to cross the blood–brain barrier and to be converted in the brain to dopamine by the enzyme dopa-decarboxy-lase. To minimize systemic conversion of levodopa to dopamine, the DOPA-decarboxylase inhibitor carbidopa is added to levodopa. Carbidopa does not cross the blood–brain barrier, so CNS conver-sion of levodopa is unaffected. Levodopa is con-verted to dopamine within the dopamine neuron cell body and transported via axoplasmic flow to the nerve terminal. Levodopa is also converted to
dopamine at the distant presynaptic nerve termi-nal, where it is taken up and stored by the nerve ter-minal. Dopamine agonists, such as bromocriptine and pramipexole, cross the blood–brain barrier to act directly upon D1 or D2 postsynaptic terminals in the striatum (Figure 12-3).
Levodopa is the most potent of all drugs and is particularly helpful in reducing bradykinesia.
Controversy exists as to whether its early usage may accelerate the time to developing levodopa complications, but the weight of evidence suggests the neurotoxic effect is minimal, if any.
In early Parkinson’s disease, complete relief of the bradykinesia is achieved with levodopa and carbidopa in low doses three times a day (tid) or from a slow release formulation given once (qd) to twice (bid) daily. Anticholinergic drugs may help the tremor but have considerable side effects in the elderly, including constipation, urinary retention, confusion, memory loss, and hallucinations.
After 5 years’ duration, it becomes increasingly difficult to achieve and maintain ideal CNS levels of dopamine. Patients often develop dyskinesias or
“on” phenomena 1 to 2 hours after taking levodopa medication; this is felt to represent excessively ele-vated CNS drug levels, which stimulate nonessen-tial dopamine pathways. Patients experience involuntary movements of their arms, legs, and 128 FUNDAMENTALS OF NEUROLOGIC DISEASE
Table 12-2 Clinical Features of Parkinson’s disease
Disease
Clinical Feature Description Stage
Bradykinesia Paucity or slowness in movements E, I, L
Cogwheel Rigidity Ratchet sensation upon moving elbow or wrist E, I, L Resting Tremor “Pill-rolling” tremor of hands; often asymmetrical E, I, L
Masked Facies Diminished spontaneous facial expressions E, I, L
Gait Difficulties Start hesitancy, shuffling short steps, stooped posture, and trouble I, L stopping and turning
Hypokinetic Dysarthria Low volume, monotone, and garbled speech without aphasia I, L Balance Problems Tendency to fall while walking or standing, especially with eyes closed I, L
Constipation Slow peristalsis made worse from some drugs I, L
Orthostatic Hypotension Fall in blood pressure upon arising that causes dizziness and syncope L Sleep Disturbances Insomnia, restless legs, and daytime drowsiness I, L Cognitive Disorders Hallucinations, depression, and dementia in 40% I, L Decreased Arm Swing Lack of associated arm swing on walking; often asymmetrical E, I, L
* Stages: E = early (1 to 5 years after diagnosis), I = intermediate (5 to 10 years), L = late (>10 years) 123-132_Davis12 3/2/05 4:28 PM Page 128
face in an irregular fashion during a time when their bradykinesia is minimal. The levodopa level then rapidly falls below optimal CNS levels, pro-ducing freezing spells or “off ” periods where the patient can hardly move. It is felt that “on–off ” phe-nomena represent disease-related loss of dopamine buffering capacity and storage capacity by striatal dopamine nerve terminals. It is common for patients to experience hallucinations that are often visual, occur in the evening, and may or may not be frightening to the patient. About 40% of patients also develop dementia that may be from dementia with Lewy bodies or the coexistence of two com-mon diseases of the elderly, Alzheimer’s disease and Parkinson’s disease. Dopamine agonists are often given to smooth out the “on-off ” phenomena in the intermediate stage. Unfortunately in the advanced stage, dopamine agonists are less success-ful and have a similar side effect profile.
To treat the advanced stage of Parkinson’s dis-ease, experimental surgical therapies are being explored using ablation, deep-brain stimulation, or transplantation. Ablative surgery (thalamotomy, pallidotomy, and subthalamic nucleotomy) use stereotactic approaches to lesion critical basal gan-glia regions in an attempt to restore more normal circuitry. Ablative therapy is irreversible, carries surgical risks, and has considerable complications
if done bilaterally. Deep-brain stimulation uses electrodes placed stereotactically in the globus pal-lidus interna or subthalamic nucleus to enable high-frequency stimulation of specific brain regions. Deep-brain stimulation is reversible but carries the infectious risk of long-term implanta-tion of foreign material in the brain. Both tech-niques are more effective for tremor rather than bradykinesia, do not completely relieve symptoms, and require continued use of some antiparkinson-ism medications. At present, the achieved response from deep-brain stimulation is similar to the best clinical improvement of the patient on an optimal dosage of levodopa but without accompanying dyskinesias.
The goal of transplantation is to replace neu-ronal circuitry lost by the death of substantia nigra neurons with dopamine neurons from fetal mes-encephalon or adult adrenal medulla. Studies of patients receiving transplantation of fetal mesen-cephalon into the striatum have demonstrated survival of the dopamine neurons and even the formation of some synapses to striatal neurons.
However, clinical benefit to the patient has been minimal presumably because the transplanted dopamine neurons do not spontaneously fire and release dopamine into synapses to stimulate the striatal neurons.
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Figure 12-3 Dopaminergic therapy for Parkinson’s disease.
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Education of both the patient and family about Parkinson’s disease is important, as this is a slowly progressive illness. Patients should be taught to avoid sofalike seats since arising from a chair is easier; to use bars in the bathroom to minimize falls; and eventually to use walkers to improve bal-ance while walking. A hip fracture in a patient with Parkinson’s disease is serious. There is a slow recovery and a 25% mortality risk.