There is no investigation that supports a viral etiology for PD. After the pandemic of encephalitis lethargica (1919–1926), many cases of parkinsonism were observed but no definite causal relation was established implicating a specific virus. Transient parkinsonian features may occur during the acute or convalescent phases of a variety of viral encephalitides, including measles, Japanese B, and western equine. Rarely, parkinsonism may remain as a permanent sequela (Schapira et al., 1992).

Unrecognized environmental toxins structurally similar to MPTP may play a role in the etiology of PD. The major culprits are suspected to be industrial chemicals, herbicides, and pesticides in well water. Exposure to manganese dust or carbon disulfide causes parkinsonian symptoms and the diagnosis is suggested by an accurate occupational history. Parkinsonism sometimes occurs as a result of severe carbon monoxide poisoning.

Endogenous toxins may also be responsible. In particular, the normal neurotransmitter dopamine readily oxidizes to produce free radicals that destroy the dopaminergic nerves. Although the precise role of dopamine itself remains unclear, the evidence relating PD to damage by free radicals remains compelling. This evidence includes increased iron levels, increased lipid peroxidation, decreased peroxidase and catalase levels, increased superoxide dismutase levels, and decreased glutathione levels.

NEUROANATOMY

Movement disorders result from disease of the basal ganglia. This consists of the caudate and the putamen (together called the striatum), the internal and external segments of the globus pallidus, the subthalamic nucleus (STN), and the substantia nigra. Cortically initiated movements are facilitated and competing movements are inhibited through the influence of the basal ganglia.

The activity of the output structures of the basal ganglia (the internal segment of the globus pallidus and the pars reticulata of the substantia nigra) is controlled by two opposing striatal pathways. The direct pathway consists of the striatal projections to the substantia nigra pars reticulata and the globus pallidus interna (GPi). This pathway is gamma-aminobutyric acid (GABA)-ergic and inhibitory, expressed mainly on the dopamine D₁ receptor. This direct route then functions to facilitate thalamocortical projections that reinforce cortically initiated movement. An alternative polysynaptic (indirect) pathway involves striatal GABA-ergic, inhibitory neurons that express the dopamine D₂ receptors and project to the globus pallidus externa, which has an inhibitory effect on the STN (Hutchinson, Levy, Dostrovsky, Lozano, & Lang, 1997). This nucleus has excitatory glutamatergic feedback on the globus pallidus externa and excitatory glutamatergic input on the substantia nigra pars reticulata and the GPi. The final effect of the indirect pathway is that striatal activity would lead to disinhibition of the STN, which in turn leads to higher activity of the neurons in the basal ganglia output nuclei and a stronger inhibition of their targets.

A balance between direct and indirect pathways is crucial for the normal functioning of the basal ganglia-thalamocortical circuits. It is also important to the balance among dopamine receptors in each pathway because dopamine has opposing effects on the two striatal output pathways—a stimulatory effect on the D₁ receptor-containing direct pathway and a suppressory effect on the D₂ receptor-containing indirect pathway (Groenewegen, 1997).

In PD, loss of dopaminergic cells in the substantia nigra leads to striatal dopamine depletion. This depletion results in decreased activity of the direct pathway and increased activity of the indirect pathway. This ultimately causes a reduced thalamic excitation of the motor cortex and loss of facilitation of cortically initiated movement. The two striatal output pathways are out of balance and act in the same direction. This may explain, at least in part, the hypokinesia characteristic of PD. The resting tremor of PD is less readily explained by the model but may result from effects on cholinergic interneurons in the striatum (Schapira et al., 2006).

EPIDEMIOLOGY

PD usually commences in middle or late life and leads to progressive disability with time. There are approximately 5 million people with PD worldwide, depending on the diagnostic criteria used (Scherzer et al., 2007). One study compared nondemented elderly people in the same community with PD patients and found a two- to fivefold increased risk of death. The risk is strongly related to the presence of severe extrapyramidal symptoms, especially bradykinesia (Louis, Marder, Cote, Tang, & Mayeux, 1997).

There is some discrepancy in the ethnic and sex distribution of PD. Some researchers believe the disease occurs more commonly in men than women; others insist it has an equal sex distribution. Although the disease occurs in all ethnic groups, most reports show that PD is more common among Whites than non-Whites. The prevalence is approximately 1 per 100 and 2.5 per 100 for people older than 65 and 80 years, respectively (Van Den Eeden et al., 2003). The disease is uncommon among the young, although about 5% of PD patients develop the illness before the age of 40 years.

HISTORY AND PHYSICAL EXAMINATION

Diagnostic mistakes can occur early in the course of the disease as health care providers differentiate initial symptoms. The diagnosis can be made with certainty only when three cardinal signs are present: resting tremor, rigidity, and bradykinesia.

Resting tremor is usually the first cardinal sign to appear in PD (70% of presenting patients; Findley, Gresty, & Halmagyi, 1981). This tremor is relatively slow (4–6 Hz) and can be appreciated when a limb is supported or relaxed (arm resting in lap or hanging by the side). Resting tremors are normally abolished by complete relaxation (during sleep) or by voluntary movement of the limb (Nutt, 1997). The tremor generally begins intermittently in one hand, to-and-fro flexion movement of the wrist, hand, thumb, and fingers that is most apparent when the patient sits comfortably. The cupped hand’s appearance of shaking pills gave rise to the name “pill-rolling” tremor (Friedman, 1994). Then from one hand, the tremor spreads to the ipsilateral foot, subsequently to the contralateral limbs, and perhaps to the tongue and jaw. It is important to distinguish the Parkinson’s resting tremor, which is frequently asymmetrical, from the essential tremor, which is symmetrical and commonly affects upper extremities, head, and voice, but rarely the legs. Patients with essential tremors display large and irregular (tremorous) handwriting while patients with other parkinsonism display rather small (micrographia) handwriting.

Rigidity, defined as an increase in resistance to passive movement, is a common clinical feature that accounts for the flexed posture of many patients. Rigidity also begins unilaterally (typically on the same side as the initial tremor) but eventually becomes contralateral over time. On examination, rigidity can be tested by manipulating the patient’s limbs. Cogwheel rigidity (ratchet resistance to full-range limb movements) as well as lead-pipe rigidity (smooth resistance throughout entire range of motion) are appreciable in approximately 90% of PD patients (Scott, Brody, Schwab, & Cooper, 1970).

The most disabling cardinal feature of PD is likely bradykinesia. Bradykinesia is a slowness of voluntary movement associated with a reduction in coordinated automatic movements such as the swinging of both arms when walking. Patients with bradykinesia have difficulty initiating voluntary movement and may appear weak or uncoordinated. Other findings can include mask-like facies with widened palpebral fissures and infrequent blinking. There may be blepharoclonus (fluttering of the closed eyelids), blepharospasm (involuntary closure of the eyelids), and drooling of saliva from the mouth. Patients have difficulty rising from bed or an easy chair and tend to assume a flexed posture when standing upright.

Patients with postural instability have impaired balance and have a greater tendency for falls. The other three cardinal symptoms are likely already established, as postural instability does not appear until the later stages of PD.

Patients with PD can have other motor impairments in addition to the cardinal symptoms. Patients may have difficulty turning over in bed. This difficulty in turning when lying flat is the result of an inability to execute the sequence of axial movements required to achieve the task. This disability becomes more prominent with longer disease duration (Steiger, Thompson, & Marsden, 1996). Walking can be difficult to initiate and patients may have to lean forward increasingly until they can advance. The tension reflexes are unaltered and the plantar responses are flexor. Repetitive tapping over the glabella produces a sustained blink response (Myerson’s sign), in contrast to the response of normal subjects. Other findings include impaired craniofacial movements, psychomotor retardation, fatigue, sleep disorder, blurred vision, speech impairment, and unilateral findings. This presentation may lead to the misdiagnosis of depression or stroke.

Fifty percent of patients presenting with tremor do not have PD and a broader differential diagnosis must be considered. The history should focus on the development of neurologic symptoms, depression, other concurrent medical illnesses (e.g., hypothyroidism), medications, injuries (e.g., falls), and occupational hazards. Drug-induced disease should be ruled out by the elimination of offending drugs such as neuroleptics, antiemetics (e.g., metoclopramide), and antihypertensives (e.g., reserpine, methyldopa). The physical examination should include a thorough mental status and neurologic examination. Passive movement of the wrist or elbow may reveal cogwheel rigidity.

The gait features marche a petit pas (characterized by short steps with a tendency to accelerate), shuffling, lack of arm swing, and the turning of the body en bloc. Speech is often soft and monotonal, and it may be inaudible. Autonomic insufficiency may result in constipation, impotence, and orthostatic hypotension.

Nonmotor symptoms can also be debilitating in PD. Mental changes such as dementia occur in about 15% to 20% of people with PD, and in 40% of patients older than 70 years (Hussl, Seppi, & Poewe, 2013). The so-called subcortical dementia of PD is distinguished from the cortical dementia of Alzheimer’s disease. Depression affects almost 50% of PD patients and psychosis is present in at least 10%. Visual hallucinations, delusions, and chronic confusion are the most common psychotic features. This psychosis is most often attributable to a combination of dementia, antiparkinsonian medications, and the toxic-metabolic encephalopathy from other illnesses (Politis et al., 2010).

DIAGNOSTIC STUDIES

Brain Imaging

In single-photon emission computed tomographic imaging (SPECT), radioactive iodine (¹²³I Beta-CIT) is used to label dopamine transporters and is therefore a marker of the neurons that degenerate in PD. SPECT with ¹²³I Beta-CIT showed that the radioactivity in striatal regions in healthy subjects increased during a 2-day imaging study, whereas that in parkinsonian patients peaked earlier at lower levels than in healthy subjects. Kinetic analysis of the radioactivity in plasma and the brain suggested that this decrease was the result of an approximately 65% loss of target sites in patients versus healthy subjects; greater losses occurred in the putamen than in the caudate. These preliminary results suggest that ¹²³I Beta-CIT is a marker for the loss of striatal dopamine terminals in patients with PD and may be useful for early diagnosis of the disorder, monitoring the progression of the disease, and distinguishing the idiopathic disorder from other parkinsonian syndromes with more widespread pathology (Olanow & Schapira, 2013).

Magnetic Resonance Imaging

MRI with high field strength can be performed to rule out structural brain abnormalities and exclude findings of atypical parkinsonism. Neuroimaging is considered nondiagnostic and further studies must be performed to explore its diagnostic abilities (Vaillancourt et al., 2009).

Blood Analysis

Parker, Boyson, and Parks (1989) reported a reduction of mitochondrial complex I (NADH ubiquinone oxidoreductase) in the platelets of patients with idiopathic parkinsonism. Others have reported reduced S-oxidation capacity in patients with idiopathic parkinsonism. There is also an increase in the ratio of cysteine to sulfate, and this may impair the body’s ability to metabolize environmental toxins.

MAO-B in platelets deaminates endogenous dopamine. It may also activate environmental protoxins. The oxidation of dopamine may produce increased free radicals, which in turn may damage dopaminergic neurons. Researchers have found a highly significant increase in the generation of oxygen free radicals (in leukocytes) in idiopathic parkinsonism. Malondialdehyde is a product of tissue injury by lipid peroxidation of membrane phospholipids, and levels are elevated in the serum of patients with idiopathic PD.

Physiologic Testing

Long-latency stretch reflexes, increased latency of the visual evoked potential, and a deficit in olfactory discrimination have been found in patients with PD. Lewy bodies are not limited to the substantia nigra in PD; they can be found in sympathetic ganglia and in the mesenteric plexi of the whole gastrointestinal tract, particularly the lower esophagus. This may lead to a possible diagnostic evaluation for idiopathic parkinsonism through biopsy of a more accessible location and may be the subject of further exploration.

DIFFERENTIAL DIAGNOSIS