Parkinsonism can occur rarely after a single stroke in the basal ganglia or brainstem or as the cumulative result of several strokes. Patients with vascular parkinsonism tend to have a long history of hypertension and a stepwise progression of symptoms that may correlate with each acute clinical stroke. Evidence for stroke may be noted on examination. Gait may be shuffling or magnetic, a term used synonymously with transient freezing. Patients should have evidence of cerebrovascular disease on CT scan or MRI, although asymptomatic ischemic changes are common in older patients and do not independently make the diagnosis of vascular parkinsonism (43).

Hydrocephalus can cause parkinsonian signs and symptoms. Normal pressure hydrocephalus (NPH) is a syndrome characterized by the triad of gait instability, urinary incontinence, and cognitive dysfunction (55,89). As with vascular parkinsonism, gait in NPH is classically magnetic, but other gait disturbances, especially “gait ignition failure” and “frontal gait” (67), have been described in NPH. Brain imaging (CT or MRI) shows communicating hydrocephalus with ventricles enlarged out of proportion to atrophy of the cerebral cortical sulci. This is an important disorder to consider in any patient with a parkinsonian gait, cognitive impairment, and urinary frequency or incontinence because ventriculoperitoneal shunting may lead to the dramatic reversal of a severe disability. For this reason, every patient with parkinsonism deserves to have a computed imaging study of the brain, either CT or MRI, at some time during the course of illness; the sooner it is performed the better to get the question out of the way.

Drug-induced parkinsonism is a critically important entity because it is one of the few reversible causes of parkinsonism. The most common offenders are the antipsychotics, also known as neuroleptics, which as a class can cause parkinsonism because of their dopamine receptor-blocking properties. These include phenothiazines, butyrophenones, and thioxanthenes (45). The antiemetic prochlorperazine (Compazine) and the gastrointestinal promotility agent metoclopramide (Reglan) are also dopamine receptor blockers that have the potential to induce parkinsonism and other “extrapyramidal” involuntary movements, such as dystonia and tardive dyskinesia (TD) (44). Clozapine (Clozaril), the first “atypical” neuroleptic, was introduced to the American market in 1990 after prior experience in Europe as a major breakthrough for treating schizophrenia because its antipsychotic effect is mediated by nondopaminergic neural circuits. Therefore, it relieves symptoms of psychosis without causing parkinsonism or other extrapyramidal side effects. Several other atypical neuroleptics have followed, including olanzapine (Zyprexa), risperidone (Risperdal), ziprasidone (Geodon), and aripiprazole (Abilify), although each has greater affinity for the dopamine receptor than clozapine and can, therefore, produce varying degrees of extrapyramidal side effects. Quetiapine (Seroquel) is one of the more recently developed atypical neuroleptics with an extrapyramidal side effect profile similar to clozapine. Other drugs with a tendency to induce parkinsonism include the antihypertensives methyldopa, verapamil (38), reserpine, and the antiepileptic valproic acid (Depakote). Reserpine can induce signs of parkinsonism by depleting dopamine storage vesicles presynaptically instead of blocking postsynaptic dopamine receptors. Treatment of parkinsonism in this setting consists of a combination of a high index of suspicion and prudent withdrawal of the offending drug.

Neurodegenerative diseases other than PD often have clinical parkinsonian features. Alzheimer disease (AD), the most common cause of dementia, may be accompanied by varying degrees of parkinsonism in up to 50% of patients (13), usually late in the course of the dementia. In AD, the dementia precedes the parkinsonian signs and is disproportionately more severe. Dementia and parkinsonism also co-occur in the pathologic entity diffuse LB disease, also known clinically as dementia with LB (DLB), which is associated pathologically with widespread distribution of LBs throughout the cerebral cortex. The clinical presentation in DLB consists of prominent and early cognitive decline, fluctuations in cognitive function, spontaneous visual hallucinations that have no other cause, and parkinsonism (62). The parkinsonian signs consist of bradykinesia, rigidity, and a prominent gait disorder; rest tremor is seen less frequently than in PD (26,64). A diagnosis of DLB may be difficult to differentiate from AD or from typical PD with dementia (PDD). However, in PDD, the interval between the onset of parkinsonism and onset of the cognitive disturbance is usually more than a year (62).

PSP, MSA, and CBD closely resemble PD and may be clinically indistinguishable in the early stages of progression, but they usually emerge as distinct clinical
entities as the disease evolves. Each has a distinctive neuropathology. PSP presents as an akinetic-rigid syndrome with a prominent gait disorder early in the course of illness. In contrast, walking is usually not a major issue in PD until late in the course. Truncal posture in PSP tends to be upright instead of stooped, and axial and asymmetric limb dystonia may be present (29). Tremor is much less common in PSP than in PD (29). Cognitive impairment occurs earlier than in PD, but the dementia of PSP is usually not as severe as it is in PD, CBD, and some of the other parkinsonian syndromes. Many patients demonstrate a pseudobulbar affect, marked by uncontrollable and inappropriate laughing or crying. Several characteristic eye movement abnormalities are seen, the most important of which is a supranuclear paresis of conjugate gaze, beginning with symptomatic slowing of gaze in the vertical plane. Patients often complain of having trouble looking up, looking at their food during meals, or hitting a golf ball. Examination may reveal impaired voluntary gaze, spontaneous minimyoclonic jerks of the eyes (square wave jerks), and loss of optokinetic nystagmus, which can be elicited in the normal subject by passing a sequence of stripes or other similar repetitively occurring graphic objects horizontally or vertically across the field of vision (29). Reflex eye movements are preserved because the pathology of PSP interrupts the neural circuits descending from the centers of voluntary gaze in the frontal lobe before they damage the oculomotor nuclei in the brainstem; hence, the term “supranuclear” to the paresis of voluntary gaze in PSP. These relatively well-preserved reflexive eye movements may be demonstrated using the doll’s head maneuver, in which the patient is asked to visually fixate a target while the examiner passively moves the patient’s head in the horizontal or vertical plane. Preserved reflexive eye movements allow patients to hold their eyes on target despite the head movements. In the late stages of PSP, voluntary and reflexive eye movements in all directions, including the horizontal plane, are severely impaired. MRI may show atrophy of the dorsal midbrain (85).

MSA is a diagnostic grouping of three disorders that are distinguished by parkinsonism, cerebellar ataxia, and autonomic insufficiency in combination with one of the three as the primary presenting deficit. Pyramidal tract deficits can also be seen as part of the mix. By convention, the most prominent neurologic theme determines the subclassification within the overarching domain of MSA, although any assortment of the four types of signs can occur in the same patient. Thus, a mix of parkinsonism and severe autonomic dysfunction (orthostatic hypotension, atonic bladder, and impotence) would be called autonomic MSA or the Shy-Drager syndrome. Pure parkinsonism is called striatonigral MSA or MSA-p; and cerebellar ataxia without a family history is called cerebellar MSA, MSA-c, or olivopontocerebellar atrophy in the old terminology (57). Cerebellar ataxia with a family history is included in the large and growing classification of the spinocerebellar ataxias (88). Autonomic failure and postural instability are early findings. As in PSP, tremor is rare. The MRI scan, which is normal in PD and in most cases of MSA, may sometimes show a combination of shrinkage of the brainstem and cerebellum and an abnormally large area of low signal in the putamen (28). The course of MSA is generally faster than that of PD. In most patients with MSA, especially the parkinsonian form, cognitive function is preserved.

CBD is characterized by highly asymmetric parkinsonism that is associated early on with cognitive impairment and pathognomonic signs that may escape the notice of the naive observer. An early and common sign of CBD is a clumsy or “useless arm” due to rigidity, dystonia, akinesia, or motor apraxia in some combination. Other early features include gait impairment, if onset is in the leg, due to lateralized stiffness or apraxia (60). In addition to dementia, other manifest higher cortical signs are ideational apraxia, aphasia, cortical sensory abnormalities (e.g., loss of spatial orientation), and alien-limb phenomenon. Additional hyperkinetic movements include coarse action tremor and myoclonus (53). Tremor is less likely to be present in CBD than in PD, but when it does manifest, it can be differentiated from Parkinson tremor because it occurs mainly with action, is coarser and higher in frequency, and is associated with marked rigidity of the affected limb or limbs. In cases of suspected CBD, MRI scan may show asymmetric shrinkage of one half of the parietofrontal cortex. The diagnosis of CBD early in its course can be difficult due to the overlap of symptoms with other neurodegenerative diseases, especially PSP, MSA, DLB, and AD.

PSP, MSA, and CBD usually respond poorly to levodopa and other anti-Parkinson drugs. However, a trial of levodopa of as much as 1,000 mg per day may be needed to exclude PD with a high response threshold. Failure to respond is strong evidence that MSA, not PD, is the probable diagnosis. The therapeutic response in patients with PSP, MSA, or CBD is not only disappointing, but the effect may be counterproductive because of aggravation of orthostatic hypotension, particularly in MSA. If patients fail to respond to levodopa, there is no reason to try other dopaminergic agents because they have less therapeutic potency and usually cause more side effects than levodopa. Botulinum toxin (BTX) injections may be useful for focal dystonia, such as eyelid opening apraxia, in PSP and MSA. Autonomic insufficiency,
particularly orthostatic hypotension, can be treated with specific drugs. Nonpharmacologic therapies, such as speech therapy, swallowing therapy for dysphagia, and physical therapy, are also an important part of patient care.

The care of patients with PD is best accomplished through a multidisciplinary approach, which should include access to psychological counseling; occupational, physical, and speech therapy; and support groups. Nonpharmacologic intervention can be as important as medications and should be started early in the course of PD. Aerobic and strengthening exercise is vitally important as a health maintenance routine and as a method of exerting psychological control over a chronic, variably progressive disease. Many patients benefit from the mantra, “I have PD but it doesn’t have me.”

Levodopa Levodopa was shown to be the first truly effective drug for treating parkinsonism 40 years ago, a distinction that has not been eclipsed by the half dozen or more drugs introduced to the marketplace since then (Table 22-2). Levodopa, the inert precursor of dopamine, was developed as an anti-Parkinson drug because it has long been known that dopamine does not cross the blood-brain barrier, whereas levodopa does. Hence, levodopa enters the brain, where it is decarboxylated by dopa decarboxylase to the therapeutically active dopamine. Levodopa works most efficiently and with fewest side effects when administered in combination with carbidopa, an inhibitor of peripheral dopa decarboxylase, which greatly diminishes the amount of “unprotected” levodopa available to cross the blood-brain barrier into the central nervous system for conversion to dopamine. Carbidopa is joined with levodopa in different ratios (10/100, 25/100, or 25/250) in short-acting and controlled-release formulations. A typical starting dose of carbidopa/levodopa (Sinemet) is one half of a 25/100-mg tablet three times a day (with meals to prevent nausea). Once tolerance is established at a low dose, the amount of carbidopa/levodopa per dose can be slowly increased, usually in half-tablet increments, to an optimal therapeutic level compatible with realistic expectations for the individual patient. Average daily consumption in early stages of disease ranges between 300 and 600 mg/day in three divided doses. The total required daily dose of levodopa tends to increase as the disease progresses, and closer spacing of doses is required to combat the “wearing-off effect” (10). Most patients with typical PD will have a gratifying and smooth initial response to levodopa. Many symptoms improve, but most patients will observe that bradykinesia improves the most. Tremor suppression often lags behind, but it, too, can be well controlled by levodopa.

One of the major drawbacks of levodopa is its short half-life of 90 minutes, which has a major impact on patient satisfaction as the disease progresses. In the
early phase of PD when patients with typical PD first begin using levodopa, the overall response is positive and smooth throughout the day. Few doses per 24 hours are required because of the brain’s ability to store the drug in the axon terminals of the still adequate supply of nigrostriatal neurons that have not been decimated by the underlying degenerative process. As more neurons degenerate, the brain’s storage capacity declines, and at some point, which varies with the individual’s inherent rate of progression, the physiologically smooth long-duration response (LDR) to levodopa gives way to the physiologically short-duration response (SDR). Clinical expression of the SDR occurs in the form of motor fluctuations, which are characterized by a “wearing off” of the benefit of a dose of carbidopa/levodopa, usually 3 to 4 hours after a dose is taken. The patient will notice a gradual re-emergence of parkinsonian symptoms during this interlude, which at its nadir is called the “off” period. The reciprocal “on” response is gradually re-established (usually
within 30 minutes) after the next dose of levodopa is swallowed and transported by gastric contraction to the absorption site in the proximal duodenum or jejunum. Levodopa-induced choreiform or dystonic involuntary movements, called “dyskinesia,” commonly begin to occur at the stage of the disease when motor fluctuations start to appear, usually at peak effect 1 to 2 hours after a dose (20). In most patients, dyskinesias are dose related and can be so severe and disabling that they greatly interfere with all activities of daily living. They can be abolished by lowering the dose of levodopa but often at the expense of the benefit provided.