Sleep-related rhythmic movement disorder
Mar. 18, 2023
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Despite the development of atypical antipsychotic drugs, parkinsonism is still a common problem among patients treated with these drugs as well as with dopamine receptor blocking antiemetics. Because drug-induced parkinsonism frequently produces disability in the elderly, it is a more significant problem than tardive syndromes due to the increased risk of falls and institutionalization. It is often underrecognized. Despite the FDA’s concern about increased mortality with these drugs, carried in a “black box warning,” these drugs are widely used in the elderly, particularly in nursing homes. Aripiprazole is one of the most commonly prescribed drugs in the United States, and other neuroleptics are increasingly used in treating major depression and depression in bipolar disorder. Distinguishing purely drug-induced parkinsonism from idiopathic Parkinson disease is often clinically impossible. In this article, the author discusses phenomenology, pathophysiology, diagnosis, and treatment.
• Parkinsonism is a common side effect of all the atypical antipsychotic drugs except quetiapine and clozapine, certain calcium channel blockers, tetrabenazine, and its derivative vesicular monoamine transporter type 2 (VMAT2) blockers. It may also be seen with valproic acid, lithium, and amiodarone.
• Although most drugs causing parkinsonism do so in a dose-related manner, there is an enormous variation in individual susceptibility, so even very small doses may cause parkinsonism.
• Drug-induced parkinsonism is less likely to produce tremor than idiopathic Parkinson disease, and it is more likely to be symmetric, but the two syndromes cannot be distinguished in any individual.
• Drug-induced parkinsonism often persists for weeks to months after the offending drug is stopped.
• The availability of the DaT SPECT scan likely makes it much easier to distinguish drug-induced parkinsonism from drug-exacerbated Parkinson disease, although it is not approved for this purpose.
• Patients with Parkinson disease and dementia with Lewy bodies are particularly sensitive to the motor side effects of neuroleptic drugs.
Drug-induced parkinsonism in this review refers to an akinetic-rigid syndrome that mimics idiopathic Parkinson disease and is usually reversible (21). Drug-induced parkinsonism was first recognized in the 1950s, when reserpine was tested as an antipsychotic drug. Reserpine was known to induce an akinetic state in animals and was noted to cause a parkinsonian state in humans (11). This observation, coupled with the known histopathology of Parkinson disease, led to the discovery that dopamine is severely depleted in idiopathic Parkinson disease (19).
The success of the antipsychotic drugs known as neuroleptics (meaning "to grip the nerves"), which block dopamine D2 receptors, led to the common occurrence of drug-induced parkinsonism (27). For a time, it was theorized that proper control of psychosis could only be achieved once drug-induced parkinsonism occurred, but this has been clearly disproved, leaving drug-induced parkinsonism as an undesirable adverse effect of the neuroleptic drugs. However, the parkinsonian side effects have been the goal when the drugs were used as “chemical strait jackets” to reduce mobility in violent patients, an approach greatly discouraged. The class of antipsychotics, "atypical neuroleptics," is at least as effective as the older antipsychotics, and although these are widely believed to cause fewer extrapyramidal disorders than the first generation of drugs, the data on this are conflicting, with large, well-performed studies showing no differences in parkinsonism or other movement disorders, in general (55) although there were differences between some of the atypicals.
It is unclear if neuroleptics might produce permanent parkinsonism (52). One pathological study suggests this is not the case (62). However, this has not been adequately studied as most patients taking neuroleptics require lifelong therapy with them, and the cases were reported before DaT scans were available. Non-neuroleptics have been observed to cause nonprogressive parkinsonism lasting over 15 years after the offending drug was discontinued, raising the question of permanence (12) and whether parkinsonism may be a tardive syndrome.
The clinical syndrome of drug-induced parkinsonism exactly mimics idiopathic Parkinson disease in individual patients, so one cannot reliably distinguish drug-induced parkinsonism from idiopathic Parkinson disease in a patient taking a dopamine-blocking drug (21). Even though this is a drug-induced syndrome, signs may be asymmetric in half the patients (33; 72). Not all of the cardinal features of idiopathic Parkinson disease are necessarily present, and they are variably severe in an idiosyncratic manner, so some patients have tremor but little else, whereas others may be more akinetic or rigid. Patients tend to be unaware of their parkinsonism when mild except for tremor (47). Nonmotor features of idiopathic Parkinson disease have not been well studied in drug-induced parkinsonism, and two studies of olfaction have obtained conflicting results of smell impairment (43; 41). Other nonmotor features common in Parkinson disease are likely not present (44). A study comparing residual effects of drug-induced parkinsonism caused by first- and second-generation antipsychotic drugs and calcium channel blockers in 157 subjects, found differences in clinical profiles, but not significant enough to allow definitive diagnostic distinctions (56).
Drug-induced parkinsonism tends to develop slowly, over days to weeks (27; 04). The onset is dose-related, and most patients develop signs within about 3 weeks (27; 45). Some patients develop parkinsonism after years on a stable dose of a drug, raising the question as to whether they have developed idiopathic Parkinson disease or have simply become more sensitive. Rigidity and impaired arm-swing are the most common early signs, with tremor marking the onset in only about one third of cases (04).
The cardinal features of Parkinson disease are rigidity, akinesia, bradykinesia, tremor at rest, and impaired posture and balance. Minor features, helpful but not reliable for diagnosis, include micrographia, difficulty performing two different tasks simultaneously, fatigue, and hypophonic speech with hesitancy or even stuttering.
Other nonmotor problems present in Parkinson disease such as depression, loss of interest and initiative, and a sense of weakness may overlap with the underlying psychiatric illness. There also may be drug side effects that are unrelated to the parkinsonism, such as orthostatic hypotension, weight gain, hormonal dysregulation, diabetes, sleep disturbances, and others.
Akinesia refers to the absence of, but more accurately the paucity of, spontaneous unconscious movements. Parkinsonian patients blink less and swallow less (hence the drooling) than normal patients. This is usually but not always associated with bradykinesia, the slowness of motor activities. Parkinsonian patients initiate movements and complete them more slowly than normal. This is manifest in slower dressing, toileting, walking, writing, cooking, etc. On testing coordinated movements, one sees not only slowness but also a loss of amplitude on repeating tasks such as rapid alternating hand movements, finger tapping, or heel tapping. There is also an irregularity of movement due to occasional brief movement arrests. Patients lose dexterity for tasks such as buttoning, using zippers, and sewing, which then exaggerate the slowness of the grosser movements. It should be noted that occasional patients have a dissociation between akinesia and bradykinesia.
The tremor is a rest tremor that resolves with movement but is often present with sustained postures. Typically, as in Parkinson disease, it affects fingers, hands, jaw, and, less frequently, tongue and feet. The head is almost invariably spared. A case report of a single patient with neuroleptic parkinsonism with a re-emergent tremor, a tremor that developed in the tongue after it was protruded for a period of time, was used to refute a claim that re-emergent was only seen in idiopathic Parkinson disease (60). Rigidity is the resistance felt when moving a limb that is relaxed. Cogwheeling is not a sine qua non of the disorder. Cog-wheeling and the glabellar reflex, although increased in parkinsonism, are often seen in other disorders and often absent in idiopathic Parkinson disease. Rigidity may affect any joint, including the neck. Postural abnormalities are common. Parkinsonian patients have a flexed posture both sitting and standing, so they appear stooped. This is not always due to rigidity or dystonia, but rather, can represent an aberrant orientation that may even result in tilting to one side in addition to being flexed. Balance may be impaired as well. The parkinsonian gait is stereotypical with a reduced stride, reduced arm-swing, and a tendency to turn en bloc. In younger drug-induced parkinsonism patients, mild stooping and reduced arm-swing are the only gait abnormalities, and these may be so minor as to escape detection on routine exam.
Individual susceptibility to all the extrapyramidal side effects of dopamine-blocking drugs is highly variable. Some patients develop no sign of drug-induced parkinsonism on huge doses whereas others are sensitive. Most people, however, show signs of drug-induced parkinsonism if treated with high doses of neuroleptics. Although drug-induced parkinsonism may exactly mimic idiopathic Parkinson disease, there tends to be significantly less tremor in drug-induced parkinsonism patients (01). This could be due to the younger age of most patients with drug-induced parkinsonism or to differences between the two conditions.
The course of drug-induced parkinsonism is also variable (33). Many patients maintained only on neuroleptics without antiparkinson drugs improve over time, but what percentage and to what degree are unclear. Most patients reach a plateau in terms of their drug-induced parkinsonism on a stable dose of neuroleptic and maintain this level or improve. Only in the elderly is this not true and progressive parkinsonism may occur, presumably due either to the onset of idiopathic Parkinson disease or to increased sensitivity of the aging brain.
Drug-induced parkinsonism is generally believed to be always reversible and is not associated with histological brain changes (62). However, resolution of signs may take as long as 18 months (39). In a report on the elderly, some cases had not resolved after 36 months (33), raising the question of the concomitant presence of Parkinson disease versus extreme vulnerability of the elderly. Another study reported persistent nonprogressive parkinsonism lasting seven years after drug cessation (58). In another study, 13 of 30 patients had flunarizine/cinnarizine-induced parkinsonism, and 17 subjects required L-Dopa treatment despite stopping the drugs (53). Two patients with neuroleptic parkinsonism had residual parkinsonism over 22 months after drug discontinuation, with normal DaT scans strongly supporting the absence of Parkinson disease (63).
Drug-induced parkinsonism can be severe and disabling. In a study of the elderly, prochlorperazine precipitated permanent institutionalization of a significant number of patients (83). Neuroleptics have been associated with an increased risk of falls, and, even without parkinsonism developing, a single dose of risperidone 1 mg induced increased body sway within a few hours, which was more pronounced with a 3 mg dose in healthy young adults (17).
Drug-induced parkinsonism may be a risk factor for the later development of idiopathic Parkinson disease, presumably as the result of premature “unmasking” of subclinical Parkinson disease (13; 50). An alternative approach to distinguishing idiopathic Parkinson disease from drug-induced may be ultrasonography of the brain, imaging the substantia nigra, but this remains unproven (82).
A 60-year-old woman with a history of schizophrenia diagnosed at 22 years of age had been treated with haloperidol and other antipsychotic drugs since that age. At 58 years of age, while taking risperidone, she developed a stooped posture, resting tremor in one hand, and other signs of parkinsonism. Risperidone was switched to olanzapine 15 mg/day, and the parkinsonism improved for several months before starting to slowly worsen.
The clinical question is whether or not the patient has developed Parkinson disease or has a reversible, drug-induced condition. It is well known that drug-induced parkinsonism is more likely in older women, whereas idiopathic Parkinson disease is more common in men. It is clinically impossible to distinguish pure drug-induced parkinsonism from drug-exacerbated idiopathic Parkinson disease. Functional imaging may help make the distinction. Dopamine transporter labelled SPECT imaging appears to be helpful for making this diagnosis, but data are limited by the inability to make definitive diagnoses other than by autopsy or several-year follow-ups (07; 67). Intracranial ultrasound may be helpful, but a study of fluorodopa PET scan suggests that it is less reliable than DaT SPECT scan (81).
Drug-induced parkinsonism is due primarily to drugs that block dopamine receptors, particularly the D2 receptors (75). These drugs are most often the antipsychotic drugs, called neuroleptics, such as haloperidol, chlorpromazine, and trifluoperazine, but include metoclopramide, a gastrointestinal motility enhancer, and the antiemetics prochlorperazine and droperidol. In addition, medications that block synthesis of dopamine, such as alpha-methyl para-tyrosine and alpha-methyl dopa or deplete dopamine (such as tetrabenazine, tetrabenazine derivatives, and reserpine, which block dopamine’s entry into the vesicles that are released into the synapse) also induce parkinsonism. In these cases, the pathophysiology is presumably due to diminished dopamine receptor stimulation, resulting in a pharmacologic state closely resembling Parkinson disease. However, the atypical antipsychotics also block D2 receptors. Yet there is no apparent correlation between the degree of this blockade and the risk for inducing parkinsonism. The explanation for this is uncertain. One current hypothesis is the “fast off” theory, postulating that the duration of the D2 blockade, rather than the percentage of receptors blocked, determines the likelihood of parkinsonism (70). A competing theory is that the ratio of 5 HT-2a receptor blockade versus the dopamine D2 receptor blockade is critical because of the interplay between the serotonin and dopamine systems in the brain. An older theory relating extrapyramidal side effects to anticholinergic activity is considered untenable because the concomitant use of anticholinergics does not eliminate the problem.
There have been few autopsy studies of patients with neuroleptic parkinsonism. A Canadian study of seven patients found no evidence of brain damage (76). However, two patients, whose parkinsonism resolved off the neuroleptic, had subclinical Parkinson disease pathology, and one patient, who remained on the neuroleptic, had a reduction in pars compacta cells, but without Lewy bodies.
Cholinesterase inhibitors, widely used to treat dementia, may cause worsened parkinsonism, primarily increased tremor (02). Large double-blind trials of rivastigmine, a cholinesterase-inhibiting drug, in both dementia with Lewy bodies and Parkinson disease dementia have demonstrated that rivastigmine is well tolerated without significant worsening of motor function overall, although tremor may increase (20). The other cholinesterase inhibitors have been less well studied but appear to have similar benefits and side effects.
Several other medications have been reported to cause drug-induced parkinsonism and to worsen parkinsonism in people with Parkinson disease, including the serotonin reuptake blocking antidepressants fluoxetine, sertraline, and paroxetine. Two calcium channel blockers available in Europe and South America (flunarizine and cinnarizine), which are piperazine derivatives, are thought to cause drug-induced parkinsonism by blocking dopamine receptors. Trimetazidine, an anti-anginal agent used in Europe, is in the same chemical family as cinnarizine and flunarizine and has been shown to cause reversible parkinsonism in DaT negative patients (59). Reports of parkinsonism induced by other drugs, such as lithium and amiodarone, are rare so that only after parkinsonism has developed should the possible drug effect be taken into account. Because lithium is not known to block dopamine receptors, another mechanism is likely. Some animal data implicate an effect of lithium on intercellular signaling via G-protein coupled receptors (06). One antidepressant, amoxapine, has dopamine receptor-blocking properties and, therefore, may induce parkinsonism. Parkinsonism as a transient (lasting days to weeks) side effect of alcohol withdrawal has been reported without later development of Parkinson disease, but it is unknown how common this is (73).
Valproic acid has been reported to induce parkinsonism in the majority of patients whose serum levels are over 40 (03). Although subsequent reports support the association between valproate and parkinsonism, the frequency appears to be highly variable (09). A 2021 report of nonpsychiatric patients found rest tremor in 11.6% and parkinsonism in 1.6% (05). The mean dose of patients with valproate-induced parkinsonism was 750 mg/day, and the syndrome was five times more common with valproic acid than the other anticonvulsants.
A summary of all reported cases found that serum valproic acid levels were generally in the therapeutic range, and it also found that parkinsonism improved after a few weeks off the drug and generally resolved within a few months (57). There was no significant response to levodopa.
Because tetrabenazine, in each of its three forms (tetrabenazine, deuterated tetrabenazine, and valbenazine) has become more available and more widely promoted, it is being used more commonly to treat tardive dyskinesia, tics, and other hyperkinetic disorders (36; 16; 32). The potential for drug-induced parkinsonism should not be overlooked and must be balanced against the benefits it provides (28). This is most important in the elderly due to the potential increased risk for falls.
Drug-induced parkinsonism is thought to be due to diminished dopamine D2 receptor stimulation in the striatum. This occurs primarily with the blockade of D2 receptors by neuroleptics and related drugs, but also with decreased dopamine release. Vesicular monoamine transporter type 2 (VMAT2) inhibitors, such as tetrabenazine, deutetrabenazine, and valbenazine, can also cause parkinsonism by depleting presynaptic dopamine (36).
Antipsychotics can be categorized by potency. In general, the more potent drugs have greater affinity for the D2 receptor, fewer anticholinergic effects, and have both greater antipsychotic effects and more parkinsonian effects at lower doses (64). The severity of the drug-induced parkinsonism reflects the combined effects of the patient's sensitivity, presumably reflecting the untreated state of the striatum, the D2-blocking effects of the drug, counterbalanced by the drug's effects on other neurotransmitter systems, which usually include some degree of anticholinergic, antihistamine activity as well as effects on neuropeptides and other systems.
In most cases the explanation for the variable individual sensitivity to the drugs is unknown. Receptor differences are a hypothetical explanation. Clearly older patients are more susceptible, and this presumably reflects the known decline in nigral neurons and striatal dopamine that occurs with normal aging (61). There also may be different sensitivity to neuroleptic motor side effects with different psychiatric disorders as well as with age of onset of the psychiatric disorder (77). Why women are more susceptible is unknown. Men are at greater risk for developing idiopathic Parkinson disease.
The clinical course of drug-induced parkinsonism, reaching a plateau and then remitting, is thought to be due to two factors known to occur in animals. Initially the dopamine neurons release increased amounts of dopamine in response to receptor blockade; over time, upregulation of D2 receptors occurs, thus, bypassing some of the blockade effects. It is also likely that changes develop in other neurotransmitter systems as well as in the neurophysiology of basal ganglia neuronal populations.
Rarely, drug-induced parkinsonism persists for a long time or indefinitely and may even progress after the offending neuroleptic has been discontinued. Some of these cases of “tardive parkinsonism” may actually represent underlying Parkinson disease, whose clinical symptoms were precipitated by the introduction of the dopamine-receptor blocking drug (26; 68).
A possibly overlooked entity, worsened parkinsonism due to neuroleptic withdrawal, has been documented and has been suggested to be a relatively common occurrence possibly due to tardive parkinsonism (24).
• Medication causes of parkinsonism
- Valproic acid (also used for migraines, bipolar disease, mood stabilizer)
• Treatments for tardive dyskinesia
A newly reported cause of iatrogenic parkinsonism is chimeric antigen receptor T (CAR-T), which is used in treating multiple myeloma (80; 51). In CAR-T treatment, the patient’s T cells are genetically modified to attack a particular tumor-related protein, multiplied in vitro, then infused back into the patient. Parkinsonism appears to be a rare occurrence, related to the chosen target antigen, and not likely a feature of CAR-T therapy in general. The cases developed several months after treatment was initiated, and the course of this disorder remains unknown.
The epidemiology of drug-induced parkinsonism reflects the epidemiology of the disorder being treated, the doses required, and the sensitivity of the population. The vast majority of patients who develop drug-induced parkinsonism have psychiatric disorders, generally schizophrenia; however, two atypical drugs, olanzapine and aripiprazole, have been approved for treatment of refractory depression. Drug-induced parkinsonism is uncommon in children, although one report on adolescents reported that 30% of patients developed parkinsonism on aripiprazole 30 mg/day (23). Although younger psychotic patients require more drugs than older ones, they are less likely to develop drug-induced parkinsonism (04). Women are at greater risk than men, and older patients are at greater risk than younger ones. It is believed by many that brain damage also puts one at risk for drug-induced parkinsonism. A large population-based study found that intellectually handicapped people were more likely to develop neuroleptic parkinsonism than nonhandicapped, independent of typical versus atypical neuroleptics (74). High potency and high doses are risk factors (04), although there is no correlation with drug serum levels (79).
One of the difficulties in understanding the epidemiology of drug-induced parkinsonism is the reporting of various drug trials. Drug trials tend to use the Simpson-Angus Scale, which is heavily weighted toward rigidity. In a review of scales used for neuroleptic trials, 17 were found, none matching the one used in virtually all studies of idiopathic Parkinson disease, the Unified Parkinson Disease Rating Scale (UPDRS) (40). None were thought to be both ideal and fully validated.
In a door-to-door survey in Spain in 2004 to determine the prevalence of parkinsonism in an island community, the rate of drug-induced parkinsonism matched that of presumed idiopathic Parkinson disease (71).
It is the experience of this author that much parkinsonism is underappreciated, particularly in nursing homes (30; 48). This holds true for idiopathic Parkinson disease as well as drug-induced parkinsonism. As a result, it is possible that even in published reports the prevalence of this problem is actually greater than reported.
The vast majority of prescriptions for antipsychotics in the United States have been for atypical drugs the past few years, and the percentage has been increasing each year.
A 15-year prospective study of almost 3000 elderly patients suggested that neuroleptic use was associated with the later onset of Parkinson disease (25); however, this requires confirmation.
Because drug-induced parkinsonism is related to potency and dose of the drug, one can prevent or reduce the severity of drug-induced parkinsonism by using low-potency drugs and the lowest effective dose of whatever drug is chosen.
The use of prophylaxis against extrapyramidal neuroleptic side effects is somewhat controversial. Anticholinergic drugs, such as benztropine and trihexyphenidyl, are frequently given on initiating first generation antipsychotic drug therapy, generally to prevent acute dystonic reactions. The controversy centers over whether the side effects of these drugs, dry mouth, constipation, blurred vision, and memory impairment, are offset by the benefit. The few studies that have reported on the efficacy of antiparkinsonian medication in preventing drug-induced parkinsonism are positive (34; 14; 38). There are no data comparing severity of drug-induced parkinsonism in patients on prophylaxis versus those treated on an as-needed basis.
The development of atypical neuroleptics (currently including clozapine, risperidone, olanzapine, sertindole, ziprasidone, aripiprazole, and quetiapine, which have been alleged to have few extrapyramidal side effects) had been expected to reduce the incidence of drug-induced parkinsonism; however, studies comparing parkinsonism in patients treated with standard neuroleptics to those treated with the atypicals have revealed that higher doses of atypicals are often used that negate their better “EPS profile” so that levels of parkinsonism is not different (46; 65). Methodological problems, however, make this interpretation unclear (15). It should be noted that these drugs have different degrees of parkinsonism associated with them, none for clozapine, none for quetiapine, mild for olanzapine, and moderate for risperidone (66; 84; 55). In a large placebo-controlled, double-blind study of adolescents, almost one third having been neuroleptic naive, aripiprazole caused dose-dependent parkinsonism, affecting 30% at 30 mg/day (23). Ziprasidone has also been reported to exacerbate motor function in patients with Parkinson disease (29; 69). Complicating our understanding of the motor effects of the atypicals are reports that quetiapine and clozapine both reduce L-Dopa-induced dyskinesias in idiopathic Parkinson disease without worsening motor function (37).
The differential diagnoses for drug-induced parkinsonism are minimal. In young patients, the question is usually whether the presence of a masked facial appearance and bradykinesia are signs of primary neurologic parkinsonism, depression, catatonia, or severe obsessive compulsive disorder. Sometimes two conditions are present. A typical drug-induced parkinsonism patient is not depressed, making the distinction easy. When a patient is depressed, mute, or unreliable, then physical signs assume greater importance and one looks for rigidity, gait changes, and resting tremor, which may be present only intermittently, particularly when the patient is anxious.
When drug-induced parkinsonism is severe, it can be difficult to distinguish from catatonia if tremor is not prominent. Again, when the patient's mental state permits assessment, the distinction may be easy as catatonic patients are always negative and uncooperative. When the patient is uncommunicative, one checks tone. Drug-induced parkinsonism does not induce waxy flexibility or sustained nonparkinsonian postures such as keeping an arm outstretched. Tremor is not present in catatonia. The gait in catatonia should not be typical of parkinsonism, whereas severe drug-induced parkinsonism produces the gait of advanced Parkinson disease. Severe drug-induced parkinsonism patients may drool and have dysarthria and dysphagia. However, a catatonic patient treated with neuroleptics may well have both syndromes. If the patient arrives in the emergency room with an unknown or unreliable history, a toxicology screen should be obtained before any medication is administered. When drug-induced parkinsonism is severe, a major response to antiparkinsonian medication is often not seen, so a treatment trial may not be helpful in distinguishing the two syndromes. Severe obsessional-compulsive disorders can also mimic parkinsonism, but without tremor. Psychogenic parkinsonism is an uncommon but well recognized syndrome that may be difficult to diagnose in a patient on an antipsychotic drug.
In young patients, one must consider Wilson and Huntington diseases as causes of both parkinsonism and psychosis. Wilson disease typically causes a prominent tremor and dysarthria. Huntington disease usually causes chorea in adults and parkinsonism in children, but the parkinsonian (Westphal) variant can occur in young adults. Hypoparathyroidism is a rare consideration. Finally, 5% of true Parkinson disease begins in patients under the age of 40 years.
In older patients, the list of differential diagnoses is even smaller. Elderly patients have either drug-induced parkinsonism or true Parkinson disease, unmasked or exacerbated by the drugs. Clinically, there is no way to distinguish these conditions. Presumably in the near future, commercially available SPECT scanning with beta-CIT or PET scanning will permit distinction between these disorders; this, though, is not yet possible (22). Ligands that bind to the dopamine transporter have been used in SPECT imaging to distinguish idiopathic Parkinson disease from drug-induced Parkinson disease (49). The ligands label the presynaptic dopamine secreting neuron, thus, indirectly providing an estimate for the number of dopamine secreting nigral neurons. This should be normal in drug-induced parkinsonism and reduced in idiopathic Parkinson disease. Older patients also are subject to Alzheimer disease, which when advanced, can cause signs of parkinsonism that will be exaggerated by neuroleptics (10). Other forms of parkinsonism must also be considered. In the demented elderly who are treated with an antipsychotic to control behavior problems, it becomes impossible to determine if the parkinsonism is due to the medications or the underlying dementing illness. In the previously psychotic, neuroleptic-treated patient, the diagnosis of catatonia must also be entertained.
No evaluation is needed in clear cases where a neurologically normal person develops parkinsonism on medications. When the drug exposure history is uncertain, toxicology screens are helpful only if the drug was taken recently. The extrapyramidal effects of neuroleptics far outlast measurable serum levels. In young patients an evaluation for Wilson disease may be important. The gene test for Huntington disease is available. Imaging studies are only occasionally helpful, mainly in the elderly where subdural hematoma or normal-pressure hydrocephalus and multiple small strokes are suspected. Spinal fluid and brain wave testing are useless. Checking spinal fluid levels of dopamine and its metabolites is not helpful. DaT SPECT scans, which label the dopamine transporter protein, hence, dopamine secreting cells, are commercially available and are believed to reliably distinguish Parkinson disease from neuroleptic-induced parkinsonism (78; 07). In addition, the presence of a DaT deficit also predicted a better response to L-Dopa (78). Although transcranial ultrasound (TCUS) has been used to help diagnose Parkinson disease and distinguish it from essential tremor and other disorders that do not affect the substantia nigra, TCUS has been reported to have the same “hyperechogenic” characteristics (enlarged substantia nigra region compared to normal) in neuroleptic parkinsonism as in idiopathic Parkinson disease (08). High-field MRI may be another approach for identifying idiopathic Parkinson disease in patients taking neuroleptics (42).
Drug-induced parkinsonism is a problem only if its presence causes a problem for the patient, socially or functionally. By itself it is not necessarily a harbinger of a worse movement disorder (such as tardive dyskinesia), and it has no known implications for the treatment of the underlying psychosis. Most reports indicate that anticholinergics and amantadine are helpful in ameliorating drug-induced parkinsonism but that after 3 months most drug-induced parkinsonism resolves spontaneously. It is, therefore, good practice to continue these drugs only if their use provides clear improvement. After 3 months, tapering of these drugs should be attempted (35). Because there are no special long-term complications of these agents, they may be continued as long as they are needed. Levodopa is of less certain benefit (33; 76). In some severe cases, it appears helpful, but it has also been implicated in exacerbating psychosis. The possibility that adenosine antagonists, which are being tested in idiopathic Parkinson disease, may be useful in drug induced parkinsonism has not been explored (54). Because neuroleptics block D2 receptors, the use of drugs that act on nondopamine receptors makes intuitive sense.
In cases of severe drug-induced parkinsonism, unresponsive to concomitant use of anticholinergics and amantadine, a low-potency neuroleptic should be substituted for a higher-potency drug if a neuroleptic must be continued. Strong consideration should be given to the use of an atypical neuroleptic. Resolution of the drug-induced parkinsonism may take a long time, however. An alternative, and faster, approach would be to use electroconvulsive therapy when appropriate, which temporarily ameliorates parkinsonism and treats psychosis (31). After electroconvulsive therapy an atypical neuroleptic can be introduced to provide ongoing antipsychotic treatment.
Because the masked facial expression of parkinsonism may be interpreted as blunted affect, doctors should be wary of confusing “negative symptoms” of schizophrenia and medication side effects. In addition, the neuroleptics may induce an element of mental slowing along with the motor retardation (18).
There is no reason to believe that the fetus carried by a woman with drug-induced parkinsonism is at more risk than the fetus carried by a woman on the same medications without drug-induced parkinsonism. The risk of labor and delivery conceivably could be greater if the drug-induced parkinsonism is severe, but severe drug-induced parkinsonism is uncommon in adults in this age group. The few reported pregnant women with Parkinson disease have not had increased problems with labor, delivery, or offspring.
Patients with drug-induced parkinsonism should probably not receive droperidol as an induction agent, as it can exacerbate parkinsonism.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Joseph H Friedman MD
Dr. Friedman, Chief, Division of Movement Disorders, Department of Neurology, at the Warren Alpert Medical School of Brown University and Stanley Aronson Chair in Neurodegenerative Disorders at Butler Hospital received consultant fees from EPI-Q.See Profile
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.See Profile
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