Antihypertensives

Antiarrythmics

Amiodarone is a class III antiarrhythmic, typically prescribed for supraventricular tachycardia. It carries a variety of neurological side effects including neuropathy, ataxia, visual problems, fatigue, dizziness, and tremor (19). Neurological side effects tend to be dose-dependent and can be seen during the loading period or after long-term use. Tremor is the most common neurological symptom, with 30% of users exhibiting this complication (19). Most of the time, the tremor resembles essential tremor. It has a postural predilection and a frequency of 6 to 10 Hz (20). However, it can take on a distinctly parkinsonian character as well (21). Werner and Olanow reviewed the literature and described several cases of parkinsonism caused by amiodarone (22). Most cases did not resemble PD, but instead had nonspecific extrapyramidal syndromes featuring tremor, which interestingly included jaw tremor. Amiodarone can also cause a pure akinetic syndrome (23).

The amount of time from withdrawal to resolution of symptoms depends on the duration of exposure. Symptoms appearing with short courses of amiodarone only take days to improve, while longer courses may take several months (21). Tremor is a dose-dependent side effect and it can be reduced by lowering the dosage (20). Also, adding propranolol may be helpful in treating the postural component of tremor (20).

Aprindine is a lesser known antiarrhythmic medication which reportedly caused parkinsonism in a single case report (24). A 78-year-old man developed disorientation and parkinsonism after a month’s use then recovered a few days after withdrawal. The mechanism by which amiodarone and aprindine cause parkinsonism is unknown, but they have been shown to block D1 and D2 receptors as part of in vivo and in vitro studies (25). In addition, amiodarone has been shown to interfere with mitochondrial function (26), which could explain its side effect profile. There have been two amiodarone-induced parkinsonian cases with pathological reports and they showed discrepant findings. LeMair presented a case whose pathology demonstrated depigmentation of the substantia nigra, without Lewy Bodies (27), whereas Ishida’s case revealed a lack of Lewy Bodies, with normal pigmentation of the substantia nigra (28). The former case might suggest that amiodarone has a toxic effect on nigral neurons. Further study is needed.

Antiischemic

Trimetazidine is an antiischemic medication that has been tied to parkinsonism. Two retrospective case series with 21 cases by Masmoudi (29) and 20 cases by Martí Massó (30) demonstrate this convincingly. Parkinsonism would develop over months to years and symptoms would generally improve weeks to months after withdrawal of the drug. This medication has the same piperazine core as the aforementioned calcium channel blockers, cinnarizine and flunarizine. Therefore, it is thought that the D2 receptor antagonism leads to the development of parkinsonism.

Valproic acid

Valproic acid (VPA) is well known to cause a reversible form of parkinsonism in pediatric populations (31–36). Features include marked bradykinesia and bradyphrenia which is sometimes associated with a reversible atrophic appearance of the brain called “pseudoatrophy.” VPA-induced parkinsonism is also a well described clinical entity in adult populations (37). VPA is best known as a cause of nonparkinsonian postural hand tremor that has been estimated to occur in up to 45% of users and is not dose- or serum level–related (38). A smaller percentage of patients have been identified to develop actual parkinsonian features. In addition to causing de novo DIP, VPA was shown to worsen symptoms in those with preexisting parkinsonism (39). The studies that have examined the frequency of DIP from VPA have primarily looked at an exclusively epileptic patient population. There were disparate rates of parkinsonism described (39–43), with the highest estimates finding parkinsonism in 10% of those exposed. The incidence in the elderly treated for bipolar disorder remains unknown.

The diagnosis can sometimes be challenging in the elderly since this is the demographic in which one would expect to see PD, and normal aging is associated with mild parkinsonism. VPA-induced parkinsonism can present as an akinetic-rigid state or, as mixed postural/rest tremors, and it can look identical to PD with a unilateral bradykinesia and rest tremor. The parkinsonism that VPA causes is not a consequence of medication overdosage or toxicity, as low doses and therapeutic serum drug concentrations can result in this complication. For instance, one patient from our own series was on a dose of only 250 mg per day when she developed her symptoms (44). Further complicating the distinction between VPA-induced parkinsonism and PD is the fact that VPA-induced parkinsonism takes months to years to develop, so symptoms do not appear upon initiation of the offending agent as more typically seen with neuroleptics. Furthermore, symptoms typically require weeks to months to resolve after discontinuation of the VPA, so it takes time to assess for clinical improvement and clarify the diagnosis. The average duration in our series was seven months (44). Yet another confounding factor to distinguish between VPA-induced parkinsonism and PD is the fact that it is responsive to levodopa (44, 45) and one can even see levodopa-induced dyskinesia (44).

The mechanism by which VPA causes parkinsonism is unknown. Like other causes of DIP, it displays normal dopamine transporter density on SPECT scan (41), hence it does not appear to be toxic to presynaptic dopaminergic neurons. Based on the fact that this condition can be levodopa responsive, one would not expect a postsynaptic dopaminergic blockade to be the cause. Theories with regard to the mechanism of development of DIP include GABAergic effects, since VPA is known to increase GABAergic transmission (38), which is significant in the basal ganglia, including the substantia nigra. This may result in a net inhibition of dopaminergic activity (46). Other theories include the slow accumulation of a toxic metabolite of VPA in the substantia nigra (47), inhibition of mitochondrial metabolism (48), and inhibition of neurite outgrowth (49).

Phenytoin

There are only two cases in the literature of parkinsonism associated with phenytoin. The first case described a 68-year-old man with seizures as a result of cranial injury who developed parkinsonism and tremors within one month of initiating the drug. Symptoms resolved over 6 months after switching to an alternative antiepileptic medication (50). The other case describes parkinsonism, tremor, and cerebellar ataxia within two weeks of phenytoin exposure, but his drug level was exceptionally high, at 40 mg/dL (51). Both patients had a history of severe cerebral trauma, so perhaps phenytoin requires the substrate of brain injury to cause parkinsonism.

Lithium

Lithium is known to cause a variety of movement disorders including tremor, parkinsonism, and chorea (52). Like VPA, lithium causes a postural and action high frequency tremor that is distinct from PD, similar to essential tremor, and is thought to be a form of enhanced physiologic tremor (53). In fact, it might be the most common form of drug-induced tremor seen (52), with an incidence as high 33%–65% (54). The variance among different estimates of incidence is the result of lithium frequently being prescribed with other tremor-producing medications. The tremor can occur even when the drug levels are therapeutic.

The notion that lithium can cause parkinsonism has been a controversial and complicated one. Certainly, when it does truly cause parkinsonism, it does so rarely. But patients who are prescribed lithium usually take it for bipolar disorder, often with neuroleptic drugs. Furthermore, much of the early literature on the matter probably overdiagnosed parkinsonism based on the physical exam findings of postural tremor and cogwheel phenomena without true rigidity. Cogwheeling is a nonspecific exam finding that does not necessarily indicate rigidity and is noted in patients with all types of postural tremor, probably as an extension of the tremor itself.

The first two papers on the matter examined randomly selected lithium users for “cogwheel rigidity” (55, 56), but it was not made clear if this represented true parkinsonism. In addition, in the first paper it was not clear if any were treated concomitantly with neuroleptics. Kane et al. then reported on 38 patients with therapeutic levels of lithium, two of whom had parkinsonian features, but both had been on neuroleptics in the year prior (57). It has been shown that neuroleptic-induced parkinsonism can last that long or even longer after neuroleptic discontinuation, complicating interpretation (1). Asnis evaluated the largest series of patients, 97, but again focused on cogwheeling instead of true parkinsonian signs (58).

The more solid evidence that lithium causes parkinsonism comes from more recent case reports, as summarized by Factor (52). Cogwheeling along with such parkinsonian traits as bradykinesia, rigidity, resting tremor, masked facies, and postural instability solidified the diagnosis of parkinsonism in these cases. All patients were on chronic lithium therapy, some with therapeutic, others with toxic serum levels. One can draw the conclusion based on these cases that the duration of lithium treatment, older age, and higher therapeutic levels of lithium appear to be risk factors for the development of parkinsonism. However, dopamine transporter SPECT scanning was not available for these cases, so it is possible some or all actually had PD.

Lithium’s mechanism of action for improving bipolar disorder is unknown, and the same is true for inducing parkinsonism. Lithium affects many different neurotransmitters and modulates several biochemical pathways. For instance, lithium has been shown to block inositol phospholipid hydrolysis, part of a second-messenger system which has been theorized to explain lithium’s benefit in affective disorder. This may be related to its upstream effect of blocking the stimulus-based release and the enhancement of reuptake of norepinephrine in animal models. Lithium also affects serotonin, GABA, glutamate, and several neuropeptides. Animal studies yield conflicting data for how lithium might cause parkinsonism, with lithium exerting contrasting effects on the dopaminergic system (52).

Cyclosporine

Causal relationships are difficult to determine when there are many medications given simultaneously. This especially becomes murky when it is against a background of an acute underlying illness. Such is the case when trying to attribute parkinsonism to an agent used in an organ transplant recipient. However, there are several convincing case reports of the calcineurin-inhibitor immunosuppressant agent cyclosporine (also referred to as cyclosporine A) causing a reversible form of parkinsonism (59–63). Cyclosporine is better known to cause action tremor (occurs in approximately 20%), and can also cause cerebellar ataxia, myoclonus, seizures, headache, cortical blindness, visual hallucinations, and encephalopathy (61, 63).

Cases of cyclosporine-induced parkinsonism varied in duration of exposure, ranging from days to years. The clinical syndrome includes rest tremor, bradykinesia, hypomimia, and rigidity. This could develop even with therapeutic serum levels of the drug. Generally resolution was fairly rapid, over days to weeks, upon stopping the medication. The parkinsonian symptoms in these cases sometimes responded to levodopa. Unfortunately, none of these cases included functional dopamine transporter imaging.

Amphotericin

Amphotericin B is prescribed for life-threatening fungal infections and frequently used alongside chemotherapeutic agents in immunosuppressed patients with leukemia. There are reports of amphotericin itself causing parkinsonism (64). Amphotericin may have some synergistic effects with the chemotherapeutic agent cytosine arabinoside (65, 66, 67) to cause parkinsonism. This parkinsonian syndrome is characterized by bradykinesia, rigidity, and resting tremor, which can resolve over days to months after discontinuation of the offending medication. Levodopa appears to be of no benefit.