Drug-induced parkinsonism (DIP) represents one of the most prevailing diagnostic dilemmas in movement disorders clinics and is the second most common cause of parkinsonism (1, 2). While there may be clinical clues to help differentiate DIP from Parkinson’s disease (PD) or other forms of degenerative parkinsonian syndromes, in many patients DIP is clinically indistinguishable (3, 4). Age is a primary risk factor for DIP, which may be in part related to the loss of dopaminergic neurons with increasing age (5). It is estimated that approximately 18% of the population presenting with parkinsonism have a drug-induced disorder (6) and about 7% of patients initially diagnosed with PD are later reclassified as having DIP, thus underscoring the difficulties in accurately diagnosing DIP (7). To add to the complexity, clinical differentiation usually requires withdrawal of the offending agent for several months, which is often difficult, and in some cases impossible, in the setting of active psychiatric symptoms. In addition, drug-induced extrapyramidal symptoms are one of the main causes of treatment noncompliance in psychiatric patients, often leading to hospital admission and ultimately a poorer prognosis (8).
Patients with suspected drug-induced parkinsonism (DIP) should be considered a unique population with regard to assessing diagnostic accuracy for parkinsonism. The key driver in clarifying the diagnosis of DIP versus an underlying degenerative parkinsonian syndrome is the potential impact on treatment decisions and prognosis. While DIP is mainly related to striatal D2 receptor blockade (9), a distinctive feature of patients with suspected DIP is that evidence of subclinical drug-exacerbated parkinsonism may become apparent in some patients. After drug withdrawal, 60%–70% have resolution of parkinsonian features in seven weeks, although some can take up to 12 months (10). In a subset of patients, the symptoms persist beyond 12 months, suggesting that the offending drug exacerbated or unmasked a neurodegenerative parkinsonian syndrome earlier than would have otherwise been expected. There are also reports of patients with initial improvement upon discontinuation of the drug who again develop parkinsonian symptoms 1–2 years later, suggesting that the drug had unmasked a subclinical parkinsonian syndrome (3, 11). Further evidence supporting this phenomenon comes from a report by Rajput (12) in which two cases of DIP, in the setting of neuroleptic treatment with complete recovery upon drug withdrawal, were found on postmortem to have pathology revealing nigral degeneration and Lewy bodies. The data from this report suggests that preclinical PD in these cases was unmasked by the neuroleptic treatment. Treatment with levodopa in patients with suspected subclinical parkinsonism that has been unmasked by dopamine blocking agents has been shown to be useful, thus underscoring the benefit of making an accurate diagnosis of subclinical parkinsonism, as it can often influence therapeutic decisions (13, 14). Therefore, the relevance of learning whether there is an underlying neurodegenerative process is that in patients with evidence of a degenerative process based on either imaging markers or lack of clinical improvement following drug withdrawal, the treatment should be carefully considered. Specifically, if neuroleptic treatment is necessary, use of atypical neuroleptics to minimize the severity of extrapyramidal symptoms should be prescribed. In addition, a trial of dopaminergic replacement may also be warranted.
DIP usually occurs secondary to the use of a broad range of substances including dopaminergic blocking agents (neuroleptics), antidepressants, and calcium channel blocking agents (15, 16). Neuroleptics are the most common offending drugs and act by blocking the dopaminergic D2 receptors, located primarily on the postsynaptic neurons. DIP has been shown to occur in 15%–60% of neuroleptic treated patients (12, 17–20). The onset of DIP appears to be dose-dependent, and one report suggests an expectation for DIP in patients on doses of dopamine receptor blocking agents that reach a level of 80% blockade of D2 receptors (21). In neuroleptic-induced parkinsonism, there is blockade of the D2 receptors located on the postsynaptic membrane, while the presynaptic terminals remain unaffected. Therefore in pure DIP it is anticipated that there is normal uptake of DAT SPECT tracers and [18F]-Dopa in the striatum, thus differentiating these patients from neurodegenerative forms of parkinsonism (20).
Access to diagnostic markers for degenerative parkinsonian syndromes offers the possibility of making this differentiation between DIP and a subclinical drug-exacerbated degenerative parkinsonism in a more objective fashion and at an earlier stage of the condition. DIP has been reported as the second most common form of parkinsonism; however, there are a relatively limited number of studies investigating the utility of the imaging modalities as potential tools to improve diagnostic accuracy. This chapter will provide a review of the current literature investigating the imaging modalities that play a potential role in clarifying the diagnosis of DIP.
Advances in nuclear medicine imaging have led to the development of several radioligands relevant to DIP targeting the presynaptic dopaminergic terminal. The availability and application of these imaging techniques as diagnostic tools has resulted in an improvement in our ability to establish a more accurate diagnosis in cases where the clinical evaluation may be unclear. The presynaptic dopamine transporters (DAT) can be evaluated with several positron emission tomography (PET) and single-photon emission tomography (SPECT) ligands including 123I-(2)-2β-carboxymethoxy-3b-(4-iodophenyl)tropane ([123I]-β-CIT) (Dopascan; Guilford Pharmaceuticals Inc.); 123I-N-3-fluoropropyl-2b-carboxymethoxy-3b-(4-iodophenyl)tropane ([123I]-FP-CIT) (DaTSCAN; GE Healthcare); and 123I-altropane. The PET ligand, 18 F-3,4-dihydroxyphenylalanine ([18 F]-Dopa), provides a marker of the presynaptic dopaminergic function through measuring terminal dopamine decarboxylase activity and dopamine turnover. In addition, radioligands targeting vesicular monoamine transporter (VMAT2) available in the research setting, including 9-[18 F]fluoropropyl(+)-dihydrotetrabenazine ([18 F]-AV-133) and 11 C-or 18 F-dihydrotetrabenazine, provide another means for evaluating the integrity of presynaptic dopaminergic neurons. Using DAT imaging, early parkinsonian patients show a bilateral reduction in putaminal uptake, with a more pronounced reduction in the putamen contralateral to the most affected limbs (22), while the uptake in the region of the caudate is relatively preserved. Early PD patients have a loss of approximately 40%–50% of putaminal uptake when observed at the time of initial clinical symptoms (22, 23).
There are imaging studies reported in the literature comparing clinically probable PD and other conditions that mimic PD clinically, but without degeneration of the presynaptic dopaminergic neurons. In a study comparing striatal DAT imaging with [123I]-FP-CIT SPECT in probable PD and essential tremor patients, a sensitivity and specificity of greater than 90% has been shown (24). In cases for which the diagnosis is uncertain, DAT imaging performance has been evaluated through three main clinical trials: the Query study comparing clinical diagnosis to DAT imaging over a 6-month period in patients with an uncertain diagnosis (25); the Clinically Uncertain Parkinsonian Syndromes (CUPS)(26), and the European multicenter study in which the clinical diagnosis was prospectively compared to DAT imaging over a 3-year period (27). These studies have consistently demonstrated that clinicians have high sensitivity and low specificity (as low as 30% in some studies) in identifying the correct diagnosis, whereas DAT imaging offers high specificity in differentiating PD from nondegenerative forms of parkinsonism, including DIP (25, 28). The long-term impact of having a normal DAT scan has been studied by Marshall and colleagues (28), who followed 150 patients with normal [123I]-FP-CIT imaging obtained for diagnostic purposes. Approximately 20 of these subjects were ultimately given a clinical diagnosis of DIP after 2-year clinical follow-up. Although 4/120 subjects (3%) demonstrated clinical progression consistent with PD, none of these cases were suspected of having DIP at baseline.
While DIP represents one of the best indications for a [18 F]-Dopa PET or DAT SPECT imaging, there are relatively few published studies evaluating the role of dopaminergic imaging in this setting. [123I]-FP-CIT SPECT is the only approved imaging procedure to aid in establishing a diagnosis of PD, and the indication is limited to differentiating PD from other conditions presenting with tremor, encompassing only a subset of individuals with DIP. Studies specifically aimed at evaluating the diagnostic accuracy of [123I]-FP-CIT as a useful tool in differentiating PD from DIP provide support for the role of DAT imaging in cases of suspected DIP, which are summarized below. Given that [123I]-FP-CIT is more widely available than the other imaging agents, most studies to date have been conducted with this ligand; however, other radioligands interrogating the presynaptic dopaminergic terminal, available primarily in research settings, would be expected to be equally effective in establishing an accurate diagnosis in suspected DIP cases.
It should be noted that drugs known to cause parkinsonism, including dopamine receptor binding agents, have been shown to have negligible affinity for DAT (29, 30). Imaging the presynaptic dopaminergic neuronal integrity with DAT radioligands demonstrates normal symmetric uptake in pure DIP cases, even for those exhibiting significant parkinsonism clinically. Whereas in cases of a reduction DAT uptake in the striatum, particularly when the reduction is asymmetrical, a diagnosis of subclinical drug-exacerbated PD or other degenerative parkinsonian syndrome needs to be considered.
Romero and Padillo (31) conducted a prospective study evaluating 19 DIP patients completing [123I]-FP-CIT SPECT at the time of discontinuation of the offending drug, which was most frequently a neuroleptic (39%), and at a mean follow-up of 8.8 (range 6–34) months. The final clinical diagnosis was subclinical drug-exacerbated PD in 31% (6/19 subjects), 4 subjects with a reduction in [123I]-FP-CIT uptake, and 2 with normal uptake. In this study, [123I]-FP-CIT SPECT demonstrated a sensitivity of 66.7% and specificity of 100% (negative predictive value 86.7%) using the clinical diagnosis as the “gold standard.” There may be an underrepresentation of patients with subclinical parkinsonism unmasked by a medication, given that only subjects capable of withdrawal from the medication were included in the study.
Lorberboym and colleagues (32) studied 20 patients who had developed parkinsonism while on neuroleptic agents and ten age-matched healthy controls using [123I]FP-CIT SPECT. Nine (45%) of the patients had normal scans and 11 (55%) showed a reduction in striatal binding, supporting the predescribed concept (3, 4, 11) that a significant proportion of patients have evidence of subclinical degenerative changes based on imaging predisposing the onset of parkinsonism when dopamine receptor blocking agents are administered. This study is also particularly instructive in demonstrating that DIP was clinically indistinguishable from PD, including significant asymmetry of symptoms, even in the patients with normal imaging. In addition, gait freezing, a symptom usually present in more advanced PD, was noted in two patients with normal imaging. The authors concluded that DAT SPECT imaging is effective in determining whether these conditions are entirely drug-induced or an exacerbation of subclinical PD (32).
A key to understanding the accuracy of DAT imaging in differentiating DIP from a subclinical degenerative parkinsonian syndrome is through determining the most accurate clinical diagnosis with longitudinal follow-up. In the first prospective, longitudinal study evaluating suspected DIP patients, 32 patients who had developed parkinsonism on neuroleptic treatment were consecutively recruited for [123I]FP-CIT imaging (33). There was normal putaminal [123I]FP-CIT binding in 18 (55%) patients and reduced binding in 14 (45%) patients. Clinically, the groups were similar, with the exception of more frequent symmetrical and oral-buccal dyskinetic cases in the group with normal binding. Nineteen of the 32 patients (ten with normal [123I]FP-CIT uptake and nine with reduced uptake) were reassessed clinically and with [123I]FP-CIT SPECT imaging at 9–13 months following initial evaluation (14). Patients in the normal [123I]FP-CIT group also had normal uptake on follow-up imaging and no substantial change in UPDRS scores from their baseline. For patients with a reduction in [123I]FP-CIT, the uptake remained abnormal at follow-up and UPDRS motor scores were higher than at baseline. This longitudinal study provides critical evidence that DAT imaging with [123I]FP-CIT SPECT at baseline is a sensitive marker for identifying patients with pure DIP compared to those with a subclinical degenerative parkinsonian syndrome at follow-up. In addition, all patients in this study underwent a 3-month trial of levodopa treatment (400–800 mg/day), resulting in improvement of motor symptoms in 3/10 patients with normal [123I]FP-CIT uptake and 8/9 patients with reduced [123I]FP-CIT uptake, which was a novel finding in this study. Interestingly, there were no psychiatric side effects reported as a result of the dopaminergic treatment.
Given the relatively high percentage of DIP cases with a reduction in DAT binding (43%–55%) (14, 32, 33), Tinazzi and colleagues (19) designed a study in a large population of schizophrenic subjects aimed at evaluating the prevalence of DIP and rate of DAT deficit in this population. Schizophrenic patients treated with neuroleptics for at least 6 months were eligible for participation in the clinical and [123I]FP-CIT SPECT imaging. Parkinsonian signs were present in 149/448 (33%) patients and 97 agreed to undergo imaging, 41 (42%) of whom showed a reduction in [123I]FP-CIT uptake. Two-year clinical follow-up of this cohort was completed in 60 (33 with normal [123I]FP-CIT uptake and 27 with reduced uptake) patients. The UPDRS scores showed significant worsening in the patients with reduced [123I]FP-CIT uptake at baseline, while there was no difference in those with normal imaging. In addition, only the patients with reduced [123I]FP-CIT uptake demonstrated an improvement in motor symptoms with levodopa treatment. The results of these studies suggest that parkinsonism in patients with neuroleptic exposure has at least two etiologies: in patients with normal [123I]FP-CIT uptake parkinsonism is likely to be pure DIP and related to neuroleptic-induced D2 receptor blocking activity, whereas in patients with a reduction in [123I]FP-CIT uptake, blocking of the D2 receptors occurs in the setting of a subclinical degeneration of presynaptic dopaminergic neurons.
The only published study utilizing [18F]-Dopa PET imaging to distinguish DIP from presynaptic dopaminergic neuronal degeneration included a cohort of 13 patients classified as relatively severe DIP, warranting referral to a movement disorders clinic (20). All cases were willing and able to withdraw from the offending medication(s) and 12/13 were followed clinically for a median of 23.5 months. Putaminal [18F]-Dopa uptake was normal in 8/9 patients with longitudinal follow-up, which was predictive of an improvement in the clinical signs of parkinsonism in all cases and resolution in 3 cases. In patients with a reduction in [18F]-Dopa, 3/4 (75%) had a progression in clinical parkinsonian symptoms despite discontinuation of the dopamine receptor blocking agent(s). While the authors claim that 31% (4/13) of cases demonstrating a reduction in [18F]-Dopa was higher than expected, it is consistent with the prevalence in more recently conducted studies (19, 32). Nevertheless, they attribute the higher than expected number of cases with reduced [18F]-Dopa uptake to the severity of the cases. The results from this study indicate that normal [18F]-Dopa PET imaging is well correlated with improvement in parkinsonian signs in DIP, while the majority of patients with a reduction in [18F]-Dopa uptake show worsening parkinsonian signs off medications at follow-up. There is data to support the notion that chronic treatment with dopamine receptor blocking agents may in fact result in a compensatory increase in presynaptic dopamine metabolism (34, 35), which would be expected to result in increased [18F]-Dopa uptake and be inconsistent with the result of this study.
A retrospective analysis was performed by Diaz-Corrales et al. (36) involving 32 patients clinically diagnosed with DIP, 25 patients with PD unmasked by neuroleptic treatment, and 22 patients with PD with no history of neuroleptic treatment. Clinical diagnosis was determined during a follow-up period after withdrawal of the neuroleptic. [123I]-FP-CIT SPECT images obtained at symptom onset were analyzed by nuclear medicine experts blinded to the clinical information. The [123I]-FP-CIT SPECT was normal in 90.6% (29/32) patients diagnosed with DIP, while all patients diagnosed with PD or PD unmasked by neuroleptic treatment showed a reduction in [123I]-FP-CIT SPECT uptake.
In a study aimed at elucidating the influence of neuroleptics on DAT binding using [123I]FP-CIT SPECT in schizophrenic patients (10 drug naïve, 8 previously treated with neuroleptics and now drug-free, and 15 treated with olanzapine or risperidone), no difference in [123I]FP-CIT binding was found between any of the groups and the ten age-matched healthy subjects (29). These findings are consistent with a study using [123I]β-CIT SPECT demonstrating no difference in striatal dopamine transporter density in schizophrenic patients compared to healthy subjects (37), and with postmortem pathological studies showing no change in dopamine transporter density in schizophrenic patients compared to those without schizophrenia (38, 39). In contrast, another study to understand if schizophrenic patients are at increased risk for a degenerative parkinsonian syndrome was conducted by Mateos and colleagues (40) and evaluated first-episode schizophrenic subjects (ten with DIP and ten without DIP) and ten age-matched healthy subjects using [123I]FP-CIT SPECT 4 weeks after initial treatment with risperidone (6 mg/day ± 2 mg). While there was no significant difference in the uptake of striatal [123I]FP-CIT among the schizophrenic patients with and without DIP, this study showed a significant reduction in uptake when comparing all schizophrenic subjects and healthy subjects. The authors suggest there may be a dysfunction in the presynaptic dopamine pathway in schizophrenic patients, which could explain the increase in the higher prevalence of observed parkinsonism in response to administration of neuroleptic therapies in this population. Based on the data presented in this study, there is a fair amount of overlap in striatal uptake in the schizophrenic patients and healthy subjects; and while the difference reaches statistical significance, there may be a specific population of schizophrenic subjects who are at increased risk for dysfunction in the presynaptic dopamine pathway, requiring further evaluation.
While PET and SPECT imaging techniques have proven to be useful diagnostic tools in parkinsonism and other extrapyramidal disorders, in recent years the utility of these imaging techniques for measuring brain receptor occupancy has come to the forefront. Specifically, D2 receptor ligands [123I]iodobenzamide (123I-IBZM) with SPECT and [11C]-raclopride used with PET have been shown to be useful in evaluating the occupancy of dopamine receptors by neuroleptic agents in human trials (41, 42). PET studies have shown that D2 receptor occupancy at levels greater than 80% invariably results in extrapyramidal side effects including, but not limited to, parkinsonian symptoms. Using imaging techniques to elucidate the occupancy of specific receptors offers the possibility of developing medications with therapeutic effect while minimizing the occurrence of extrapyramidal side effects.
Dose occupancy studies performed over the past several years have informed researchers regarding the doses required to reach adequate efficacy with reducing the risk for side effects. A result of these studies is that, in general, lower doses of antipsychotic medications are being recommended. An example of data to support the use of lower doses is a study evaluating 5 and 20 mg of olanzapine which showed a higher D2 receptor occupancy at 20 mg (60 vs. 83%, respectively), demonstrating no difference in clinical efficacy at these doses (43). Another direct application of imaging informing neuroleptic doses is a PET study showing that a 4 mg dose of risperidone results in 70%–80% occupancy, therefore making this the highest recommended dose (44). As a result of D2 receptor occupancy imaging studies, both classical and atypical neuroleptic occupancy has been described as a saturation hyperbole. Specifically, by increasing low doses by small increments the result is a large increase in D2 occupancy, whereas the increase in higher doses showed a plateau or no further increase (45, 46). Several studies have demonstrated that lower doses of antipsychotic medications may provide equal efficacy than higher doses, with less risk for extrapyramidal symptoms, leading to the trend to use lower doses (47, 48).
Novel radioligands to evaluate the binding to other relevant receptor or enzyme targets in the brain, including serotonin receptor, phosphodiesterase 10(PDE10), the dopamine D1 receptor, and the muscarinic and GABA receptors, are under development, offering the ability to develop additional drugs with novel targets having the potential for fewer extrapyramidal side effects.