Young age and severity of motor function are risk factors for psychosis after subthalamic nucleus deep brain stimulation for Parkinson's disease

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for motor symptoms in advanced Parkinson's disease (PD). Various postoperative psychiatric symptoms have been reported following STN-DBS, including delirium, mania, depressive states, aggression, hallucinations, and delusions.1, 2 We retrospectively analyzed delirium and psychosis after DBS in a consecutive series of patients who underwent bilateral STN-DBS for treatment of PD. This is a retrospective observational study. Delirium was defined according to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition), and postoperative psychosis was defined as organic hallucination based on ICD-10. Patients with major psychiatric problems (e.g., severe depressive episodes, schizophrenia) were excluded. We enrolled 143 patients (75 males, 68 females) who underwent bilateral STN-DBS for PD between August 2015 and September 2018 at Juntendo University Hospital. Before DBS, we assessed the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Japanese version, Frontal Assessment Battery (FAB), Delirium Rating Scale, and Unified Parkinson's Disease Rating Scale Part III of the International Parkinson and Movement Disorder Society (MDS-UPDRS III). The UPDRS ratio was calculated as follows: [(MDS-UPDRS IIIoff) – (MDS-UPDRS IIIon)/(MDS-UPDRS IIIoff)]. We calculated the levodopa equivalent daily dose (LEDD) three times: before DBS, and 14 and 21 days after DBS. We defined ‘change over time in LEDD’ as [(LEDDbaseline) – (LEDD14 days after DBS)]/(LEDDbaseline), and ‘proportion of dopamine agonist (DA)’ as [(DA LEDD)/(total LEDD)]. The clinical features of the patients are summarized in Table S1. Of the 143 patients, six (4.2%) patients had psychosis after DBS, all within a day after increasing the stimulation. Four patients recovered within several weeks. One patient left the hospital with psychotic symptoms. One patient died by suicide (Table S2). Five of six patients with postoperative psychosis had preoperative pareidolia. Minor preoperative hallucinations may be associated with postoperative psychosis. We reinitiated the stimulation immediately after the psychosis, and DAs were decreased or stopped. If the symptoms still did not improve, patients were treated with antipsychotic medications. We gradually increased the stimulation after the symptoms improved or disappeared (Table S2). In addition, five of six patients with postoperative psychosis presented with dyskinesia, suggesting that postoperative psychosis was associated with dopamine sensitivity. Patients with psychosis were significantly younger than patients with no psychosis (P = 0.0485) (Fig. S1). The MDS-UPDRS III score in the medication-off period before DBS was significantly higher in patients with postoperative psychosis than in patients with no psychosis (P = 0.00136) (Fig. S1). LEDD at 14 and 21 days after DBS was not significantly different in the psychosis group compared to the no psychosis group (Table S1). To compare changes in dopamine over time from baseline to 14 days after DBS, we calculated the change over time in total LEDD [(baseline – 14 days after DBS)/baseline]. We found no significant difference between patients with and without psychosis. It is said that DAs are related to hallucinations and delusions. We compared the proportion of DAs in the total LEDD, which was calculated as (DA LEDD)/(total LEDD). The proportion of DAs in the psychosis group was significantly higher than in the no psychosis group at 14 days after DBS (t[141] = −2.082, P = 0.0391). However, we found no significant difference between the psychosis and no psychosis groups before surgery (Table S1 and Fig. S1). Age, MMSE, and FAB in patients with delirium were significantly different from patients with no delirium (p[age] = 0.000545, p[MMSE] = 0.0140, p[FAB] = 0.0180) (Table S3). The incidence of hallucination in patients with PD receiving medical treatment is 16.2%, and the incidence of postoperative delirium in elderly non-PD individuals is 10–70%.3, 4 Our results suggest that DBS surgery did not confer a higher risk of postoperative mental confusion. Shiina (2015) evaluated 32 patients who underwent DBS. At 3 months, 12 patients with psychiatric symptoms had worsened due to DBS. At one year, six patients had some psychiatric symptoms caused by DBS.5 In our study, continuing DAs without reducing the dose after surgery was a trigger for postoperative psychotic symptoms. Further studies are needed to reveal the mechanisms involved. We identified three interesting differences between psychosis and delirium. First, patients with psychosis were younger than patients with no psychosis. On the other hand, patients with delirium were older than patients with no delirium. Second, cognitive function was related to delirium but not postoperative psychosis. Third, the time of onset was different for delirium compared to psychosis. Delirium was detected immediately after surgery, but psychosis occurred after increasing stimulation. Further studies are needed to reveal the mechanisms involved. This study was funded by the Juntendo Mental Health Institute (2019-001). The authors have no conflicts of interest to report regarding this paper. Dr. Ito, Dr. Sasaki, Dr. Katsuta, Dr. Sekimoto, Dr. Jo, Dr. Nakamura, Dr. Nakajima, and Dr. Ohnuma have nothing to disclose. Dr. Oyama has received speaker honoraria from Medtronic and Boston Scientific, outside the submitted work. Dr. Shimo reports other honoraria from Medtronic and other honoraria from Boston Scientific, outside the submitted work. Dr. Iwamuro reported that the Department of Research and Therapeutics for Movement Disorders, Juntendo University Graduate School of Medicine, is an endowment department supported with an unrestricted grant from Medtronic and Boston Scientific, outside the submitted work. Dr. Umemura reports that the Department of Research and Therapeutics for Movement Disorders, Juntendo University Graduate School of Medicine, is an endowment department supported with an unrestricted grant from Medtronic and Boston Scientific. Dr. Umemura received speaker honoraria from Medtronic and Boston Scientific. Dr. Hattori reports that the Department of Research and Therapeutics for Movement Disorders, Juntendo University Graduate School of Medicine, is an endowment department supported with an unrestricted grant from Medtronic and Boston Scientific outside the submitted work. Table S1. Characteristics of participants with and without psychosis after DBS. Table S2. Cases with psychosis after DBS. Table S3. Characteristics of participants with and without delirium after DBS. Figure S1. A: Age. This is a box and whisker chart. Patients with psychosis after DBS were significantly younger than patients with no psychosis (t[141] = 1.990, P = 0.0485). The upper and lower limits of each box indicate the third and first quartiles. The horizontal line in the box indicates the median. The cross indicates the mean. The upper whisker indicates the maximum, and the lower whisker indicates the minimum. B: MDS-UPDRS III. This is a box and whisker chart. The MDS-UPDRS III score in the medication-off period before DBS was significantly higher in patients with postoperative psychosis than in patients with no psychosis (t[141] = −3.268, P = 0.00136). C: Age vs. UPDRS-III. The x axis indicates age, and the y axis indicates the MDS-UPDRS III score in the medication-off period. Black circles show patients with postoperative psychosis, and white circles show patients with no psychosis. We found no significant relationship between age and the MDS-UPDRS III score. D: LEDD. This bar graph shows the change over time in the levodopa equivalent daily dose (LEDD). LEDD was significantly reduced from baseline at 14 and 21 days after DBS (F[2,426] = 114.28, P = 1.856 × 10−40; post-hoc P[baseline-14days] = 3.380 × 10−26, P[baseline-21days] = 1.559 × 10−37 and P[14days-21days] = 0.0148). The LEDD at each time point was not significantly different between psychosis and no psychosis. Error bars show the standard error. E: Proportion of DA. This bar graph shows the change over time in the dopamine agonist (DA) ratio in total LEDD. The y axis on the left indicates [(LEDD of DA)/(total LEDD)]. The x axis indicates days after DBS. The proportion of DA in the psychosis group was significantly higher than that in the no psychosis group at 14 days after DBS (t[141] = −2.082, P = 0.0391). However, we found no significant difference before DBS (Table S1). Figure S2. IMP-SPECT. This bar graph shows regional cerebral blood flow as assessed with 123I-IMP-SPECT. The left graph indicates the left hemisphere, and the right graph indicates the right hemisphere. We divided the brain into 31 areas. The black bar represents “no psychosis”, and the gray bar represents “psychosis” after DBS. The y axis on the left indicates the relative blood flow in each area. We found no significant different between psychosis and no psychosis. Error bars show the standard error. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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