Subcortical Atrophy and Motor Outcomes in Pallidal Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Appropriate patient selection is critical for successful deep brain stimulation (DBS) for Parkinson disease (PD). Subcortical atrophy is a possible determinant of postoperative DBS outcomes in patients with idiopathic PD, but it has not been well evaluated for DBS of the globus pallidus interna (GPi). We investigated perioperative subcortical atrophy measures in patients with PD and their relationship to postoperative motor response in bilateral GPi-targeted DBS. METHODS: A retrospective cohort study examined correlations among indices of subcortical volumetry, disease duration, and age with postoperative outcomes at 6 months (Unified Parkinson's Disease Rating Scale Part III motor score quotient, levodopa equivalent daily dosing, and 39-item Parkinson's Disease Questionnaire mobility subscore). Subcortical volumetry was assessed by bicaudate ratio, Evans index, and third ventricular width on perioperative imaging. Linear regression models established correlations between preoperative variables and postoperative outcomes. RESULTS: Data from 34 patients with PD who were treated with GPi-targeted DBS were evaluated. Age was found to exhibit statistically significant positive correlations with all 3 measures of subcortical atrophy (P ≤ 0.002). None of the measures correlated with disease duration. Only Evans index and third ventricular width correlated with preoperative medication response (P < 0.05). Age and all 3 measures of atrophy exhibited statistically significant correlations with Unified Parkinson's Disease Rating Scale Part III motor score quotient (P ≤ 0.01), but not with levodopa equivalent daily dosing or 39-item Parkinson's Disease Questionnaire motor subscores (P > 0.05). CONCLUSIONS: Perioperative age and subcortical atrophy as measured in this study correlated with motor responsiveness at 6 months postoperatively among patients receiving bilateral GPi-targeted DBS stimulation for PD.

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

The Relationship Between Social Anxiety Disorder and Motor Symptoms of Parkinson Disease: A Pilot Study.

BACKGROUND: In patients with Parkinson disease (PD), motor symptoms coexist with several nonmotor neuropsychiatric symptoms. Various anxiety subtypes (generalized anxiety disorder, panic disorder, and social anxiety disorder [SAD]) are more prevalent in patients with PD than in the general population. OBJECTIVE: We estimated the prevalence of SAD in early patients with PD and the relationship between severity of SAD and PD symptoms. METHODS: The Liebowitz Social Anxiety Scale (LSAS) and Unified Parkinson's Disease Rating Scale (UPDRS) III, which assess function impairment, were used to grade symptom severity among 41 patients with early PD. Ratings were compared and analyzed in relation to UPDRS subdivisions. RESULTS: UPDRS III and LSAS scores were not significantly correlated (r = 0.23, P = 0.14), but LSAS and UPDRS I, which evaluate nonanxiety psychiatric symptoms, were significantly correlated (r = 0.44; P = 0.004) and were stronger in the group not treated for PD (r = 0.82) but were in the group treated for PD (r = 0.28), although this difference did not reach statistical significance (P = 0.07 using the Fisher r-to-z transformation). LSAS also correlated with total UPDRS and UPDRS II (P ≤ 0.04). CONCLUSIONS: Results suggest that SAD symptoms in patients with PD correlate with PD symptoms as evaluated by the total UPDRS and UPDRS I and II. In our pilot study, this correlation was higher in levodopa-untreated patients with PD but was not statistically significant. Because the UPDRS III and LSAS were not statistically significantly correlated, a direct motor correlation with SAD symptoms cannot be suggested. Further investigation is needed to clarify the relationship of SAD in patients with PD and potential treatment options.

Nilotinib-Induced Dystonia and Cognitive Deficits in a Neurologically Normal Patient with Chronic Myeloid Leukemia.

Nilotinib is a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia (CML). This agent is also being studied in neurodegenerative disorders including Parkinson disease. Studies have shown that nilotinib may decrease the accumulation of parkin substrates and decrease the loss of dopaminergic cells. The use of nilotinib in neurologic disorders is relatively new, and little information about this use has been published. We report on a patient receiving nilotinib for CML. The patient had no previous neurologic deficits, and developed intermittent dystonic posturing of the left upper extremity and cognitive impairment after she began nilotinib treatment. The mechanisms behind this adverse effect are not clear; however, her symptoms began after nilotinib was introduced, decreased with dose reduction, stopped with its cessation, and re-emerged when the medication was restarted. To our knowledge, this is the first reported patient with neurologic symptoms secondary to nilotinib use.

Clinical outcomes following awake and asleep deep brain stimulation for Parkinson disease.

OBJECTIVE: Recent studies have shown similar clinical outcomes between Parkinson disease (PD) patients treated with deep brain stimulation (DBS) under general anesthesia without microelectrode recording (MER), so-called "asleep" DBS, and historical cohorts undergoing "awake" DBS with MER guidance. However, few studies include internal controls. This study aims to compare clinical outcomes after globus pallidus internus (GPi) and subthalamic nucleus (STN) DBS using awake and asleep techniques at a single institution. METHODS: PD patients undergoing awake or asleep bilateral GPi or STN DBS were prospectively monitored. The primary outcome measure was stimulation-induced change in motor function off medication 6 months postoperatively, measured using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). Secondary outcomes included change in quality of life, measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39), change in levodopa equivalent daily dosage (LEDD), stereotactic accuracy, stimulation parameters, and adverse events. RESULTS: Six-month outcome data were available for 133 patients treated over 45 months (78 GPi [16 awake, 62 asleep] and 55 STN [14 awake, 41 asleep]). UPDRS-III score improvement with stimulation did not differ between awake and asleep groups for GPi (awake, 20.8 points [38.5%]; asleep, 18.8 points [37.5%]; p = 0.45) or STN (awake, 21.6 points [40.3%]; asleep, 26.1 points [48.8%]; p = 0.20) targets. The percentage improvement in PDQ-39 and LEDD was similar for awake and asleep groups for both GPi (p = 0.80 and p = 0.54, respectively) and STN cohorts (p = 0.85 and p = 0.49, respectively). CONCLUSIONS: In PD patients, bilateral GPi and STN DBS using the asleep method resulted in motor, quality-of-life, and medication reduction outcomes that were comparable to those of the awake method.

Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease.

Purpose/Aim of the study: To study finger displacement in patients with Parkinson disease dementia (PDD) and in patients with Alzheimer disease (AD). METHODS: We examined 56 patients with PDD and 35 with AD. Patients were examined during their regular outpatient clinic visit. Finger displacement was measured by observers not actively involved in the study using a creative grid ruler for all PDD and AD patients. Finger displacement was examined by asking patients to point their index fingers toward the grid ruler with the nails facing upward. Patients were asked to maintain the pointing position for 15 s. After 15 s, patients were asked to close their eyes for another 15 s while maintaining the same position. A positive result was downward index finger displacement of ≥5 cm within the 15-second time window with eyes closed. RESULTS: Of the 56 PDD patients, 53 had bilateral finger displacement of >5 cm. In comparison, of the 35 AD patients, only 1 patient had minimal displacement. CONCLUSIONS: Results of the non-invasive finger displacement test may provide insight, on an outpatient basis, of the integrity of subcortical-cortical circuits. Downward finger displacement, especially bilateral downward displacement, may signal the extensive disruption of subcortical-cortical circuits that occurs in PDD patients. ABBREVIATIONS: AChE: acetylcholinesterase; AD: Alzheimer disease; DLB: dementia with Lewy bodies; ET: essential tremor; MDS-UPDRS: Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination; PD: Parkinson disease; PDD: Parkinson disease dementia.

Intraoperative test stimulation versus stereotactic accuracy as a surgical end point: a comparison of essential tremor outcomes after ventral intermediate nucleus deep brain stimulation.

OBJECTIVE Ventral intermediate nucleus deep brain stimulation (DBS) for essential tremor is traditionally performed with intraoperative test stimulation and conscious sedation, without general anesthesia (GA). Recently, the authors reported retrospective data on 17 patients undergoing DBS after induction of GA with standardized anatomical coordinates on T1-weighted MRI sequences used for indirect targeting. Here, they compare prospectively collected data from essential tremor patients undergoing DBS both with GA and without GA (non-GA). METHODS Clinical outcomes were prospectively collected at baseline and 3-month follow-up for patients undergoing DBS surgery performed by a single surgeon. Stereotactic, euclidean, and radial errors of lead placement were calculated. Functional (activities of daily living), quality of life (Quality of Life in Essential Tremor [QUEST] questionnaire), and tremor severity outcomes were compared between groups. RESULTS Fifty-six patients underwent surgery: 16 without GA (24 electrodes) and 40 with GA (66 electrodes). The mean baseline functional scores and QUEST summary indices were not different between groups (p = 0.91 and p = 0.59, respectively). Non-GA and GA groups did not differ significantly regarding mean postoperative percentages of functional improvement (non-GA, 47.9% vs GA, 48.1%; p = 0.96) or QUEST summary indices (non-GA, 79.9% vs GA, 74.8%; p = 0.50). Accuracy was comparable between groups (mean radial error 0.9 ± 0.3 mm for non-GA and 0.9 ± 0.4 mm for GA patients) (p = 0.75). The mean euclidean error was also similar between groups (non-GA, 1.1 ± 0.6 mm vs GA, 1.2 ± 0.5 mm; p = 0.92). No patient had an intraoperative complication, and the number of postoperative complications was not different between groups (non-GA, n = 1 vs GA, n = 10; p = 0.16). CONCLUSIONS DBS performed with the patient under GA to treat essential tremor is as safe and effective as traditional DBS surgery with intraoperative test stimulation while the patient is under conscious sedation without GA.

Parkinson's disease outcomes after intraoperative CT-guided "asleep" deep brain stimulation in the globus pallidus internus.

OBJECTIVE: Recent studies show that deep brain stimulation can be performed safely and accurately without microelectrode recording ortest stimulation but with the patient under general anesthesia. The procedure couples techniques for direct anatomical targeting on MRI with intraoperative imaging to verify stereotactic accuracy. However, few authors have examined the clinical outcomes of Parkinson's disease (PD) patients after this procedure. The purpose of this study was to evaluate PD outcomes following "asleep" deep brain stimulation in the globus pallidus internus (GPi). METHODS: The authors prospectively examined all consecutive patients with advanced PD who underwent bilateral GPi electrode placement while under general anesthesia. Intraoperative CT was used to assess lead placement accuracy. The primary outcome measure was the change in the off-medication Unified Parkinson's Disease Rating Scale motor score 6 months after surgery. Secondary outcomes included effects on the 39-Item Parkinson's Disease Questionnaire (PDQ-39) scores, on-medication motor scores, and levodopa equivalent daily dose. Lead locations, active contact sites, stimulation parameters, and adverse events were documented. RESULTS: Thirty-five patients (24 males, 11 females) had a mean age of 61 years at lead implantation. The mean radial error off plan was 0.8 mm. Mean coordinates for the active contact were 21.4 mm lateral, 4.7 mm anterior, and 0.4 mm superior to the midcommissural point. The mean off-medication motor score improved from 48.4 at baseline to 28.9 (40.3% improvement) at 6 months (p < 0.001). The PDQ-39 scores improved (50.3 vs 42.0; p = 0.03), and the levodopa equivalent daily dose was reduced (1207 vs 1035 mg; p = 0.004). There were no significant adverse events. CONCLUSIONS: Globus pallidus internus leads placed with the patient under general anesthesia by using direct anatomical targeting resulted in significantly improved outcomes as measured by the improvement in the off-medication motor score at 6 months after surgery.

Distinguishing the tremor of Parkinson's disease from essential tremor: finger displacement.

Although, the tremor of Parkinson's disease (PD) usually, but not always, differs from essential tremor (ET), there is no simple bedside test to distinguish PD from ET. We believe we have made such an observation. We studied 50 consecutive tremor-dominant PD patients (mean age: 63.4 years; mean disease duration: 4.9 years) and 35 consecutive ET patients (mean age: 64.1 years; mean disease duration: 12.5 years). Among PD patients, 31 had a bilateral tremor and among ET patients, 29 patients had a bilateral tremor. Patients sat opposite the examiner and pointed both index fingers at the examiner's index fingers. Then they closed their eyes. Within 15 s, one or rarely both of the patient's index fingers moved, was displaced, either upward or laterally. Finger displacement occurred only with bilateral simultaneous pointing with the patient's eyes closed. All the tremor-dominant PD patients exhibited displacement of an index finger. In 46 patients, it occurred on the side of dominant tremor, in 4, it occurred bilaterally. In 31 of 35 ET patients, no displacement occurred. In 4 of 35 ET patients, it occurred unilaterally on the side of dominant tremor. Odds ratio of distinguishing PD from ET: 89.62 at 95% confidence limits (5.31-1513.4), p = 0. 0018. Sensitivity 100% (0.91-1), specificity 89% (0.72-0.96). Finger displacement can distinguish the tremor of PD from ET. The unilateral movement with eyes closed suggests the tremor of PD unlike ET may impact circuits involving the parietal and supplementary motor cortices.

Finger displacement in Parkinson disease: up? down? sideways?

We previously reported that patients with tremor preponderant Parkinson disease (PD) displayed upward or lateral displacement of their more tremulous finger when they pointed both their index fingers at a target and closed their eyes for 15 seconds. In this study, we examined the phenomenon in 104 PD patients: 72 patients without tremor and 32 with minimal tremor to see if the displacement is related to the disease or the tremor. Sixty-eight of the 72 patients without tremor, 94%, exhibited finger displacement suggesting the phenomenon is related to the disease. None of the 104 patients were demented: mini-mental status examination (MMSE) score 29.0 ± 0. 75. Ninety patients displayed upward displacement (56 patients) or lateral or medial displacement (34 patients). MMSE score of the 90 patients: 29.2 ± 0.74 with no score < 28. Eight patients (6 without tremor) displayed downward displacement. MMSE score of the 8 patients: 27.5 ± 0.35 with 5 having MMSE score of 27. Although not significant the results suggest that patients with downward displacement and lower MMSE score may be evolving a dementia. Upward displacement with eyes closed for 15 seconds requires an ability to "remember" the position of the finger in space and to alter tone to overcome gravity. Downward displacement implies an inability to "remember" the position of the finger in space an inability to overcome the effects of gravity. This may be more likely in patients who are evolving a dementia. Two patients, with PD-like symptoms, and specific anatomical abnormalities are also presented as they illustrate the anatomy of finger displacement.

A simple question about falls to distinguish balance and gait difficulties in Parkinson's disease.

Although gait and balance difficulties often occur together in Parkinson's disease (PD) patients, it is believed that they are actually two eparate symptoms. However, there are no simple tests to distinguish them. We have developed the self-administered Barrow Neurological Institute (BNI) question to distinguish between gait and balance issues in PD and it was tested in 102 consecutive PD patients. The responses were compared with those of the walking and balance question (item # 2.12) of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and the MDS-UPDRS motor examination and its subsets such as gait and postural stability (PS). Fifty-five patients reported balance difficulty on the BNI question and 64 reported walking and balance difficulty on the MDS-UPDRS question. Of the patients who reported balance difficulty on the BNI question, 74.5% had a PS score ≥2 and 25.4% fell at least three times per month. Of the patients who reported walking and balance difficulty on the MDS-UPDRS question, only 59.4% had a PS score ≥2 and only 10.9% fell three or more times per month. These statistically significant results suggest that the BNI question is better able to detect balance difficulty and its associated falls in PD and can be a supplement to the MDS-UPDRS or a stand-alone question to evaluate balance difficulty and its associated falls in PD.

Impaired self-awareness of motor deficits in Parkinson's disease: association with motor asymmetry and motor phenotypes.

BACKGROUND: This study investigated impaired self-awareness of motor deficits in nondemented, nondepressed Parkinson's disease (PD) patients during a defined clinical on state. METHODS: Twenty-eight PD patients were examined. Patients' self-ratings and experts' ratings of patients' motor performance were compared. Patient-examiner discrepancies and level of impairment determined severity of impaired self-awareness. Motor exam assessed overall motor functioning, hemibody impairment, and 4 motor phenotypes. Neuropsychological tests were also conducted. RESULTS: Signs of impaired self-awareness were present in 17 patients (60.7%). Higher severity of impaired self-awareness correlated significantly with higher postural-instability and gait-difficulty off scores (r = .575; P = .001), overall motor off scores (r = .569; P = .002), and higher left hemibody off scores (r = .490; P = .008). In multiple linear regression analyses, higher postural-instability and gait-difficulty off scores remained as the only significant predictor of impaired self-awareness severity. CONCLUSIONS: Postural instability and gait difficulties, disease severity, and right hemisphere dysfunction seem to contribute to impaired self-awareness.

Head tremor secondary to MS resolved with rituximab.

We describe the case of a 33-year-old woman who presented with a 2-month history of worsening head tremor. The medical evaluation led to the new diagnosis of MS and the MRI of brain demonstrated prominently active disease. Intravenous rituximab was started according to the HERMES trial, and significant improvement was noted. She has received additional rituximab dosing approximately every 6 months, and at the 2-year follow-up the tremor has not recurred. The resolution of head tremor likely resulted from the complete suppression of MS disease activity, which must have allowed restoration of normal neural circuitry. In agreement with a growing body of evidence that supports early control of MS disease activity to prevent accumulation of fixed disability, this case advocates for aggressive immunological therapy at the onset of tremor in MS patients.