Head movement dynamics in dystonia: a multi-centre retrospective study using visual perceptive deep learning.

Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.

Long-Term Medication Profiles in Parkinson's Disease under Subthalamic Deep Brain Stimulation: A Controlled Study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking. OBJECTIVE: To compare longitudinal trajectories of antiparkinsonian medication in STN-DBS treated patients to non-surgically treated control patients. METHODS: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex-distribution, and comorbidities. RESULTS: In 74 DBS patients levodopa-equivalent daily dose (LEDD) were reduced by 33.9-56.0% in relation to the preoperative baseline over the 14-year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug-classes was observed for dopamine agonists. CONCLUSION: In PD patients, chronic STN-DBS was associated with a lower LEDD compared with control patients over 14 years.

Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Has Deep Brain Stimulation Changed the Very Long-Term Outcome of Parkinson's Disease? A Controlled Longitudinal Study.

BACKGROUND: The long-term impact of deep brain stimulation (DBS) on Parkinson's disease (PD) is difficult to assess and has not yet been rigorously evaluated in comparison to its natural history. OBJECTIVE: Comparison of key disability milestones (recurrent falls, psychosis, dementia, and institutionalization) and death in patients with PD with versus without DBS. METHODS: We collected retrospective information from clinical notes of patients with PD at our center that were implanted with subthalamic DBS >8 years ago (1999-2010) and a control group of PD patients without DBS similar in age at onset, age at baseline, sex distribution, and number of comorbidities at baseline (extracted from a registry study performed in 2004). Cox regression models were used to calculate hazard ratios, adjusted for potential baseline confounding variables (age, sex, disease duration, disease severity, and number of comorbidities). RESULTS: A total of 74 DBS-treated and 61 control patients with PD were included. For a median observational period of 14 years, patients treated with DBS were at lower risk of experiencing recurrent falls (hazard ratio = 0.57; 95% confidence interval, 0.37-0.90; P = 0.015) and psychosis (hazard ratio = 0.26; 95% confidence interval, 0.12-0.59; P = 0.001) compared with control patients. There was no significant difference in risk for dementia, institutionalization, or death. Disease progression as assessed by Hoehn and Yahr scores was not slower in DBS-treated patients. CONCLUSIONS: Treatment with chronic subthalamic DBS was associated with lower risk for recurrent falls and psychotic symptoms, effects that may be mediated through improved motor symptom control and reduction in dopaminergic therapies, respectively. There was no evidence for DBS effects on underlying disease progression.

Evaluation of the radiosurgical treatment of cerebral arteriovenous malformations: a retrospective single-center analysis of three decades.

BACKGROUND: Gamma Knife radiosurgery (GKRS) in the treatment of arteriovenous malformations (AVMs) is still controversially discussed. OBJECTIVE: To present long-term follow-up data on patients after Gamma Knife radiosurgery for cerebral AVMs. METHODS: Overall, 516 patients received radiosurgery for cerebral AVMs between 1992 and 2018 at our department, of whom 265 received radiosurgery alone and 207 were treated with a combined endovascular-radiosurgical approach. Moreover, 45 patients were treated with a volume-staged approach. Two eras were analyzed, the pre-modern era between 1992 and 2002 and the modern era thereafter. RESULTS: In GKRS-only treated patients, median time to nidus occlusion was 3.8 years. Spetzler-Ponce (SP) class was a significant predictor for time to obliteration in the whole sample. Median time to obliteration for the combined treatment group was 6.5 years. Patients in the pre-modern era had a significantly higher obliteration rate than those treated in the modern era. Overall, the calculated yearly hemorrhage risk in the observation period after first GKRS was 1.3%. Permanent post-radiosurgical complications occurred in 4.9% of cases but did not differ between the treatment groups or treatment eras. The obliteration rate was significantly lower and the hemorrhage rate was higher in volume-staged treated patients than in conventionally treated patients. CONCLUSION: GKRS is an effective treatment option for SP class A and B cerebral AVMs. After combined endovascular-radiosurgical treatment, the outcome of selected SP class C AVMs aligns with that of SP class B lesions. Both the combined therapy and radiosurgery alone constitute sound methods for treatment of cerebral AVMs.

Somatosensory functional MRI tractography for individualized targeting of deep brain stimulation in patients with chronic pain after brachial plexus injury.

BACKGROUND: The optimal targets for deep brain stimulation (DBS) in patients with refractory chronic pain are not clearly defined. We applied sensory functional MRI (fMRI)- and diffusion tensor imaging (DTI)-based DBS in chronic pain patients into 3 different targets to ascertain the most beneficial individual stimulation site. METHODS: Three patients with incapacitating chronic pain underwent DBS into 3 targets (periventricular gray (PVG), ventroposterolateral thalamus (VPL), and posterior limb of the internal capsule according to fMRI and DTI (PLIC). The electrodes were externalized and double-blinded tested for several days. Finally, the two electrodes with the best pain reduction were kept for permanent stimulation. The patients were then followed up for 12 months. Outcome measures comprised the numerical rating scale (NRS), short-form McGill's score (SF-MPQ), and health-related quality of life (SF-36). RESULTS: Continuous pain (mean NRS 6.6) was reduced to NRS 3.6 after 12 months. Only with stimulation of the PLIC pain attacks, that occurred at least 3 times a week (mean NRS 9.6) resolved in 2 patients and improved in one patient concerning both intensity (NRS 5) and frequency (twice a month). The mean SF-MPQ decreased from 92.7 to 50. The health-related quality of life improved considerably. CONCLUSION: fMRI- and DTI-based DBS to the PLIC was the only target with a significant effect on pain attacks and seems to be the most promising target in chronic pain patients after brachial plexus injury. The combination with PVG or VPL can further improve patients' outcome especially in terms of reducing the continuous pain.

Probabilistic mapping of the antidystonic effect of pallidal neurostimulation: a multicentre imaging study.

Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent 'normative brain' analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (<25% benefit). We defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated (VTA) in normative atlas space and ranking voxel-wise for outcome distribution. We found a significant relation between motor outcome and the stimulation volume, but not the electrode location per se. The highest probability of stimulation induced motor benefit was found in a small volume covering the ventroposterior globus pallidus internus and adjacent subpallidal white matter. We then used the aggregated VTA-based outcome maps to rate patient individual VTAs and trained a linear regression model to predict individual outcomes. The prediction model showed robustness between the predicted and observed clinical improvement, with an r2 of 0.294 (P < 0.0001). The predictions deviated on average by 16.9 ± 11.6 % from observed dystonia improvements. For example, if a patient improved by 65%, the model would predict an improvement between 49% and 81%. Results were validated in an independent cohort of 10 dystonia patients, where prediction and observed benefit had a correlation of r2 = 0.52 (P = 0.02) and a mean prediction error of 10.3% (±8.9). These results emphasize the potential of probabilistic outcome brain mapping in refining the optimal therapeutic volume for pallidal neurostimulation and advancing computer-assisted planning and programming of deep brain stimulation.

Evaluation of a programming algorithm for deep brain stimulation in dystonia used in a double-blind, sham-controlled multicenter study.

BACKGROUND: Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. METHODS: A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. RESULTS: The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (n = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (n = 63) and 53 ± 31% at 5 years (n = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (n = 9) correlated significantly with improvement after 3 years, but not 5 years. CONCLUSIONS: Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT00142259.

Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study.

OBJECTIVE The authors present long-term follow-up data on patients treated with Gamma Knife radiosurgery (GKRS) for acoustic neuroma. METHODS Six hundred eighteen patients were radiosurgically treated for acoustic neuroma between 1992 and 2016 at the Department of Neurosurgery, Medical University Vienna. Patients with neurofibromatosis and patients treated too recently to attain 1 year of follow-up were excluded from this retrospective study. Thus, data on 557 patients with spontaneous acoustic neuroma of any Koos grade are presented, as are long-term follow-up data on 426 patients with a minimum follow-up of 2 years. Patients were assessed according to the Gardner-Robertson (GR) hearing scale and the House-Brackmann facial nerve function scale, both prior to GKRS and at the times of follow-up. RESULTS Four hundred fifty-two patients (81%) were treated with radiosurgery alone and 105 patients (19%) with combined microsurgery-radiosurgery. While the combined treatment was especially favored before 2002, the percentage of cases treated with radiosurgery alone has significantly increased since then. The overall complication rate after GKRS was low and has declined significantly in the last decade. The risk of developing hydrocephalus after GKRS increased with tumor size. One case (0.2%) of malignant transformation after GKRS was diagnosed. Radiological tumor control rates of 92%, 91%, and 91% at 5, 10, and 15 years after GKRS, regardless of the Koos grade or pretreatment, were observed. The overall tumor control rate without the need for additional treatment was even higher at 98%. At the last follow-up, functional hearing was preserved in 55% of patients who had been classified with GR hearing class I or II prior to GKRS. Hearing preservation rates of 53%, 34%, and 34% at 5, 10, and 15 years after GKRS were observed. The multivariate regression model revealed that the GR hearing class prior to GKRS and the median dose to the cochlea were independent predictors of the GR class at follow-up. CONCLUSIONS In small to medium-sized spontaneous acoustic neuromas, radiosurgery should be recognized as the primary treatment at an early stage. Although minimizing the cochlear dose seems beneficial for hearing preservation, the authors, like others before, do not recommend undertreating intracanalicular tumors in favor of low cochlear doses. For larger acoustic neuromas, radiosurgery remains a reliable management option with tumor control rates similar to those for smaller acoustic neuromas; however, careful patient selection and counseling are recommended given the higher risk of side effects. Microsurgery must be considered in acoustic neuromas with significant brainstem compression or hydrocephalus.

Optical Neuronavigation without Rigid Head Fixation During Awake Surgery.

OBJECTIVE: Optical neuronavigation without rigid pin fixation of the head may lead to inaccurate results because of the patient's movements during awake surgery. In this study, we report our results using a skull-mounted reference array for optical tracking in patients undergoing awake craniotomy for eloquent gliomas. METHODS: Between March 2013 and December 2014, 18 consecutive patients (10 men, 8 women) with frontotemporal (n = 16) or frontoparietal (perirolandic; n = 2) lesions underwent awake craniotomy without rigid pin fixation. All patients had a skull-mounted reference array for optical tracking placed on the forehead. Accuracy of navigation was determined with pointer tip deviation measurements on superficial and bony anatomic structures. Good accuracy was defined as a tip deviation <2 mm. RESULTS: Gross total resection (>98%) was achieved in 7 patients (38%); >90% of tumor was resected in 8 patients (44%). In 3 patients, only subtotal resection or biopsy was performed secondary to stimulation results. In all patients, good accuracy of the optical neuronavigation system could be demonstrated without intraoperative peculiarities or complications. The reference array had to be repositioned because of loosening in 1 patient. Neuronavigation could be reliably applied to support stimulation-based resection. CONCLUSIONS: A skull-mounted reference array is a simple and safe method for optical neuronavigation tracking without rigid pin fixation of the patient's head.

Long-term follow-up of motor cortex stimulation for neuropathic pain in 23 patients.

BACKGROUND: Motor cortex stimulation (MCS) is being offered to patients suffering from neuropathic pain. Outcome prediction, programming and especially sustaining a long-term treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months. OBJECTIVES: To investigate the time course of the treatment effect in MCS for neuropathic pain. METHODS: Twenty-three closely followed patients treated with MCS were retrospectively analyzed. Reduction in pain measured on a visual analogue scale (VAS) was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. RESULTS: The mean VAS under best medical treatment was 7.8 (SD 1.2, range 5-9) with escalation to 9.3 (SD 0.9, range 6-10) when the patients' medications were missed or delayed. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The best treatment results were seen at the 3-month follow-up (mean VAS 4.8, SD 1.9, -37.2% compared to baseline). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Six patients had their devices explanted during the follow-up period due to loss of treatment effect. CONCLUSIONS: In this study, MCS failed to provide long-term pain control for neuropathic pain. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. Means must be developed to overcome the problems in this promising technique.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial.

BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 µs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.

Fronto-cerebellar fiber tractography in pediatric patients following posterior fossa tumor surgery.

OBJECTIVE: Fronto-cerebellar association fibers (FCF) are involved in neurocognitive regulatory circuitry. This may also be relevant for cerebellar mutism syndrome (CMS) as a complication following posterior fossa tumor removal in children. In the present study, we investigated FCF by diffusion tensor imaging in affected children and controls. METHODS: Diffusion-weighted MR imaging at 3 T (GE) allowed tractography of FCF using a fiber tracking algorithm software (Brainlab 2.6) in 29 patients after posterior fossa tumor removal and in 10 healthy peers. Fiber tract volumes were assessed and fiber signals were evaluated in a semiquantitative manner along the anatomical course. RESULTS: Volumes of FCF revealed significant diminished values in pediatric patients with symptoms of CMS (19.3 ± 11.7 cm(3)) when compared with patients without symptoms of CMS (26.9 ± 11.9 cm(3)) and with healthy peers (36.5 ± 13.82 cm(3)). In medulloblastoma patients, the volume of FCF was also significantly reduced in patients with symptoms of CMS despite having the same antitumor therapy. In semiquantitative analysis of the fiber tract signals, differences were observed in the superior cerebellar peduncles and midline cerebellar structures in patients with symptoms of CMS. CONCLUSION: Using DTI, which allows the visualization of fronto-cerebellar fiber tracts, lower FCF tract volumes and diminished fiber signal intensities at the level of the superior cerebellar peduncles and in midline cerebellar structures were identified in patients with postoperative symptoms of CMS. Our study refers to the role of a neural circuitry between frontal lobes and the cerebellum being involved in neurocognitive impairment after posterior fossa tumor treatment in children.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial.

BACKGROUND: Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. METHODS: In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). FINDINGS: An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. FUNDING: Medtronic.

Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial.

BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. METHODS: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687. FINDINGS: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. INTERPRETATION: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. FUNDING: Bayer HealthCare AG.

Cranial nerve monitoring during subpial dissection in temporomesial surgery.

OBJECTIVE: Cranial nerves (CNs) crossing between the brainstem and skull base at the level of the tentorial hiatus may be at risk in temporomesial surgery involving subpial dissection and/or tumorous growth leading to distorted anatomy. We aimed to identify the surgical steps most likely to result in CN damage in this type of surgery. METHODS: Electromyographic responses obtained with standard neuromonitoring techniques and a continuous free-running EMG were graded as either contact activity or pathological spontaneous activity (PSA) during subpial resection of temporomesial structures in 16 selective amygdalohippocampectomy cases. Integrity of peripheral motor axons was tested by transpial/transarachnoidal electrical stimulation while recording compound muscle action potentials from distal muscle(s). RESULTS: Continuous EMG showed pathological activity in five (31.2%) patients. Nine events with PSA (slight activity, n = 8; strong temporary activity, n = 1) were recorded. The oculomotor nerve was involved three times, the trochlear nerve twice, the facial nerve once, and all monitored nerves on three occasions. Surgical maneuvers associated with PSA were the resection of deep parts of the hippocampus and parahippocampal gyrus (CN IV, twice; CN III, once), lining with or removing cotton patties from the resection cavity (III, twice; all channels, once) and indirect exertion of tension on the intact pia/arachnoid of the uncal region while mobilizing the hippocampus and parahippocampal gyrus en bloc (all channels, once; III, once). CMAPs were observed at 0.3 mA in two patients and at 0.6 mA in one patient, and without registering the exact amount of intensity in three patients. CONCLUSION: The most dangerous steps leading to cranial nerve damage during mesial temporal lobe surgery are the final stages of the intervention while the resection is being completed in the deep posterior part and the resection cavity is being lined with patties. Distant traction may act on nerves crossing the tentorial hiatus via the intact arachnoid.

Frame-based vs frameless placement of intrahippocampal depth electrodes in patients with refractory epilepsy: a comparative in vivo (application) study.

BACKGROUND: Despite progress in imaging technologies, documentation of unifocal electrical excitability is pivotal in patient selection for epilepsy surgery. OBJECTIVE: To compare the application accuracy of the Vogele-Bale-Hohner system (VBH), a maxillary fixation system with an external fiducial frame permitting frameless stereotactic guidance, with that of conventional frame-based stereotaxy for placement of intrahippocampal depth electrodes (DEs) in patients with refractory epilepsy. METHODS: Retrospective study. Comparison of two patient cohorts with DEs implanted along the occipitotemporal axis (group A, VBH; group B, frame-based stereotaxy). In vivo accuracy (lateral target localization error [TLE]), determined postoperatively by measuring the normal distance between virtual target and real electrode position at the tip and at 4cm from the tip, number of electrode contacts within the target structure, and diagnostic quality of electroencephalogram recordings were compared. RESULTS: Seventeen DEs (A, 6 electrodes, 60 contacts; B, 11 electrodes, 90 contacts) were placed. electroencephalogram recordings via DEs supported further treatment decisions in all patients. TLE was 2.433 ± 0.977 mm (SD) (95% confidence interval [CI], 1.715-3.214 mm) (A) and 1.803 ± 0.392 mm (SD) (95% CI,1.511-2.195 mm) (B) (P = .185). Maximal error was 4 mm (A) and 3.2 mm (B). TLE 4 cm from the tip was 2.166 ± 2.188 mm (SD) (95% CI,0.438-3.916 mm) (A) and 1.372 ± 0.548 mm (SD) (95% CI,1.049-1.695 mm) (B) (P = .39). Maximal error 4 cm from the tip was 6.4 mm (A) and 2.14 mm (B). On average, 7 (A) and 5 (B) electrode contacts were placed in the target region. CONCLUSION: The VBH and frame-based systems offer similar in vivo accuracy for intrahippocampal DE placement. With frame-based methods, accuracy is higher but the number of contacts per side is lower. This does not translate to clinically important differences.