Amelioration of Parkinsonian tremor evoked by DBS: which role play cerebello-(sub)thalamic fiber tracts?

BACKGROUND: Current pathophysiological models of Parkinson's disease (PD) assume a malfunctioning network being adjusted by the DBS signal. As various authors showed a main involvement of the cerebellum within this network, cerebello-cerebral fiber tracts are gaining special interest regarding the mediation of DBS effects. OBJECTIVES: The crossing and non-decussating fibers of the dentato-rubro-thalamic tract (c-DRTT/nd-DRTT) and the subthalamo-ponto-cerebellar tract (SPCT) are thought to build up an integrated network enabling a bidimensional communication between the cerebellum and the basal ganglia. The aim of this study was to investigate the influence of these tracts on clinical control of Parkinsonian tremor evoked by DBS. METHODS: We analyzed 120 electrode contacts from a cohort of 14 patients with tremor-dominant or equivalence-type PD having received bilateral STN-DBS. Probabilistic tractography was performed to depict the c-DRTT, nd-DRTT, and SPCT. Distance maps were calculated for the tracts and correlated to clinical tremor control for each electrode pole. RESULTS: A significant difference between "effective" and "less-effective" contacts was only found for the c-DRTT (p = 0.039), but not for the SPCT, nor the nd-DRTT. In logistic and linear regressions, significant results were also found for the c-DRTT only (pmodel logistic = 0.035, ptract logistic = 0,044; plinear = 0.027). CONCLUSIONS: We found a significant correlation between the distance of the DBS electrode pole to the c-DRTT and the clinical efficacy regarding tremor reduction. The c-DRTT might therefore play a major role in the mechanisms of alleviation of Parkinsonian tremor and could eventually serve as a possible DBS target for tremor-dominant PD in future.

Factors influencing the reliability of intraoperative testing in deep brain stimulation for Parkinson's disease.

BACKGROUND: Several meta-analyses comparing the outcome of awake versus asleep deep brain stimulation procedures could not reveal significant differences concerning the postoperative improvement of motor symptoms. Only rarely information on the procedural details is provided for awake operations and how often somnolence and disorientation occurred, which might hamper the reliability of intraoperative clinical testing. The aim of our study was to investigate possible influencing factors on the occurrence of somnolence and disorientation in awake DBS procedures. METHODS: We retrospectively analyzed 122 patients with Parkinson's disease having received implantation of a DBS system at our centre. Correlation analyses were performed for the duration of disease prior to surgery, number of microelectrode trajectories, AC-PC-coordinates of the planned target, UPDRS-scores, intraoperative application of sedative drugs, duration of the surgical procedure, perioperative application of apomorphine, and the preoperative L-DOPA equivalence dosage with the occurrence of intraoperative somnolence and disorientation. RESULTS: Patients with intraoperative somnolence were significantly older (p=0.039). Increased duration of the DBS procedure (p=0.020), delayed start of the surgery (p=0.049), higher number of MER trajectories (p=0.041), and the patients' % UPDRS improvement (p=0.046) also correlated with the incidence of intraoperative somnolence. We identified the main contributing factor to intraoperative somnolence as the use of sedative drugs applied during skin incision and burr hole trepanation (p=0.019). Perioperatively applied apomorphine could reduce the occurrence of somnolent phases during the operation (p=0.026). CONCLUSION: Several influencing factors were found to seemingly increase the risk of intraoperative somnolence and disorientation, while the use of sedative drugs seems to be the main contributing factor. We argue that awake DBS procedures should omit the use of sedatives for best clinical outcome. When reporting on awake DBS surgery these factors should be considered and adjusted for, to permit reliable interpretation and comparison of DBS study results.

A multicenter, open-label, controlled trial on acceptance, convenience, and complications of rechargeable internal pulse generators for deep brain stimulation: the Multi Recharge Trial.

OBJECTIVE: Rechargeable neurostimulators for deep brain stimulation have been available since 2008, promising longer battery life and fewer replacement surgeries compared to non-rechargeable systems. Long-term data on how recharging affects movement disorder patients are sparse. This is the first multicenter, patient-focused, industry-independent study on rechargeable neurostimulators. METHODS: Four neurosurgical centers sent a questionnaire to all adult movement disorder patients with a rechargeable neurostimulator implanted at the time of the trial. The primary endpoint was the convenience of the recharging process rated on an ordinal scale from "very hard" (1) to "very easy" (5). Secondary endpoints were charge burden (time spent per week on recharging), user confidence, and complication rates. Endpoints were compared for several subgroups. RESULTS: Datasets of 195 movement disorder patients (66.1% of sent questionnaires) with Parkinson's disease (PD), tremor, or dystonia were returned and included in the analysis. Patients had a mean age of 61.3 years and the device was implanted for a mean of 40.3 months. The overall convenience of recharging was rated as "easy" (4). The mean charge burden was 122 min/wk and showed a positive correlation with duration of therapy; 93.8% of users felt confident recharging the device. The rate of surgical revisions was 4.1%, and the infection rate was 2.1%. Failed recharges occurred in 8.7% of patients, and 3.6% of patients experienced an interruption of therapy because of a failed recharge. Convenience ratings by PD patients were significantly worse than ratings by dystonia patients. Caregivers recharged the device for the patient in 12.3% of cases. Patients who switched from a non-rechargeable to a rechargeable neurostimulator found recharging to be significantly less convenient at a higher charge burden than did patients whose primary implant was rechargeable. Age did not have a significant impact on any endpoint. CONCLUSIONS: Overall, patients with movement disorders rated recharging as easy, with low complication rates and acceptable charge burden.

Validation of diffusion tensor imaging tractography to visualize the dentatorubrothalamic tract for surgical planning.

OBJECTIVE The dentatorubrothalamic tract (DRTT) has been suggested as the anatomical substrate for deep brain stimulation (DBS)-induced tremor alleviation. So far, little is known about how accurately and reliably tracking results correspond to the anatomical DRTT. The objective of this study was to systematically investigate and validate the results of different tractography approaches for surgical planning. METHODS The authors retrospectively analyzed 4 methodological approaches for diffusion tensor imaging (DTI)-based fiber tracking using different regions of interest in 6 patients with essential tremor. Tracking results were analyzed and validated with reference to MRI-based anatomical landmarks, were projected onto the stereotactic atlas of Morel at 3 predetermined levels (vertical levels -3.6, -1.8, and 0 mm below the anterior commissure-posterior commissure line), and were correlated to clinical outcome. RESULTS The 4 different methodologies for tracking the DRTT led to divergent results with respect to the MRI-based anatomical landmarks and when projected onto the stereotactic atlas of Morel. There was a statistically significant difference in the lateral and anteroposterior coordinates at the 3 vertical levels (p < 0.001, 2-way ANOVA). Different fractional anisotropy values ranging from 0.1 to 0.46 were required for anatomically plausible tracking results and led to varying degrees of success. Tracking results were not correlated to postoperative tremor reduction. CONCLUSIONS Different tracking methods can yield results with good anatomical approximation. The authors recommend using 3 regions of interest including the dentate nucleus of the cerebellum, the posterior subthalamic area, and the precentral gyrus to visualize the DRTT. Tracking results must be cautiously evaluated for anatomical plausibility and accuracy in each patient.

Educational attainment and motor burden in advanced Parkinson's disease - The emerging role of education in motor reserve.

OBJECTIVE: To explore the relationship of motor burden and educational attainment in patients with advanced stage PD. MATERIALS AND METHODS: We included 102 consecutive patients who underwent a complete evaluation for DBS surgery, including detailed neuropsychological testing and UPDRSIII in a standardized Levodopa challenge. Years of education (YoE) were calculated as the highest grade attained in secondary school plus years for post-secondary training. RESULTS: The OFF medication UPDRS-III score was associated with YoE (p=0.006; t=-2.82) and age (p=0.007; t=-2.75) in our multivariable linear regression model even while including disease duration (p=0.8; t=0.21), presence of mild cognitive impairment (MCI) (p=0.9; t=0.16) or current IQ (p=0.2; t=1.25) as additional covariables. In a subgroup of 60 patients two years after DBS, the ON/ON UPDRS score was associated with YoE (p=0.01; t=-2.42) and diagnosis of PD dementia (p=0.05, t=1.95), while age (p=0.08, t=1.75), disease duration (p=0.6t=0.48) and LEDD (p=0.3; t=1.05) showed no significant association to ON/ON UPDRS score. CONCLUSIONS: We found an inverse correlation between years of education and lower (better) UPDRS -III motor score after adjusting for important covariables. Education may lead to an increased ability to compensate disturbances in basal ganglia circuits affecting not only for cognitive, but also for motor aspects of PD. Thus, educational attainment may play an important role in the concept of motor reserve.

Underutilization of deep brain stimulation for Parkinson's disease? A survey on possible clinical reasons.

BACKGROUND: Only 10% of the up to 15% of patients with advanced Parkinson's disease (PD) eligible for deep brain stimulation (DBS) are referred to specialized centers. This survey evaluated the reasons for the reluctance of patients and referring physicians regarding DBS. METHODS: Two different questionnaires containing multiple choice and open verbalized questions were developed, one for neurologists and one for patients with PD. The first questionnaire was sent to 87 neurologists in private practice in the catchment area of the authors' medical center, the second to patient support groups in the same region with the help of the German Parkinson Association. RESULTS: Of the addressed neurologists, 56.3% completed the questionnaire; 61.2% of them estimated the risk of intracerebral hemorrhage as the most severe complication at 4.3% on average; 30.6% were concerned about patients developing mood changes or depression after DBS. Only 16.3% felt unable to care for patients after DBS; 61.2% already had personal experience with patients after DBS and reported good clinical outcome in 90.0% of patients. Although 87.8% claimed to know the specific criteria for DBS, only 40.8% could actively describe them. Only 14.0% could state each of the three main criteria. Of the 46 patients, 88.1% completing the questionnaire had obtained information on DBS from regional patient organizations and 54.8% also from a physician; 44.7% assumed the risk of severe complications to be ≥5.0%. Not being satisfied with their medical treatment was reported by 22.2%, of whom more than 70% considered DBS a further treatment option. CONCLUSIONS: The latter numbers indicate that treating neurologists tend to overestimate the reluctance of their patients to undergo DBS. Therefore, education of patients and neurologists should be improved and give more realistic figures on the actual outcomes and frequencies of possible complications.

Predictors of facet joint syndrome after lumbar disc surgery.

Postoperative facet joint syndrome (pFJS) requiring intervention is a common problem following lumbar disc surgery (LDS). The aim of this retrospective study was to identify possible predictors, surgical aspects or individual characteristics that may contribute to the development of pFJS and may allow prevention of this frequent postoperative problem. We included 509 patients who underwent open, microsurgical discectomy in our neurosurgical department between 2006 and 2009 and who presented to our outpatient clinic for follow-up. We recorded gender, age, preoperative and postoperative clinical and neurological status, surgical technique, duration of the surgical procedure, disc herniation relapse, rehabilitation treatment and development of pFJS. Forty-three patients (8.4%) developed clinically evident pFJS, confirmed by a successful facet joint injection. Patients with pFJS were significantly older than those without pFJS (55.7 years compared with 50.9 years; p=0.03) and had more frequent recurrent disc herniation (p=0.001). Furthermore, the duration of the surgical procedure (p=0.01), intraoperative and postoperative complications (for example, postoperative bleeding, dural injury; p=0.001) and general comorbidity (p=0.001) were associated with pFJS. In addition, an extended discectomy compared with sequesterotomy (p=0.049) and rehabilitation treatment compared with no rehabilitation (p=0.019) were correlated to pFJS in the multivariate analysis. Thus, we were able to identify factors associated with the development of pFJS following LDS: advanced age, long operative time, intraoperative complications, history of recurrent disc prolapse, discectomy and lack of rehabilitation. Our results characterize a profile for patients at high risk for the development of clinically evident pFJS.

TGF-ß2 signaling in high-grade gliomas.

High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-ß), in particular the TGF-ß2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-ß2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-ß2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-ß2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-ß2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.

Doppler ultrasound measurement of blood flow volume in the extracranial internal carotid artery for evaluation of brain perfusion after aneurysmal subarachnoid hemorrhage.

Monitoring of cerebral blood flow (CBF) is an essential part in the early diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). Several methods have been established to monitor cerebral perfusion in these patients. During last few years, a new sonographic approach has been introduced, the so called 'angle independent ultrasound system' for monitoring volume flow in the internal carotid artery (ICA). The angle independent Doppler ultrasound system Quantix ND (Cardiosonix Ltd, Israel) determines the diameter of the ICA as well as the velocity of blood flow in the extracranial part of this vessel. Thus, a determination of the global CBF in the anterior circulation can be achieved. Aim of our study was to compare the Quantix ND system and the commonly used transcranial Doppler sonography (TCD) in patients suffering from aneurysmal SAH. We included 11 patients (eight female and three male; Hunt and Hess I-V) and performed post-operatively/post-interventionally daily measurement of blood flow volume in the ICA, and determined the blood flow velocity in middle and anterior cerebral artery (MCA and ACA) with TCD. Six patients post-operatively/post-interventionally developed cerebral vasospasm, resulting in ischemia and territorial infarction. Three patients were chosen as case studies. In contrast to the TCD, we found a strong significant correlation of blood flow volume with Quantix ND in the ICA and the occurrence of cerebral infarction (p<0.001). These preliminary data justify further investigation of this angle independent Doppler ultrasound device. We postulate that this new tool might be effective for monitoring the CBF in the critical post-operative/post-interventional interval following aneurysmal SAH.

Effects of spinal cord stimulation on cortical excitability in patients with chronic neuropathic pain: a pilot study.

BACKGROUND: Despite a broad clinical use, the mechanism of action of SCS is poorly understood. Current information suggests that the effects of SCS are mediated by a complex set of interactions at several levels of the nervous system including spinal and supraspinal mechanisms. AIMS: The study was undertaken to investigate the influence of SCS on distinct parameters of cortical excitability using single- and paired-pulse transcranial magnetic stimulation (TMS). METHODS: Five patients with chronic neuropathic pain were examined with the SCS stimulator on and off by means of TMS. Pain was assessed using a visual-analogue scale. Electrophysiological and pain parameters of patients during this procedure were compared by means of a linear mixed effect model. RESULTS: SCS induced a significant modulation of cortical excitability, especially by influencing the parameter "intracortical facilitation" (t=-2.657; df=8; p=0.029). A significant relationship between this parameter and "perceived pain" could be obtained (t=-4.798; df=8; p=0.002). CONCLUSIONS: These results suggest that SCS is able to influence neurobiological processes at the supraspinal level and that clinical effects of SCS may be at least in part of cortical origin.