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.

Does Temporary Externalization of Electrodes After Deep Brain Stimulation Surgery Result in a Higher Risk of Infection?

OBJECTIVES: Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery. MATERIALS AND METHODS: In this retrospective study, we analyzed a consecutive series of 624 DBS surgeries, including 266 instances with temporary externalization of DBS electrodes for a mean of 6.1 days. Patients were available for follow-up of at least one year, except in 15 instances. In 14 patients with negative test stimulation, electrodes were removed. All kinds of infections related to implantation of the neurostimulation system were accounted for. RESULTS: Overall, infections occurred in 22 of 624 surgeries (3.5%). Without externalization of electrodes, infections were noted after 7 of 358 surgeries (2.0%), whereas with externalization, 15 of 252 infections were found (6.0%). This difference was significant (p = 0.01), but it did not reach statistical significance when comparing groups within different diagnoses. The rate of infection with externalized electrodes was highest in psychiatric disorders (9.1%), followed by Parkinson's disease (7.3%), pain (5.7%), and dystonia (5.5%). The duration of the externalization of the DBS electrodes was comparable in patients who developed an infection (6.1 ± 3.1 days) with duration in those who did not (6.0 ± 3.5 days). CONCLUSIONS: Although infection rates were relatively low in our study, there was a slightly higher infection rate when DBS electrodes were externalized. On the basis of our results, the indication for electrode externalization should be carefully considered, and patients should be informed about the possibility of a higher infection risk when externalization of DBS electrodes is planned.

Deep brain stimulation in patients on chronic antiplatelet or anticoagulation treatment.

BACKGROUND: In the aging society, many patients with movement disorders, pain syndromes, or psychiatric disorders who are candidates for deep brain stimulation (DBS) surgery suffer also from cardiovascular co-morbidities that require chronic antiplatelet or anticoagulation treatment. Because of a presumed increased risk of intracranial hemorrhage during or after surgery and limited knowledge about perioperative management, chronic antiplatelet or anticoagulation treatment often has been considered a relative contraindication for DBS. Here, we evaluate whether or not there is an increased risk for intracranial hemorrhage or thromboembolic complications in patients on chronic treatment (paused for surgery or bridged with subcutaneous heparin) as compared to those without. METHODS: Out of a series of 465 patients undergoing functional stereotactic neurosurgery, 34 patients were identified who were on chronic treatment before and after receiving DBS. In patients with antiplatelet treatment, medication was stopped in the perioperative period. In patients with vitamin K antagonists or novel oral anticoagulants (NOACs), heparin was used for bridging. All patients had postoperative stereotactic CT scans, and were followed up for 1 year after surgery. RESULTS: In patients on chronic antiplatelet or anticoagulation treatment, intracranial hemorrhage occurred in 2/34 (5.9%) DBS surgeries, whereas the rate of intracranial hemorrhage was 15/431 (3.5%) in those without, which was statistically not significant. Implantable pulse generator pocket hematomas were seen in 2/34 (5.9%) surgeries in patients on chronic treatment and in 4/426 (0.9%) without. There were only 2 instances of thromboembolic complications which both occurred in patients without chronic treatment. There were no hemorrhagic complications during follow-up for 1 year. CONCLUSIONS: DBS surgery in patients on chronic antiplatelet or anticoagulation treatment is feasible. Also, there was no increased risk of hemorrhage in the first year of follow-up after DBS surgery. Appropriate patient selection and standardized perioperative management are necessary to reduce the risk of intracranial hemorrhage and thromboembolic complications.

Long-Term Deep Brain Stimulation in Treatment-Resistant Obsessive-Compulsive Disorder: Outcome and Quality of Life at Four to Eight Years Follow-Up.

BACKGROUND: Obsessive compulsive disorder (OCD) is a severe disabling disease, and around 10% of patients are considered to be treatment-resistant (tr) in spite of guideline-based therapy. Deep brain stimulation (DBS) has been proposed as a promising treatment for patients with trOCD. However, the optimal site for stimulation is still a matter of debate, and clinical long-term follow-up observations including data on quality of life are sparse. We here present six trOCD patients who underwent DBS with electrodes placed in the bed nucleus of the stria terminalis/anterior limb of the internal capsule (BNST/ALIC), followed for four to eight years after lead implantation. MATERIALS AND METHODS: In this prospective observational study, six patients (four men, two women) aged 32-51 years and suffering from severe to extreme trOCD underwent DBS of the BNST/ALIC. Symptom severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and quality of life using the World Health Organization Quality of Life assessment scale (WHO-QoL BREF). Follow-up was obtained at least for four years in all patients. RESULTS: With chronic DBS for four to eight years, four of the six patients had sustained improvement. Two patients remitted and two patients responded (defined as >35% symptom reduction), while the other two patients were considered nonresponders on long-term. Quality of life markedly improved in remitters and responders. We did not observe peri-interventional side effects or adverse effects of chronic stimulation. CONCLUSIONS: Chronic DBS of ALIC provides long-term benefit up to four to eight years in trOCD, although not all patients take profit. Targeting the BNST was not particularly relevant since no patient appeared to benefit from direct stimulation of the BNST. Quality of life improved in DBS responders, documented by improved QoL scores and, even more important, by regaining of autonomy and improving psychosocial functioning.

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.

Microelectrode recording and hemorrhage in functional neurosurgery: a comparative analysis in a consecutive series of 645 procedures.

OBJECTIVE: Functional stereotactic neurosurgery including deep brain stimulation (DBS) and radiofrequency lesioning is well established and widely used for treatment of movement disorders and various other neurological and psychiatric diseases. Although functional stereotactic neurosurgery procedures are considered relatively safe, intracranial hemorrhage resulting in permanent neurological deficits may occur in 1%-3% of patients. Microelectrode recording (MER) has been recognized as a valuable tool for refining the final target in functional stereotactic neurosurgery. Moreover, MER provides insight into the underlying neurophysiological pathomechanisms of movement disorders and other diseases. Nevertheless, there is an ongoing controversy on whether MER increases the risk for hemorrhage. The authors aimed to compare the risk of hemorrhage in functional stereotactic neurosurgical procedures with regard to the use of MER. METHODS: The authors performed a comparative analysis on a consecutive series of 645 functional neurosurgery procedures, including 624 DBS surgeries and 21 radiofrequency lesionings, to evaluate whether the use of MER would increase the risk for hemorrhage. MER was performed in 396 procedures, while no MER was used in 249 cases. The MER technique involved the use of a guiding cannula and a single trajectory when feasible. Postoperative CT scans were obtained within 24 hours after surgery in all patients and screened for the presence of hemorrhage. RESULTS: Twenty-one intracranial hemorrhages were detected on the postoperative CT scans (3.2%). Of the 21 intracranial hemorrhages, 14 were asymptomatic and 7 were symptomatic. Symptoms were transient except in 1 case. There was no statistically significant correlation between hemorrhage and the use of MER at any site (subdural, ventricle, trajectory, target, whether asymptomatic or symptomatic). There were 4 cases of symptomatic hemorrhage in the MER group (1%) and 3 cases in those without MER (1.2%). CONCLUSIONS: Intraoperative MER did not increase the overall risk of hemorrhage in the authors' experience using primarily a single MER trajectory and a guiding cannula.

Neuroimaging-based analysis of DBS outcomes in pediatric dystonia: Insights from the GEPESTIM registry.

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity to a specific distribution pattern within brain networks. Such information is usually collected using group-level analysis, which relies on the availability of normative imaging resources (atlases and connectomes). Analysis of DBS data in children with debilitating neurological disorders such as dystonia would benefit from such resources, especially given the developmental differences in neuroimaging data between adults and children. We assembled pediatric normative neuroimaging resources from open-access datasets in order to comply with age-related anatomical and functional differences in pediatric DBS populations. We illustrated their utility in a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources. METHODS: An average pediatric brain template (the MNI brain template 4.5-18.5 years) was implemented and used to localize the DBS electrodes in 20 patients from the GEPESTIM registry cohort. A pediatric subcortical atlas, analogous to the DISTAL atlas known in DBS research, was also employed to highlight the anatomical structures of interest. A local pallidal sweetspot was modeled, and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcomes. Additionally, a pediatric functional connectome of 100 neurotypical subjects from the Consortium for Reliability and Reproducibility was built to allow network-based analyses and decipher a connectivity fingerprint responsible for the clinical improvements in our cohort. RESULTS: We successfully implemented a pediatric neuroimaging dataset that will be made available for public use as a tool for DBS analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46, permuted p = 0.019). The functional connectivity fingerprint of DBS outcomes was determined to be a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30, permuted p = 0.003). CONCLUSIONS: Local sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcomes in dystonia using pediatric neuroimaging surrogate data. Implementation of this pediatric neuroimaging dataset might help to improve the practice and pave the road towards a personalized DBS-neuroimaging analyses in pediatric patients.

Stereotactic biopsy of a brain lesion caused by hormographiella aspergillata.

Background: Invasive fungal infections are an increasing problem in immunosuppressed patients. In patients with the central nervous system involvement, there is a high case fatality rate. There is a very limited experience with infections caused by Hormographiella aspergillata (HA) in such cases and most often diagnosis is only confirmed postmortem. Case Description: We report the case of a 53-year-old woman with acute myeloid leukemia. After primary therapy with daunorubicin, cytarabine, and gemtuzumab ozogamicin, the patient developed pneumonia and later neurological symptoms caused by multiple gadolinium-enhancing brain lesions in magnetic resonance imaging (MRI). Stereotactic biopsy of a frontal precentral lesion was performed and revealed HA infection. The patient died in the further course secondary to cardiopulmonary problems. Conclusion: Stereotactic biopsy is a safe way to establish the diagnosis of unclear lesions such as HA infection. We recommend to perform stereotactic biopsy early in immunocompromised patients with brain lesions to guide further treatment.

Case report: Pallidal deep brain stimulation for treatment of tardive dystonia/dyskinesia secondary to chronic metoclopramide medication.

Objectives: Tardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal deep brain stimulation (DBS) has become an accepted treatment for TDD secondary to neuroleptic medication, there is much less knowledge about its effects on metoclopramide-induced TDD. Methods: We present the case of a woman with metoclopramide-induced TDD, whose symptoms were initially misjudged as "functional." After 8 years of ineffective medical treatments, she received bilateral implantation of quadripolar electrodes into the posteroventral lateral globus pallidus internus (GPi). Results: GPi DBS led to significant symptom reduction [Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score 24/44 at admission and 7/44 at discharge]. Chronic stimulation led to full recovery from TDD symptoms 9 years after surgery. The BFMDRS motor score decreased to 0.5 (98% improvement). Discussion: Pallidal DBS may result in sustained improvement of TDD secondary to chronic metoclopramide intake in the long term.

Are Transventricular Approaches Associated With Increased Hemorrhage? A Comparative Study in a Series of 624 Deep Brain Stimulation Surgeries.

BACKGROUND: Deep brain stimulation (DBS) surgery has advanced tremendously, for both clinical applications and technology. Although DBS surgery is an overall safe procedure, rare side effects, in particular, hemorrhage, may result in devastating consequences. Although there are certain advantages with transventricular trajectories, it has been reasoned that avoidance of such trajectories would likely reduce hemorrhage. OBJECTIVE: To investigate the possible impact of a transventricular trajectory as compared with a transcerebral approach on the occurrence of symptomatic and asymptomatic hemorrhage after DBS electrode placement. METHODS: Retrospective evaluation of 624 DBS surgeries in 582 patients, who underwent DBS surgery for movement disorders, chronic pain, or psychiatric disorders. A stereotactic guiding cannula was routinely used for DBS electrode insertion. All patients had postoperative computed tomography scans within 24 hours after surgery. RESULTS: Transventricular transgression was identified in 404/624 DBS surgeries. The frequency of hemorrhage was slightly higher in transventricular than in transcerebral DBS surgeries (15/404, 3.7% vs 6/220, 2.7%). While 7/15 patients in the transventricular DBS surgery group had a hemorrhage located in the ventricle, 6 had an intracerebral hemorrhage along the electrode trajectory unrelated to transgression of the ventricle and 2 had a subdural hematoma. Among the 7 patients with a hemorrhage located in the ventricle, only one became symptomatic. Overall, a total of 7/404 patients in the transventricular DBS surgery group had a symptomatic hemorrhage, whereas the hemorrhage remained asymptomatic in all 6/220 patients in the transcerebral DBS surgery group. CONCLUSION: Transventricular approaches in DBS surgery can be performed safely, in general, when special precautions such as using a guiding cannula are routinely applied.

Rechargeable Pacemaker Technology in Deep Brain Stimulation: A Step Forward, But Not for Everyone.

BACKGROUND: Rechargeable implantable pulse generator (IPG) technology has several advantages over non-rechargeable systems and is routinely used now in deep brain stimulation (DBS). Little is known about the occasional need and the circumstances for switching back to non-rechargeable technology. CASES: Out of a cohort of 640 patients, 102 patients received a rechargeable IPG at first implantation or at the time of replacement surgery. Out of these, 3 patients underwent preemptive replacement with non-rechargeable devices for the following reasons: dissatisfaction with handling and recharge frequency (pallidal DBS in advanced Parkinson's disease/dystonia), severe DBS OFF status subsequent to missed recharging (subthalamic DBS in Parkinson's disease) and twiddler's syndrome (nucleus accumbens DBS in alcohol dependency). CONCLUSIONS: Although rechargeable IPG technology has been received well and is used widely, there are unexpected scenarios that require replacement surgery with non-rechargeable IPGs.

Centromedian-Parafascicular and Somatosensory Thalamic Deep Brain Stimulation for Treatment of Chronic Neuropathic Pain: A Contemporary Series of 40 Patients.

Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian-parafascicular (CM-Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM-Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3-180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM-Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.

Detection of bacterial DNA on neurostimulation systems in patients without overt infection.

OBJECTIVE: Hardware-related infection remains a major problem in patients with neurostimulation systems. The role of bacterial colonization and the formation of biofilm on the surface of implanted devices remain unclear. Here, we analysed the incidence of bacterial DNA on the surface of implantable pulse generators (IPGs) using 16S rRNA gene sequencing in a consecutive series of patients who underwent routine IPG replacement without clinical signs of infection. PATIENTS AND METHODS: We included 36 patients who underwent scheduled replacement surgery of 44 IPGs. The removed IPGs were processed and whole genomic DNA was extracted. The detection of bacterial DNA was carried out by Polymerase Chain Reaction (PCR) using universal bacterial primers targeting the 16S rRNA gene. The DNA strands were analysed by single-strand conformation polymorphism (SSCP) analysis. RESULTS: Indications for chronic neurostimulation were Parkinson disease, tremor, dystonia, neuropathic pain and peripheral artery occlusion disease. Mean age of patients at the time of implantation was 48 ±â€¯17.6 years. The mean interval between implantation and replacement of the IPG was 24.8 months. PCR/SSCP detected bacterial DNA of various species in 5/36 patients (13.9%) and in 5/44 pacemakers (11.4%), respectively. There was no evidence of clinical infection or wound healing impairment during follow-up time of 45.6 ±â€¯19.6 months. CONCLUSION: Bacterial DNA can be detected on the surface of IPGs of neurostimulation systems in patients without clinical signs of infection by using PCR techniques. It remains unclear, similar to other permanently implanted devices, which mechanisms and processes promote progression to the point of overt infection.

Reinforcement magnitudes modulate subthalamic beta band activity in patients with Parkinson's disease.

We set out to investigate whether beta oscillations in the human basal ganglia are modulated during reinforcement learning. Based on previous research, we assumed that beta activity might either reflect the magnitudes of individuals' received reinforcements (reinforcement hypothesis), their reinforcement prediction errors (dopamine hypothesis) or their tendencies to repeat versus adapt responses based upon reinforcements (status-quo hypothesis). We tested these hypotheses by recording local field potentials (LFPs) from the subthalamic nuclei of 19 Parkinson's disease patients engaged in a reinforcement-learning paradigm. We then correlated patients' reinforcement magnitudes, reinforcement prediction errors and response repetition tendencies with task-related power changes in their LFP oscillations. During feedback presentation, activity in the frequency range of 14 to 27 Hz (beta spectrum) correlated positively with reinforcement magnitudes. During responding, alpha and low beta activity (6 to 18 Hz) was negatively correlated with previous reinforcement magnitudes. Reinforcement prediction errors and response repetition tendencies did not correlate significantly with LFP oscillations. These results suggest that alpha and beta oscillations during reinforcement learning reflect patients' observed reinforcement magnitudes, rather than their reinforcement prediction errors or their tendencies to repeat versus adapt their responses, arguing both against an involvement of phasic dopamine and against applicability of the status-quo theory.

Reversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia.

Background: DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available. Case Report: A pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved. Discussion: This case study demonstrates that medication-resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS.