Deep Brain Stimulation-Withdrawal Syndrome in Parkinson's Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency.

BACKGROUND AND OBJECTIVES: Subthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson's disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called "DBS-withdrawal syndrome." In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation. MATERIALS AND METHODS: We conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation. RESULTS: A long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p < 0.005). In addition, a trend for older age at the event and higher Unified Parkinson's Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p < 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state. CONCLUSIONS: The patients' clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.

Stereotactic radiosurgery combined with anti-PD1 for the management of melanoma brain metastases: A retrospective study of safety and efficacy.

BACKGROUND: Brain metastases can be effectively treated with stereotactic radiosurgery (SRS). Immune checkpoint inhibitors are now pivotal in metastatic melanoma care, but some concerns have emerged regarding the safety of their combination with radiation therapy. METHODS: We present a retrospective analysis of a cohort of patients treated by anti-PD1 and SRS as a sole modality of radiation therapy (no whole brain radiation therapy at any time) in a single institution. We included patients on anti-PD1 at the time of SRS or patients who started anti-PD1 within a maximum period of 3 months following SRS and were treated at least one year before the analysis. Clinical and serial imaging data were reviewed to determine the efficacy and the rate of adverse radiation effectss of the combination. RESULTS: A total of 50 patients were included. SRS targeted 1, 2 to 3 and >3 brain metastases in 17, 16 and 17 patients, respectively. Two patients died before the first evaluation. Nine patients presented with an increase in peritumoral oedema, three with intracranial haemorrhage and one patient with both oedema and haemorrhage. Median follow-up was 38.89 months (interquartile range 24.43; 45.28). Median overall survival from SRS was 16.62 months with 1-, 2- and 3-year rates of 60%, 40% and 35%, respectively. Median brain-Progression Free Survival was 13.2 months with 1, 2 and 3-year rates of 62.1%, 49.7% and 49.7%, respectively. CONCLUSIONS: This real-world cohort of patients treated with a homogeneous strategy combining upfront stereotactic radiosurgery and anti-PD1 shows remarkable survival rates and does not reveal unexpected toxicity.

Stereotactic radiosurgery for thalamus arteriovenous malformations.

BACKGROUND: Cerebral arteriovenous malformations or angiomas are congenital vascular anomalies defined by abnormal arteriovenous shunt. MATERIALS AND METHODS: We conducted a retrospective study between January 1992 and December 2010 at the Timone Hospital radiosurgery unit, 1557 patients were treated by radiosurgery for arteriovenous malformation of which 53 for thalamic localization (3,4%). RESULTS: The mean age was 35.8-/+16.6 years (4-75). 14 patients underwent pre-radiosurgical embolization (26.4%), discovery mode for 47 patients (88.7%) was haemorrhage. The average treatment volume was 1.43 cm3. The average RBAS score was 1.36. The average prescription to the 50% isodose envelope delivered was 22.9 +/-2.9 Gy (12-30), the median margin dose was 24 Gy. Our global obliteration rate after one or two procedures 66.7% for an average follow-up period of 56.7 months. We noted 3.9% of mortality, 5.9% of bleeding after procedure and 3.9% of radio-induced neurological deficit. CONCLUSION: Radiosurgery became indispensable in the treatment of thalamic AVM even when there is a persistent risk of haemorrhage until total recovery.

Stereotactic Radiosurgery for Spetzler-Martin Grade I and II Arteriovenous Malformations: International Society of Stereotactic Radiosurgery (ISRS) Practice Guideline.

BACKGROUND: No guidelines have been published regarding stereotactic radiosurgery (SRS) in the management of Spetzler-Martin grade I and II arteriovenous malformations (AVMs). OBJECTIVE: To establish SRS practice guidelines for grade I-II AVMs on the basis of a systematic literature review. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant search of Medline, Embase, and Scopus, 1986-2018, for publications reporting post-SRS outcomes in ≥10 grade I-II AVMs with a follow-up of ≥24 mo. Primary endpoints were obliteration and hemorrhage; secondary outcomes included Spetzler-Martin parameters, dosimetric variables, and "excellent" outcomes (defined as total obliteration without new post-SRS deficit). RESULTS: Of 447 abstracts screened, 8 were included (n = 1, level 2 evidence; n = 7, level 4 evidence), representing 1102 AVMs, of which 836 (76%) were grade II. Obliteration was achieved in 884 (80%) at a median of 37 mo; 66 hemorrhages (6%) occurred during a median follow-up of 68 mo. Total obliteration without hemorrhage was achieved in 78%. Of 836 grade II AVMs, Spetzler-Martin parameters were reported in 680: 377 were eloquent brain and 178 had deep venous drainage, totaling 555/680 (82%) high-risk SRS-treated grade II AVMs. CONCLUSION: The literature regarding SRS for grade I-II AVM is low quality, limiting interpretation. Cautiously, we observed that SRS appears to be a safe, effective treatment for grade I-II AVM and may be considered a front-line treatment, particularly for lesions in deep or eloquent locations. Preceding publications may be influenced by selection bias, with favorable AVMs undergoing resection, whereas those at increased risk of complications and nonobliteration are disproportionately referred for SRS.

Predictive Factors of Early Postoperative and Long-Term Facial Nerve Function After Large Vestibular Schwannoma Surgery.

OBJECTIVE: The preservation of acceptable facial nerve (FN) function after surgery is the key concern for most patients with vestibular schwannomas (VS). To assess predictive factors of early postoperative and long-term FN function in patients harboring large VS operated with a FN-sparing technique. METHODS: Single-center retrospective cohort study with 169 consecutive large VS operated on between January 2003 and May 2015. Clinical, radiologic, and intraoperative factors were assessed according to FN function. RESULTS: At last follow-up examination, among the 145 patients without preoperative FN palsy, FN function was good (House-Brackmann [HB] grades I or II) in 84% and moderate (HB grade III) in 15% of patients. Only 1 patient presented with poor HB grade IV function. Multivariate logistic regression model showed the mean preoperative VS extrameatal diameter as being an independent predictor of an unfavorable initial FN outcome (odds ratio [OR], 1.062; P = 0.038). Surgical anatomic preservation of the cochlear nerve was associated with better FN outcomes (OR, 0.237; P = 0.012). A history of previous surgery seemed to be related to long-term impaired FN function (OR, 71.405; P = 0.042), as well as early postoperative FN function (OR, 19.068; P = 0.000). No correlation was found between a history of previous Gamma Knife surgery treatment (P = 0.225) or the extent of resection (P = 0.438) and impaired FN outcomes. History of previous surgery was identified as an unfavorable predictive recovery factor of impaired postoperative FN function (P = 0.034). CONCLUSIONS: As long as the extent of resection or additional Gamma Knife surgery have not been identified as predictive risk factors of postoperative FN palsy, we suggest that optimal resection is the main option for patients harboring large VS.

Quality of life predicts outcome of deep brain stimulation in early Parkinson disease.

OBJECTIVE: To investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications. METHODS: We performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) (UPDRS-III "off" and "on" medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI. RESULTS: PDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group. CONCLUSION: Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. CLINICALTRIALSGOV IDENTIFIER: NCT00354133.

Adjunctive Gamma Knife Surgery or Wait and Scan Policy After Optimal Resection of Large Vestibular Schwannomas: Clinical and Radiologic Outcomes.

OBJECTIVES: Patients with large vestibular schwannomas (VSs) will require surgical treatment owing to the potential consequences of long tract and cranial nerve compression. We assessed the long-term clinical and radiologic outcomes of patients harboring large VSs treated with a facial nerve (FN)-sparing technique. METHODS: We performed a single-center retrospective cohort study of 169 consecutive large VSs treated surgically from January 2003 to May 2015. The postoperative volume of the tumor residue was assessed using thin-slice magnetic resonance imaging 6 months after surgery. Postoperatively, the patients were allocated to a wait and rescan (W&reS) or an upfront gamma knife surgery (GKS) policy. RESULTS: At the last follow-up examination, FN function was good (House-Brackmann grade I or II) in 84% of the patients. Of the 169 patients, 11% had undergone gross total resection, 59% near total, 21% subtotal, and 9% partial resection. In the 143 patients without gross total resection, the overall median tumor residue volume was 0.39 cm3. Of these 143 patients, 66 had been allocated to the W&reS policy and 77 to upfront GKS. Overall tumor control was achieved in 83% of cases, with a mean follow-up of 62 months. Of the 27 growing residues, 17 required salvage treatment (11% failure rate). The 1-, 5-, and 7-year progression-free survival rate was 95%, 82%, and 76% in the W&reS group and 99%, 81%, and 78% in the GKS group, respectively (P = 0.57). CONCLUSIONS: Functional nerve-sparing resection provides satisfactory FN preservation. The low probability of long-term regrowth of small remnants is an argument for a W&reS protocol. GKS is a legitimate option for salvage treatment.

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

Evidence of Archaeal Methanogens in Brain Abscess.

Background: Methanogens are antibiotic-resistant anaerobic archaea that escape routine detection in clinical microbiology. We hypothesized that methanogens are part of the anaerobic community that cause brain abscess. Methods: Methanogens were investigated in 1 index sample using specific polymerase chain reaction (PCR) sequencing and culture. The pathogenesis of a methanogen isolate was assessed in a mouse model. Archaea-specific quantitative (q) PCR and metagenomics were used to detect specific archaeal sequences in brain abscess samples and controls. Results: In 1 index sample, routine culture found Porphyromonas endodontalis and Streptococcus intermedius, and specific culture found Methanobrevibacter oralis susceptible to metronidazole and fusidic acid. Archaea-targeted PCR sequencing and metagenomics confirmed M. oralis along with 14 bacteria, including S. intermedius. Archaea-specific qPCR yielded archaea in 8/18 brain abscess specimens and 1/27 controls (P < .003), and metagenomics yielded archaea, mostly methanogens, in 28/32 brain abscess samples, and no archaea in 71 negative controls (P < 10-6). Infection of mice brains yielded no mortality in 14 controls and death in 17/22 M. oralis-inoculated mice (P < 10-6), 32/95 S. intermedius-inoculated mice (P < 10-6), and 75/104 mice inoculated with M. oralis mixed with S. intermedius (P < 10-6) 7 days post-inoculation. Conclusion: Methanogens belong to the anaerobic community responsible for brain abscess, and M. oralis may participate in the pathogenicity of this deadly infection. In mice, a synergy of M. oralis and S. intermedius was observed. Antibiotic treatment of brain abscess should contain anti-archaeal compounds such as imidazole derivatives in most cases.

Simultaneous deblurring and iterative reconstruction of CBCT for image guided brain radiosurgery.

One of the limiting factors in cone-beam CT (CBCT) image quality is system blur, caused by detector response, x-ray source focal spot size, azimuthal blurring, and reconstruction algorithm. In this work, we develop a novel iterative reconstruction algorithm that improves spatial resolution by explicitly accounting for image unsharpness caused by different factors in the reconstruction formulation. While the model-based iterative reconstruction techniques use prior information about the detector response and x-ray source, our proposed technique uses a simple measurable blurring model. In our reconstruction algorithm, denoted as simultaneous deblurring and iterative reconstruction (SDIR), the blur kernel can be estimated using the modulation transfer function (MTF) slice of the CatPhan phantom or any other MTF phantom, such as wire phantoms. The proposed image reconstruction formulation includes two regularization terms: (1) total variation (TV) and (2) nonlocal regularization, solved with a split Bregman augmented Lagrangian iterative method. The SDIR formulation preserves edges, eases the parameter adjustments to achieve both high spatial resolution and low noise variances, and reduces the staircase effect caused by regular TV-penalized iterative algorithms. The proposed algorithm is optimized for a point-of-care head CBCT unit for image-guided radiosurgery and is tested with CatPhan phantom, an anthropomorphic head phantom, and 6 clinical brain stereotactic radiosurgery cases. Our experiments indicate that SDIR outperforms the conventional filtered back projection and TV penalized simultaneous algebraic reconstruction technique methods (represented by adaptive steepest-descent POCS algorithm, ASD-POCS) in terms of MTF and line pair resolution, and retains the favorable properties of the standard TV-based iterative reconstruction algorithms in improving the contrast and reducing the reconstruction artifacts. It improves the visibility of the high contrast details in bony areas and the brain soft-tissue. For example, the results show the ventricles and some brain folds become visible in SDIR reconstructed images and the contrast of the visible lesions is effectively improved. The line-pair resolution was improved from 12 line-pair/cm in FBP to 14 line-pair/cm in SDIR. Adjusting the parameters of the ASD-POCS to achieve 14 line-pair/cm caused the noise variance to be higher than the SDIR. Using these parameters for ASD-POCS, the MTF of FBP and ASD-POCS were very close and equal to 0.7 mm-1 which was increased to 1.2 mm-1 by SDIR, at half maximum.

Differential dynamic of action on cortical and subcortical structures of anesthetic agents during induction of anesthesia.

BACKGROUND: Dynamic action of anesthetic agents was compared at cortical and subcortical levels during induction of anesthesia. Unconsciousness involved the cortical brain but suppression of movement in response to noxious stimuli was mediated through subcortical structures. METHODS: Twenty-five patients with Parkinson disease, previously implanted with a deep-brain stimulation electrode, were enrolled during the implantation of the definitive pulse generator. During induction of anesthesia with propofol (n = 13) or sevoflurane (n = 12) alone, cortical (EEG) and subcortical (ESCoG) electrogenesis were obtained, respectively, from a frontal montage (F3-C3) and through the deep-brain electrode (p0-p3). In EEG and ESCoG spectral analysis, spectral edge (90%) frequency, median power frequency, and nonlinear analysis dimensional activation calculations were determined. RESULTS: Sevoflurane and propofol decreased EEG and ESCoG activity in a dose-related fashion. EEG values decreased dramatically at loss of consciousness, whereas there was little change in ESCoG values. Quantitative parameters derived from EEG but not from ESCoG were able to predict consciousness versus unconsciousness. Conversely, quantitative parameters derived from ESCoG but not from EEG were able to predict movement in response to laryngoscopy. CONCLUSION: These data suggest that in humans, unconsciousness mainly involves the cortical brain, but that suppression of movement in response to noxious stimuli is mediated through the effect of anesthetic agents on subcortical structures.

Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy.

PURPOSE: To assess retrospectively a strategy that uses Gamma-Knife radiosurgery (GKR) in the management of patients with brain metastases (BMs) of malignant melanoma (MM). METHODS: GKR without whole-brain radiotherapy (WBRT) was performed for patients with Karnofsky Performance Status (KPS) of 60 or above who harbored 1 to 4 BMs of 30 mm or less and was repeated as often as needed. Survival was assessed in the whole population, whereas local-control rates were assessed for patients with follow-up longer than 3 months. RESULTS: A total of 221 BMs were treated in 106 patients; 61.3% had a single BM. Median survival from the time of GKR was 5.09 months. Control rate of treated BMs was 83.7%, with 14% of complete response (14 BMs), 42% of partial response (41 BMs), and 43% of stabilization (43 BMs). In multivariate analysis, survival prognosis factors retained were KPS greater than 80, cortical or subcortical location, and Score Index for Radiosurgery (SIR) greater than 6. On the basis of KPS, BM location, and age, a score called MM-GKR, predictive of survival in our population, was defined. CONCLUSION: Gamma-Knife radiosurgery provides a surgery-like ability to obtain control of a solitary BM and could be consider as an alternative treatment to the combination of GKR+WBRT as a palliative strategy. MM-GKR classification is more adapted to MM patients than are SIR, RPA and Brain Score for Brain Metastasis.