Nicholas J. Brandmeir

Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis

Importance Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR) and outcome remains undefined, notwithstanding many relevant studies. Objective To determine whether greater EOR is associated with improved 1- and 2-year overall survival and 6-month and 1-year progression-free survival in patients with GBM. Data Sources Pubmed, CINAHL, and Web of Science (January 1, 1966, to December 1, 2015) were systematically reviewed with librarian guidance. Additional articles were included after consultation with experts and evaluation of bibliographies. Articles were collected from January 15 to December 1, 2015. Study Selection Studies of adult patients with newly diagnosed supratentorial GBM comparing various EOR and presenting objective overall or progression-free survival data were included. Pediatric studies were excluded. Data Extraction and Synthesis Data were extracted from the text of articles or the Kaplan-Meier curves independently by investigators who were blinded to each others results. Data were analyzed to assess mortality after gross total resection (GTR), subtotal resection (STR), and biopsy. The body of evidence was evaluated according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria and PRISMA guidelines. Main Outcome and Measures Relative risk (RR) for mortality at 1 and 2 years and progression at 6 months and 1 year. Results The search produced 37 studies suitable for inclusion (41 117 unique patients). The meta-analysis revealed decreased mortality for GTR compared with STR at 1 year (RR, 0.62; 95% CI, 0.56-0.69; P < .001; number needed to treat [NNT], 9) and 2 years (RR, 0.84; 95% CI, 0.79-0.89; P < .001; NNT, 17). The 1-year risk for mortality for STR compared with biopsy was reduced significantly (RR, 0.85; 95% CI, 0.80-0.91; P < .001). The risk for mortality was similarly decreased for any resection compared with biopsy at 1 year (RR, 0.77; 95% CI, 0.71-0.84; P < .001; NNT, 21) and 2 years (RR, 0.94; 95% CI, 0.89-1.00; P = .04; NNT, 593). The likelihood of disease progression was decreased with GTR compared with STR at 6 months (RR, 0.72; 95% CI, 0.48-1.09; P = .12; NNT, 14) and 1 year (RR, 0.66; 95% CI, 0.43-0.99; P < .001; NNT, 26). The quality of the body of evidence by the GRADE criteria was moderate to low. Conclusion and Relevance This analysis represents the largest systematic review and only quantitative systematic review to date performed on this subject. Compared with STR, GTR substantially improves overall and progression-free survival, but the quality of the supporting evidence is moderate to low.

Robot Assisted Stereotactic Laser Ablation for a Radiosurgery Resistant Hypothalamic Hamartoma.

Hypothalamic hamartomas (HH) are benign tumors that can cause significant morbidity in adults as a cause of epilepsy, particularly gelastic seizures. Open and endoscopic resections of HH offer good seizure control but have high rates of morbidity and are technically challenging. Stereotactic radiosurgery has been an alternative treatment; however, it results in comparably poor seizure control. Recently, in children, stereotactic laser ablation has shown promise as a surgical technique that can combine the best features of both of these approaches for the treatment of HH. Here we present the first reported use of a frameless robot-assisted stereotactic system to treat an HH. The patient had failed two previous Gamma Knife radiosurgery treatments. Post-procedure he had a stable, but unintentional weight loss of 20 kg and a transient episode of hemiparesis the night of the operation. At six months postoperatively the patient remained seizure free. Stereotactic laser ablation may represent a new standard in the treatment of HH in adults, especially in those who have failed radiosurgery. Further study is warranted in this population to determine efficacy and safety profiles.

A Prospective Evaluation of an Outpatient Assessment of Postural Instability to Predict Risk of Falls in Patients with Parkinson's Disease Presenting for Deep Brain Stimulation

Postural instability (PI) and falls, major causes of morbidity in patients with PD, are often overlooked. DBS is a mainstay therapy for Parkinsons disease (PD) and has been purported to both worsen and improve PI. An effective PI evaluation that can predict fall risk in patients with PD presenting for DBS is needed.

Robotic-Guided Bihippocampal and Biparahippocampal Depth Placement for Responsive Neurostimulation in Bitemporal Lobe Epilepsy

BACKGROUND Patients with bitemporal lobe epilepsy are generally not considered for surgical resection. Fortunately, responsive neurostimulation provides another avenue for the management of this challenging disease process. In conjunction with our epileptologist, we consider responsive neurostimulation for patients who have clinical features of temporal lobe epilepsy without clear localization on imaging and stereoelectroencephalography. METHODS Here we describe our technique for implanting a responsive neurostimulator (NeuroPace, NeuroPace Inc., Mountain View, California) with depth electrodes monitoring the hippocampus and parahippocampus using stereotactic robotic guidance (ROSA, Medtech SA, Montpeillier, France). RESULTS We have used this technique with 5 patients without morbidity. Four of 5 patients have received clinical benefit (Engel classification I-III). Promisingly, long-term seizure monitoring with use of the NeuroPace system has suggested lateralizing information on 3 of these patients that was not apparent on previous invasive monitoring. CONCLUSIONS Robotically implanted responsive neurostimulation is a safe and effective treatment for bitemporal epilepsy and can possibly lead to valuable diagnostic information to guide future surgical management in patients who previously were not considered candidates for resective or ablative surgery.

An Analysis of Scalp Thickness and Other Novel Risk Factors for Deep Brain Stimulator Infections.

Introduction: Deep brain stimulator (DBS) infections are a persistent problem for patients undergoing this procedure. They may require further surgery, treatment with antibiotics, or even removal of the device. To date, no consensus exists on the best practices to avoid DBS infections or what factors predispose patients to an eventual infection. The goal of this study was to examine several patient factors for association with DBS infection. Methods: A single-center, single-surgeon quality improvement database was queried. All patients who experienced an infection were identified. The primary variable analyzed was scalp thickness. Other pre-specified, secondary variables included routine intraoperative cultures, operative time, diagnosis, and age. Results: None of the independent variables examined were significantly associated with DBS infections. Only two of the 46 infections qualified as surgical site infections as defined by the Centers for Disease Control. Conclusion: DBS infections are independent of all of the predictor variables analyzed. Surgical site infections, according to traditional definitions, are not the optimal definition for evaluating DBS infections/erosions. New studies must examine new variables that are not routinely gathered in this population. Also, because of the rare event rates and difficulty in randomizing patients to exposures, a large, multicenter registry may be the optimal study design to solve this clinical problem.

Deep Brain Stimulation for Parkinson Disease Does not Worsen or Improve Postural Instability: A Prospective Cohort Trial

BACKGROUND Falls and postural instability (PI) are major sources of morbidity in Parkinson disease (PD). Deep brain stimulation (DBS) is a major therapy for PD. The effects of DBS on PI and falls remain controversial. OBJECTIVE To study if DBS worsens PI, validated measures of PI (Timed Up and Go, Berg Balance Scale, Unified Parkinsons Disease Rating Scale 3.12 [Pull Test], and the Biodex Sway Index with eyes closed on a firm and soft surface) and reported falls were used to prospectively evaluate the effect of DBS on PI at 3 and 12 mo postoperatively compared to baseline measurements. The primary outcomes were a positive result on 4 out of the 5 PI tests and falls. METHODS Patients presenting for DBS were prospectively enrolled and evaluated at presentation and, 3 and 12 mo postoperatively. All tests were performed at each visit. RESULTS At 3 mo 4 of 5 positive showed noninferiority to baseline, with a rate of 28% vs 41% (relative risk [RR] 0.8 [0.5-1.3]). At 12 mo, 4 of 5 positive had a rate of 35% vs 30% (RR 1.2 [0.8-1.8]) and falls had a rate of 54% vs 46% (RR 1.2 [0.6-2.3]). These did not meet criteria to prove noninferiority. Sensitivity analysis at 12 mo showed noninferiority for 4 of 5 (RR 0.9 [0.6-1.5]) but not falls (RR 1.1 [0.5-2.3]). CONCLUSION This evidence is consistent with the hypothesis that DBS does not worsen PI when measured at 3 and 12 mo postoperatively.

The Leg Wound of King Philip II of Macedonia

Objective King Philip II, the father of Alexander the Great, suffered a penetrating wound to the leg from a spear that left him severely handicapped. His skeletal remains represent the first and only case of an injury from ancient Greece that can be directly compared to its historical record. The objective of the study was to confirm the identity of the male occupant of Royal Tomb I in Vergina, Greece as Philip II of Macedonia by providing new evidence based on anatomical dissection and correlation with the historical description of the wounds. Methods Radiographs and photographs of the leg in Royal Tomb I in Vergina were examined. Anatomical dissection of a cadaver with a reconstructed wound similar to Philip’s was also completed to identify associated soft-tissue injuries. Results The left leg was penetrated by an object at the knee which resulted in joint diastasis, external rotation of the tibia, knee ankylosis, and formation of a granuloma around the related object. This caused massive trauma to the joint but spared the popliteal artery. This resulted in ligamentous injury as well as injury to the peroneal nerve and probably the tibial nerve, resulting in a complete palsy of those nerves. Conclusion This evidence exactly matches the historical sources and shows conclusively that the leg and Tomb I belong to Philip II. The anatomic and archaeologic evidence also serve as independent verification of some of the historical record of that period, better enabling scholars to judge the reliability of various texts. Furthermore, it gives invaluable information about surgical practices in ancient Greece according to Hippocratic methods and their outcomes. Finally, this sheds new light on the occupants of Royal Tomb II including the fact that the armor recovered there may have belonged to Alexander the Great.

Utilizing neuronavigation for virtual electrode representation and safe resection following SEEG; a technical report

Abstract Purpose: One of the most effective treatments for epilepsy is resection, but it remains underutilized. Efforts must be made to increase the ease, safety, and efficacy of epilepsy resection to improve utilization. Studies have shown an improved risk profile of stereoelectroencephalography (SEEG) over subdural grids (SDG) for invasive monitoring. One limitation to increased adoption of SEEG at epilepsy centers is the theoretical difficulty of planning a delayed resection once electrodes are removed. Our objective was to develop and present a technique using readily available neuronavigation technology to guide a cortical, non-lesional epilepsy resection with co-registration of imaging during invasive monitoring to imaging in an explanted patient, allowing for virtual visualization of electrodes. Methods: An example case taking advantage of the technique described above as an adjunct for an anatomically guided resection is presented with technical details and images. Results: Intraoperative neuronavigation was successfully used to virtually represent previously removed SEEG electrodes and accuracy could be easily verified by examining scars on the scalp, bone, dura and pia. Conclusions: The simple technique presented can be a useful adjunct to resection following SEEG. This may help increase the adoption of SEEG, even when resection is planned.

Letter to the Editor. Stereotactic laser ablation for hypothalamic hamartomas after SRS failure

TO THE EDITOR: We read with interest the article by Burrows et al.2 (Burrows AM, Marsh WR, Worrell G, et al: Magnetic resonance imaging–guided laser interstitial thermal therapy for previously treated hypothalamic hamartomas. Neurosurg Focus 41[4]:E8, October 2016). We previously reported achieving a seizure-free outcome utilizing laser interstitial thermal therapy (LITT) in an adult patient with a hypothalamic hamartoma (HH) after failure of stereotactic radiosurgery (SRS). This article by Burrows and colleagues adds to the collective experience. We agree that LITT is an excellent surgical treatment for epilepsy in this patient population, and there are some alternative technical approaches that we have developed at our center that may be of interest to the reader. Burrows and colleagues report using a Leksell Frame (Elekta AB) and consulting a stereotactic atlas for planning. They further report developing their stereotactic plan on the day of surgery. Our preference is to develop the plan based on contrast-enhanced MRI ahead of time for improved efficiency and then merge that with a skullfiducial CT scan on the day of surgery. We also utilize a frameless, robotic stereotactic system (ROSA, MedTech Surgical Inc.).1 We find that this system allows highly accurate, direct targeting of the lesion without relying on atlases, and detailed planning can be done well in advance. These technical variations can be very helpful at centers where LITT is carried out in a diagnostic rather than an intraoperative scanner. More importantly, the growing but limited experience in adults with HH and epilepsy demonstrates excellent seizure control but higher rates of hypothalamic dysfunction. The patient in our report, who was treated 1 year ago, has Engel Class I seizure control. He also had an unintentional 20-kg weight loss that has been sustained for 1 year. This is in comparison to the moderate weight gain that Burrows and colleagues reported for 1 patient. Combining our experience with the report of Burrows et al., the rate of hypothalamic complications in adult patients with HH undergoing LITT who have been previously treated with SRS is 50%. This stands in contrast to Wilfong and Curry’s report of 14 child and adolescent patients with no hypothalamic complications.3 It is unclear whether this difference is a result of the relatively advanced age of Burrows and colleagues’ patients or the previous SRS (only 1 patient in Wilfong and Curry’s series had a previous SRS treatment). Although the numbers are small and we are comparing results across 3 separate trials and the purpose of this analysis is clearly only to generate hypotheses, analysis of the data with a Fisher exact test shows that the population in Wilfong and Curry’s series had a relative risk (RR) of 0.5 of getting a hypothalamic complication when compared with our report as well as that of Burrows et al. (RR 0.5, 95% CI 0.15–0.85, p = 0.0392). It is clear that LITT as a treatment for adult epilepsy secondary to HH will continue to grow. This is a relatively young treatment, and technical variations and nuances should continue to be encouraged and reported, especially because of the high variability in the availability of resources between different hospitals. Also, it is becoming clear that there may be a different side-effect profile for adult patients with HH undergoing LITT and/or patients with HH previously treated with SRS and now undergoing LITT compared with the landmark series in children.3 Larger reports will be needed to evaluate these issues, but the valuable report by the authors and similar experiences will be important for clinicians as they provide preoperative counseling to patients presenting for this procedure.

Response to Comment on: A Prospective Evaluation of an Outpatient Assessment of Postural Instability to Predict Risk of Falls in Patients with Parkinson's Disease Presenting for Deep Brain Stimulation

We thank the authors for their questions and thoughts on the problem of postural instability and the risk of falling in patients with Parkinson’s disease. To answer their questions, the majority of our patients’ elevated scores on part IV (complications of therapy) of the Unified Parkinson’s Disease Rating Scale were from subsections 4.5 and 4.6, which ask about the unpredictability of off times and painful dystonias, respectively. The score on item 4.2, which asks about the impact of dyskinesias, was rarely above 0 or 1, indicating that the patients had no functional problems from their dyskinesias or that their problems were slight. Nonetheless, it is possible that dyskinesias played a role in generating the scores we used to assess postural instability, especially in patients who were seeking deep brain stimulation surgery; because, presumably, their motor complications have reached an unacceptable state. This fact makes it even more imperative for scales of motor function and postural instability to be validated in the patient population of interest before their widespread clinical adoption. The writers also correctly point out the limitations of the Biodex system in detecting and compensating for dyskinesias when assessing a patient’s risk of falling. This is consistent with our empiric validation of the Biodex measures in predicting the fall risk in these patients and may very likely explain their overall poor performance compared with some other measures in this specific population (many of the Biodex measures we routinely collected in our patient cohort did not correlate at all with falls and were not included in the article describing our system for assessing postural instability). On the question of orthostatic hypotension, those data were not specifically collected; however, patients with “Parkinson’s plus” syndromes were excluded as much as possible given the clinical nature of these diagnoses. We agree that wearables represent a new and exciting development in the monitoring of postural instability and other facets of patient life (such as sleep patterns). Unfortunately, in the population served by our center, there are several barriers to the adoption of wearables in the foreseeable future. Our patients are generally unfamiliar with new technology, and their adoption of it is generally delayed. Furthermore, most patients with Parkinson’s disease in the United States live on a fixed income and rely on medical insurance for expenditures associated with their health care costs. For this reason, it is unlikely that wearable technology will find a large use among this population until a device receives approval from the US Food and Drug Administration for this indication and is a covered expense by Medicare. The goal of our study was to develop and validate a tool for assessing postural instability in patients with Parkinson’s disease who present for deep brain stimulator surgery. The tool we developed, whatever its form, would have to be available now to most community practitioners and patients to be useful for that purpose. We agree that, in the future, the optimal approach would be a clinical evaluation combined with objective, high-quality data that can only be obtained with a wearable device.