Clinical outcomes after MRI connectivity-guided radiofrequency thalamotomy for tremor.

OBJECTIVE: Radiofrequency thalamotomy (RF-T) is an established treatment for refractory tremor. It is unclear whether connectivity-guided targeting strategies could further augment outcomes. The aim of this study was to evaluate the efficacy and safety of MRI connectivity-guided RF-T in severe tremor. METHODS: Twenty-one consecutive patients with severe tremor (14 with essential tremor [ET], 7 with Parkinson's disease [PD]) underwent unilateral RF-T at a single institution between 2017 and 2020. Connectivity-derived thalamic segmentation was used to guide targeting. Changes in the Fahn-Tolosa-Marin Rating Scale (FTMRS) were recorded in treated and nontreated hands as well as procedure-related side effects. RESULTS: Twenty-three thalamotomies were performed (with 2 patients receiving a repeated intervention). The mean postoperative assessment time point was 14.1 months. Treated-hand tremor scores improved by 63.8%, whereas nontreated-hand scores deteriorated by 10.1% (p < 0.01). Total FTMRS scores were significantly better at follow-up compared with baseline (mean 34.7 vs 51.7, p = 0.016). Baseline treated-hand tremor severity (rho = 0.786, p < 0.01) and total FTMRS score (rho = 0.64, p < 0.01) best correlated with tremor improvement. The most reported side effect was mild gait ataxia (n = 11 patients). CONCLUSIONS: RF-T guided by connectivity-derived segmentation is a safe and effective option for severe tremor in both PD and ET.

Neuronavigation-assisted bedside placement of bolt external ventricular drains in the intensive care setting: a technical note.

BACKGROUND: The insertion of bolt external ventricular drains (EVD) on the intensive care unit (ICU) has enabled rapid cranial cerebrospinal fluid (CSF) diversion. However, bolt EVDs tend to be perceived as a more challenging technique, particularly when dealing with small ventricles or when there is midline shift distorting the ventricular morphology. Furthermore, if neuronavigation guidance is felt to be necessary, this usually assumes a transfer to an operating theatre. In this technical note, we describe the use of electromagnetic neuronavigation for bolt EVD insertion on the ICU and assess the protocol's feasibility and accuracy. METHODS: Case series of neuronavigation-assisted bolt EVD insertion in ICU setting, using Medtronic Flat Emitter for StealthStation EM. RESULTS: Neuronavigation-guided bolt EVDs were placed at the bedside in n = 5 patients on ICU. Their widest frontal ventricular horn diameter in the coronal plane ranged from 11 to 20 mm. No procedural complications were encountered. Post-procedural CT confirmed the optimal placement of the EVDs. CONCLUSIONS: Electromagnetic neuronavigation is feasible at the ICU bedside and can assist the insertion of bolt EVDs in this setting. The preference for a bolt EVD to be inserted in ICU-as is standard practice at this unit-should not prohibit patients from benefitting from image guidance if required.

A Novel Neurosurgery Referral Course: Feasibility, Validation, and Inferences for Patient Care.

OBJECTIVE: The speciality of neurosurgery is under-represented in the majority of medical school curriculums, and those rotating within this specialty tend to be those with career aspirations within this field. Consequently, few emergency medicine trainees are exposed to this specialty. The aim of this educational project was to develop and validate a neurosurgery referral course for the target audience of emergency medics. DESIGN: Development of a single day neurosurgery referral course, developed with accreditation from the Royal College of Surgeons England. The curriculum covered commonly referred pathologies. Content validity was assessed using a 5-point Likert Scale. Median Likert scores were compared to "indifferent" (3) (indifferent = 3 in this study Likert scale) using the Wilcoxon matched-pairs signed-rank test. Construct validity was assessed using a standardized pre and postcourse 10-single best answer exam and results compared using paired t tests. SETTING: A pilot "Neurosurgery for Emergency Medics" referral course, hosted at a single UK based neurosurgery unit. PARTICIPANTS: A cohort of 19 delegates, working in emergency departments various regions within the UK. RESULTS: The subjective feedback showed significantly higher than the expected median Likert scale satisfaction scores (p = 0.0001). Construct validity was confirmed, with significant improvement in proportion of students getting the answers in the single best answer exam after the days training course (p = 0.017). CONCLUSIONS: We demonstrate feasibility, content, and construct validity and conclude that this pilot "Neurosurgery for Emergency Medics" course was beneficial. Integration of this 1-day course into local doctor's induction programmes for emergency medicine and neurosurgery may advance both local and national standards for referrals and consults alike, with the ultimate goal of improving patient care.

Symptomatic Outcome after Bone-only Suboccipital Decompression in Adult Patients with Chiari Type I Malformations in the Absence of Hydromyelia or Hydrocephalus.

Background Type I Chiari malformation presents without an associated hydromyelia in 30 to 70% of cases, yet there is no agreement regarding the optimal surgical treatment for these patients. We review our experience for treating symptomatic adult type I Chiari malformation without hydromyelia using a suboccipital bone decompression of the hindbrain and no duraplasty in 12 adult patients. Outcome was measured according to the Chicago Chiari Outcome Scale (CCOS). Results Nine of 12 patients were female; average age at surgery was 34.4 years (range: 17-67 years). Average duration of symptoms prior to surgery was 9.6 years (2 months-29 years). The most common symptom was head and/or neck pain (11/12 patients). All patients additionally presented with at least one non-pain symptom. Mean degree of tonsillar herniation on magnetic resonance imaging was 6.8 mm (range: 5-12 mm) below McRae's line. Operative time was on average 68 minutes (range: 47-120 minutes). No surgical complications were noted in any patient. Length of hospital stay was 2 days (1 overnight) for all patients. Mean follow-up was 167 weeks (range: 13-378 weeks). CCOS for all patients on average was 14.50 (range: 12-16). Pain symptoms underwent improvement (7/11 [63.6%]) or complete resolution (4/11 [36.4%]) in all affected patients. A shorter duration of preoperative symptoms significantly correlated with a better CCOS (p = 0.03). Degree of tonsillar herniation had no significant effect on CCOS (p = 0.67). Of non-pain symptoms, paresthesias/dysesthesias and visual symptoms improved or resolved completely in all affected patients. No patient experienced a worsening of either pain or non-pain symptoms. Conclusion In the subset of adult patients with a type I Chiari malformation and no associated hydromyelia, a craniectomy without an additional opening of the dura may achieve good overall results according to the CCOS.

Pineal cyst resection in the absence of ventriculomegaly or Parinaud's syndrome: clinical outcomes and implications for patient selection.

OBJECT: Surgical indications for patients with pineal cysts are controversial. While the majority of patients harboring a pineal cyst require no treatment, surgery is a well-accepted option for a subset of those patients with secondary hydrocephalus or Parinaud's syndrome. The majority of pineal cysts are identified incidentally during workup for other potential conditions, which may or may not be related to the presence of the cyst. In the absence of clear obstruction of CSF pathways, the treatment of presumed symptomatic pineal cysts is debatable. To clarify the role of surgery in these borderline cases, the authors reviewed their experience with resection of pineal cysts in the absence of ventriculomegaly or Parinaud's syndrome. METHODS: The authors retrospectively reviewed medical records and imaging of all patients surgically treated between 2001 and 2014 with a pineal cyst in the absence of ventriculomegaly and Parinaud's syndrome. The presenting symptoms, preoperative cyst size, preoperative radiographic aqueductal compression, extent of resection, and radiographic and clinical follow-up were documented. RESULTS: Eighteen patients (14 female and 4 male; mean age 24 years, range 4-47 years) underwent cyst resection in the absence of ventriculomegaly or Parinaud's syndrome. Presenting symptoms included headache (17 patients), visual disturbances (10 patients), gait instability (5 patients), dizziness (5 patients), episodic loss of consciousness (2 patients), and hypersomnolence (1 patient). The mean preoperative cyst diameter was 1.5 cm (range 0.9-2.2 cm). All patients had a complete resection. At a mean clinical follow-up of 19.1 months (range postoperative to 71 months), 17 (94%) patients had resolution or improvement of their presenting symptoms. CONCLUSIONS: The authors' results suggest that ventriculomegaly and Parinaud's syndrome are not absolute requisites for a pineal cyst to be symptomatic. Analogous to colloid cysts of the third ventricle, intermittent occlusion of cerebrospinal fluid pathways may cause small pineal cysts to become intermittently symptomatic. A select cohort of patients with pineal cysts may benefit from surgery despite a lack of hydrocephalus or other obvious compressive pathology.

Multigene profiling to identify alternative treatment options for glioblastoma: a pilot study.

UNLABELLED: Glioblastoma (GBM) is a highly aggressive malignancy and the most effective treatment regime has a high relapse rate. Increasingly, the development of therapies involves defining drug-diagnostic combinations where the presence of a molecular target or marker identifies patients who are most likely to respond to a specific therapy. Trials in other solid cancers have demonstrated clear utility in the incorporation of biomarkers to stratify patients to targeted treatment, however, there are no mutations that are currently used to inform treatment options for GBM. AIMS: We piloted the use of high-throughput next-generation sequencing technology to identify genetic mutations in 44 GBM specimens that may be amenable to current or future targeted therapeutic strategies. METHOD: Somatic mutation profiling was performed using the AmpliSeq Cancer Hotspot Panel v2 and semiconductor sequencing technology. RESULTS: A total of 66 mutations were detected in 35/44 (80%) patients. The number of mutations per tumour ranged from 0 to 4 (average per tumour=1.5). The most frequent mutations were in TP53 (n=12), PTEN (n=9), EGFR (n=8) and PIK3CA (n=5). Clinically actionable somatic mutations were detected in 24/35 (69%) patients. CONCLUSIONS: This study demonstrates that the use of an 'off-the-shelf' oncogene primer panel and benchtop next-generation sequencer can identify mutations and potentially actionable targets in the majority of GBM patients. Data from this pilot highlights the potential for targeted genetic resequencing to identify mutations that may inform treatment options and predict outcomes.

A metabolic shift favoring sphingosine 1-phosphate at the expense of ceramide controls glioblastoma angiogenesis.

Studies in cell culture and mouse models of cancer have indicated that the soluble sphingolipid metabolite sphingosine 1-phosphate (S1P) promotes cancer cell proliferation, survival, invasiveness, and tumor angiogenesis. In contrast, its metabolic precursor ceramide is prodifferentiative and proapoptotic. To determine whether sphingolipid balance plays a significant role in glioma malignancy, we undertook a comprehensive analysis of sphingolipid metabolites in human glioma and normal gray matter tissue specimens. We demonstrate, for the first time, a systematic shift in sphingolipid metabolism favoring S1P over ceramide, which increases with increasing cancer grade. S1P content was, on average, 9-fold higher in glioblastoma tissues compared with normal gray matter, whereas the most abundant form of ceramide in the brain, C18 ceramide, was on average 5-fold lower. Increased S1P content in the tumors was significantly correlated with increased sphingosine kinase 1 (SPHK1) and decreased sphingosine phosphate phosphatase 2 (SGPP2) expression. Inhibition of S1P production by cultured glioblastoma cells, using a highly potent and selective SPHK1 inhibitor, blocked angiogenesis in cocultured endothelial cells without affecting VEGF secretion. Our findings validate the hypothesis that an altered ceramide/S1P balance is an important feature of human cancers and support the development of SPHK1 inhibitors as antiangiogenic agents for cancer therapy.

MMSAT: automated quantification of metabolites in selected reaction monitoring experiments.

Selected reaction monitoring (SRM) is a mass spectrometry-based approach commonly used to increase analytical sensitivity and selectively for specific compounds in complex metabolomic samples. While the goal of well-designed SRM methods is to monitor for unique precursor-product ion pairs, in practice this is not always possible due to the diversity of the metabome and the resolution limits of mass spectrometers that are capable of SRM. Isobaric or near-isobaric precursor ions with different chromatographic properties but identical product ions often arise in complex samples. Without analytical standards, such metabolites will go undetected by conventional data analysis methods. Furthermore, a single SRM method may include simultaneous monitoring of tens to hundreds of different metabolites across multiple samples making quantification of all detected ions a challenging task. To facilitate the analysis of SRM data from complex metabolomic samples, we have developed the Metabolite Mass Spectrometry Analysis Tool (MMSAT). MMSAT is a web-based tool that objectively quantifies every metabolite peak detected in a set of samples and aligns peaks across multiple samples to enable quantitative comparison of each metabolite between samples. The analysis incorporates quantification of multiple peaks/ions that have different chromatographic retention times but are detected within a single SRM transition. We compare the performance of MMSAT against existing tools using a human glioblastoma tissue extract and illustrate its ability to automatically quantify multiple precursors within each of three different transitions. The Web-interface and source code is avaliable at http://www.cancerresearch.unsw.edu.au/crcweb.nsf/page/MMSAT .