Andrew S. Jack

International subarachnoid aneurysm trial – ISAT Part II: Study protocol for a randomized controlled trial

BackgroundThe International Subarachnoid Aneurysm Trial (ISAT) demonstrated improved one-year clinical outcomes for patients with ruptured intracranial aneurysms treated with endovascular coiling compared to surgical clipping. Patients included in ISAT were mostly good grade subarachnoid hemorrhage (SAH) patients with small anterior circulation aneurysms. The purported superiority of coiling is commonly extrapolated to patients not studied in the original trial or to those treated using new devices not available at the time. Conversely, many patients are treated by clipping despite ISAT, because they are thought either to be better candidates for surgery, or to offer more durable protection from aneurysm recurrences. These practices have never been formally validated. Thus, for many ruptured aneurysm patients the question of which treatment modality leads to a superior clinical outcome remains unclear.Methods/trial designISAT II is a pragmatic, multicenter, randomized trial comparing clinical outcomes for non-ISAT patients with subarachnoid hemorrhage allocated to coiling or clipping. Inclusion criteria are broad. The primary end-point is the incidence of poor clinical outcome (defined as mRS >2) at one year, just as in ISAT. Secondary end-points include measures of treatment safety for a number of pre-specified subgroups, with efficacy end-points including the presence of a major recurrence at one year; 1,896 patients (862 each arm plus 10% losses) are required to demonstrate a significant difference between coiling and clipping, hypothesizing 23% and 30% poor clinical outcome rates, for coiling and clipping, respectively. The trial should involve at least 50 international centers, and will take approximately 12 years to complete. Analysis will be by intention-to-treat.Trial registrationISAT II is registered at clinicaltrials.gov: NCT01668563.

Predicting recurrence after chronic subdural haematoma drainage.

BACKGROUND Recurrence of chronic subdural haematomas (CSDHs) after surgical drainage is a significant problem with rates up to 20%. This study focuses on determining factors predictive of haematoma recurrence and presents a scoring system stratifying recurrence risk for individual patients. METHODS Between the years 2005 and 2009, 331 consecutive patients with CSDHs treated with surgery were included in this study. Univariate and multivariate analyses were performed searching for risk factors of increased post-operative haematoma volume and haematoma recurrence requiring repeat drainage. RESULTS We found a 12% reoperation rate. CSDH septation (seen on computed tomogram scan) was found to be an independent risk factor for recurrence requiring reoperation (p=0.04). Larger post-operative subdural haematoma volume was also significantly associated with requiring a second drainage procedure (p<0.001). Independent risk factors of larger post-operative haematoma volume included septations within a CSDH (p<0.01), increased pre-operative haematoma volume (p<0.01), and a greater amount of parenchymal atrophy (p=0.04). A simple scoring system for quantifying recurrence risk was created and validated based on patient age (< or ≥ 80 years), haematoma volume (< or ≥ 160 cc), and presence of septations within the subdural collection (yes or no). CONCLUSION Septations within CSDHs are associated with larger post-operative residual haematoma collections requiring repeat drainage. When septations are clearly visible within a CSDH, craniotomy might be more suitable as a primary procedure as it allows greater access to a septated subdural collection. Our proposed scoring system combining haematoma volume, age, and presence of septations might be useful in identifying patients at higher risk for recurrence.

Flow diverters: inter and intra-rater reliability of porosity and pore density measurements

Background and purpose Porosity and pore density (PD) are important characteristics of flow diverters (FDs), because they may influence device efficacy and safety. Reliable measurement of these parameters would seem to be required for comparisons between devices, device selection at the time of clinical usage, as well as for research purposes. Because there is no standard method of measurement, our aim was to assess the intra-rater and inter-rater reliability of PD measurements and of three different ways of measuring porosity. Methods Six microphotographs of two fully deployed FDs were taken overlying two different millimetric reference grids: one flat and the other corrected to match the cylindrical stent. Standardized protocols for independently measuring PD and porosity according to three different methods were used by three trained observers and by the same observer twice. Bland–Altman plots and intra-class correlation coefficients (ICC) were used to study the reliability of the measurements. Results For porosity, satisfactory agreement occurred only when the same method of measurement was performed by the same observer. Intra-observer and inter-observer agreement were poor for measures of porosity when different methods were used (with differences in the range of 5–10%, ICC <0.6 for all methods). Measurement of PD was more reliable within (ICC 0.991 (0.946 to 0.999)) and between (ICC 0.945 (0.781 to 0.991)) observers. Conclusions Without standardization, the porosity of different devices cannot reliably be compared because use of different methods or different observers substantially changes results. Pore density seems to be more reliably measured than porosity.

Nonfusion Does Not Prevent Adjacent Segment Disease: Dynesys Long-term Outcomes With Minimum Five-year Follow-up.

Study Design. Case series. Objective. The aim of this study was to determine the relationship between fusion and adjacent segment disease via Dynesys long-term outcomes. Summary of Background Data. Dynesys is a dynamic stabilization system meant to improve symptoms by stabilizing the spine without fusion and avoiding the development of adjacent segment disease. However, few studies have evaluated long-term outcomes. Methods. All patients were operated on with Dynesys from 2006 to 2009 by a single surgeon at a single institution. We prospectively collected 18 variables among the following categories: patient characteristics, comorbidities, surgical indications, and OR variables. We analyzed two primary endpoints: solid fusion on X-ray and clinical adjacent segment disease (ASD) both at 5 years. Secondary endpoints were time to fusion, time to ASD, reoperation, Oswestry disability index (ODI), and visual analogue scale (VAS) leg pain. We conducted a multivariate analysis via the random forest method. Mann-Whitney U test and Fisher exact test were then used to qualify relationship between variables. Results. We had 52 patients to review in the database. Eight had preexisting ASD. Mean follow-up was 92 months (median 87 months). Fifteen had ASD (29%) during follow-up at a mean 45 months (Median 35 months). Nine had a solid fusion (17%), 2 of which also had ASD. Mean time to fusion was 65 months (median 71 months). Differences in improvement of ODI (P = 0.005) and VAS leg pain (P = 0.002) were significant favoring patients without ASD. The multivariate analysis revealed four variables associated with ASD: prior ASD (OR 11.3, P = 0.005), neurological deficit (OR 8.5, P = 0.018), revision OR (OR 8.5, P = 0.018), and multilevel degeneration (OR 0.184, P = 0.026). No variable was associated with fusion. Conclusion. Dynesys was associated with a high rate of ASD over long-term follow-up despite maintaining a low fusion rate. Prior ASD was the strongest predictor of progressive ASD. Level of Evidence: 3

Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas

Tumor immune microenvironment has been gradually recognized as a key contributor to tumor development, progression, and control. Immune cell infiltrates in brain tumors have been increasingly studied, but few have published on immune cell infiltrates in pituitary adenomas. We quantitatively assessed the infiltration of macrophages and lymphocytes in 35 pituitary adenomas, including 9 densely granulated growth hormone (DG-GH), 9 sparsely granulated growth hormone (SG-GH), 9 null cell (NC), and 8 adrenocorticotropic hormone (ACTH) adenomas. All the adenomas showed varying degrees of CD68+ macrophage infiltration. While SG-GH adenomas were significantly larger in size than DG-GH and ACTH adenomas, the infiltration of CD68+ macrophages was significantly greater in SG-GH than in DG-GH and ACTH adenomas. Similarly, NC adenomas that were significantly larger than DG-GH and ACTH adenomas had significantly greater infiltration of CD68+ macrophages than DG-GH and ACTH adenomas. The numbers of CD68+ macrophages were positively correlated with the tumor sizes and Knosp classification grades for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but GH adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. Both DG-GH and SG-GH adenomas had significantly more CD4+ cells than ACTH adenomas and significantly more CD8+ cells than NC adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in the pituitary adenoma size and invasiveness. Our observation contributes to understanding the growth environment of pituitary adenomas, for which adjuvant immunotherapy may help to constrain the tumor enlargement and invasiveness.

Primary lymphoma isolated to the trigeminal nerve.

included computed tomography (CT), magnetic resonance imaging (MRI) (Figure 1A and B), and cerebrospinal fluid analysis. Medical treatment for trigeminal neuralgia was started, however this proved to be unsuccessful. His pain worsened, and repeat MRI showed an enlarged, non-enhancing lesion at the root entry zone of the trigeminal nerve (Figure 1C). A neoplastic etiology was suspected, and the patient was investigated for metastatic disease. Normal studies included a CT of the neck, chest, abdomen, and pelvis, multiple lumbar punctures, two positron emission tomography (PET) studies, a bone marrow biopsy, and lab and hematological work-up for inflammatory and paraneoplastic causes. Neurosurgical referral was then made for tumor biopsy. Via a retrosigmoid approach the nerve was found to be grossly

Adjacent Segment Pathology: Progressive Disease Course or a Product of Iatrogenic Fusion?

OBJECTIVE Cervical spine clinical adjacent segment pathology (CASP) has a reported 3% annual incidence and 26% ten-year prevalence. Its pathophysiology remains controversial, whether due to mechanical stress of a fusion segment on adjacent levels or due to patient propensity to develop progressive degenerative change. We investigate this relationship by comparing prevalence of CASP in traumatic and spondylotic patient cohorts. METHOD A retrospective review of traumatic cervical spine fusion cases performed by the local group of neurosurgeons from 2004-2008 was completed. Surgery for CASP and presence of radiological adjacent segment pathology (RASP) were identified by telephone and electronic medical record (EMR) review, and compared to those in patients having elective cervical fusion for degenerative disease. RESULTS There was a higher proportion of males (50/100 vs. 37/46, p0.05). Mean follow-up times were different (6.4 years in the trauma group, 7.1 years in the degenerative group; p<0.01), although this was not thought to be clinically significant. The degenerative group was found to have a significantly higher reoperation rate for CASP (10/100 vs. 0/46, p=0.031, Fishers Exact Test), and rate of RASP (20/100 vs. 1/32, p=0.025) Conclusion: This is the only cohort study to our knowledge comparing surgery for CASP in trauma patients to those with degenerative disease. A higher rate of repeat surgery in degenerative disease patients was found. This suggests that CASP is more related to patient factors predisposing to progressive degenerative disease and not increased mechanical stress.

Pre-operative Embolization of an Intraventricular Meningioma Using Onyx.

Intraventricular meningiomas are primarily a surgical disease. One of the most important aspects in their operative treatment is controlling their arterial blood supply. In an attempt to reduce the vascularity of meningiomas, pre-operative particulate embolization is often used. However, the potential for unwanted reflux within the intracranial vasculature usually limits this approach to those lesions supplied by arteries from the external circulation. Because intraventricular meningiomas are supplied by branches from the intracranial circulation, these lesions are not typically embolized due to the risk of particulate reflux. Onyx (Covidien, Irvine, CA, USA) is a liquid embolic agent that potentially offers better operator control than particles and may be appropriate for embolization of some tumours. Here we present a case of an intraventricular meningioma with arterial supply from a lateral posterior choroidal artery in which Onyx was used to successfully devascularize the lesion prior to operation.

Eosinophil Infiltrates in Pilocytic Astrocytomas of Children and Young Adults

OBJECTIVE Eosinophils may affect each stage of tumour development. Many studies have suggested that tumour-associated tissue eosinophilia (TATE) is associated with favourable prognosis in some malignant tumours. However, only a few studies exist on TATE in central nervous system (CNS) tumours. Our recent study exhibited eosinophils in atypical teratoid/rhabdoid tumours (AT/RTs), pediatric malignant CNS tumours with divergent differentiation. This study examines eosinophils in pilocytic astrocytomas (PAs). METHODS The study included 44 consecutive cases of patients with PAs and no concurrent CNS inflammatory disease. RESULTS We found eosinophils in 19 (43%) of 44 PAs (patient age range, 0.5-72 years). Eosinophils were intratumoural and clearly distinguishable. The density of eosinophils was rare to focally scattered. PAs containing eosinophils were located throughout the CNS. Furthermore, eosinophilic infiltration was identified in 18 (62%) of 29 pediatric (age range, 0.5-18 years) PAs but only 1 (7%) of 15 (p<0.001, significantly less) adult (age range, 20-72 years) PAs. Eosinophilic infiltration showed no significant differences between PAs with and without MRI cystic formation, surgical procedures, or PAs with and without leptomeningeal infiltration. In comparison, eosinophils were absent in 10 pediatric (age range, 0.5-15 years) ependymomas (or anaplastic ependymomas). CONCLUSIONS These results suggest that eosinophils are common in pediatric PAs but rare in adult PAs. This difference is probably related to the developing immune system and different tumour-specific antigens in children. TATE may play a functional role in the development of pediatric PAs, as well as some other pediatric CNS tumours such as AT/RTs.

Angiographic demonstration of upward transtentorial herniation.

A 47-year-old female experienced a sudden onset headache with associated nausea and vomiting, and was found on computed tomogram (CT) scan to have suffered a Grade 3 subarachnoid hemorrhage (SAH) with associated vermian hemorrhage. Subsequent CTA demonstrated a posterior fossa arteriovenous malformation (AVM) with two flow-associated aneurysms, a posterior inferior cerebellar artery (PICA) aneurysm, and a superior cerebellar artery (SCA) aneurysm, which was felt responsible for the hemorrhage (Figure A). During hospital transfer, her level of consciousness became compromised, decreasing to a Glasgow Coma Score (GCS) of 10. An external ventricular drain (EVD) was placed, releasing cerebrospinal fluid (CSF) under moderate pressure. An hour following placement of the EVD, her GCS further decreased to 6, with a loss of her left corneal and gag reflexes, in spite of a supratentorial intracranial pressure (ICP) of 14 mm H20. While the surgical team was mobilized for posterior fossa decompression, the patient was treated with 500 mL of 20%