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Background Continuous spike wave in sleep (CSWS) is an electroencephalogram (EEG) pattern associated with developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This etiologically heterogeneous syndrome may occur because of genetic factors and congenital or acquired brain lesions. We studied the pattern of clinical presentation and underlying etiologies in patients with DEE-SWAS that respond to resective surgery. Methods We reviewed our clinical and research databases for patients who had resolution of CSWS following surgical resection of a focal lesion. Results We identified 5 patients meeting inclusion criteria. In 3 of 5, an epileptogenic structural abnormality was not apparent on brain magnetic resonance imaging (MRI). In all 3 patients, focal cortical dysplasia was identified through intracranial EEG monitoring. Significance DEE-SWAS may be a secondary bilateral network epilepsy syndrome, which can be treated with resection of the inciting focal lesion. In patients with drug-resistant CSWS, clinicians should consider a complete epilepsy presurgical workup, including intracranial EEG monitoring.

Objective To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. Methods We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. Results Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. Significance Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Objective No validated tools exist to assess satisfaction with epilepsy surgery. We aimed to develop and validate a new measure of patient satisfaction with epilepsy surgery, the 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19). Methods An initial 31-item measure was developed based on literature review, patient focus groups, thematic analysis, and Delphi panels. The questionnaire was administered twice, 4-6 weeks apart, to 229 adults (≥18 years old) who underwent epilepsy surgery ≥1 year earlier, at three centers in Canada and one in Sweden. Participants also completed seven validated questionnaires to assess construct validity. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) assessed the factorial structure of the questionnaire. Cronbach alpha and intraclass correlation coefficients (ICCs) assessed the internal consistency and test-retest reliability of the ESSQ-19. Spearman and polyserial correlations assessed construct validity. Results Median age of participants and time since surgery were 42 years (interquartile range [IQR] = 32-54) and 5 years (IQR = 2-8.75), respectively. EFA and CFA yielded 18 items that segregated into four domains (mean score [SD]), namely, seizure control (76.4 [25]), psychosocial functioning (67.3 [26]), surgical complications (84 [22]), and recovery from surgery (73 [24]), one global satisfaction item, and a summary global score (74 [21]). The domain and summary scores demonstrated good to excellent internal reliability (Cronbach ⍺ range = .84-.95) and test-retest reliability (ICC range = 0.71-0.85). Construct validity was supported by predicted correlations with other instruments. Significance The ESSQ-19 is a new, valid, and reliable measure of patient satisfaction with epilepsy surgery that can be used in clinical and research settings.

ObjectiveThe aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy.MethodsThe Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit).ResultsTen study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR]=1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR=2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE).InterpretationIn comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939.

ObjectiveThis study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom.MethodsWe conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-eventmethod andcalculated using the Kaplan-Meier survival method.ResultsData for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittalhemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI]=53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI=78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI=74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI=86.3%-91.5%) at 1-year to 72.1% (95% CI=66.9%-76.7%) at 5-year to 57.2% (95% CI=46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p=.01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio=2.56, 95% CI=1.08-6.04, p=.03) and increased seizure recurrence odds (odds ratio=3.67, 95% CI=1.05-12.86, p=.04) compared to those undergoing the vertical hemispherotomy technique.SignificanceThis pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or arandomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Purpose Amygdala enlargement (AE) has been reported in drug resistant lesional and non-lesional temporal lobe epilepsy (TLE). Its contribution to development of intractability of epilepsy is at best uncertain. Our aim was to study the natural course of AE in a heterogenous group of TLE patients with follow-up imaging and clinical outcomes. Methods A prospective observational study in patients with TLE with imaging features of AE recruited from epilepsy clinics between 1994 and 2018. Demographic data, details of epilepsy syndrome, outcomes and follow up neuroimaging were extracted. Results Forty-two patients were recruited including 19 males (45 %). Mean age at onset of epilepsy was 30.6 years and mean duration of epilepsy was 19.9 years. On MRI, 33 patients had isolated unilateral AE and eleven had AE with hippocampal enlargement (HE). Twenty (48 %) underwent temporal resections with most common histopathology being amygdalar gliosis (40 %). Engel Class IA outcome at last follow up (mean, 10 years) was 60 %. Thirty-four patients had neuroimaging follow up of at least 1 year (mean, 5 years). AE resolved in 6, persisted in 25, evolved into bilateral HS in 1, bilateral mesial temporal atrophy in 1 and ipsilateral mesial temporal atrophy in 1. Resolution of AE was associated with better seizure free outcomes (p = 0.013). Conclusions TLE with AE is associated with favourable prognosis yet not benign. Over 50 % were drug resistant and surgical outcomes were similar to mTLE. Resolution of AE on follow up neuroimaging was associated with better seizure free outcomes.

Moyamoya disease is a chronic progressive cerebrovascular occlusive disease of the terminal portion of the internal carotid arteries associated with an acquired abnormal vascular network at the base of the brain, often leading to ischemic or hemorrhagic stroke. Moyamoya disease is a relatively common cause of pediatric stroke with a specific racial and well-identified clinical and imaging phenotype. Moyamoya disease is more prevalent in East Asian countries compared with other geographic regions with a higher incidence of familial cases and clinically more aggressive form. Moyamoya disease is one of the few causes of stroke that is amenable to effective surgical revascularization treatment. There are various surgical options available for revascularization, including the direct, indirect, or combined bypass techniques, each with variable responses. However, due to the heterogeneity of the diseases, different clinical course, geographical variables associated with the disease, and availability of a wide variety of surgical revascularization procedures, optimal selection of a surgical candidate and the surgical technique becomes challenging, particularly in the pediatric population. This brief review presents pertinent literature of clinical options for the diagnosis and surgical treatment of moyamoya disease in children.

The use of intraoperative MRI (iMRI) during treatment of gliomas may increase extent of resection (EOR), decrease need for early reoperation, and increase progression-free and overall survival, but has not been fully validated, particularly in the pediatric population. To assess the accuracy of iMRI to identify residual tumor in pediatric patients with glioma and determine the effect of iMRI on decisions for resection, complication rates, and other outcomes. We retrospectively analyzed a multicenter database of pediatric patients (age ≤ 18 years) who underwent resection of pathologically confirmed gliomas. We identified 314 patients (mean age 9.7 ± 4.6 years) with mean follow-up of 48.3 ± 33.6 months (range 0.03–182.07 months) who underwent surgery with iMRI. There were 201 (64.0%) WHO grade I tumors, 57 (18.2%) grade II, 24 (7.6%) grade III, 9 (2.9%) grade IV, and 23 (7.3%) not classified. Among 280 patients who underwent resection using iMRI, 131 (46.8%) had some residual tumor and underwent additional resection after the first iMRI. Of the 33 tissue specimens sent for pathological analysis after iMRI, 29 (87.9%) showed positive tumor pathology. Gross total resection was identified in 156 patients (55.7%), but this was limited by 69 (24.6%) patients with unknown EOR. Analysis of the largest multicenter database of pediatric gliomas resected using iMRI demonstrated additional tumor resection in a substantial portion of cases. However, determining the impact of iMRI on EOR and outcomes remains challenging because iMRI use varies among providers nationally. Continued refinement of iMRI techniques for use in pediatric patients with glioma may improve outcomes.

Objective The 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19) is a validated and reliable post hoc means of assessing patient satisfaction with epilepsy surgery. Prediction models building on these data can be used to counsel patients. Methods The ESSQ-19 was derived and validated on 229 patients recruited from Canada and Sweden. We isolated 201 (88%) patients with complete clinical data for this analysis. These patients were adults (≥18 years old) who underwent epilepsy surgery 1 year or more prior to answering the questionnaire. We extracted each patient's ESSQ-19 score (scale is 0-100; 100 represents complete satisfaction) and relevant clinical variables that were standardized prior to the analysis. We used machine learning (linear kernel support vector regression [SVR]) to predict satisfaction and assessed performance using the R2 calculated following threefold cross-validation. Model parameters were ranked to infer the importance of each clinical variable to overall satisfaction with epilepsy surgery. Results Median age was 41 years (interquartile range [IQR] = 32-53), and 116 (57%) were female. Median ESSQ-19 global score was 68 (IQR = 59-75), and median time from surgery was 5.4 years (IQR = 2.0-8.9). Linear kernel SVR performed well following threefold cross-validation, with an R2 of .44 (95% confidence interval = .36-.52). Increasing satisfaction was associated with postoperative self-perceived quality of life, seizure freedom, and reductions in antiseizure medications. Self-perceived epilepsy disability, age, and increasing frequency of seizures that impair awareness were associated with reduced satisfaction. Significance Machine learning applied postoperatively to the ESSQ-19 can be used to predict surgical satisfaction. This algorithm, once externally validated, can be used in clinical settings by fixing immutable clinical characteristics and adjusting hypothesized postoperative variables, to counsel patients at an individual level on how satisfied they will be with differing surgical outcomes.

OBJECTIVE Chiari 1.5 malformation is a subgroup of the Chiari malformation in which tonsillar descent into the foramen magnum is accompanied by brainstem descent. No data exist on whether operative decompression in patients with Chiari 1.5 improves sleep-related breathing disorders (SRBDs) and whether there are radiological parameters predicting improvement. METHODS The authors performed a retrospective cohort study of consecutive pediatric patients with Chiari 1.5 malformation and SRBDs at the Alberta Children’s Hospital. An SRBD was characterized using nocturnal polysomnography (PSG), specifically with the apnea-hypopnea index (AHI), the obstructive apnea index, and the central apnea index. Preoperative values for each of these indices were compared to those following surgical decompression. The authors also compared preoperative radiographic factors as predictors to both preoperative AHI and the change in AHI with surgery. Radiological factors included tonsillar and obex descent beneath the basion–opisthion line, the presence of syringomyelia, the frontooccipital horn ratio, the pB–C2 line, and the clivoaxial angle. RESULTS Seven patients (5 males, 2 females) met inclusion criteria. One patient had two surgical decompressions, each with pre- and postoperative PSG studies (n = 8). The median age was 9 years. Before surgical decompression, 75% underwent tonsillectomy/adenoidectomy. The majority (87.5%) experienced snoring/witnessed apnea preoperatively. The median tonsillar and obex descent values were 21.3 mm and 11.2 mm, respectively. The median values for the pB–C2 line and clivoaxial angle were 5.4 mm (interquartile range [IQR] 4.5 mm, 6.8 mm) and 144° (IQR 139°, 167°), respectively. There was a statistically significant change from preoperative to postoperative AHI (19.7 vs 5.1, p = 0.015) and obstructive apnea index (4.5 vs 1.0, p = 0.01). There was no significant change in the central apnea index with surgery (0.9 vs 0.3, p = 0.12). No radiological factors were statistically significant in predicting preoperative AHI and change in AHI. CONCLUSIONS This is the first series of pediatric patients with Chiari 1.5 with SRBDs who demonstrated a marked improvement in their PSG results postdecompression. Sleep apnea has a significant impact on learning and development in children, highlighting the urgency to recognize Chiari 1.5 as a more severe form of the Chiari I malformation.

Background Epilepsy surgery is likely underutilised. Our goal was to study the utilisation of epilepsy surgery in the general population, using Canada as a model of a high-income country with universal medical coverage. Methods We systematically identified all epilepsy surgery centres in Canada that were active in 2015. A standardised questionnaire was completed by every centre. Descriptive statistics are reported. Comparisons were made to a 2003 survey of paediatric epilepsy surgery. Results Twelve adult and 11 paediatric epilepsy surgery centres were identified, performing a total of 456 and 206 surgical procedures, respectively, in 2015. Adult centres were in only six of 10 provinces; paediatric centres were in seven. Two thirds of adult centres and one third of paediatric centres were high-volume centres. Per capita volume per province varied between 7.0 and 20.5 therapeutic surgeries per million adult residents, and between 7.8 and 48.4 per million paediatric residents. Temporal lobe resections accounted for 59.8% and 33.5% of all adult and paediatric treatments, respectively. Eleven adult and nine paediatric centres possessed facilities to carry out intracranial investigations but only six and two, respectively, performed at least six intracranial implantations in 2015. There was a modest increase in the per capita number of paediatric surgeries between 2003 and 2015. Conclusions There is dramatic inter-centre and interprovincial variability in the epilepsy services available and the type of surgical interventions performed with significant gaps identified in some regions. Our findings are pivotal for the future optimisation of care offered to this vulnerable patient population.

Patient satisfaction with therapeutic interventions is an important outcome of care. Although generic measures of patient satisfaction exist, there is no validated scale for measuring patient satisfaction with epilepsy surgery. We aimed to systematically obtain patient-identified factors related to satisfaction with epilepsy surgery as a means of informing clinicians about the ways that patients evaluate outcomes of their treatment and as a conceptual basis for the future development of epilepsy surgery patient satisfaction scales. Focus group discussions with epilepsy surgery patients (n=9) were conducted to identify themes relevant to patient satisfaction with epilepsy surgery and to draft initial items of importance. Consensus methodology (Delphi technique) was used to obtain expert opinion (n=13) to refine the items. Member-checking with focus group participants was performed to ensure the identified items were relevant, clear, and inclusive. A list of 31 items embodied 12 themes related to patient-reported satisfaction with epilepsy surgery. These included adverse effects, medical care or rehabilitation, seizure control, post-operative recovery, anti-seizure medication, independence, seizure worry, ability to drive, social relationships, self-confidence, improved cognitive function, and improved physical health. This study used a systematic approach to identify factors that are important to patients when assessing satisfaction with epilepsy surgery. This knowledge can assist clinicians caring for these patients and is also a critical step towards the validation of a formal scale to assess satisfaction with epilepsy surgery.

Objectives Epilepsy surgery is offered in resistant focal epilepsy. Non-invasive investigations like scalp video EEG monitoring (SVEM) help delineate epileptogenic zone. Complex cases may require intracranial video EEG monitoring (IVEM). Stereoelectroencephalography (SEEG)-based intracerebral electrode implantation has better spatial resolution, lower morbidity, better tolerance, and superiority in sampling deep structures. Our objectives were to assess IVEM using SEEG with regard to reasoning behind implantation, course, surgical interventions, and outcomes. Materials and methods Seventy-two admissions for SEEG from January 2014 to December 2018 were included in the study. Demographic and clinical data were retrospectively collected. Results The cohort comprised of 69 adults of which 34 (47%) had lesional MRI. Reasons for SEEG considering all cases included non-localizing ictal onset (76%), ictal-interictal discordance (21%), discordant semiology (17%), proximity to eloquent cortex (33%), nuclear imaging discordance (34%), and discordance with neuropsychology (19%). Among lesional cases, additional reasons included SVEM discordance (68%) and dual or multiple pathology (47%). Forty-eight patients (67%) were offered resective surgery, and 41 underwent it. Twenty-three (56%) had at least one year post-surgical follow-up of which 14 (61%) had Engels class I outcome. Of the remaining 23 who were continued on medical management, 4 (17%) became seizure-free and 12 (51%) had reduction in seizure frequency. Conclusion SEEG monitoring is an important and safe tool for presurgical evaluation with good surgical and non-surgical outcomes. Whether seizure freedom following non-surgical management could be related to SEEG implantation, medication change, or natural course needs to be determined.

Introduction: Epilepsy is one of the most common neurological disorders and is often difficult to control with medication. Intractable epilepsy often results in compromised quality of life (QOL), neurologic morbidity and even mortality. In carefully selected cases, resective surgery offers the best potential for cure or seizure control. However, a large proportion of patients are not suitable for resective epilepsy surgery. Neuromodulation techniques are increasingly being used to treat such refractory cases. Recently, the FDA approved Magnetic Resonance-guided Focused Ultrasound (MRgFUS) for essential tremor and this novel technology is also being explored in several other neuropsychiatric conditions and neurological disorders, including epilepsy. Area covered: While the literature is scant and scattered, the pertinent literature of the MRgFUS is reviewed with an emphasis on research relevant to its application for epilepsy. Expert opinion: Limited preliminary clinical experiences and research studies with MRgFUS ablation or neuromodulation for epilepsy have shown promising results; however, this procedure remains experimental requiring further investigations. Safe and reversible opening of the blood-brain barrier (BBB) with MRgFUS adds an additional therapeutic avenue by allowing targeted delivery of neurotherapeutics in neurological disorders, potentially including epilepsy. Ongoing clinical trials and research coupled with technological advancements contribute to strengthening the MRgFUS epilepsy field. MRgFUS could be the future technology of choice for 'ablation' or 'sononeuromodulation', and/or a 'targeted therapeutics' for epilepsy.

Objective No standard, widely accepted criteria exist to determine who should be referred for an epilepsy surgical evaluation. As a result, indications for epilepsy surgery evaluation vary significantly between centers. We review the literature to assess what criteria have been used to select patients for resective epilepsy surgery and examine whether these have changed since the publication of the first epilepsy surgery randomized controlled trial in 2001. Methods A systematic review was conducted using PubMed and EMBASE, bibliographies of reviews and book chapters identifying focal epilepsy resective series. Abstract, full text review and data abstraction (i.e. indications for surgery) were performed independently by two reviewers. Descriptive historical analysis was done to examine indications over time. Results Out of 5061 articles related to epilepsy surgery, 384 articles met all eligibility criteria. Most common criteria for selecting patients for evaluation for resective surgery were: AED resistance ( n =303, most commonly >2 AEDs=46), epilepsy duration ( n =53, most commonly >1 year=42) and seizure frequency (most commonly at least one seizure/month, n =29). Out of the prospective studies the most notable change over time (pre-2000 vs. post-2000) was failure of ≥2 AEDs (8% vs. 43% respectively, p Conclusions Important variations between studies make it difficult to identify consistent criteria to guide surgical candidacy or changes in indications over time. With increasing evidence that earlier surgery is associated with better outcomes, it is recommended that patients be evaluated as soon as they have failed two AEDs, consistent with the new definition of drug resistant epilepsy. Furthermore, low seizure frequency should not be a barrier to epilepsy surgery. Anyone with drug resistant epilepsy should be promptly evaluated for possible surgery, regardless of seizure frequency.

Occult tethered cord syndrome, in which there is normal neuroanatomic imaging despite clinical and urodynamic evidence of neuropathic bladder behavior, is controversial. Several uncontrolled series describe improvement in bladder function following section of the filum terminale. We performed a pilot randomized, controlled study comparing medical treatment to surgical section of the filum plus medical treatment in children with occult tethered cord syndrome.Children refractory to standard medical management for 1 year or more with normal conus position on magnetic resonance imaging and abnormal urodynamics were randomized. Exclusion criteria included any neurological conditions, spinal dysraphism, bladder outlet obstruction and an atonic bladder. Patients were assessed at randomization and 1 year later with a standardized urodynamic score, the validated PEMQOL (Pediatric Enuresis Module on Quality of Life™) scale, and a validated bowel and bladder dysfunction score.After 8 years we accrued 21 patients. The bowel and bladder dysfunction score improved in the surgical and medical arms (20% and 24%) and the urodynamic score improved slightly (6% and 4%, respectively). The PEMQOL Child and Family Impact Scales improved modestly in both groups. All differences were nonsignificant. Interim analysis indicated that more than 700 patients in each arm would be required to demonstrate a statistical difference with respect to urodynamic score based on our preliminary data.There appears to be no objective difference in urological outcome between medical management plus or minus filum section for patients with occult tethered cord syndrome. These data challenge the existence of the concept of occult tethered cord syndrome, in which bowel and bladder dysfunction score is attributed to tethering by the filum despite a normally located conus.

Aims The purpose is to demonstrate heterotopic neurones and their synaptic plexi within the U-fibre layer beneath focal cortical dysplasias (FCD). Materials and methods This prospective qualitative neuropathological study included 23 patients, ages from 3 months to 17 years: resections at epileptogenic foci in 10 FCD Ia; 6 FCD IIa,b; 2 FCD IIIa,d; 3 HME; 2 TSC; 8 controls. Techniques immunoreactivities for synaptophysin, NeuN, MAP2, SMI32, calretinin, GFAP, vimentin, α-B-crystallin. Bielschowsky silver; LFB; mitochondrial enzyme histochemistry (frozen sections). Results Subcortical white matter in FCD exhibited neuronal dispersion within U-fibres in FCD I, II and also deep white matter neuronal clusters in FCD II, HME, TSC. Neurones reacted for NeuN, MAP2; few for calretinin. Synaptophysin well demonstrated elaborate U-fibre plexi including axones between U-fibre neurones and projecting to overlying cortex. Deep white matter axones interconnected heterotopia but did not penetrate U-fibres to reach cortex. Mitochondrial enzymatic activity was intense in some neurones, normal in others. Glial α-B-crystallin served as a marker of epileptogenic zones identified electrographically. Conclusion U-fibre synaptic plexi contribute to excitatory circuitry in the cortex and thus to epileptic networks. Deep white matter neurones form local, less integrated plexi except transmantle dysplasias continuous with cortex. U-fibres may be a barrier to axonal penetration from deep heterotopia. Hypermetabolic neurones suggest repetitive ictogenic depolarizations. Gyral resections should include the U-fibre layer. Neuropathology reports should describe subcortical plexi. Synaptophysin immunoreactivity is a valuable supplement for this purpose. .

We reported previously that microglia decreased the growth of human brain tumor-initiating cells (BTICs). Through microarray analyses of BTICs exposed in vitro to microglia, we found the induction of several genes ascribed to have roles in cell cycle arrest, reduced cell proliferation and differentiation. Herein, we tested the hypothesis that one of these genes, growth arrest specific 1 (Gas1), is a novel growth reduction factor that is induced in BTICs by microglia. We found that microglia increased the expression of Gas1 transcript and protein in glioblastoma patient-derived BTIC lines. Using neurosphere assay we show that RNAi-induced reduction of Gas1 expression in BTICs blunted the microglia-mediated BTIC growth reduction. The role of Gas1 in mediating BTIC growth arrest was further validated using orthotopic brain xenografts in mice. When microglia-induced Gas1-expressing BTIC cells (mGas1-BTICs) were implanted intra-cranially in mice, tumor growth was markedly decreased; this was mirrored in the remarkable increase in survival of mGas1-BT025 and mGas1-BT048 implanted mice, compared to mice implanted with non-microglia-exposed BTIC cells. In conclusion, this study has identified Gas1 as a novel factor and mechanism through which microglia arrest the growth of BTICs for anti-tumor property.

Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989–2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53 % of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13 % for unithalamic tumors compared to 37 ± 32 % for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.

Background Microglial activation is thought to be a key pathophysiological mechanism underlying disease activity in all forms of MS. Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory properties that is widely used in the treatment of rheumatological diseases. In this series of experiments, we explore the effect of HCQ on human microglial activation in vitro and on the development of experimental autoimmune encephalitis (EAE) in vivo. Methods We activated human microglia with lipopolysaccharide (LPS), and measured concentrations of several pro- and anti-inflammatory cytokines in untreated and HCQ pretreated cultures. We investigated the effect of HCQ pretreatment at two doses on the development of EAE and spinal cord histology. Results HCQ pretreatment reduced the production of pro-inflammatory (TNF-alpha, IL-6, and IL-12) and anti-inflammatory (IL-10 and IL-1 receptor antagonist) cytokines in LPS-stimulated human microglia. HCQ pretreatment delayed the onset of EAE, and reduced the number of Iba-1 positive microglia/macrophages and signs of demyelination in the spinal cords of HCQ treated animals. Conclusion HCQ treatment reduces the activation of human microglia in vitro, delays the onset of EAE, and decreases the representation of activated macrophages/microglia and demyelination in the spinal cord of treated mice. HCQ is a plausible candidate for further clinical studies in MS.

Background:Cognitive dysfunction is a common complaint associated with obstructive hydrocephalus. The purpose of this study was to determine the effect of endoscopic third ventriculostomy (ETV) on the neuropsychological outcome in patients presenting with cognitive decline and obstructive hydrocephalus.Methods:A retrospective review of patients who underwent ETV at the University of Calgary and had both pre and post operative neuropsychological testing, was completed. Presenting clinical features, etiology of hydrocephalus and ventricle size utilizing frontal occipital horn ratio was obtained. Outcomes and complications of the ETV were recorded. Detailed measures of intelligence, attention and concentration, executive function, visual and verbal memory, language functions and fine motor skills were completed. Post treatment change was determined utilizing Reliable Change Index.Results:A total of 13 patients were identified. Etiology of the hydrocephalus was aqueductal stenosis in 8 and tectal glioma in 4. The majority of patients (11 of 13, 85%) demonstrated cognitive dysfunction at the borderline (≤1 SD) or impairment level (≤1.5 SDs) in at least one domain. Nine patients (69%) showed reliable improvement in at least one cognitive domain. The greatest improvement was seen with visual memory (42%). One quarter to one third of patients demonstrated improvement on tests of intelligence quotient, verbal memory, attention and concentration, and executive function. Two patients declined in executive functioning. Ventricle size improved in eight patients.Conclusions:ETV is a safe effective procedure, capable of producing reliable improvements in cognitive dysfunction with hydrocephalus. Patients with cognitive complaints alone may benefit from ETV.

Background Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. Methods Children diagnosed with epilepsy [N = 43, mean age = 11.7 years, standard deviation = 3.7 years, 53% male] underwent a DTI sequence (6 directions, 2 × 2 × 3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). Results Diffusion variables showed low variability (CV = 2.7–8.8%) and very high reliability (ICC = .97–.99) except for limbic tracts [fornix (ICC = .75–.94); cingulum (ICC = .71–.98)]. Tract volume measurements showed high variability (CV = 21.9–62.0%) and moderate reliability (ICC = .54–.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. Conclusions This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity.

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.

Background:In this study, we conducted a retrospective investigation of our initial single-centre experience with the clinical use of functional magnetic resonance imaging (fMRI) of hemisphere dominance for language processing (i.e., language lateralization). We demonstrated its association with surgical outcome and its potential impact on surgical planning and patient management.Methods:Fifty-two cases were reviewed, covering the period from July 2007 to July 2010. Clinical fMRI reports were examined to determine the hemisphere dominance for language processing. Neurological reports were examined to determine if new language deficits were present post-surgery. Neurosurgeon notes were also reviewed to determine if fMRI had an impact on surgical planning.Results:Of the cases reviewed, 49 (94%) generated conclusive fMRI. Eleven (22%) patients exhibited fMRI language lateralization contralateral to pathology; zero of nine of these patients that had surgery experienced post-surgical deficits. Twenty-two (44%) patients exhibited fMRI language lateralization ipsilateral to pathology; three of 13 of these patients that had surgery experienced post-surgical deficits. Sixteen (34%) patients exhibited bilateral lateralization of language; five of 13 of these patients that had surgery experienced post-surgery deficits. Several post-fMRI reports indicated that fMRI results had an impact on surgical planning.Conclusions:Our results suggest that fMRI demonstrations of language processing within the hemisphere ipsilateral to pathology (either ipsilateral alone or bilateral) is associated with a greater risk for post-surgical language deficits, and in these cases, fMRI results should be taken into consideration for pre-surgical planning.

SummaryPurpose Underutilization of epilepsy surgery remains a major problem and is in part due to physicians' misconceptions about the risks associated with epilepsy surgery. The purpose of this study was to systematically review the literature on complications of focal epilepsy surgery. Methods A literature search was conducted using PubMed and Embase to identify studies examining epilepsy surgery complications. Abstract and full text review, along with data extraction, was done in duplicate. Minor medical and neurologic complications were defined as those that resolved completely within 3 months of surgery, whereas major complications persisted beyond that time frame. Descriptive statistics were used to report complication proportions. Key Findings Invasive monitoring: Minor complications were reported in 7.7% of patients, whereas major complications were reported in only 0.6% of patients undergoing invasive monitoring. Resective surgery: Minor and major medical complications were reported in 5.1% and 1.5% of patients respectively, most common being cerebrospinal fluid (CSF) leak. Minor neurologic complications occurred in 10.9% of patients and were twice as frequent in children (11.2% vs. 5.5%). Minor visual field defects were most common (12.9%). Major neurologic complications were noted in 4.7% of patients, with the most common being major visual field defects (2.1% overall). Perioperative mortality was uncommon after epilepsy surgery, occurring in only 0.4% of temporal lobe patients (1.2%extratemporal). Significance The majority of complications after epilepsy surgery are minor or temporary as they tend to resolve completely. Major permanent neurologic complications remain uncommon. Mortality as a result of epilepsy surgery in the modern era is rare.

Diencephalic syndrome (DS) related to hypothalamic/chiasmatic region tumor has mainly been reported with low-grade glioma. We described 2 young children with DS related to pilomyxoid astrocytoma. Despite the recognized more agressive clinical behavior of this histologic subtype, we report successful resolution of DS and sustained tumor response with prolonged use of single-agent vinblastine.

OBJECTIVES: The purpose of this paper was to investigate the contributions of sociodemographic, neurologic, and neuropsychological variables to health-related quality of life (HRQoL) in children with epilepsy and high seizure burden. Focus was placed on the relationship between memory and HRQoL, which has not been previously investigated. METHODS: Ninety children with epilepsy receiving clinical care at a tertiary-level children’s hospital were retrospectively identified. Primary assessment measures were verbal memory (California Verbal Learning Test–Children’s Version) and HRQoL. Other neuropsychological variables included intellectual function, executive function, emotional and behavioral function, and adaptive function. Sociodemographic and neurologic variables were extracted from chart review. RESULTS: No significant correlations were found between HRQoL and sociodemographic or neurologic variables. Moderate correlations were found between neuropsychological variables and HRQoL. Emotional function (Child Behavior Checklist) and verbal memory (California Verbal Learning Test–Children’s Version) emerged as significant predictor variables of HRQoL. Low verbal memory was associated with a twofold risk of low HRQoL, emotional and behavioral difficulty with a 10-fold risk, and the combination of emotional and behavioral difficulty and low verbal memory with a 17-fold risk. CONCLUSIONS: Verbal memory and emotional and behavioral difficulty are associated with increased risk of low HRQoL, even when other important variables are considered in children with high seizure burden. The results reinforce the importance of neuropsychological assessment in clinical care in pediatric epilepsy and suggest important areas of focus for psychological intervention.

To compare long-term neurodevelopmental and growth (NDG) outcomes at 3 y corrected gestational age (GA) in premature infants with grade ≥ III intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus who were treated with ventriculo-peritoneal shunt with those who were not treated with shunt. In a retrospective cohort study, NDG outcomes were compared between preterm infants of

A case-controlled epidemiologic study of multiple sclerosis (MS) was carried out in London, Ontario, and its surrounding Middlesex County for the period 1974–1983. The prevalence rates for clinically definite/probable MS on January 1, 1984 were 94/100,000 for the city and 91/100,000 for the county. The estimated annual incidence rate for the decade 1974–83 was 3.4/100,000. The female-to-male sex ratio was 2.5:1. A familial history of MS was recorded in 14.4% of close relatives and a total of 17% when distant relatives are included. The MS group is predominantly of British (70%) and European (23%) origin. The urban-rural residence pattern analysis indicates no significant regional influence on the risk of developing MS.

Rationale The purposes of this study were to 1) conduct a review of neuropsychological (NP) outcomes after epilepsy surgery for DNET and 2) present pre/post-surgical NP results from a series of children with DNET. Methods First, a systematic literature review was conducted with specific inclusion criteria. Second, a review of DNET surgical patients seen at two tertiary-care hospitals using reliable change methods of NP functioning was conducted. Results Of 300 citations retrieved, 7 studies met criteria. Studies reported low average to average pre-surgical IQ. Engel Class I outcome was approximately 85%. Case Series: Thirteen children completed pre/post-surgical NP assessments. Pre-surgically, children demonstrated low average to average functioning. Post-surgically, few patients showed reliable change. One-third of children demonstrated psychological improvement. Conclusions NP outcome following DNET has not been well-described. Children with DNET demonstrate low average to average NP functioning pre-surgically, good seizure outcome, and stable NP functioning post-surgically.

Glioma cells in situ are surrounded by microglia, suggesting the potential of glioma-microglia interactions to produce various outcomes. As chemokines are important mediators of cell-cell communication, we sought first to identify commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage chemoattractant protein-1) messenger RNA to be expressed by the majority of glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which has low basal level of CCL2, to investigate the hypothesis that glioma-secreted CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 12-fold elevation of CCL2 have similar growth rate and invasive capacity as vector controls when cultured in isolation. However, in coculture with microglia in a three-dimensional collagen gel matrix, the invasiveness of CCL2-overexpressing clones was increased. Gene array analyses were then undertaken and they revealed that interleukin (IL)-6 was consistently increased in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated glioma invasiveness. Finally, we found that human glioma specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ cells. This study has uncovered a mechanism by which glioma cells exploit microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable malignant gliomas.

Background:Repetitively discharging neurons in epileptic foci have a high energy requirement that might be demonstrated histochemically as increased mitochondrial enzymatic activity in brain resections for epilepsy in children.Materials and Methods:Frozen sections were studied histochemically of 10 brain resections from 7 epileptic children, 2 months to 17 years of age. None had mitochondrial disease. Three patients had tuberous sclerosis (TS) or hemimegalencephy (HME). Tissues included hippocampus and neocortex. Oxidative enzymes were studied for respiratory chain complexes I, II, IV, using the muscle biopsy protocol. In addition, immunoreactivities of α-B-crystallin and transmission electron microscopy (EM) were performed.Results:Oxidative activities were variable in adjacent neurons within a field: a minority were intense, adjacent to neurons with weaker mitochondrial activity exhibiting poor contrast of the soma because of similar oxidative activity in surrounding neuropil. Endothelium of vessels uniformly exhibits strong activity. Alpha-B-crystallin reactivity was strong at these foci. EM confirmed an abundance of neuronal mitochondria with normal cristae. In TS and HME, many dysplastic neurons showed intense activity; balloon cells had sparse activity.Conclusions:Histochemistry of mitochondrial oxidative enzymes reveals scattered and clustered neurons with stronger activities than others at epileptic foci. Such intensely staining neurons may be functionally “hypermetabolic” but they do not signify mitochondrial disease. Individual intensely stained neurons might be epileptogenic, but do not denote an epileptogenic field in the same manner as α-B-crystallin, which also was strongly reactive in these foci.

Investigating the biology of oligodendroglioma and its characteristic combined deletion of chromosomal arms 1p and 19q, mediated by an unbalanced translocation, t(1;19)(q10;p10), has been hampered by the lack of cell lines that harbor these traits. We grew cells from 2 anaplastic oligodendrogliomas in serum-free conditions. Serial propagation and expansion led to the establishment of permanent cell lines that maintained the genetic signature of the parent oligodendrogliomas and displayed features of brain tumor stem cells in vitro. One line was established from a treatment-naïve tumor and the other from a temozolomide resistant recurrent tumor. These lines may be important tools for understanding the biology of oligodendrogliomas and the function of their defining genetic traits.

Summary Objective: To determine the clinical characteristics, surgical challenges, and outcome in children younger than 3 years of age undergoing epilepsy surgery in Canada. Methods: Retrospective data on patients younger than age 3 years who underwent epilepsy surgery at multiple centers across Canada from January 1987 to September 2005 were collected and analyzed. Results: There were 116 patients from eight centers. Seizure onset was in the first year of life in 82%, and mean age at first surgery was 15.8 months (1–35 months). Second surgeries were done in 27 patients, and a third surgery in 6. Etiologies were malformations of cortical development (57), tumor (22), Sturge-Weber syndrome (19), infarct (8), and other (10). Surgeries comprised 40 hemispheric operations, 33 cortical resections, 35 lesionectomies, 7 temporal lobectomies, and one callosotomy. There was one surgical mortality. The most common surgical complications (151 operations in 116 patients) were infection (17) and aseptic meningitis in 13. Of 107 patients with seizure outcome assessed more than one year postoperatively, 72 (67.3%) were seizure free (Engel I), 15(14%) had >90% improvement (Engel II), 12 had >50% improvement (Engel III), and 8 did not benefit from surgery (Engel IV). Development improved in 55.3% after surgery. Conclusion: Epilepsy surgery in children younger than 3 years of age is relatively safe and is effective in controlling seizures. Very young age is not a contraindication to surgery in children with refractory epilepsy, and early surgery may impact development positively.

Objective Platelet-derived growth factor (PDGF)–responsive neural precursors (PRPs; also known as oligodendrocyte progenitor cells) are one of the best characterized precursor cell populations of the rodent central nervous system. Yet little is known about the biology of human PRPs because of an apparent inability to culture and expand them in large numbers. This study was designed to establish an approach that allows direct comparisons between the biology of fetal and adult human PRPs, as a means to address potential differences in intrinsic myelin-production capabilities. Methods We used the neurosphere culture system, under low plating density, to isolate, culture, and compare the properties of fetal and adult human PRPs. Results PDGF stimulated fetal human PRPs to generate neurospheres that differentiated primarily into oligodendrocytes, which acquired myelin basic protein expression, as well as neurons and a small number of astrocytes. Together with PDGF, fibroblast growth factor 2 promoted fetal human PRP expansion. In contrast, adult human PRPs isolated from the corpus callosum required twice the culture period to generate neurospheres, which contained oligodendrocytes, as well as astrocytes, but not neurons. Strikingly, fibroblast growth factor 2 did not promote adult human PRP self-renewal. Interpretation Differences in the intrinsic proliferation, phenotype, and self-renewal properties of fetal and adult human PRPs suggest they are distinct populations, which may result in distinct myelin-production capabilities. Ann Neurol 2008;64:127–142

Microglia are resident immune cells within the central nervous system (CNS). They become activated following neurological insults and increase their expression of cytokines. Also elevated in CNS injuries are proteases, including matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). The spectrum of metalloproteinase members expressed by microglia and by the systemic leukocytes that infiltrate the injured CNS is unknown, as are their functions. We determined the levels of transcripts encoding all 24 MMPs, nine ADAMs, and their four physiological antagonists, tissue inhibitor of metalloproteinases (TIMPs), in human microglia, B and T cells, monocytes, and neutrophils. We found a distinct pattern for each immune subset and an enrichment of metalloproteinases in microglia compared with leukocytes. When microglia were activated, there was an upregulation of transcripts for nine metalloproteinases, and reduction of TIMP3. Activation of microglia also resulted in increased levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-10 protein in the conditioned media of cells. The amount of secreted TNF-a ,b ut not IL-1b or IL-10, was suppressed by BB94, a broad spectrum metalloproteinase inhibitor, and by TIMP3 but not TIMP1 or TIMP2. This inhibitory profile suggests the involvement of an ADAM member in TNF-a secretion. We conclude that microglia bear a metalloproteinase signature distinct from systemic cells, and that following activation, microglia upregulate TNF-a protein levels through a combination of elevated cytokine transcripts, increased metalloproteinase level and activity, and through the decrease of TIMP3. The results have implications for the regulation of neuroinflammation and its outcomes following CNS injuries. V C 2007 Wiley-Liss, Inc.

OBJECT Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care. METHODS This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation. RESULTS Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8–17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3–7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6–8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9–17.9 years) after treatment. CONCLUSIONS In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.

ETV is emerging as the treatment of choice for aqueductal stenosis caused by anatomic, inflammatory, and selected neoplastic etiologies. The technique has also proven useful in the pathologic diagnosis and treatment of these conditions. Long-term results of this procedure and comparison to standard shunting procedures are necessary to define indications for patients with pathologic findings in the intermediate response groups. Development of new studies for pre-operative assessment of CSF absorptive capacity and quantitative postoperative measures of ventriculostomy function would be invaluable additions to our ability to assess candidates for this procedure and their eventual outcome. Further study and technical refinements will, no doubt, lead to many more potential uses for these procedures in the treatment of hydrocephalus and its associated etiologies. The challenge for neuro-surgeons will be to define the operative indications and outcomes, while refining techniques for safely performing these useful procedures.

✓ Late failure following successful third ventriculostomy for obstructive hydrocephalus is rare, and death caused by failure of a previously successful third ventriculostomy has been reported only once. The authors present three patients who died as a result of increased intracranial pressure (ICP) after late failure of a third ventriculostomy. Through a collaborative effort, three patients were identified who had died following third ventriculostomy at one of the authors' institutions. A 13-year-old girl with neurofibromatosis Type 1 underwent third ventriculostomy for obstructive hydrocephalus caused by a tectal lesion. Three years later her condition deteriorated rapidly over the course of 6 hours and she was found dead at home. A 4-year-old boy treated with third ventriculostomy for aqueductal stenosis presented 2 years postoperatively with symptoms of increased ICP. This patient suffered a cardiorespiratory arrest while under observation and died despite external ventricular drainage. A 10-year-old boy with previous ventriculoperitoneal (VP) shunt placement underwent conversion to a third ventriculostomy and shunt removal. Eight months after the procedure his condition deteriorated, with evidence of raised ICP, and he underwent emergency insertion of another VP shunt, but remained in a vegetative state and died of complications. Neuropathological examinations in two cases demonstrated that the third ventriculostomy was not patent, and there was also evidence of increased ICP. Late failure of third ventriculostomy resulting in death is a rare complication. Delay in recognition of recurrent ICP symptoms and a false feeling of security on the part of family and caregivers because of the absence of a shunt and the belief that the hydrocephalus has been cured may contribute to fatal complications after third ventriculostomy. Patients with third ventriculostomies should be followed in a manner similar to patients with cerebrospinal fluid shunts.

Le service de neurochirurgie du Vancouver General Hospital a recu un nombre adeptes de la planche a neige souffrant de blessures serieuses a la tete hors de proportion avec celui des skieurs presentant de telles blessures. Le but de cette etude etait de determiner si les adeptes de la planche a neige avaient plus de blessures serieuses a la tete que les skieurs dans la region desservie par Vancouver. Methodes: Le registre des traumatismes de la Colombie-Britannique a ete consulte pour identifier les patients qui avaient subi des blessures a la tete en ski ou en planche a neige dans les centres de sports d'hiver de la Colombie-Britannique pendant la periode de janvier 1992 a decembre 1997. Les patients etaient inclus dans l'etude s'ils etaient admis a l'hopital et avaient eu une consultation en neurochirurgie. Resultats: Au total, 40 skieurs et 14 adeptes de la planche a neige rencontraient les criteres decrits ci-haut. Parmi les skieurs, 15% avaient subi une blessure severe a la tete selon le score GCS et 30% avaient subi une blessure moderee, par rapport a 29% des adeptes de la planche a neige qui avaient subi des blessures severes et 36% des blessures moderees. 60% des skieurs et 21% des adeptes de la planche a neige avaient subi une commotion cerebrale. Les adeptes de la planche a neige avaient subi une hemorragie intracrânienne dans 71% des cas par rapport a 28% des skieurs. Une crâniotomie a ete effectuee en urgence chez 10% des skieurs et 29% des adeptes de la planche a neige. Trois patients sont decedes de leurs blessures a la tete, dont un adepte de la planche a neige. Tous sauf un des skieurs survivants ont pu retourner chez eux, alors que quatre des 13 adeptes de la planche a neige survivants ont eu besoin de rehabilitation additionnelle pendant leur sejour a l'hopital ou d'un transfert a un autre hopital de soins aigus. Conclusions: Dans cette serie de cas, Les adeptes de la planche a neige ont subi plus de blessures severes a la tete que les skieurs et sont plus susceptibles que les skieurs d'avoir besoin d'une intervention intracrânienne. A notre avis, ceci indique que des mesures de securite additionnelles, surtout quant au port obligatoire du casque, devraient etre considerees par les centres de ski et leurs clients.

Surgical removal of cystic craniopharyngiomas in children is associated with significant operative morbidity and recurrence rates. The purpose of this study was to review our experience with a less invasive therapy, namely, intratumoral bleomycin, in the treatment of predominantly cystic craniopharyngiomas. All children with craniopharyngiomas treated at a tertiary care pediatric neurosurgical center since 1994, when bleomycin was first used, were reviewed retrospectively. Seven patients received intratumoral bleomycin therapy. Patients received 2–5 mg bleomycin per dose, 3 times per week, for 3–5 weeks as an initial course. Mean follow-up of these patients was 3 years. In 4 patients, treatment resulted in a significant decrease (>50%) in tumor size, which has remained stable. Two patients’ tumors progressed and underwent resection, and 1 patient had surgical removal because of persistent headaches, although no growth of residual tumor had been noted. One patient developed peritumoral edema as a result of bleomycin therapy. Intratumoral bleomycin is a useful alternative therapy for cystic craniopharyngiomas, and may control tumor growth and delay potentially harmful resection and/or radiotherapy in young children.

OBJECTIVE: The clinicopathological spectra of a dysembryoplastic neuroepithelial tumor (DNT) and a rosette-forming glioneuronal tumor (RGNT) are expanding. We report here the autopsy findings of a case of complex glioneuronal tumor with combined histological features of both a DNT and an RGNT. CLINICAL PRESENTATION: A 79-year-old man presented with a 1-month history of confusion and gait difficulties. A magnetic resonance imaging scan revealed obstructive hydrocephalus attributed to a mass in the posterior third ventricle. INTERVENTION: A third ventriculostomy was performed. Postoperatively, the mass remained unchanged in size for more than 14 months. Thirty-eight months after his initial manifestations, he experienced minor head trauma and was then hospitalized. Despite placement of an external ventricular drain and other supportive treatment, he deteriorated and died. A full autopsy was performed, with emphasis on the brain. The mass lesion and a few independent microfoci situated primarily around the third ventricle showed histological features of pilocytic astrocytoma with recurrent hemorrhage. Far more numerous were microfoci with histological features of a DNT, including floating neurons, as well as typical RGNT-associated, synaptophysin-positive rosettes and perivascular pseudorosettes. CONCLUSION: The advanced age of the patient, the coexisting histological features of the DNT and RGNT, and the distinctive anatomic distribution of the lesions, being centered on the third ventricle, may lend insight into the histogenetic relationship of a DNT, an RGNT, and mixed glioneuronal tumors.

Hemimegalencephaly (HME) is a hamartomatous malformation of one cerebral hemisphere. As this is a disorder of cellular growth and lineage, we sought evidence of an early ontogenetic disturbance of microtubular assembly or function.Three male infants with HME had brain resections for refractory epilepsy. One died postoperatively at 2.5 months and an autopsy was performed. Two were isolated cases and one has Proteus syndrome. The phosphorylated form of the microtubule-associated protein tau was studied, transmission electron microscopy (EM) was performed, and activation of the mTOR pathway was defined.The hippocampus and neocortex of HME exhibited cytoarchitectural abnormalities and intense tau immunoreactivity. The post-mortem non-HME hemisphere exhibited sparse dysmorphic tau-reactive cortical neurones, intense only in the cingulate gyrus, a few isolated dysmorphic white matter neurons and none in subcortical structures. Numerous enlarged and dysmorphic cells exhibited P-4E-BP1 and phosphoribosomal P-S6 immunoreactivity, indicating mTOR activation. Control brains were negative for tau expression and mTOR activation. EM in each case showed abundant lipid in neurones and astrocytic end-feet on capillaries, and well-preserved mitochondria; oil red O in frozen sections and semi-thin sections also showed lipid storage by light microscopy.Because HME tissue exhibited enhanced levels of phosphorylated tau protein and evidence of mTOR hyperactivation, we propose that the pathogenesis of HME may involve an early defect in microtubules, likely related to the AKT3 gene. Lipidosis of neurones and glia suggests metabolic impairment of yet undetermined type and relation to tauopathy in HME. Perinatal treatment of HME with everolimus theoretically is plausible.

OBJECTIVE The efficacy of endoscopic third ventriculostomy (ETV) for the treatment of pediatric hydrocephalus has been extensively reported in the literature. However, ETV-related long-term outcome data are lacking for the adult hydrocephalus population. The objective of the present study was to assess the role of ETV as a primary or secondary treatment for hydrocephalus in adults. METHODS The authors performed a retrospective chart review of all adult patients (age ≥ 18 years) with symptomatic hydrocephalus treated with ETV in Calgary, Canada, over a span of 20 years (1994–2014). Patients were dichotomized into a primary or secondary ETV cohort based on whether ETV was the initial treatment modality for the hydrocephalus or if other CSF diversion procedures had been previously attempted respectively. Primary outcomes were subjective patient-reported clinical improvement within 12 weeks of surgery and the need for any CSF diversion procedures after the initial ETV during the span of the study. Categorical and actuarial data analysis was done to compare the outcomes of the primary versus secondary ETV cohorts. RESULTS A total of 163 adult patients with symptomatic hydrocephalus treated with ETV were identified and followed over an average of 98.6 months (range 0.1–230.4 months). All patients presented with signs of intracranial hypertension or other neurological symptoms. The primary ETV group consisted of 112 patients, and the secondary ETV consisted of 51 patients who presented with failed ventriculoperitoneal (VP) shunts. After the initial ETV procedure, clinical improvement was reported more frequently by patients in the primary cohort (87%) relative to those in the secondary ETV cohort (65%, p = 0.001). Additionally, patients in the primary ETV group required fewer reoperations (p < 0.001), with cumulative ETV survival time favoring this primary ETV cohort over the course of the follow-up period (p < 0.001). Fifteen patients required repeat ETV, with all but one experiencing successful relief of symptoms. Patients in the secondary ETV cohort also had a higher incidence of complications, with one occurring in 8 patients (16%) compared with 2 in the primary ETV group (2%; p = 0.010), although most complications were minor. CONCLUSIONS ETV is an effective long-term treatment for selected adult patients with hydrocephalus. The overall ETV success rate when it was the primary treatment modality for adult hydrocephalus was approximately 87%, and 99% of patients experience symptomatic improvement after 2 ETVs. Patients in whom VP shunt surgery fails prior to an ETV have a 22% relative risk of ETV failure and an almost eightfold complication rate, although mostly minor, when compared with patients who undergo a primary ETV. Most ETV failures occur within the first 7 months of surgery in patients treated with primary ETV, but the time to failure is more prolonged in patients who present with failed previous shunts.

Pediatric neuroscience nurses deal with many children with hydrocephalus. This paper will provide a review of hydrocephalus with a specific focus on third ventriculostomy. Endoscopic third ventriculostomy (ETV) is an accepted treatment option for patients with obstructive hydrocephalus. At the Alberta Children's Hospital in Calgary, Alberta, we have been performing ETV for 15 years. This experience has helped us better understand the complications and benefits of ETV. The author will provide data on the complications specific to ETV in pediatric patients at the Alberta Children's Hospital. A case report comparing neurocognitive testing before and after ETV will be shared. An additional case report of a patient with a spontaneous third ventriculostomy will help illustrate our understanding of the natural history of hydrocephalus.

Summary Purpose: High frequency oscillations (HFOs) >200 Hz are believed to be associated with epileptic processes. The spatial distribution of HFOs and their evolution over time leading up to seizure onset is unknown. Also, recording HFOs through conventional intracranial electrodes is not well established. We therefore wished to determine whether HFOs could be recorded using commercially available depth macroelectrodes. We also examined the spatial distribution and temporal progression of HFOs during the transition to seizure activity. Methods: Intracranial electroencephalography (EEG) recordings of 19 seizures were obtained from seven patients with temporal lobe epilepsy using commercial depth or subdural electrodes. EEG recordings were analyzed for frequency content in five spectral bands spanning DC-500 Hz. We examined the spatial distribution of the different spectral bands 5 s before and 5 s after seizure onset. Temporal changes in the spectral bands were studied in the 30-s period leading up to seizure onset. Results: Three main observations were made. First, HFOs (100–500 Hz) can be recorded using commercial depth and subdural grid electrodes. Second, HFOs, but not

The complexity of multiple sclerosis (MS) genetics has made the search for novel genes using traditional sharing methods problematic. In order to minimize the genetic heterogeneity present in the MS population we have screened the Canadian MS population for individuals belonging to the Hutterite Brethren. Seven Hutterites with clinically definite MS were ascertained and are related to a common founder by eight generations. Six of the 7 affected individuals and 21 of their unaffected family members (total = 27) were genotyped for 807 markers. Haplotypes were then inspected for sharing among the six MS patients. There were three haplotypes shared among all six MS patients. The haplotypes were located at 2q34-35, 4q31-32, and 17p13. An additional 15 haplotypes were shared among five of the six Hutterites MS patients. The HLA Class II region was one of the highlighted regions; however, the shared MHC haplotype bore the DRB1*04 allele and not the MS-associated DRB1*15 allele providing further evidence of the complexity of the MHC. Additional genotyping to refine the haplotypes followed by screening for potential variants may lead to the identification of a novel MS susceptibility gene(s) in this unique population.

Objectif : La resection endoscopique des kystes colloides comme alternative a la resection microchirurgicale et a l'aspiration stereotaxique est realisee depuis 1982. A ce jour, peu d'etudes comparant ces interventions ont ete publiees. Dans cette etude, nous presentons la plus grande serie de resections endoscopiques publiee a ce jour et nous comparons les resultats a ceux d'une cohorte de patients ayant subi une resection microchirurgicale dans la meme institution. Methodes: Nous avons procede a une revision des dossiers de tous les patients qui ont subi une resection d'un kyste colloide entre 1991 et 2004 dans la region sanitaire de Calgary. Nous avons compare les patients traites par resection endoscopique a ceux traites par resection microchirurgicale. Resultats: Vingt-cinq interventions endoscopiques et neuf interventions microchirurgicales ont ete pratiquees. La resection a ete complete dans 24 des 25 interventions du groupe traite par endoscopie et dans les 9 interventions pratiquees par microchirurgie. Le temps operatoire etait plus court chez les patients traites par endoscopie, soit une duree moyenne de 104 minutes versus 217 minutes pour le groupe traite par microchirurgie, et le sejour hospitalier etait plus court, soit 3,8 jours par rapport a 8,4 jours, pour le groupe traite par microchirurgie. Un patient du groupe traite par endoscopie a subi une complication (hemiparesie/embolie pulmonaire). Trois patients du groupe traite par microchirurgie ont subi des complications (crise convulsive, ventriculite/infection du volet osseux et perte de memoire transitoire). Il y a eu une recidive dans chaque groupe, toutes deux decouvertes au cours du suivi, 5 ans apres la chirurgie. La duree moyenne du suivi etait de 38 mois pour le groupe traite par endoscopie et de 33 mois pour le groupe traite par microchirurgie. Conclusion: La resection endoscopique de kystes colloides comporte significativement moins de risques de complications que la resection microchirurgicale et donne des resultats equivalents. Le temps operatoire et la duree d'hospitalisation sont significativement plus courts pour la resection endoscopique.