George M. Ibrahim

Anterior Cervical Discectomy with Arthroplasty versus Arthrodesis for Single-Level Cervical Spondylosis: A Systematic Review and Meta-Analysis

Objective To estimate the effectiveness of anterior cervical discectomy with arthroplasty (ACDA) compared to anterior cervical discectomy with fusion (ACDF) for patient-important outcomes for single-level cervical spondylosis. Data sources Electronic databases (MEDLINE, EMBASE, Cochrane Register for Randomized Controlled Trials, BIOSIS and LILACS), archives of spine meetings and bibliographies of relevant articles. Study selection We included RCTs of ACDF versus ACDA in adult patients with single-level cervical spondylosis reporting at least one of the following outcomes: functionality, neurological success, neck pain, arm pain, quality of life, surgery for adjacent level degeneration (ALD), reoperation and dysphonia/dysphagia. We used no language restrictions. We performed title and abstract screening and full text screening independently and in duplicate. Data synthesis We used random-effects model to pool data using mean difference (MD) for continuous outcomes and relative risk (RR) for dichotomous outcomes. We used GRADE to evaluate the quality of evidence for each outcome. Results Of 2804 citations, 9 articles reporting on 9 trials (1778 participants) were eligible. ACDA is associated with a clinically significant lower incidence of neurologic failure (RR  = 0.53, 95% CI  = 0.37–0.75, p = 0.0004) and improvement in the Neck pain visual analogue scale (VAS) (MD  = 6.56, 95% CI  = 3.22–9.90, p = 0.0001; Minimal clinically important difference (MCID)  = 2.5. ACDA is associated with a statistically but not clinically significant improvement in Arm pain VAS and SF-36 physical component summary. ACDA is associated with non-statistically significant higher improvement in the Neck Disability Index Score and lower incidence of ALD requiring surgery, reoperation, and dysphagia/dysphonia. Conclusions There is no strong evidence to support the routine use of ACDA over ACDF in single-level cervical spondylosis. Current trials lack long-term data required to assess safety as well as surgery for ALD. We suggest that ACDA in patients with single level cervical spondylosis is an option although its benefits and indication over ACDF remain in question.

Resilience of developing brain networks to interictal epileptiform discharges is associated with cognitive outcome

The effects of interictal epileptiform discharges on neurocognitive development in children with medically-intractable epilepsy are poorly understood. Such discharges may have a deleterious effect on the brains intrinsic connectivity networks, which reflect the organization of functional networks at rest, and in turn on neurocognitive development. Using a combined functional magnetic resonance imaging-magnetoencephalography approach, we examine the effects of interictal epileptiform discharges on intrinsic connectivity networks and neurocognitive outcome. Functional magnetic resonance imaging was used to determine the location of regions comprising various intrinsic connectivity networks in 26 children (7-17 years), and magnetoencephalography data were reconstructed from these locations. Inter-regional phase synchronization was then calculated across interictal epileptiform discharges and graph theoretical analysis was applied to measure event-related changes in network topology in the peri-discharge period. The magnitude of change in network topology (network resilience/vulnerability) to interictal epileptiform discharges was associated with neurocognitive outcomes and functional magnetic resonance imaging networks using dual regression. Three main findings are reported: (i) large-scale network changes precede and follow interictal epileptiform discharges; (ii) the resilience of network topologies to interictal discharges is associated with stronger resting-state network connectivity; and (iii) vulnerability to interictal discharges is associated with worse neurocognitive outcomes. By combining the spatial resolution of functional magnetic resonance imaging with the temporal resolution of magnetoencephalography, we describe the effects of interictal epileptiform discharges on neurophysiological synchrony in intrinsic connectivity networks and establish the impact of interictal disruption of functional networks on cognitive outcome in children with epilepsy. The association between interictal discharges, network changes and neurocognitive outcomes suggests that it is of clinical importance to suppress discharges to foster more typical brain network development in children with focal epilepsy.

Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis.

Objective To perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery. Data Sources Electronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions. Study Selection We included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion. Data Extraction One author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes. Data Synthesis To identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable. Results Of 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2–8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1–24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4–7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8–13.5, p = 0.002) were associated with a good postoperative seizure outcome. Conclusions Small retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review.

Impaired development of intrinsic connectivity networks in children with medically intractable localization-related epilepsy

Typical childhood development is characterized by the emergence of intrinsic connectivity networks (ICNs) by way of internetwork segregation and intranetwork integration. The impact of childhood epilepsy on the maturation of ICNs is, however, poorly understood. The developmental trajectory of ICNs in 26 children (8–17 years) with localization‐related epilepsy and 28 propensity‐score matched controls was evaluated using graph theoretical analysis of whole brain connectomes from resting‐state functional magnetic resonance imaging (fMRI) data. Children with epilepsy demonstrated impaired development of regional hubs in nodes of the salience and default mode networks (DMN). Seed‐based connectivity and hierarchical clustering analysis revealed significantly decreased intranetwork connections, and greater internetwork connectivity in children with epilepsy compared to controls. Significant interactions were identified between epilepsy duration and the expected developmental trajectory of ICNs, indicating that prolonged epilepsy may cause progressive alternations in large‐scale networks throughout childhood. DMN integration was also associated with better working memory, whereas internetwork segregation was associated with higher full‐scale intelligence quotient scores. Furthermore, subgroup analyses revealed the thalamus, hippocampus, and caudate were weaker hubs in children with secondarily generalized seizures, relative to other patient subgroups. Our findings underscore that epilepsy interferes with the developmental trajectory of brain networks underlying cognition, providing evidence supporting the early treatment of affected children. Hum Brain Mapp 35:5686–5700, 2014.

Dynamic modulation of epileptic high frequency oscillations by the phase of slower cortical rhythms

Pathological high frequency oscillations (pHFOs) have been proposed to be robust markers of epileptic cortex. Oscillatory activity below this frequency range has been shown to be modulated by phase of lower frequency oscillations. Here, we tested the hypothesis that dynamic cross-frequency interactions involving pHFOs are concentrated within the epileptogenic cortex. Intracranial electroencephalographic recordings from 17 children with medically-intractable epilepsy secondary to focal cortical dysplasia were obtained. A time-resolved analysis was performed to determine topographic concentrations and dynamic changes in cross-frequency amplitude-to-phase coupling (CFC). CFC between pHFOs and the phase of theta and alpha rhythms was found to be significantly elevated in the seizure-onset zone compared to non-epileptic regions (p<0.01). Data simulations showed that elevated CFC could not be attributed to the presence of sharp transients or other signal properties. The phase of low frequency oscillations at which pHFO amplitudes were maximal was inconsistent at seizure initiation, yet consistently at the trough of the low frequency rhythm at seizure termination. Amplitudes of pHFOs were most significantly modulated by the phase of alpha-band oscillations (p<0.01). These results suggest that increased CFC between pHFO amplitude and alpha phase may constitute a marker of epileptogenic brain areas and may be relevant for understanding seizure dynamics.

Neocortical pathological high-frequency oscillations are associated with frequency-dependent alterations in functional network topology

Synchronization of neural oscillations is thought to integrate distributed neural populations into functional cell assemblies. Epilepsy is widely regarded as a disorder of neural synchrony. Knowledge is scant, however, regarding whether ictal changes in synchrony involving epileptogenic cortex are expressed similarly across various frequency ranges. Cortical regions involved in epileptic networks also exhibit pathological high-frequency oscillations (pHFOs, >80 Hz), which are increasingly utilized as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to epileptic network connectivity. By calculating phase-locking values among intracranial electrodes implanted in children with intractable epilepsy, we constructed ictal connectivity networks and performed graph theoretical analysis to characterize their network properties at distinct frequency bands. Ictal data from 17 children were analyzed with a hierarchical mixed-effects model adjusting for patient-level covariates. Epileptogenic cortex was defined in two ways: 1) a hypothesis-driven method using the visually defined seizure-onset zone and 2) a data-agnostic method using the high-frequency amplitude of each electrode. Epileptogenic cortex exhibited a logarithmic decrease in interregional functional connectivity at high frequencies (>30 Hz) during seizure initiation and propagation but not at termination. At slower frequencies, conversely, epileptogenic cortex expressed a relative increase in functional connectivity. Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding theoretical support for their utility in the presurgical evaluation of intractable epilepsy. The view that abnormal network synchronization plays a critical role in ictogenesis and seizure dynamics is supported by the observation that functional isolation of epileptogenic cortex at high frequencies is absent at seizure termination.

Attributing Hypodensities on CT to Angiographic Vasospasm Is Not Sensitive and Unreliable

Background and Purpose— The presence of low-density areas on CT is used in clinical decision-making regarding treatment of angiographic vasospasm as well as in research as a surrogate marker for severity of angiographic vasospasm. We assess the interobserver variability in attributing hypodensities on CT to angiographic vasospasm-related delayed ischemic neurological deficit. Methods— Three experienced reviewers, 2 neurosurgeons, and a neuroradiologist independently reviewed CT scans of 413 patients enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) trial, who universally underwent catheter angiography to determine severity of angiographic vasospasm. Interobserver variability was calculated using the &kgr; statistic and the &khgr;2 test was used to determine associations between dichotomized outcomes. Results— There was considerable interobserver variability in attributing CT hypodensities to vasospasm-related delayed ischemic neurological deficit (&kgr;=0.51–0.78; 95% CI, 0.35–0.90). Patients with hypodensities attributed to delayed ischemic neurological deficit were significantly more likely to have severe angiographic vasospasm (P=0.001), but a substantial proportion of these patients (19%) also had mild or no spasm. CT hypodensities had a sensitivity and specificity of 41% and 93%, respectively, in identifying patients with severe angiographic vasospasm, even with expert consensus that these represent angiographic vasospasm-related delayed ischemic neurological deficit. Conclusions— We find considerable interobserver variability in attributing CT hypodensities to angiographic vasospasm and propose that they may not be a robust marker of severity of angiographic vasospasm, even with unanimous expert agreement that they are a result of vasospasm-related delayed ischemic neurological deficit. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00111085.

Clinical, laboratory, and radiographic predictors of the occurrence of seizures following aneurysmal subarachnoid hemorrhage

OBJECT At present, the administration of prophylactic antiepileptic medication following aneurysmal subarachnoid hemorrhage (SAH) is controversial, and the practice is heterogeneous. Here, the authors sought to inform clinical decision making by identifying factors associated with the occurrence of seizures following aneurysm rupture. METHODS Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring after Subarachnoid Hemorrhage), a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. The association among clinical, laboratory, and radiographic covariates and the occurrence of seizures following SAH were determined. Covariates with a significance level of p < 0.20 on univariate analysis were entered into a multivariate logistic regression model. Receiver operating characteristic (ROC) curve analysis was used to define optimal predictive thresholds. RESULTS Of the 413 patients enrolled in the study, 57 (13.8%) had at least 1 seizure following SAH. On univariate analysis, a World Federation of Neurosurgical Societies grade of IV-V, a greater subarachnoid clot burden, and the presence of midline shift and subdural hematomas were associated with seizure activity. On multivariate analysis, only a subarachnoid clot burden (OR 2.76, 95% CI 1.39-5.49) and subdural hematoma (OR 5.67, 95% CI 1.56-20.57) were associated with seizures following SAH. Using ROC curve analysis, the optimal predictive cutoff for subarachnoid clot burden was determined to be 21 (of a possible 30) on the Hijdra scale (area under the curve 0.63). CONCLUSIONS A greater subarachnoid clot burden and subdural hematoma are associated with the occurrence of seizures after aneurysm rupture. These findings may help to identify patients at greatest risk for seizures and guide informed decisions regarding the prescription of prophylactic anticonvulsive therapy. Clinical trial registration no.: NCT00111085 (ClinicalTrials.gov).

Magnetoencephalography-guided resection of epileptogenic foci in children

OBJECT Resective surgery is increasingly used in the management of pediatric epilepsy. Frequently, invasive monitoring with subdural electrodes is required to adequately map the epileptogenic focus. The risks of invasive monitoring include the need for 2 operations, infection, and CSF leak. The aim of this study was to evaluate the feasibility and outcomes of resective epilepsy surgery guided by magnetoencephalography (MEG) in children who would have otherwise been candidates for electrode implantation. METHODS The authors reviewed the records of patients undergoing resective epilepsy surgery at the Hospital for Sick Children between 2001 and 2010. They identified cases in which resections were based on MEG data and no intracranial recordings were performed. Each patients chart was reviewed for presentation, MRI findings, MEG findings, surgical procedure, pathology, and surgical outcome. RESULTS Sixteen patients qualified for the study. All patients had localized spike clusters on MEG and most had abnormal findings on MRI. Resection was carried out in each case based on the MEG data linked to neuronavigation and supplemented with intraoperative neuromonitoring. Overall, 62.5% of patients were seizure free following surgery, and 20% of patients experienced an improvement in seizures without attaining seizure freedom. In 2 cases, additional surgery was performed subsequently with intracranial monitoring in attempts to obtain seizure control. CONCLUSIONS MEG is a viable alternative to invasive monitoring with intracranial electrodes for planning of resective surgery in carefully selected pediatric patients with localization-related epilepsy. Good candidates for this approach include patients who have a well-delineated, localized spike cluster on MEG that is concordant with findings of other preoperative evaluations and patients with prior brain pathologies that make the implantation of subdural and depth electrodes somewhat problematic.

Disruption of Rolandic Gamma-Band Functional Connectivity by Seizures is Associated with Motor Impairments in Children with Epilepsy

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits.