Hemispherectomy at The Hospital for Sick Children: expanded indications and lessons learned over 35 years.

OBJECTIVE: Functional hemispherectomy is an effective surgical intervention for select patients with drug-resistant epilepsy. The last several decades have seen dramatic evolutions in preoperative evaluation, surgical techniques, and postoperative care. Here, the authors present a retrospective review of the medical records of 146 children who underwent hemispherectomy between 1987 and 2022 at The Hospital for Sick Children, providing a unique overview of the evolution of the procedure and patient outcomes over 35 years. METHODS: The medical records of all children who underwent hemispherectomy at The Hospital for Sick Children between 1987 and 2022 were reviewed. Demographic information, preoperative clinical features, short-term and long-term seizure outcomes, and details regarding postoperative complications were recorded. RESULTS: The seizure outcomes of 146 children were analyzed. There were 68 females and 78 males with a mean age of 5.08 years, 123 of whom demonstrated seizure freedom (Engel class IA) in the short-term postoperative follow-up period and 89 in the long term. The effectiveness of hemispherectomy in achieving long-term seizure control has improved over time (ß = 0.06, p < 0.001). Factors associated with overall seizure freedom included younger age at the time of hemispherectomy and stroke as the etiology of seizures, as well as complete disconnection during the first surgery. Additionally, the etiologies of epilepsy for which hemispherectomy is performed have expanded over time, while complication rates have remained unchanged. CONCLUSIONS: Hemispherectomy is an increasingly effective treatment for certain cases of drug-resistant epilepsy. The etiologies of epilepsy for which hemispherectomy is performed are broadening, with no change in its safety profile. Seizure outcomes are better when the etiology of epilepsy is an ischemic injury, and the most common complication after the procedure is hydrocephalus. These findings reinforce the ongoing use of hemispherectomy as a safe and effective treatment option for certain individuals with drug-resistant epilepsy, support its application to a broader range of etiologies, and highlight areas of future investigation.

Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas.

BACKGROUND AND OBJECTIVES: Gelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. METHODS: Children who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. RESULTS: Twelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DISCUSSION: Successful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

Postoperative cerebellar mutism syndrome is an acquired Autism-like network disturbance.

BACKGROUND: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. METHODS: In this study, we analyzed post-operative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and paediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n=427). RESULTS: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the paediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours. CONCLUSIONS: Our findings indicate that CMS-associated lesions result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

Surgical targeting of large hypothalamic hamartomas and seizure-freedom following MR-guided laser interstitial thermal therapy.

BACKGROUND: Large hypothalamic hamartomas (HH) are often associated with difficult-to-treat, refractory seizures. Although magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a useful tool to treat these challenging lesions, postoperative outcomes are variable and potentially related to differences in surgical targeting. PURPOSE: We sought to identify differences in the anatomic localization of laser ablations that either did or did not result in seizure freedom. METHODS: Four children who underwent MRgLITT for large HH (3 seizure-free and 1 not seizure-free) were included in the analysis. Ablation volumes were segmented, normalized, and overlaid on a high-resolution hypothalamic atlas. For each lesion, the size, spatial extent, and degree of overlap with key hypothalamic nuclei and surrounding brain regions were computed and compared between ablations that did and did not result in seizure freedom. RESULTS: Ablation masks that resulted in seizure freedom were smaller and located more centrally than the ablation mask that did not. In addition, ablation masks that resulted in seizure freedom overlapped with regions including the paraventricular nucleus, the posterior hypothalamus and the zona incerta, fornix, and mammillothalamic tract, whereas the single non-seizure-free ablation did not. CONCLUSION: Differences in the size, position, and anatomical localization of ablation volumes may be a potential contributor to the variability in postoperative outcomes of large HH treated with MRgLITT. A novel, high-resolution MRI atlas of the hypothalamus identifies a number of regions at the interface of large HH that are preferentially disconnected in seizure-free patients. This method of anatomical localization not only serves as a potential clinical tool for surgical targeting but may also provide novel insights into the mechanisms of epileptogenesis in hypothalamic hamartomas.

Brainstem Associated Somatosensory Evoked Potentials and Response to Vagus Nerve Stimulation: An Investigation of the Vagus Afferent Network.

Despite decades of clinical usage, selection of patients with drug resistant epilepsy who are most likely to benefit from vagus nerve stimulation (VNS) remains a challenge. The mechanism of action of VNS is dependent upon afferent brainstem circuitry, which comprises a critical component of the Vagus Afferent Network (VagAN). To evaluate the association between brainstem afferent circuitry and seizure response, we retrospectively collected intraoperative data from sub-cortical recordings of somatosensory evoked potentials (SSEP) in 7 children with focal drug resistant epilepsy who had failed epilepsy surgery and subsequently underwent VNS. Using multivariate linear regression, we demonstrate a robust negative association between SSEP amplitude (p < 0.01), and seizure reduction. There was no association between SSEP latency and seizure outcomes. Our findings provide novel insights into the mechanism of VNS and inform our understanding of the importance of brainstem afferent circuitry within the VagAN for seizure responsiveness following VNS.

Technical and radiographic considerations for magnetic resonance imaging-guided focused ultrasound capsulotomy.

OBJECTIVE: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is an emerging treatment modality that enables incisionless ablative neurosurgical procedures. Bilateral MRgFUS capsulotomy has recently been demonstrated to be safe and effective in treating obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Preliminary evidence has suggested that bilateral MRgFUS capsulotomy can present increased difficulties in reaching lesional temperatures as compared to unilateral thalamotomy. The authors of this article aimed to study the parameters associated with successful MRgFUS capsulotomy lesioning and to present longitudinal radiographic findings following MRgFUS capsulotomy. METHODS: Using data from 22 attempted MRgFUS capsulotomy treatments, the authors investigated the relationship between various sonication parameters and the maximal temperature achieved at the intracranial target. Lesion volume and morphology were analyzed longitudinally using structural and diffusion tensor imaging. A retreatment procedure was attempted in one patient, and their postoperative imaging is presented. RESULTS: Skull density ratio (SDR), skull thickness, and angle of incidence were significantly correlated with the maximal temperature achieved. MRgFUS capsulotomy lesions appeared similar to those following MRgFUS thalamotomy, with three concentric zones observed on MRI. Lesion volumes regressed substantially over time following MRgFUS. Fractional anisotropy analysis revealed a disruption in white matter integrity, followed by a gradual return to near-baseline levels concurrent with lesion regression. In the patient who underwent retreatment, successful bilateral lesioning was achieved, and there were no adverse clinical or radiographic events. CONCLUSIONS: With the current iteration of MRgFUS technology, skull-related parameters such as SDR, skull thickness, and angle of incidence should be considered when selecting patients suitable for MRgFUS capsulotomy. Lesions appear to follow morphological patterns similar to what is seen following MRgFUS thalamotomy. Retreatment appears to be safe, although additional cases will be necessary to further evaluate the associated safety profile.

Identification of neural networks preferentially engaged by epileptogenic mass lesions through lesion network mapping analysis.

Lesion network mapping (LNM) has been applied to true lesions (e.g., cerebrovascular lesions in stroke) to identify functionally connected brain networks. No previous studies have utilized LNM for analysis of intra-axial mass lesions. Here, we implemented LNM for identification of potentially vulnerable epileptogenic networks in mass lesions causing medically-refractory epilepsy (MRE). Intra-axial brain lesions were manually segmented in patients with MRE seen at our institution (EL_INST). These lesions were then normalized to standard space and used as seeds in a high-resolution normative resting state functional magnetic resonance imaging template. The resulting connectivity maps were first thresholded (pBonferroni_cor < 0.05) and binarized; the thresholded binarized connectivity maps were subsequently summed to produce overall group connectivity maps, which were compared with established resting-state networks to identify potential networks prone to epileptogenicity. To validate our data, this approach was also applied to an external dataset of epileptogenic lesions identified from the literature (EL_LIT). As an additional exploratory analysis, we also segmented and computed the connectivity of institutional non-epileptogenic lesions (NEL_INST), calculating voxel-wise odds ratios (VORs) to identify voxels more likely to be functionally-connected with EL_INST versus NEL_INST. To ensure connectivity results were not driven by anatomical overlap, the extent of lesion overlap between EL_INST, and EL_LIT and NEL_INST was assessed using the Dice Similarity Coefficient (DSC, lower index ~ less overlap). Twenty-eight patients from our institution were included (EL_INST: 17 patients, 17 lesions, 10 low-grade glioma, 3 cavernoma, 4 focal cortical dysplasia; NEL_INST: 11 patients, 33 lesions, all brain metastases). An additional 23 cases (25 lesions) with similar characteristics to the EL_INST data were identified from the literature (EL_LIT). Despite minimal anatomical overlap of lesions, both EL_INST and EL_LIT showed greatest functional connectivity overlap with structures in the Default Mode Network, Frontoparietal Network, Ventral Attention Network, and the Limbic Network-with percentage volume overlap of 19.5%, 19.1%, 19.1%, and 12.5%, respectively-suggesting them as networks consistently engaged by epileptogenic mass lesions. Our exploratory analysis moreover showed that the mesial frontal lobes, parahippocampal gyrus, and lateral temporal neocortex were at least twice as likely to be functionally connected with the EL_INST compared to the NEL_INST group (i.e. Peak VOR > 2.0); canonical resting-state networks preferentially engaged by EL_INSTs were the Limbic and the Frontoparietal Networks (Mean VOR > 1.5). In this proof of concept study, we demonstrate the feasibility of LNM for intra-axial mass lesions by showing that ELs have discrete functional connections and may preferentially engage in discrete resting-state networks. Thus, the underlying normative neural circuitry may, in part, explain the propensity of particular lesions toward the development of MRE. If prospectively validated, this has ramifications for patient counseling along with both approach and timing of surgery for lesions in locations prone to development of MRE.

Predicting response to psychiatric surgery: a systematic review of neuroimaging findings.

Background: Psychiatric surgery, including deep brain stimulation and stereotactic ablation, is an important treatment option in severe refractory psychiatric illness. Several large trials have demonstrated response rates of approximately 50%, underscoring the need to identify and select responders preoperatively. Recent advances in neuroimaging have brought this possibility into focus. We systematically reviewed the psychiatric surgery neuroimaging literature to assess the current state of evidence for preoperative imaging predictors of response. Methods: We performed this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) frameworks, and preregistered it using PROSPERO. We systematically searched the Medline, Embase and Cochrane databases for studies reporting preoperative neuroimaging analyses correlated with clinical outcomes in patients who underwent psychiatric surgery. We recorded and synthesized the methodological details, imaging results and clinical correlations from these studies. Results: After removing duplicates, the search yielded 8388 unique articles, of which 7 met the inclusion criteria. The included articles were published between 2001 and 2018 and reported on the outcomes of 101 unique patients. Of the 6 studies that reported significant findings, all identified clusters of hypermetabolism, hyperconnectivity or increased size in the frontostriatal limbic circuitry. Limitations: The included studies were few and highly varied, spanning 2 decades. Conclusion: Although few studies have analyzed preoperative imaging for predictors of response to psychiatric surgery, we found consistency among the reported results: most studies implicated overactivity in the frontostriatal limbic network as being correlated with clinical response. Larger prospective studies are needed. Registration: www.crd.york.ac.uk/prospero/display_record.php?RecordID=131151.

The anterior limb of the internal capsule: Anatomy, function, and dysfunction.

The last two decades have seen a re-emergence of neurosurgery for severe, refractory psychiatric diseases, largely due to the advent of more precise and safe operative techniques. Nevertheless, the optimal targets for these surgeries remain a matter of debate, and are often grandfathered from experiences in the late 20th century. To better explore the rationale for one target in particular - the anterior limb of the internal capsule (ALIC) - we comprehensively reviewed all available literature on its role in the pathophysiology and treatment of mental illness. We first provide an overview of its functional anatomy, followed by a discussion on its role in several prevalent psychiatric diseases. Given its structural integration into the limbic system and involvement in a number of cognitive and emotional processes, the ALIC is a robust target for surgical treatment of refractory psychiatric diseases. The advent of novel neuroimaging techniques, coupled with image-guided therapeutics and neuromodulatory treatments, will continue to enable study on the ALIC in mental illness.

Lesion Network Localization of Seizure Freedom following MR-guided Laser Interstitial Thermal Ablation.

Treatment-resistant epilepsy is a common and debilitating neurological condition, for which neurosurgical cure is possible. Despite undergoing nearly identical ablation procedures however, individuals with treatment-resistant epilepsy frequently exhibit heterogeneous outcomes. We hypothesized that treatment response may be related to the brain regions to which MR-guided laser ablation volumes are functionally connected. To test this, we mapped the resting-state functional connectivity of surgical ablations that either resulted in seizure freedom (N = 11) or did not result in seizure freedom (N = 16) in over 1,000 normative connectomes. There was no difference seizure outcome with respect to the anatomical location of the ablations, and very little overlap between ablation areas was identified using the Dice Index. Ablations that did not result in seizure-freedom were preferentially connected to a number of cortical and subcortical regions, as well as multiple canonical resting-state networks. In contrast, ablations that led to seizure-freedom were more functionally connected to prefrontal cortices. Here, we demonstrate that underlying normative neural circuitry may in part explain heterogenous outcomes following ablation procedures in different brain regions. These findings may ultimately inform target selection for ablative epilepsy surgery based on normative intrinsic connectivity of the targeted volume.

Electroencephalography in Psychiatric Surgery: Past Use and Future Directions.

The last two decades have seen a re-emergence of surgery for intractable psychiatric disease, in large part due to increased use of deep brain stimulation. The development of more precise, image-guided, less invasive interventions has improved the safety of these procedures, even though the relative merits of modulation at various targets remain under investigation. With an increase in the number and type of interventions for modulating mood/anxiety circuits, the need for biomarkers to guide surgeries and predict treatment response is as critical as ever. Electroencephalography (EEG) has a long history in clinical neurology, cognitive neuroscience, and functional neurosurgery, but has limited prior usage in psychiatric surgery. MEDLINE, Embase, and Psyc-INFO searches on the use of EEG in guiding psychiatric surgery yielded 611 articles, which were screened for relevance and quality. We synthesized three important themes. First, considerable evidence supports EEG as a biomarker for response to various surgical and non-surgical therapies, but large-scale investigations are lacking. Second, intraoperative EEG is likely more valuable than surface EEG for guiding target selection, but comes at the cost of greater invasiveness. Finally, EEG may be a promising tool for objective functional feedback in developing "closed-loop" psychosurgeries, but more systematic investigations are required.

Presurgical and Intraoperative Augmented Reality in Neuro-Oncologic Surgery: Clinical Experiences and Limitations.

Virtual reality (VR) and augmented reality (AR) represent novel adjuncts for neurosurgical planning in neuro-oncology. In addition to established use in surgical and medical training, VR/AR are gaining traction for clinical use preoperatively and intraoperatively. To understand the utility of VR/AR in the clinical setting, we conducted a literature search in Ovid MEDLINE and EMBASE with various search terms designed to capture the use of VR/AR in neurosurgical procedures for resection of cranial tumors. The search retrieved 302 articles, of which 35 were subjected to full-text review; 19 full-text articles were included in the review. Key findings highlighted by the individual authors were extracted and summarized into themes to present the value of VR/AR in the clinical setting. These studies included various VR/AR systems applied to surgeries involving heterogeneous pathologies and outcome measures. Overall, VR/AR were found to be qualitatively advantageous due to enhanced visualization of complex anatomy and improved intraoperative lesion localization. When these technologies were compared with existing neuronavigation systems, quantitative clinical benefits were also reported. The capacity to visualize three-dimensional images superimposed on patient anatomy is a potentially valuable tool in complex neurosurgical environments. Surgical limitations may be addressed through future advances in image registration and tracking as well as intraoperatively acquired imaging with the ability to yield real-time virtual models.

Current and emerging brain applications of MR-guided focused ultrasound.

MRI guided focused ultrasound is an emerging technique that uses acoustic energy to noninvasively treat intracranial disorders. At high frequencies, it can be used to raise tissue temperatures and ablate discrete brain targets with sub-millimeter accuracy. This application is currently under investigation for a broad range of clinical applications, including brain tumors, movement disorders, and psychiatric conditions. At low frequencies MRI guided focused ultrasound can be used to modulate neuronal activity and in conjunction with injected microbubbles, can open the blood-brain barrier to enhance the delivery of therapeutic compounds. The last decade has seen dramatic advances in the science of MRI guided focused ultrasound, helping elucidate both its mechanisms and potential in pre-clinical models, and its translational promise across myriad clinical applications. This review provides an update of current and emerging MRI guided focused ultrasound applications for intracranial disorders and describes future directions and challenges for the field.