Precision medicine in pediatric temporal epilepsy surgery: optimization of outcomes through functional MRI memory tasks and tailored surgeries.

OBJECTIVE: The goal of epilepsy surgery is both seizure cessation and maximal preservation of function. In temporal lobe (TL) cases, the lack of functional MRI (fMRI) tasks that effectively activate mesial temporal structures hampers preoperative memory risk assessment, especially in children. This study evaluated pediatric TL surgery outcome optimization associated with tailored resection informed by an fMRI memory task. METHODS: The authors identified focal onset TL epilepsy patients with 1) TL resections; 2) viable fMRI memory scans; and 3) pre- and postoperative neuropsychological (NP) evaluations. They retrospectively evaluated preoperative fMRI memory scans, available Wada tests, pre- and postoperative NP scores, postoperative MRI scans, and postoperative Engel class outcomes. To assess fMRI memory task outcome prediction, the authors 1) overlaid preoperative fMRI activation onto postoperative structural images; 2) classified patients as having "overlap" or "no overlap" of activation and resection cavities; and 3) compared these findings with memory improvement, stability, or decline, based on Reliable Change Index calculations. RESULTS: Twenty patients met the inclusion criteria. At a median of 2.1 postoperative years, 16 patients had Engel class IA outcomes and 1 each had Engel class IB, ID, IIA, and IID outcomes. Functional MRI activation was linked to NP memory outcome in 19 of 20 cases (95%). Otherwise, heterogeneity characterized the cohort. CONCLUSIONS: Functional MRI memory task activation effectively predicted individual NP outcomes in the context of tailored TL resections. Patients had excellent seizure and overall good NP outcomes. This small study adds to extant literature indicating that pediatric TL epilepsy does not represent a single clinical syndrome. Findings support individualized surgical intervention using fMRI memory activation to help guide this precision medicine approach.

A clinically applicable functional MRI memory paradigm for use with pediatric patients.

OBJECTIVE: Clinically employable functional MRI (fMRI) memory paradigms are not yet established for pediatric patient epilepsy surgery workups. Seeking to establish such a paradigm, we evaluated the effectiveness of memory fMRI tasks we developed by quantifying individual activation in a clinical pediatric setting, analyzing patterns of activation relative to the side of temporal lobe (TL) pathology, and comparing fMRI and Wada test results. METHODS: We retrospectively identified 72 patients aged 6.7-20.9 years with pathology (seizure focus and/or tumor) limited to the TL who had attempted memory and language fMRI tasks over a 9-year period as part of presurgical workups. Memory fMRI tasks required visualization of autobiographical memories in a block design alternating with covert counting. Language fMRI protocols involved verb and sentence generation. Scans were both qualitatively interpreted and quantitatively assessed for blood oxygenation level dependent (BOLD) signal change using region of interest (ROI) masks. We calculated the percentage of successfully scanned individual cases, compared 2 memory task activation masks in cases with left versus right TL pathology, and compared fMRI with Wada tests when available. Patients who had viable fMRI and Wada tests had generally concordant results. RESULTS: Of the 72 cases, 60 (83%), aged 7.6-20.9 years, successfully performed the memory fMRI tasks and 12 (17%) failed. Eleven of 12 unsuccessful scans were due to motion and/or inability to perform the tasks, and the success of a twelfth was indeterminate due to orthodontic metal artifact. Seven of the successful 60 cases had distorted anatomy that precluded employing predetermined masks for quantitative analysis. Successful fMRI memory studies showed bilateral mesial temporal activation and quantitatively demonstrated: (1) left activation (L-ACT) less than right activation (R-ACT) in cases with left temporal lobe (L-TL) pathology, (2) nonsignificant R-ACT less than L-ACT in cases with right temporal lobe (R-TL) pathology, and (3) lower L-ACT plus R-ACT activation for cases with L-TL versus R-TL pathology. Patients who had viable fMRI and Wada tests had generally concordant results. SIGNIFICANCE: This study demonstrates evidence of an fMRI memory task paradigm that elicits reliable activation at the individual level and can generally be accomplished in clinically involved pediatric patients. This autobiographical memory paradigm showed activation in mesial TL structures, and cases with left compared to right TL pathology showed differences in activation consistent with extant literature in TL epilepsy. Further studies will be required to assess outcome prediction.

Pediatric hemispherectomy outcome: Adaptive functioning, intelligence, and memory.

OBJECTIVE: Our purpose was to characterize neuropsychological evaluation (NP) outcome following functional hemispherectomy in a large, representative cohort of pediatric patients. METHODS: We evaluated seizure and NP outcomes and medical variables for all post-hemispherectomy patients from Seattle Children's Hospital epilepsy surgery program between 1996 and 2020. Neuropsychological evaluation outcome tests used were not available on all patients due to the diversity of patient ages and competency that is typical of a representative pediatric cohort; all patients had at least an adaptive functioning or intelligence measure, and a subgroup had memory testing. RESULTS: A total of 71 hemispherectomy patients (37 right; 34 females) yielded 66 with both preoperative (PREOP) plus postoperative (POSTOP) NPs and 5 with POSTOP only. Median surgery age was 5.7 (IQR 2-9.9) years. Engel classification indicated excellent seizure outcomes: 59 (84%) Class I, 6 (8%) Class II, 5 (7%) Class III, and 1 (1%) Class IV. Medical variables - including seizure etiology, surgery age, side, presurgical seizure duration, unilateral or bilateral structural abnormalities, secondarily generalized motor seizures - were not associated with either Engel class or POSTOP NP scores, though considerable heterogeneity was evident. Median PREOP and POSTOP adaptive functioning (PREOP n = 45, POSTOP n = 48) and intelligence (PREOP n = 29, POSTOP n = 36) summary scores were exceptionally low and did not reveal group decline from PREOP to POSTOP. Fifty-five of 66 (85%) cases showed stability or improvement. Specifically, 5 (8%) improved; 50 (76%) showed stability; and 11 (16%) declined. Improve and decline groups showed clinically interesting, but not statistical, differences in seizure control and age. Median memory summary scores were low and also showed considerable heterogeneity. Overall median PREOP to POSTOP memory scores (PREOP n = 16, POSTOP n = 24) did not reveal declines, and verbal memory scores improved. Twenty six percent of intelligence and 33% of memory tests had verbal versus visual-spatial discrepancies; all but one favored verbal, regardless of hemispherectomy side. SIGNIFICANCE: This large, single institution study revealed excellent seizure outcome in 91% of all 71 patients plus stability and/or improvement of intelligence and adaptive functioning in 85% of 66 patients who had PREOP plus POSTOP NPs. Memory was similarly stable overall, and verbal memory improved. Medical variables did not predict group NP outcomes though heterogeneity argues for further research. This study is unique for cohort size, intelligence plus memory testing, and evidence of primacy of verbal over visual-spatial development, despite hemispherectomy side. This study reinforces the role of hemispherectomy in achieving good seizure outcome while preserving functioning.

Awake Mapping of the Auditory Cortex during Tumor Resection in an Aspiring Musical Performer: A Case Report.

INTRODUCTION: Preoperative functional MRI (fMRI) and intraoperative awake cortical mapping are established strategies to identify and preserve critical language structures during neurosurgery. There is growing appreciation for the need to similarly identify and preserve eloquent tissue critical for music production. CASE REPORT: A 19-year-old female musician, with a 3- to 4-year history of events concerning for musicogenic seizures, was found to have a right posterior temporal tumor, concerning for a low-grade glial neoplasm. Preoperative fMRI assessing passive and active musical tasks localized areas of activation directly adjacent to the tumor margin. Cortical stimulation during various musical tasks did not identify eloquent tissue near the surgical site. A gross total tumor resection was achieved without disruption of singing ability. At 9-month follow-up, the patient continued to have preserved musical ability with full resolution of seizures and without evidence of residual lesion or recurrence. CONCLUSION: A novel strategy for performing an awake craniotomy, incorporating preoperative fMRI data for music processing with intraoperative cortical stimulation, interpreted with the assistance of a musician expert and facilitated gross total resection of the patient's tumor without comprising her musical abilities.

Longitudinal cerebellar diffusion tensor imaging changes in posterior fossa syndrome.

Posterior fossa syndrome is a severe transient loss of language that frequently complicates resection of tumors of the cerebellum. The associated pathophysiology and relevant anatomy to this language deficit remains controversial. We performed a retrospective analysis of all cerebellar tumor resections at Seattle Children's Hospital from 2010 to 2015. Diffusion tensor imaging was performed on each of the patients as part of their clinical scan. Patients included in the study were divided into groups based on language functioning following resection: intact (N = 19), mild deficit (N = 19), and posterior fossa syndrome (N = 9). Patients with posterior fossa syndrome showed white matter changes evidenced by reductions in fractional anisotropy in the left and right superior cerebellar peduncle following resection, and these changes were still evident 1-year after surgery. These changes were greater in the superior cerebellar peduncle than elsewhere in the cerebellum. Prior to surgery, posterior fossa patients did not show changes in fractional anisotropy however differences were observed in mean and radial diffusivity measures in comparison to other groups which may provide a radiographic marker of those at greatest risk of developing post-operative language loss.

Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome.

INTRODUCTION: Posterior fossa tumors are the most common brain tumor of children. Aggressive resection correlates with long-term survival. A high incidence of posterior fossa syndrome (PFS), impairing the quality of life in many survivors, has been attributed to damage to bilateral dentate nucleus or to cerebellar output pathways. Using diffusion tensor imaging (DTI), we examined the involvement of the dentothalamic tracts, specifically the superior cerebellar peduncle (SCP), in patients with posterior fossa tumors and the association with PFS. METHODS: DTI studies were performed postoperatively in patients with midline (n = 12), lateral cerebellar tumors (n = 4), and controls. The location and visibility of the SCP were determined. The postoperative course was recorded, especially with regard to PFS, cranial nerve deficits, and oculomotor function. RESULTS: The SCP travels immediately adjacent to the lateral wall of the fourth ventricle and just medial to the middle cerebellar peduncle. Patients with midline tumors that still had observable SCP did not develop posterior fossa syndrome (N = 7). SCPs were absent, on either preoperative (N = 1, no postoperative study available) or postoperative studies (N = 4), in the five patients who developed PFS. Oculomotor deficits of tracking were observed in patients independent of PFS or SCP involvement. CONCLUSION: PFS can occur with bilateral injury to the outflow from dentate nuclei. In children with PFS, this may occur due to bilateral injury to the superior cerebellar peduncle. These tracts sit immediately adjacent to the wall of the ventricle and are highly vulnerable when an aggressive resection for these tumors is performed.

Tissue localization during resective epilepsy surgery.

OBJECT: Imaging-guided surgery (IGS) systems are widely used in neurosurgical practice. During epilepsy surgery, the authors routinely use IGS landmarks to localize intracranial electrodes and/or specific brain regions. The authors have developed a technique to coregister these landmarks with pre- and postoperative scans and the Montreal Neurological Institute (MNI) standard space brain MRI to allow 1) localization and identification of tissue anatomy; and 2) identification of Brodmann areas (BAs) of the tissue resected during epilepsy surgery. Tracking tissue in this fashion allows for better correlation of patient outcome to clinical factors, functional neuroimaging findings, and pathological characteristics and molecular studies of resected tissue. METHODS: Tissue samples were collected in 21 patients. Coordinates from intraoperative tissue localization were downloaded from the IGS system and transformed into patient space, as defined by preoperative high-resolution T1-weighted MRI volume. Tissue landmarks in patient space were then transformed into MNI standard space for identification of the BAs of the tissue samples. RESULTS: Anatomical locations of resected tissue were identified from the intraoperative resection landmarks. The BAs were identified for 17 of the 21 patients. The remaining patients had abnormal brain anatomy that could not be meaningfully coregistered with the MNI standard brain without causing extensive distortion. CONCLUSIONS: This coregistration and landmark tracking technique allows localization of tissue that is resected from patients with epilepsy and identification of the BAs for each resected region. The ability to perform tissue localization allows investigators to relate preoperative, intraoperative, and postoperative functional and anatomical brain imaging to better understand patient outcomes, improve patient safety, and aid in research.

Posterior fossa tumors and their impact on sleep and ventilatory control: a clinical perspective.

The cerebellum, classically viewed as a motor structure of the brain, may play a role in respiration. Brainstem dysfunction has been implicated in sleep disordered breathing (SDB), but apnea after surgery of brain tumors in the posterior fossa, not involving the brainstem has been reported. We report four cases with posterior fossa tumors without brainstem invasion who suffered SDB after surgery diagnosed by polysomnography (PSG). Advanced MRI techniques with DTI were used to find correlations with SDB. Abnormal signals in the superior, middle and inferior cerebellar peduncles were seen in these patients with the most severe changes in the inferior peduncle. SDB may be under diagnosed in the setting of posterior fossa tumors without brainstem involvement. Damage to the cerebellar peduncles, especially the inferior cerebellar peduncle, without brainstem involvement, can cause significant disruption of respiration.

Multimodality localization of the sensorimotor cortex in pediatric patients undergoing epilepsy surgery.

OBJECT: The gold-standard method for determining cortical functional organization in the context of neurosurgical intervention is electrical cortical stimulation (ECS), which disrupts normal cortical function to evoke movement. This technique is imprecise, however, as motor responses are not limited to the precentral gyrus. Electrical cortical stimulation also can trigger seizures, is not always tolerated, and is often unsuccessful, especially in children. Alternatively, endogenous motor and sensory signals can be mapped by somatosensory evoked potentials (SSEPs), functional MRI (fMRI), and electrocorticography of high gamma (70-150 Hz) signal power, which reflect normal cortical function. The authors evaluated whether these 4 modalities of mapping sensorimotor function in children produce concurrent results. METHODS: The authors retrospectively examined the charts of all patients who underwent epilepsy surgery at Seattle Children's Hospital between July 20, 1999, and July 1, 2011, and they included all patients in whom the primary motor or somatosensory cortex was localized via 2 or more of the following tests: ECS, SSEP, fMRI, or high gamma electrocorticography (hgECoG). RESULTS: Inclusion criteria were met by 50 patients, whose mean age at operation was 10.6 years. The youngest patient who underwent hgECoG mapping was 2 years and 10 months old, which is younger than any patient reported on in the literature. The authors localized the putative sensorimotor cortex most often with hgECoG, followed by SSEP and fMRI; ECS was most likely to fail to localize the sensorimotor cortex. CONCLUSIONS: Electrical cortical stimulation, SSEP, fMRI, and hgECoG generally produced concordant localization of motor and sensory function in children. When attempting to localize the sensorimotor cortex in children, hgECoG was more likely to produce results, was faster, safer, and did not require cooperation. The hgECoG maps in pediatric patients are similar to those in adult patients published in the literature. The sensorimotor cortex can be mapped by hgECoG and fMRI in children younger than 3 years old to localize cortical function.

Freehand placement of depth electrodes using electromagnetic frameless stereotactic guidance.

The presurgical evaluation of patients with epilepsy often requires an intracranial study in which both subdural grid electrodes and depth electrodes are needed. Performing a craniotomy for grid placement with a stereotactic frame in place can be problematic, especially in young children, leading some surgeons to consider frameless stereotaxy for such surgery. The authors report on the use of a system that uses electromagnetic impulses to track the tip of the depth electrode. Ten pediatric patients with medically refractory focal lobar epilepsy required placement of both subdural grid and intraparenchymal depth electrodes to map seizure onset. Presurgical frameless stereotaxic targeting was performed using a commercially available electromagnetic image-guided system. Freehand depth electrode placement was then performed with intraoperative guidance using an electromagnetic system that provided imaging of the tip of the electrode, something that has not been possible using visually or sonically based systems. Accuracy of placement of depth electrodes within the deep structures of interest was confirmed postoperatively using CT and CT/MR imaging fusion. Depth electrodes were appropriately placed in all patients. Electromagnetic-tracking-based stereotactic targeting improves the accuracy of freehand placement of depth electrodes in patients with medically refractory epilepsy. The ability to track the electrode tip, rather than the electrode tail, is a major feature that enhances accuracy. Additional advantages of electromagnetic frameless guidance are discussed.

Functional magnetic resonance imaging for presurgical evaluation of very young pediatric patients with epilepsy.

OBJECT: The authors describe their experience with functional MR (fMR) imaging in children as young as 5 years of age, or even younger in developmental age equivalent. Functional MR imaging can be useful for identifying eloquent cortex prior to surgical intervention. Most fMR imaging clinical work has been done in adults, and although children as young as 8 years of age have been included in larger clinical series, cases in younger children are rarely reported. METHODS: The authors reviewed presurgical fMR images in eight patients who were 8 years of age or younger, six of whom were 5 or 6 years of age. Each patient had undergone neuropsychological testing. Three patients functioned at a below-average level, with adaptive functioning age scores of 3 to 4 years. Self-paced finger tapping (with passive movement in one patient) and silent language tasks were used as activation tasks. The language task was modified for younger children, for whom the same (not novel) stimuli were used for extensive practice ahead of time and in the MR imaging unit. Patient preparation involved techniques such as having experienced staff present to work with patients and providing external management during imaging. Six of eight patients had extensive training and practice prior to the procedure. In the two youngest patients, this training included use of a mock MR unit. RESULTS: All cases yielded successful imaging. Finger tapping in all seven of the patients who could perform it demonstrated focal motor activation in the frontal-parietal region, with expected activation elsewhere, including in the cerebellum. Three of four patients had the expected verb generation task activations, with left-hemisphere dominance, including a 6-year-old child who functioned at the 3-year, 9-month level. The only child (an 8-year-old) who was not prepared prior to the imaging session for the verb generation task failed this task due to movement artifact. CONCLUSIONS: Despite the challenges of successfully using fMR imaging in very young and clinically involved patients, these studies can be performed successfully in children with a chronological age of 5 or 6 years and a developmental age as young as 3 or 4 years.

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma.

OBJECT: Intrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution. MATERIAL AND METHODS: The clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata. RESULTS: Routine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology. CONCLUSION: DTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive.