Nonaneurysmal perimesencephalic subarachnoid hemorrhage on noncontrast head CT: An accuracy, inter-rater, and intra-rater reliability study.

BACKGROUND AND PURPOSE: To evaluate the reliability and accuracy of nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) on Noncontrast Head CT (NCCT) between numerous raters. MATERIALS AND METHODS: 45 NCCT of adult patients with SAH who also had a catheter angiography (CA) were independently evaluated by 48 diverse raters; 45 raters performed a second assessment one month later. For each case, raters were asked: 1) whether they judged the bleeding pattern to be perimesencephalic; 2) whether there was blood anterior to brainstem; 3) complete filling of the anterior interhemispheric fissure (AIF); 4) extension to the lateral part of the sylvian fissure (LSF); 5) frank intraventricular hemorrhage; 6) whether in the hypothetical presence of a negative CT angiogram they would still recommend CA. An automatic NAPSAH diagnosis was also generated by combining responses to questions 2-5. Reliability was estimated using Gwet's AC1 (κG), and the relationship between the NCCT diagnosis of NAPSAH and the recommendation to perform CA using Cramer's V test. Multi-rater accuracy of NCCT in predicting negative CA was explored. RESULTS: Inter-rater reliability for the presence of NAPSAH was moderate (κG = 0.58; 95%CI: 0.47, 0.69), but improved to substantial when automatically generated (κG = 0.70; 95%CI: 0.59, 0.81). The most reliable criteria were the absence of AIF filling (κG = 0.79) and extension to LSF (κG = 0.79). Mean intra-rater reliability was substantial (κG = 0.65). NAPSAH weakly correlated with CA decision (V = 0.50). Mean sensitivity and specificity were 58% (95%CI: 44%, 71%) and 83 % (95%CI: 72 %, 94%), respectively. CONCLUSION: NAPSAH remains a diagnosis of exclusion. The NCCT diagnosis was moderately reliable and its impact on clinical decisions modest.

Work-up and Management of Asymptomatic Extracranial Traumatic Vertebral Artery Injury.

BACKGROUND: Non-penetrating head and neck trauma is associated with extracranial traumatic vertebral artery injury (eTVAI) in approximately 1-2% of cases. Most patients are initially asymptomatic but have an increased risk for delayed stroke and mortality. Limited evidence is available to guide the management of asymptomatic eTVAI. As such, we sought to investigate national practice patterns regarding screening, treatment, and follow-up domains. METHODS: A cross-sectional, electronic survey was distributed to members of the Canadian Neurosurgical Society and Canadian Spine Society. We presented two cases of asymptomatic eTVAI, stratified by injury mechanism, fracture type, and angiographic findings. Screening questions were answered prior to presentation of angiographic findings. Survey responses were analyzed using descriptive statistics. RESULTS: One hundred-eight of 232 (46%) participants, representing 20 academic institutions, completed the survey. Case 1: 78% of respondents would screen for eTVAI with computed topography angiography (CTA) (97%), immediately (88%). The majority of respondents (97%) would treat with aspirin (89%) for 3-6 months (46%). Respondents would follow up clinically (89%) or radiographically (75%), every 1-3 months. Case 2: 73% of respondents would screen with CTA (96%), immediately (88%). Most respondents (94%) would treat with aspirin (50%) for 3-6 months (35%). Thirty-six percent of respondents would utilize endovascular therapy. Respondents would follow up clinically (97%) or radiographically (89%), every 1-3 months. CONCLUSION: This survey of Canadian practice patterns highlights consistency in the approach to screening, treatment, and follow-up of asymptomatic eTVAI. These findings are relevant to neurosurgeons, spinal surgeons, stroke neurologists, and neuro-interventionalists.

A Canadian National Survey of the Neurosurgical Management of Intracranial Abscesses.

OBJECTIVE: Intracerebral abscess is a life-threatening condition for which there are no current, widely accepted neurosurgical management guidelines. The purpose of this study was to investigate Canadian practice patterns for the medical and surgical management of primary, recurrent, and multiple intracerebral abscesses. METHODS: A self-administered, cross-sectional, electronic survey was distributed to active staff and resident members of the Canadian Neurosurgical Society and Canadian Neurosurgery Research Collaborative. Responses between subgroups were analyzed using the Chi-square test. RESULTS: In total, 101 respondents (57.7%) completed the survey. The majority (60.0%) were staff neurosurgeons working in an academic, adult care setting (80%). We identified a consensus that abscesses >2.5 cm in diameter should be considered for surgical intervention. The majority of respondents were in favor of excising an intracerebral abscess over performing aspiration if located superficially in non-eloquent cortex (60.4%), located in the posterior fossa (65.4%), or causing mass effect leading to herniation (75.3%). The majority of respondents were in favor of reoperation for recurrent abscesses if measuring greater than 2.5 cm, associated with progressive neurological deterioration, the index operation was an aspiration and did not include resection of the abscess capsule, and if the recurrence occurred despite prior surgery combined with maximal antibiotic therapy. There was no consensus on the use of topical intraoperative antibiotics. CONCLUSION: This survey demonstrated heterogeneity in the medical and surgical management of primary, recurrent, and multiple brain abscesses among Canadian neurosurgery attending staff and residents.

Use of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in A Tertiary Care Memory Clinic.

INTRODUCTION: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are promising tools to help identify the underlying pathology of neurocognitive disorders. In this manuscript, we report our experience with AD CSF biomarkers in 262 consecutive patients in a tertiary care memory clinic. METHODS: We retrospectively reviewed 262 consecutive patients who underwent lumbar puncture (LP) and CSF measurement of AD biomarkers (Aß1-42, total tau or t-tau, and p-tau181). We studied the safety of the procedure and its impact on patient's diagnosis and management. RESULTS: The LP allowed to identify underlying AD pathology in 72 of the 121 patients (59%) with early onset amnestic mild cognitive impairment (aMCI) with a high probability of progression to AD; to distinguish the behavioral/dysexecutive variant of AD from the behavioral variant of frontotemporal dementia (bvFTD) in 25 of the 45 patients (55%) with an atypical neurobehavioral profile; to identify AD as the underlying pathology in 15 of the 27 patients (55%) with atypical or unclassifiable primary progressive aphasia (PPA); and to distinguish AD from other disorders in 9 of the 29 patients (31%) with psychiatric differential diagnoses and 19 of the 40 patients (47%) with lesional differential diagnoses (normal pressure hydrocephalus, encephalitis, prion disease, etc.). No major complications occurred following the LP. INTERPRETATION: Our results suggest that CSF analysis is a safe and effective diagnostic tool in select patients with neurocognitive disorders. We advocate for a wider use of this biomarker in tertiary care memory clinics in Canada.

University of Montreal's Clinician-Investigator Program: A 10-Year Descriptive Evaluation.

PURPOSE: Clinician-investigators have an important role in the development and implantation of new therapies and treatment modalities; however, there have been several reports highlighting a pending shortage in the clinician-investigators' workforce. In Canada, the Royal College has promoted the development of clinician-investigators programs (CIP) to facilitate the training of these individuals. There is currently a paucity of data regarding the outcomes of such programs. This study aims to identify the strengths and areas of improvement of the Montreal University CIP.  Methods: An internet-based 51-question survey was distributed to all the alumni from the University of Montreal CIP. Participation was voluntary and no incentives were provided. The response rate was 64%.  Results: Among respondents, 50% (n=16) had completed their clinical residency and all CIP requirements. The majority of these individuals (63%) had become independent investigators and had secured provincial and national funding. Satisfaction of the respondents was high regarding the overall program (85%), the research skills developed during the CIP (84%) and the financial support obtained during the program (72%). The satisfaction rate regarding career planning was lower (63%).  Conclusion: This survey demonstrates that, while indicators are favorable, some areas still require improvement. Several steps to improve the CIP have been identified; notably, the transition from the CIP to early independent career has been identified as critical in the development of clinician-investigators and steps have been taken to improve this progression.

The Behavioral/Dysexecutive Variant of Alzheimer's Disease: A Case Series with Clinical, Neuropsychological, and FDG-PET Characterization.

INTRODUCTION: It is well known that some patients with Alz-heimer's disease (AD) have atypical, nonamnestic presentations. While logopenic aphasia and posterior cortical atrophy are well-characterized atypical variants of AD, the behavioral/dysexecutive variant remains a controversial entity, lacking consensus regarding its distinctive clinical and imaging features. METHODS: We present a case series of 8 patients with biomarker confirmation of AD (cerebrospinal fluid [CSF] analysis or amyloid positron emission tomography [PET]) and a progressive frontal syndrome, defined as prominent behavioral and/or executive deficits at initial presentation. We characterize the cohort based on clinical features, cognitive performance in 4 domains (memory, visuospatial, executive, and language) as well as behavior on the Dépistage Cognitif de Québec (DCQ), and regional brain metabolism using 18F-fluorodeoxyglucose PET (FDG-PET). We compare these features with 8 age-matched patients diagnosed with the behavioral variant of frontotemporal dementia (bvFTD) and 37 patients with typical amnestic AD. RESULTS: Patients with the behavioral/dysexecutive variant of AD presented with early-onset (mean age: 59 years old) progressive executive and behavioral problems reminiscent of bvFTD, including disinhibition, loss of social conventions, and hyperorality. Patients scored higher on the Memory Index and lower on the Behavioral Index than patients with amnestic AD on the DCQ, yet they were indistinguishable from patients with bvFTD on each of the cognitive indices. Visual analysis of FDG-PET revealed half of patients with behavioral/dysexecutive AD presented with frontal hypometabolism suggestive of bvFTD and only 3/8 (37.5%) presented significant hypometabolism of the posterior cingulate cortex. Group-level analysis of FDG-PET data revealed that the most hypometabolic regions were the middle temporal, inferior temporal, and angular gyri in behavioral/dysexecutive AD and the inferior frontal gyrus, anterior cingulate cortex, caudate nucleus, and insula in bvFTD. CONCLUSION: The behavioral/dysexecutive variant of AD is a rare, atypical young-onset variant of AD defined clinically by early and prominent impairments in executive and behavioral domains. While behavioral/dysexecutive AD is hardly distinguishable from bvFTD using clinical and cognitive features alone, CSF biomarkers and temporoparietal hypometabolism help predict underlying pathology during life.

Cognitive Profile of the Logopenic Variant of Primary Progressive Aphasia Using the Dépistage Cognitif de Québec.

BACKGROUND/AIMS: The logopenic variant of primary progressive aphasia (lvPPA) is characterized by impaired word-finding and sentence repetition with phonologic errors but spared motor speech and grammar and semantic knowledge. Although its language deficits have been well studied, the full spectrum of cognitive changes in the lvPPA remains to be defined. We aimed to explore the neurocognitive profile of the lvPPA using a newly developed cognitive screening tool for atypical dementias, the Dépistage Cognitif de Québec (DCQ). METHODS: We compared 29 patients with lvPPA to 72 amnestic variant Alzheimer disease (aAD) to 438 healthy control (HC) participants. Performance on the 5 indexes of the DCQ (Memory, Visuospatial, Executive, Language and Behavioral) was compared between the 3 groups. RESULTS: Results showed a significantly lower performance for lvPPA participants in all neurocognitive domains, when compared to HC. When compared to aAD, lvPPA participants had significantly lower scores for language, executive, and visuospatial abilities, but not for memory and behavior. CONCLUSION: Altogether, these findings better define the neurocognitive changes of lvPPA.

Comorbid amyloid-ß pathology affects clinical and imaging features in VCD.

INTRODUCTION: To date, the clinical relevance of comorbid amyloid-ß (Aß) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. METHODS: We included 218 VCD patients with available cerebrospinal fluid Aß42 levels. Patients were divided into Aß+ mild-VCD (n = 84), Aß- mild-VCD (n = 68), Aß+ major-VCD (n = 31), and Aß- major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. RESULTS: Aß- patients showed more depressive symptoms than Aß+. In the major-VCD group, Aß- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aß+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aß- patients had more WMH than Aß+ patients, whereas conversely, in the major-VCD group, Aß+ patients had more WMH. Atrophy patterns did not differ between Aß+ and Aß- VCD group. DISCUSSION: Comorbid Aß pathology affects the manifestation of VCD, but effects differ by severity of VCD.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

Cognition and anatomy of adult Niemann-Pick disease type C: Insights for the Alzheimer field.

Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). However, the cognitive, psychiatric, and neuropathological features of adult NPC and their relation to AD have yet to be explored. We systematically reviewed the literature on adult NPC with a particular focus on cognitive and neuroanatomical abnormalities. The careful study of cognition in adult NPC allows drawing critical insights in our understanding of the pathophysiology of AD as well as normal cognition.

The Dépistage Cognitif de Québec: A New Clinician's Tool for Early Recognition of Atypical Dementia.

INTRODUCTION: Early recognition of atypical dementia remains challenging partly because of lack of cognitive screening instruments precisely tailored for this purpose. METHODS: We assessed the validity and reliability of the Dépistage Cognitif de Québec (DCQ; www.dcqtest.org), a newly developed cognitive screening test, to detect atypical dementia using a multicenter cohort of 628 participants. Sensitivity and specificity were compared to the Montreal Cognitive Assessment (MoCA). A predictive diagnostic algorithm for atypical dementia was determined using classification tree analysis. RESULTS: The DCQ showed excellent psychometric properties. It was significantly more accurate than the MoCA to detect atypical dementia. All correlations between DCQ indexes and standard neuropsychological measures were significant. A statistical model distinguished typical from atypical dementia with a predictive power of 79%. DISCUSSION: The DCQ is a better tool to detect atypical dementia than standard cognitive screening tests. Expanding the clinician's tool kit with the DCQ could reduce missed/delayed identification of atypical dementia and accelerate therapeutic intervention.

Evidence-based Interpretation of Amyloid-ß PET Results: A Clinician's Tool.

BACKGROUND: Amyloid-ß positron emission tomography (PET) allows for in vivo detection of fibrillar amyloid plaques, a pathologic hallmark of Alzheimer's disease (AD). However, amyloid-ß PET interpretation is limited by the imperfect correlation between PET and autopsy, and the fact that it is positive in about 20% to 30% of cognitively normal individuals and non-AD dementias, especially when older or carrying the ε4 allele of apolipoprotein E (ApoE4). When facing a positive amyloid PET, clinicians have to evaluate the probability of a pathologic false positive as well as the probability of amyloid positivity being age-related, comorbid to a primary non-AD dementia (clinicopathologic false positive). These probabilities can be calculated to reach an evidence-based interpretation of amyloid-ß. As literature review and calculations cannot be easily performed in the day-to-day clinic, we propose a clinician friendly, evidence-based Bayesian approach to the interpretation of amyloid-ß PET results in the differential diagnosis of patients with cognitive impairment. METHODS: We defined AD as a clinicopathologic entity in which amyloid-ß is the primary cause of cognitive impairment. We systematically reviewed the literature to estimate the sensitivity and specificity of amyloid-ß PET against neuropathologic examination. We inferred rates of clinicopathologic false positivity (non-AD dementia with comorbid amyloid) based on age-dependent and ApoE-dependent prevalence of amyloid positivity in normal individuals and AD patients provided in large meta-analyses published by the Amyloid Biomarker Study Group. We calculated positive predictive value (PPV) and negative predictive value (NPV) of amyloid-ß PET, which are presented in a clinician-friendly table. RESULTS: PPV of PET is highest in young ApoE4- patients with high pre-PET probability of AD. In older ApoE4+ patients with low pre-PET probability of AD, positive amyloid-ß PET scans must be interpreted with caution. A negative amyloid-ß PET makes a diagnosis of AD unlikely except in old patients with high pre-PET probability of AD. CONCLUSION: This evidence-based approach might provide guidance to clinicians and nuclear medicine physicians to interpret amyloid-ß PET results for early and differential diagnosis of patients with progressive cognitive impairment.

Impact of a Student-Driven, Virtual Patient Application on Objective Structured Clinical Examination Performance: Observational Study.

BACKGROUND: Peer-assisted learning (PAL) refers to a learning activity whereby students of similar academic level teach and learn from one another. Groupe de perfectionnement des habiletés cliniques (Clinical Skills Improvement Group), a student organization at Université Laval, Canada, propelled PAL into the digital era by creating a collaborative virtual patient platform. Medical interviews can be completed in pairs (a student-patient and a student-doctor) through an interactive Web-based application, which generates a score (weighted for key questions) and automated feedback. OBJECTIVES: The aim of the study was to measure the pedagogical impact of the application on the score at medical interview stations at the summative preclerkship Objective Structured Clinical Examination (OSCE). METHODS: We measured the use of the application (cases completed, mean score) in the 2 months preceding the OSCE. We also accessed the results of medical interview stations at the preclerkship summative OSCE. We analyzed whether using the application was associated with higher scores and/or better passing grades (≥60%) at the OSCE. Finally, we produced an online form where students could comment on their appreciation of the application. RESULTS: Of the 206 students completing the preclerkship summative OSCE, 170 (82.5%) were registered users on the application, completing a total of 3133 cases (18 by active user in average, 7 minutes by case in average). The appreciation questionnaire was answered online by 45 students who mentioned appreciating the intuitive, easy-to-use, and interactive design, the diversity of cases, and the automated feedback. Using the application was associated with reduced reported stress, improved scores (P=.04), and improved passing rates (P=.11) at the preclerkship summative OSCE. CONCLUSIONS: This study suggests that PAL can go far beyond small-group teaching, showing students' potential to create helpful pedagogical tools for their peers.

Molecular imaging in dementia: Past, present, and future.

Molecular imaging techniques using 18F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases.

Use of Invasive Brain-Computer Interfaces in Pediatric Neurosurgery: Technical and Ethical Considerations.

Invasive brain-computer interfaces hold promise to alleviate disabilities in individuals with neurologic injury, with fully implantable brain-computer interface systems expected to reach the clinic in the upcoming decade. Children with severe neurologic disabilities, like quadriplegic cerebral palsy or cervical spine trauma, could benefit from this technology. However, they have been excluded from clinical trials of intracortical brain-computer interface to date. In this manuscript, we discuss the ethical considerations related to the use of invasive brain-computer interface in children with severe neurologic disabilities. We first review the technical hardware and software considerations for the application of intracortical brain-computer interface in children. We then discuss ethical issues related to motor brain-computer interface use in pediatric neurosurgery. Finally, based on the input of a multidisciplinary panel of experts in fields related to brain-computer interface (functional and restorative neurosurgery, pediatric neurosurgery, mathematics and artificial intelligence research, neuroengineering, pediatric ethics, and pragmatic ethics), we then formulate initial recommendations regarding the clinical use of invasive brain-computer interfaces in children.

Pregnancy as a Subgroup in the Pathophysiologic Classification of Spinal Aneurysms.

BACKGROUND: Aneurysms of spinal arteries not associated with any known predisposing condition are referred to as isolated spinal aneurysms (SAs). In our series, an SA was found in 2 patients during the postpartum period. The goal of this study is to determine whether an occurrence of an SA may be related to puerperium. METHODS: In a retrospective analysis of our consecutive series of 10 cases of SAs from 2008 to 2020, we identified 2 cases of SAs during puerperium. Patients' charts and imaging were reviewed, for potential predisposing factors. RESULTS: In both cases, angiography showed fusiform aneurysms of the anterior SA with concomitant bilateral vertebral artery (VA) dissections. Serum vasculitis and inflammatory panel and genetic testing for collagen disorders were negative in both cases. Review of the literature showed that pregnancy is associated with an increased risk of arterial dissections in various locations and supports the hypothesis that hemodynamic and hormonal changes may play a role in the formation of SAs. CONCLUSIONS: Pregnancy and peripartum state may be a distinct cause of the formation of SAs, possibly as a result of increased hemodynamic stress and hormonal changes that may alter the arterial wall. It would be appropriate to add pregnancy as a subgroup in the classification of SAs. In our series, both cases were associated with bilateral VA dissections; it is possible that the bilateral VA stenosis may have contributed to the formation of the SAs. It is important to recognize this possibility when considering the occlusion of a dissected VA.

Surgical management of high-grade lumbar spondylolisthesis associated with Hajdu-Cheney syndrome: illustrative case.

BACKGROUND: Hajdu-Cheney syndrome (HCS) is a rare connective tissue disorder characterized by severe bone demineralization. In the spine, it is associated with the early onset of severe osteoporosis and can cause spondylolisthesis. Spinal instrumentation in the setting of severe osteoporosis is challenging because of poor resistance of vertebrae to biomechanical stress. OBSERVATIONS: A 59-year-old woman with known idiopathic HCS presented with a grade 4 L5-S1 spondylolisthesis and right L5 pedicle fracture associated with a left L5 pars fracture, causing a progressive L5 radiculopathy that was worse on the left side than the right side and bilateral foot drop. The authors performed decompressive lumbar surgery, which included a complete L5 laminectomy and resection of the left L5 pedicle. This was followed by multilevel lumbosacral instrumentation using cement-augmented fenestrated pedicle screws as well as transdiscal sacral screws and bilateral alar-iliac fixation. Postoperatively, the radicular pain resolved, and the left foot drop partially recovered. LESSONS: Stabilization of high-grade spondylolisthesis in the setting of bone demineralization disorders is challenging. The use of different instrumentation techniques is important because it increases biomechanical stability of the overall instrumentation construct.

Acute Effects of High-Frequency Insular Stimulation on Interictal Epileptiform Discharge Rates in Patients with Refractory Epilepsy.

Rationale: Deep brain stimulation (DBS) of several sites, such as the thalamus, has been shown to reduce seizure frequency and interictal epileptiform activity in patients with refractory epilepsy. Recent findings have demonstrated that the insula is part of the 'rich club' of highly connected brain regions. This pilot study investigated short-term effects of high-frequency (HF) insular DBS on interictal epileptiform discharge (IED) rate in patients with refractory epilepsy. Methods: Six patients with drug-resistant epilepsy undergoing an intracranial electroencephalographic study received two sets of 10 min continuous 150 Hz HF-DBS of the insula. For each patient, epileptiform activity was analyzed for a total of 80 min, starting 20 min prior to stimulation set 1 (S1), and ending 20 min after stimulation set 2 (S2). All IEDs were identified and classified according to their anatomic localization by a board-certified epileptologist. The IED rate during the 20 min preceding S1 served as a baseline for comparison with IED rate during S1, S2 and post-stimulation periods. Results: HF-DBS of the anterior insula (aINS) was performed in a patient with an aINS epileptic focus (patient 1). HF-DBS of the posterior insula (pINS) was performed in two patients with a pINS epileptic focus (patients 2 and 4), in one patient with an aINS focus (patient 3), and in two non-insular patients (patients 5 and 6). The total IED (irrespective of their location) rate significantly decreased (p < 0.01) in two patients (patients 1 and 2) during the stimulation period, whereas it significantly increased (p < 0.01) in one patient (patient 6); there was no change in the other three patients. Looking at subsets of spike localization, HF-DBS of the aINS significantly reduced aINS and orbitofrontal IEDs in patient 1 (p < 0.01), while HF-DBS of the pINS had an effect on pINS IEDs (p < 0.01) in both patients with a pINS focus; there was no significant effect of HF-DBS of the insula on IEDs in temporal or other frontal regions. Conclusion: Short-term HF-DBS of the insula had heterogeneous effects on the IED rate. Further work is required to examine factors underlying these heterogeneous effects, such as stimulation frequency, location of IEDs and subregions of the insula stimulated.