Faculty Bibliography

PURPOSE/OBJECTIVE:Neurologic determination of death (NDD) is legally accepted as death in Canada but remains susceptible to misunderstandings. In some cases, families request continued organ support after NDD. Conflicts can escalate to formal legal challenges, causing emotional, financial, and moral distress for all involved. We describe prevalence, characteristics, and common experiences with requests for continued organ support following NDD in Canada. METHODS:Mixed-methods design combining anonymous online survey with semi-structured interviews of Canadian critical care physicians (448 practitioners, adult and pediatric). RESULTS:One hundred and six physicians responded to the survey and 12 participated in an interview. Fifty-two percent (55/106) of respondents had encountered a request for continued organ support after NDD within two years, 47% (26/55) of which involved threat of legal action. Requests for continued support following NDD ranged from appeals for time for family to gather before ventilator removal to disagreement with the concept of NDD. Common responses to requests included: consultation with an additional physician (54%), consultation with spiritual services (41%), and delay of one to three days for NDD acceptance (49%). Respondents with prior experience were less likely to recommend ancillary tests (P = 0.004) or consultation with bioethics services (P = 0.004). Qualitative analysis revealed perceptions that requests for continued organ support were driven by mistrust, tensions surrounding decision-making, and cultural differences rather than a lack of specific information about NDD. CONCLUSIONS:Family requests for continued somatic support following NDD were encountered by half our sample of Canadian critical care physicians. Mitigation strategies require attention to the multifaceted social contexts surrounding these complex scenarios.

BACKGROUND:Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). METHODS:We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. RESULTS:In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. CONCLUSION/CONCLUSIONS:Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.

Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of KCNQ2-DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2-DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2-DEE‒associated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver-maintained seizure diary, completed by caregivers who are trained to recognize seizures using within-patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open-label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver-maintained seizure diaries successfully. For determining the outcome of a KCNQ2-DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2-DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.

OBJECTIVE:Treatment of ruptured cerebral aneurysms by endovascular coiling is associated with better neurologic outcome when compared to neurosurgical clipping but has a higher risk for target aneurysm rebleeding after treatment. We hypothesize that aggressive retreatment of coiled aneurysms will lead to fewer recurrent hemorrhages as compared to historical values of 2.3-3.0%. METHODS:All first time GDC embolized cerebral aneurysms were retrospectively reviewed at a single institution from 2004 to 2015. Aneurysm retreatment after first time embolization was recorded as well as time to retreatment. Retreatment at our institution is routinely performed for incomplete coiling with etiologies including incomplete initial coiling, coil compaction, aneurysmal dilatation. Aneurysm re-rupture was treated with additional coiling. Kaplan-Meier survival analysis was performed to evaluate embolization durability. RESULTS:There were 214 aneurysms which met inclusion criteria. Mean (SD) follow-up was 2.74 (2.24) years. Aneurysms that were patent or recanalized were retreated. Mean (SD) time to retreatment was 9 (9) months. Overall, 46 (21.5%) aneurysms required retreatment. Retreatment was performed for coil compaction/remnant growth, recanalization, persistent remnant, and re-bleed. Two (0.9%) patients had recurrent aneurysm hemorrhage and both were treated with additional coil embolization. There were no new long-term neurologic deficits caused by aneurysm retreatment. CONCLUSIONS:Aggressive retreatment of previously ruptured, coiled cerebral aneurysms for persistent aneurysm patency reduces the recurrent hemorrhage risk to that historically seen in neurosurgically clipped aneurysms with minimal additional morbidity. This study validates a large body of literature demonstrating the significance of post-treatment aneurysm remnants and their association with recurrent hemorrhage.

OBJECTIVE:The electroencephalographic (EEG) terms "brief potentially ictal rhythmic discharges" (BIRDs) and "paroxysmal fast activity" (PFA) are considered distinct entities; however, their definitions overlap, and they may have similar clinical significance. We investigated their clinical significance and their association with seizures and the seizure onset zone (SOZ). METHODS:We retrospectively identified an adult cohort (July 2015 to March 2018) whose long-term (>12 h) EEGs in any setting reported BIRDs (>4 Hz, lasting .5-10 s) and/or PFA. Different frequency cutoffs for PFA (>13 Hz or ≥8 Hz) were tested to compare their clinical significance. Patient demographics, clinical history, and EEG features were recorded. RESULTS:We identified 94 patients with BIRDs/PFA out of 3520 patients (3%); 36 were critically ill (12 with epilepsy), and 58 were noncritically ill (all with epilepsy). The frequency of BIRDs/PFA was largely dependent on EEG background: it tended to be slower (theta) in the absence of a posterior dominant rhythm or in the presence of continuous focal slowing in the same region (p = .01). Sixty-two of 94 patients (66%; 32/36 [89%] critically ill, 30/58 [52%] noncritically ill) had electrographic seizures during the recording. The scalp EEG SOZ colocalized with BIRDs/PFA in all cases. BIRDs with faster frequency (also qualifying as PFA by definition) had similar seizure risk to that of slower BIRDs (62%-71%), regardless of frequency cutoff used to define PFA. In addition, 30 of 30 (100%) patients with evolving BIRDs/PFA (which lasted a median of 6 s, range = 2-9.5 s) had electrographic seizures (>10 s), compared to 32 of 64 (50%) with nonevolving BIRDs (median = 1 s, range = .5-3.5 s; p < .01). SIGNIFICANCE/CONCLUSIONS:A high proportion of patients with BIRDs/PFA had seizures on EEG, regardless of their frequency (i.e., whether they also qualified as PFA), and their location colocalized with scalp SOZ in all cases. BIRDs appear to be a scalp EEG biomarker of uncontrolled seizure activity and a reliable localizing sign of the SOZ.

It is important to consider antisynthetase syndrome in the differential diagnosis of patients presenting with weakness, respiratory distress, and a constellation of complaints spanning multiple organ systems, as this will change clinical management.

OBJECTIVE:The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy. METHODS:Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy. RESULTS:Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively. SIGNIFICANCE/CONCLUSIONS:These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.