publications

2024

1. Retrospective Analysis of the Integration of Palliative Care Into the Care of Stroke Patients Admitted to a Regional Stroke Center

   H. Khosravani, M. Mahendiran, B. Sivanandan, S. Gardner, G. Saposnik, J. Brookes, A. Berall, and G.A. Perri

   American Journal of Hospice and Palliative Care, 2024
2. Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase

   D.J. Kim, N. Singh, L. Catanese, A.Y.X. Yu, A.M. Demchuk, M.I. Lloret-Villas, Y. Deschaintre, S.B. Coutts, H. Khosravani, R. Appireddy, F. Moreau, G. Gubitz, and 23 more authors

   Stroke, 2024
3. Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial

   T.T. Sajobi, O.I. Arimoro, A. Ademola, N. Singh, F. Bala, M.A. Almekhlafi, Y. Deschaintre, S.B. Coutts, S. Thirunavukkarasu, H. Khosravani, R. Appireddy, F. Moreau, and 43 more authors

   Stroke, 2024
4. Intravenous tenecteplase compared with alteplase for minor ischaemic stroke: a secondary analysis of the AcT randomised clinical trial

   R. Nair, N. Singh, M. Kate, N. Asdaghi, R. Sarmiento, F. Bala, S.B. Coutts, M. Horn, A.Y. Poppe, H. Williams, A. Ademola, I. Alhabli, and 17 more authors

   Stroke and Vascular Neurology, 2024

2023

1. Machine-learning assisted swallowing assessment: a deep learning-based quality improvement tool to screen for post-stroke dysphagia

   Rami Saab, Arjun Balachandar, Hamza Mahdi, Eptehal Nashnoush, Lucas X. Perri, Ashley L. Waldron, Alireza Sadeghian, Gordon Rubenfeld, Mark Crowley, Mark I. Boulos, Brian J. Murray, and Houman Khosravani

   Frontiers in Neuroscience, 2023

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   Post-stroke dysphagia is common and associated with significant morbidity and mortality, rendering bedside screening of significant clinical importance. Using voice as a biomarker coupled with deep learning has the potential to improve patient access to screening and mitigate the subjectivity associated with detecting voice change, a component of several validated screening protocols. In this single-center study, we developed a proof-of-concept model for automated dysphagia screening and evaluated the performance of this model on training and testing cohorts. Patients were admitted to a comprehensive stroke center, where primary English speakers could follow commands without significant aphasia and participated on a rolling basis. The primary outcome was classification either as a pass or fail equivalent using a dysphagia screening test as a label. Voice data was recorded from patients who spoke a standardized set of vowels, words, and sentences from the National Institute of Health Stroke Scale. Seventy patients were recruited and 68 were included in the analysis, with 40 in training and 28 in testing cohorts, respectively. Speech from patients was segmented into 1,579 audio clips, from which 6,655 Mel-spectrogram images were computed and used as inputs for deep-learning models (DenseNet and ConvNext, separately and together). Clip-level and participant-level swallowing status predictions were obtained through a voting method. The models demonstrated clip-level dysphagia screening sensitivity of 71% and specificity of 77% (F1 = 0.73, AUC = 0.80 [95% CI: 0.78–0.82]). At the participant level, the sensitivity and specificity were 89 and 79%, respectively (F1 = 0.81, AUC = 0.91 [95% CI: 0.77–1.05]). This study is the first to demonstrate the feasibility of applying deep learning to classify vocalizations to detect post-stroke dysphagia. Our findings suggest potential for enhancing dysphagia screening in clinical settings. https://github.com/UofTNeurology/masa-opensource

2. Evaluating Barriers and Tools to Optimize Resident Call Scheduling on Neurology In-Patient Services (P8-7.006)

   James Im, Charles Kassardjian, Houman Khosravani, and Sara Mitchell

   Tuesday, April 25, 2023
3. Evaluating the Effectiveness of the SPIKES Model to Break Bad News - A Systematic Review.

   Meera Mahendiran, Herman Yeung, Samantha Rossi, Houman Khosravani, and Giulia-Anna Perri

   The American journal of hospice & palliative care, 2023

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   Introduction: Breaking bad news to patients and families can be challenging for healthcare providers. The present study conducted a systematic review of the literature to determine if formal communication training using the SPIKES protocol improves learner satisfaction, knowledge, performance, or system outcomes. Method: MEDLINE, Embase, CINAHL Plus (Nursing & Allied Health Sciences), and PsycINFO Databases were searched with keywords BAD NEWS and SPIKES. Studies were required to have an intervention using the SPIKES model and an outcome that addressed at least one of the four domains of the Kirkpatrick model for evaluating training effectiveness. The Cochrane Risk of Bias Tool was used to conduct a risk of bias assessment. Due to heterogeneity in the interventions and outcomes, meta-analysis was not undertaken and instead, a narrative synthesis was used with the information provided in the tables to summarise the main findings of the included studies. Results: Of 622 studies screened, 37 publications met the inclusion criteria. Interventions ranged from the use of didactic lecture, role play with standardised patients (SPs), video use, debriefing sessions, and computer simulations. Evaluation tools ranged from pre and post intervention questionnaires, OSCE performance with rating by independent raters and SPs, and reflective essay writing. Conclusions: Our systematic review demonstrated that the SPIKES protocol is associated with improved learner satisfaction, knowledge and performance. None of the studies in our review examined system outcomes. As such, further educational development and research is needed to evaluate the impact of patient outcomes, including the optimal components and length of intervention.

4. Safety and Efficacy of Tenecteplase Compared With Alteplase in Patients With Large Vessel Occlusion Stroke: A Prespecified Secondary Analysis of the ACT Randomized Clinical Trial

   Fouzi Bala, Nishita Singh, Brian Buck, Ayoola Ademola, Shelagh B Coutts, Yan Deschaintre, Houman Khosravani, Ramana Appireddy, Francois Moreau, Stephen Phillips, Gord Gubitz, Aleksander Tkach, and 22 more authors

   JAMA Neurology, 2023

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   Importance It is unknown whether intravenous thrombolysis using tenecteplase is noninferior or preferable compared with alteplase for patients with acute ischemic stroke. Objective To examine the safety and efficacy of tenecteplase compared to alteplase among patients with large vessel occlusion (LVO) stroke. Design, Setting, and Participants This was a prespecified analysis of the Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada (ACT) randomized clinical trial that enrolled patients from 22 primary and comprehensive stroke centers across Canada between December 10, 2019, and January 25, 2022. Patients 18 years and older with a disabling ischemic stroke within 4.5 hours of symptom onset were randomly assigned (1:1) to either intravenous tenecteplase or alteplase and were monitored for up to 120 days. Patients with baseline intracranial internal carotid artery (ICA), M1-middle cerebral artery (MCA), M2-MCA, and basilar occlusions were included in this analysis. A total of 1600 patients were enrolled, and 23 withdrew consent. Exposures Intravenous tenecteplase (0.25 mg/kg) vs intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures The primary outcome was the proportion of modified Rankin scale (mRS) score 0-1 at 90 days. Secondary outcomes were an mRS score from 0 to 2, mortality, and symptomatic intracerebral hemorrhage. Angiographic outcomes were successful reperfusion (extended Thrombolysis in Cerebral Infarction scale score 2b-3) on first and final angiographic acquisitions. Multivariable analyses (adjusting for age, sex, National Institute of Health Stroke Scale score, onset-to-needle time, and occlusion location) were carried out. Results Among 1577 patients, 520 (33.0%) had LVO (median [IQR] age, 74 [64-83] years; 283 [54.4%] women): 135 (26.0%) with ICA occlusion, 237 (45.6%) with M1-MCA, 117 (22.5%) with M2-MCA, and 31 (6.0%) with basilar occlusions. The primary outcome (mRS score 0-1) was achieved in 86 participants (32.7%) in the tenecteplase group vs 76 (29.6%) in the alteplase group. Rates of mRS 0-2 (129 [49.0%] vs 131 [51.0%]), symptomatic intracerebral hemorrhage (16 [6.1%] vs 11 [4.3%]), and mortality (19.9% vs 18.1%) were similar in the tenecteplase and alteplase groups, respectively. No difference was noted in successful reperfusion rates in the first (19 [9.2%] vs 21 [10.5%]) and final angiogram (174 [84.5%] vs 177 [88.9%]) among 405 patients who underwent thrombectomy. Conclusions and Relevance The findings in this study indicate that intravenous tenecteplase conferred similar reperfusion, safety, and functional outcomes compared to alteplase among patients with LVO.

5. FLAIR MRI biomarkers of the Normal‐Appearing Brain Matter (NABM) are related to APOE‐4 status and CSF markers Aβ42 and Tau

   Karissa Chan, Corinne E Fischer, Houman Khosravani, Sandra E Black, Pascal Tyrrell, Pejman Jabehdar Maralani, Alan R Moody, and April Khademi

   Alzheimer’s & Dementia, 2023

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   Abstract Background Reduced amyloid‐beta‐42 (Aβ42) and elevated total tau (t‐tau) protein concentrations in the CSF are characteristic of Alzheimer’s disease (AD) pathology [1]. Aβ42 contributes to extracellular plaque formation between neurons [2]. The total level of tau, a microtubule‐stabilizer in neuron axons [3], is associated with neuronal death [1]. Additionally, presence of ApoE4 (ε4) alleles is an established identifier for increased risk of AD [4]. Non‐invasive imaging‐based correlates of the CSF markers are lacking. This study examines correlations of novel FLAIR texture, intensity, and volume biomarkers, along with white matter lesion (WML) burden, with Aβ42, t‐tau, and ε4 status. Method FLAIR volumes (n = 4044) from the ADNI database were used for analysis with CSF biomarkers. A subset (n = 921) was used for ε4 analysis based on available data. Normal‐appearing brain matter (NABM) was obtained by removing CSF and WML. Macrostructural damage (MAD), microstructural damage (MID), and integrity (MII) texture biomarkers [5] were extracted from each NABM volume (Fig. 1), along with median intensity, NABM/ICV ratio, and normalized WML volume [5]. Relationships between FLAIR biomarkers and AD markers were described using parametric statistical analyses. Statistical significance was set at p<0.05. Result All FLAIR biomarkers were statistically significantly correlated with CSF Aβ42 levels. All features except MID and WML burden were significantly correlated with CSF t‐tau levels (Table 1). MAD, MID, and WML burden showed negative correlations with Aβ42, while MAD showed a positive correlation with t‐tau. Opposite trends were seen with MII, intensity, and NABM/ICV (Fig. 2). Significant differences between groups without and with one ε4 allele were found in all FLAIR biomarkers except WML burden. Significant differences in MAD, MII and NABM/ICV were found between groups with one and two ε4 alleles (Table 2). Conclusion FLAIR biomarkers were inversely associated with CSF Aβ42 concentrations, suggesting they may be surrogate markers of Aβ plaque formation. They were associated with CSF t‐tau concentrations, suggesting they could also be indicators of GM degeneration and neuronal death. They could also be indicators for patients at increased risk of AD, as they demonstrated significant differences with the presence of ε4. Further longitudinal studies are required to establish the exact mechanism of neurodegeneration.

6. Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis

   Thalia S Field, Vanessa Dizonno, Mohammed A Almekhlafi, Fouzi Bala, Ibrahim Alhabli, Hubert Wong, Monica Norena, Maria Karina Villaluna, Princess King-Azote, Namali Ratnaweera, Steven Mancini, Stephen C Van Gaal, and 178 more authors

   Stroke, 2023

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   Background: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. Methods: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0–3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. Results: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5–73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. Conclusions: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03178864.

7. Effect of Time to Thrombolysis on Clinical Outcomes in Patients with Acute Ischemic Stroke Treated with Tenecteplase Compared to Alteplase: Analysis from the AcT Randomized Controlled Trial

   Nishita Singh, Mohammed Almekhlafi, Fouzi Bala, Ayoola Ademola, Shelagh B. Coutts, Yan Deschaintre, Houman Khosravani, Brian Buck, Ramana Appireddy, Francois Moreau, Gord Gubitz, Aleksander Tkach, and 22 more authors

   medRxiv, 2023

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   The Alteplase compared to Tenecteplase (AcT) randomized controlled trial (RCT) showed that tenecteplase is non-inferior to alteplase in treating acute ischemic stroke within 4.5 hours of symptom onset. The effect of time to treatment on clinical outcomes with alteplase is well known, however the nature of this relationship is yet to be described with tenecteplase. We assessed whether the association of time to thrombolysis treatment with clinical outcomes in patients with acute ischemic stroke differs by whether they receive intravenous tenecteplase versus alteplase. Patients included were from AcT, a pragmatic, registry linked, phase 3 RCT comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4·5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin scale(mRS) 0-1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage (sICH) and 90-day mortality rates. Mixed effects logistic regression was used to assess a)the association of stroke symptom onset to needle time (ONT), b)door (hospital arrival) to needle time(DNT) with outcomes and c)if these associations were modified by type of thrombolytic administered (tenecteplase vs. alteplase), after adjusting for age, sex, baseline stroke severity and site of intracranial occlusion. Of the 1538 patients included in this analysis, 1146(74.5%)[591: tenecteplase, 555 alteplase] presented within 3 hours vs. 392 (25.5%)[196: TNK, 196 alteplase] who presented within 3-4.5 hours of symptom onset. Baseline patient characteristics in the 0-3 hour versus 3-4.5-hour time window were similar, except patients in the 3-to-4.5-hour window had lower median baseline NIHSS (10 vs 7 respectively) and lower proportion of patients with large vessel occlusion on baseline CT Angiography (26.9% vs 18.7% respectively). Type of thrombolytic agent (tenecteplase vs. alteplase) did not modify the association between ONT(pinteraction = 0.161) or DNT(pinteraction = 0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-min reduction in ONT was associated with a 1.8% increase while every 10 min reduction in DNT was associated with a 0.2% increase in the probability of achieving 90-day mRS 0-1 respectively. The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes. In patients with acute ischemic stroke, does the effect of time to thrombolysis on clinical outcomes differ with tenecteplase vs. alteplase administration? In this analysis from the alteplase compared to tenecteplase (AcT) trial, a pragmatic, registry linked, phase 3 randomized controlled trial, each 30-min reduction in stroke onset to thrombolysis start time was associated with a 1.8% increase in the probability of achieving excellent functional outcome, which means that for every 30-minute reduction in onset to needle time two more of a 100 people achieved an excellent outcome. This effect was not modified by type of thrombolytic used (alteplase versus tenecteplase) The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes.

2022

1. Alteplase Compared to Tenecteplase in patients with Acute Ischemic Stroke (AcT) Trial: Protocol for a Pragmatic Registry linked Randomized Clinical Trial

   Tolulope Sajobi, Nishita Singh, Mohammed A Almekhlafi, Brian Buck, Ayoola Ademola, Shelagh B Coutts, Yan Deschaintre, Houman Khosravani, Ramana Appireddy, Francois Moreau, Stephen Phillips, Gord Gubitz, and 22 more authors

   Stroke: Vascular and Interventional Neurology, 2022

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   Background : Intravenous thrombolysis with alteplase is widely used in acute ischemic stroke patients presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared to alteplase. This study investigates whether intravenous tenecteplase is non‐inferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods : This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial with blinded endpoint assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non‐inferior to intravenous alteplase (0.9 mg/kg body weight, max dose 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a non‐inferiority margin of 5%, assuming incidence of 90‐day mRS 0–1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate < 5%. Results : The blinded primary endpoint is the proportion of subjects achieving a 90‐day mRS (modified Rankin scale) of 0–1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within 24‐hour period will be reported and coded using MedDRA. Outcomes are collected either centrally (primary, key secondary and safety endpoints) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusion : Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase vs. alteplase in patients with acute ischemic stroke presenting early after stroke onset. Clinical Trial Registration: NCT03889249 https://clinicaltrials.gov/ct2/show/NCT03889249 This article is protected by copyright. All rights reserved

2. AcT Trial: Protocol for a Pragmatic Registry‐Linked Randomized Clinical Trial

   Tolulope Sajobi, Nishita Singh, Mohammed A Almekhlafi, Brian Buck, Ayoola Ademola, Shelagh B Coutts, Yan Deschaintre, Houman Khosravani, Ramana Appireddy, Francois Moreau, Stephen Phillips, Gord Gubitz, and 22 more authors

   Stroke: Vascular and Interventional Neurology, 2022

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   Background Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate <5%. Results The blinded primary end point is the proportion of subjects achieving a 90‐day modified Rankin Scale score of 0 to 1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within a 24‐hour period will be reported and coded using the Medical Dictionary for Regulatory Activities. Outcomes are collected either centrally (primary, key secondary, and safety end points) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusions Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke presenting early after stroke onset.

3. Attitudes of Canadian stroke physicians regarding palliative care for patients with acute severe stroke: A national survey.

   Houman Khosravani, Meera Mahendiran, Sandra Gardner, Camilla Zimmermann, and Giulia-Anna Perri

   Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 2022

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   Palliative care (PC) aims to enhance the quality of life for patients and their families when confronted with serious illness.  As stroke continues to inflict high morbidity and mortality, the integration of palliative care within acute stroke care remains an important aspect of quality inpatient care.

4. Early identification of NORSE and transfer to care setting with appropriate supports: A proposed algorithm.

   Sarah A Vinette, Gordon Bryan Young, and Houman Khosravani

   Frontiers in neurology, 2022

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   New-onset refractory status epilepticus (NORSE) is a clinical presentation where an individual develops refractory status epilepticus without active epilepsy, or related neurological conditions. A subset of these individuals has a preceding fever and would be diagnosed with febrile infection-related epilepsy syndrome (FIRES). The underlying etiology of this condition varies and includes autoimmune and viral encephalitides. These conditions require multiple specialized health care teams working collaboratively and specific resources for investigation of the underlying etiology and management to provide optimal patient care. In this paper, we provide: (1) recommendations upon early recognition of NORSE and FIRES, (2) guidance on the resources needed to optimally provide care, and (3) guidance on considerations to initiate transfer of patients to a more specialized medical center. Additional recommendations for resource-austere centers without the ability to transfer such patients are also discussed. These recommendations are only for adult patients with NORSE as pediatric patients may require additional special considerations.

5. Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: One-Year Follow-up

   Thanh N. Nguyen, Muhammad M. Qureshi, Piers Klein, Hiroshi Yamagami, Robert Mikulik, Anna Czlonkowska, Mohamad Abdalkader, Petra Sedova, Anvitha Sathya, Hannah C. Lo, Ossama Yassin Mansour, Husitha Reddy Vanguru, and 360 more authors

   Neurology, 2022

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   Declines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020). We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, IVT treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. There were 148,895 stroke admissions in the 1 year immediately before compared with 138,453 admissions during the 1-year pandemic, representing a 7% decline (95% CI [95% CI 7.1–6.9]; p < 0.0001). ICH volumes declined from 29,585 to 28,156 (4.8% [5.1–4.6]; p < 0.0001) and IVT volume from 24,584 to 23,077 (6.1% [6.4–5.8]; p < 0.0001). Larger declines were observed at high-volume compared with low-volume centers (all p < 0.0001). There was no significant change in mechanical thrombectomy volumes (0.7% [0.6–0.9]; p = 0.49). Stroke was diagnosed in 1.3% [1.31–1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82–2.97], 5,656/195,539) of all stroke hospitalizations. There was a global decline and shift to lower-volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared with the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year. This study is registered under NCT04934020.

2021

1. Assessment of Discrepancies Between Follow-up Infarct Volume and 90-Day Outcomes Among Patients With Ischemic Stroke Who Received Endovascular Therapy

   Aravind Ganesh, Johanna M Ospel, Bijoy K Menon, Andrew M Demchuk, Ryan A McTaggart, Raul G Nogueira, Alexandre Y Poppe, Mohammed A Almekhlafi, Ricardo A Hanel, Götz Thomalla, Staffan Holmin, Volker Puetz, and 683 more authors

   JAMA Network Open, 2021

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   Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases. Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression–derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92). In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

2. Quality of anticoagulation using intravenous unfractionated heparin for cerebrovascular indications

   Tess Fitzpatrick, Courtney Wong, Cindy Shen, Peter Pham, Vincent Teo, Rita Selby, William Geerts, and Houman Khosravani

   Thrombosis Research, 2021
3. Cholinesterase Inhibitor Use in Patients With Dementia Admitted to a Palliative Care Unit.

   Giulia-Anna Perri, Jessica Wilson, Sandra Gardner, Anna Berall, Anne Kirstein, and Houman Khosravani

   The American journal of hospice & palliative care, 2021

   Abs

   Current guidelines suggest that patients with severe dementia on cholinesterase inhibitors (CHEIs) should discontinue their CHEIs by taper. This study aims to define the prevalence of patients admitted to a palliative care unit (PCU) with dementia on a CHEI and to determine whether these patients were tapered off their CHEIs according to current deprescribing guidelines.

4. Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke

   Paolo Bazzigaluppi, James Mester, Illsung L Joo, Iliya Weisspapir, Adrienne Dorr, Margaret M Koletar, Tina L Beckett, Houman Khosravani, Peter Carlen, and Bojana Stefanovic

   Journal of Cerebral Blood Flow & Metabolism, 2021

   Abs

   Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.

5. The clot thickens—enhanced integration of stroke and thrombosis training

   Stephanie Carlin, William Geerts, and Houman Khosravani

   Journal of Thrombosis and Thrombolysis, 2021

   Abs

   There is significant overlap between knowledge and its clinical application in stroke and thrombosis & vascular medicine. Formal integration of training is, however, not standard. After the hyperacute phase of management, personalized medical decisions are often needed regarding antithrombotics and anticoagulants that leverage clinical practice parameters from both disciplines with a unique emphasis on minimizing neurologic treatment complications. We completed an ad hoc survey of adult thrombosis fellowships at several North American centers. We discovered that direct integration of training programs is not prevalent, suggesting a role for more deliberate integration of training programs. We provide a framework and resources for consideration that directly improve, by design, integrated clinical experiences during training, harnessing the strengths in both stroke and thrombosis programs.

6. Global impact of COVID-19 on stroke care

   Raul G. Nogueira, Mohamad Abdalkader, Muhammed M. Qureshi, Michael R. Frankel, Ossama Yassin Mansour, Hiroshi Yamagami, Zhongming Qiu, Mehdi Farhoudi, James E. Siegler, Shadi Yaghi, Eytan Raz, Nobuyuki Sakai, and 261 more authors

   International Journal of Stroke, 2021

   Abs

   The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide. We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March–31 May 2020) compared with two control three-month periods (immediately preceding and one year prior). Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers. The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, −19.7 to −18.7), 11.5% (95%CI, −12.6 to −10.6), and 12.7% (95%CI, −13.6 to −11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (−20.5%) had greater declines in mechanical thrombectomy volumes than mid- (−10.1%) and low-volume (−8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions. The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

7. Global Impact of COVID-19 on Stroke Care and IV Thrombolysis

   Raul G. Nogueira, Muhammad M. Qureshi, Mohamad Abdalkader, Sheila Ouriques Martins, Hiroshi Yamagami, Zhongming Qiu, Ossama Yassin Mansour, Anvitha Sathya, Anna Czlonkowska, Georgios Tsivgoulis, Diana Aguiar de Sousa, Jelle Demeestere, and 450 more authors

   Neurology, 2021

   Abs

   Objective To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods. Methods We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. Results There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] −11.7 to −11.3, p < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI −13.8 to −12.7, p < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI −13.7 to −10.3, p = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2–9.8, p < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions. Conclusions The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.

8. Team debriefs during the COVID-19 pandemic in long-term care homes: Essential elements

   Giulia-Anna Perri, Warren Harris Lewin, and Houman Khosravani

   Canadian Family Physician, 2021

2020

1. Protected Code Stroke: Hyperacute Stroke Management During the Coronavirus Disease 2019 (COVID-19) Pandemic.

   Houman Khosravani, Phavalan Rajendram, Lowyl Notario, Martin G Chapman, and Bijoy K Menon

   Stroke, 2020

   Abs

   Background and Purpose- Hyperacute assessment and management of patients with stroke, termed code stroke, is a time-sensitive and high-stakes clinical scenario. In the context of the current coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus, the ability to deliver timely and efficacious care must be balanced with the risk of infectious exposure to the clinical team. Furthermore, rapid and effective stroke care remains paramount to achieve maximal functional recovery for those needing admission and to triage care appropriately for those who may be presenting with neurological symptoms but have an alternative diagnosis. Methods- Available resources, COVID-19-specific infection prevention and control recommendations, and expert consensus were used to identify clinical screening criteria for patients and provide the required nuanced considerations for the healthcare team, thereby modifying the conventional code stroke processes to achieve a protected designation. Results- A protected code stroke algorithm was developed. Features specific to prenotification and clinical status of the patient were used to define precode screening. These include primary infectious symptoms, clinical, and examination features. A focused framework was then developed with regard to a protected code stroke. We outline the specifics of personal protective equipment use and considerations thereof including aspects of crisis resource management impacting team role designation and human performance factors during a protected code stroke. Conclusions- We introduce the concept of a protected code stroke during a pandemic, as in the case of COVID-19, and provide a framework for key considerations including screening, personal protective equipment, and crisis resource management. These considerations and suggested algorithms can be utilized and adapted for local practice.

2. The Dysfunction is in the Details: Neurovascular Changes in COVID-19

   Houman Khosravani

   Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2020
3. The Code Stroke Handbook

   Andrew Micieli, Raed Joundi, Houman Khosravani, Julia Hopyan, and David J Gladstone

   The Code Stroke Handbook, 2020

   Abs

   The initial assessment of the code stroke involves identifying whether the clinical presentation is compatible with an acute stroke diagnosis, or a stroke mimic. The first two chapters of this book will provide you with the tools to answer these questions. Like a good detective, you need to gather the important clues, ignore distractions and red herrings, and eliminate the other suspects—all in a timely manner. This chapter will provide you with a stepwise approach to:❏Taking an appropriate and focused history by gathering relevant clinical information from multiple sources.❏Identifying the common symptoms associated with (and not associated with) acute stroke. Taking an appropriate and focused history by gathering relevant clinical information from multiple sources. Identifying the common symptoms associated with (and not associated with) acute stroke.

4. Symptom management and end-of-life care of residents with COVID-19 in long-term care homes.

   Houman Khosravani, Leah Steinberg, Nadia Incardona, Patrick Quail, and Giulia-Anna Perri

   Canadian family physician Medecin de famille canadien, 2020
5. Response by Khosravani et al to Letter Regarding Article, “Protected Code Stroke: Hyperacute Stroke Management During the Coronavirus Disease 2019 (COVID-19) Pandemic”

   Houman Khosravani, Phavalan Rajendram, and Bijoy K Menon

   Stroke, 2020
6. Modification to Neurology Residency Training: The Toronto Neurology COVID-19 Pandemic Experience

   Ryan T Muir, Priti Gros, Robert Ure, Sara B Mitchell, Charles D Kassardjian, Aaron Izenberg, Peter Tai, Houman Khosravani, and David K Chan

   Neurology: Clinical Practice, 2020

   Abs

   We describe the University of Toronto Adult Neurology Residency Program’s early experiences with and response to the coronavirus disease 2019 pandemic, including modifications to the provision of neurologic care while upholding neurology education and safety. All academic and many patient-related activities were virtualized. This maintained physical distancing while creating a city-wide videoconference-based teaching curriculum, expanding the learning opportunities to trainees at all academic sites. Furthermore, we propose a novel split-team model to promote resident safety through physical distancing of teams and to establish a capacity to rapidly adapt to redeployment, service needs, and trainee illness. Finally, we developed a unique protected code stroke framework to safeguard staff and trainees during hyperacute stroke assessments in this pandemic. Our shared experiences highlight considerations for contingency planning, maintenance of education, sustainability of team members, and promotion of safe neurologic care. These interventions serve to promote trainee safety, wellness, and resiliency.

7. The Virtual Neurologic Exam: Instructional Videos and Guidance for the COVID-19 Era

   Mariam Al Hussona, Monica Maher, David Chan, Jonathan A Micieli, Jennifer D Jain, Houman Khosravani, Aaron Izenberg, Charles D Kassardjian, and Sara B Mitchell

   Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2020

   Abs

   ABSTRACT Objective: To outline features of the neurologic examination that can be performed virtually through telemedicine platforms (the virtual neurological examination [VNE]), and provide guidance for rapidly pivoting in-person clinical assessments to virtual visits during the COVID-19 pandemic and beyond. Methods: The full neurologic examination is described with attention to components that can be performed virtually. Results: A screening VNE is outlined that can be performed on a wide variety of patients, along with detailed descriptions of virtual examination maneuvers for specific scenarios (cognitive testing, neuromuscular and movement disorder examinations). Conclusions: During the COVID-19 pandemic, rapid adoption of virtual medicine will be critical to provide ongoing and timely neurological care. Familiarity and mastery of a VNE will be critical for neurologists, and this article outlines a practical approach to implementation.

8. Pandemic Guidance for Stroke Centers Aiding COVID-19 Treatment Teams.

   Charles R Wira, Mayank Goyal, Andrew M Southerland, Kevin N Sheth, Norma D McNair, Houman Khosravani, Anne Leonard, Peter Panagos, and  Council, AHA/ASA Stroke Council Science Subcommittees: Emergency Neurovascular Care (ENCC), Telestroke and the Neurovascular Intervention Committees; and on behalf of the Stroke Nursing Science Subcommittee of the AHA/ASA Cardiovascular and Stroke Nursing

   Stroke, 2020

   Abs

   The coronavirus disease 2019 (COVID-19) pandemic has in some regions overwhelmed the capacity and staffing needs of healthcare systems, necessitating the provision of resources and staff from different disciplines to aid COVID treatment teams. Stroke centers have multidisciplinary clinical and procedural expertise to support COVID treatment teams. Staff safety and patient safety are essential, as are open lines of communication between stroke center leaders and hospital leadership in a pandemic where policies and procedures can change or evolve rapidly. Support needs to be allocated in a way that allows for the continued operation of a fully capable stroke center, with the ability to adjust if stroke center volume or staff attrition requires.

9. Crisis Resource Management and High-Performing Teams in Hyperacute Stroke Care

   Phavalan Rajendram, Lowyl Notario, Cliff Reid, Charles R Wira, Jose I Suarez, Scott D Weingart, and Houman Khosravani

   Neurocritical Care, 2020

   Abs

   Management of stroke patients in the acute setting is a high-stakes task with several challenges including the need for rapid assessment and treatment, maintenance of high-performing team dynamics, management of cognitive load affecting providers, and factors impacting team communication. Crisis resource management (CRM) provides a framework to tackle these challenges and is well established in other resuscitative disciplines. The current Coronavirus Disease 2019 (COVID-19) pandemic has exposed a potential quality gap in emergency preparedness and the ability to adapt to emergency scenarios in real time. Available resources in the literature in other disciplines and expert consensus were used to identify key elements of CRM as they apply to acute stroke management. We outline essential ingredients of CRM as a means to mitigate nontechnical challenges providers face during acute stroke care. These strategies include situational awareness, triage and prioritization, mitigation of cognitive load, team member role clarity, communication, and debriefing. Incorporation of CRM along with simulation is an established tool in other resuscitative disciplines and can be incorporated into acute stroke care. As stroke care processes evolve during these trying times, the importance of consistent, safe, and efficacious care facilitated by CRM principles offers a unique avenue to alleviate human factors and support high-performing teams.

10. Outcomes of Endovascular Thrombectomy for Basilar Artery Occlusion

    Christopher R Pasarikovski, Houman Khosravani, Leodante da Costa, Chinthaka Heyn, Stefano M Priola, Jerry C Ku, Sandra E Black, David J Gladstone, and Victor X D Yang

    Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2020

    Abs

    ABSTRACT: Background and Purpose: Large prospective observational studies have cast doubt on the common assumption that endovascular thrombectomy (EVT) is superior to intravenous thrombolysis for patients with acute basilar artery occlusion (BAO). The purpose of this study was to retrospectively review our experience for patients with BAO undergoing EVT with modern endovascular devices. Methods: All consecutive patients undergoing EVT with either a second-generation stent retriever or direct aspiration thrombectomy for BAO at our regional stroke center from January 1, 2013 to March 1, 2019 were included. The primary outcome measure was functional outcome at 1 month using the modified Rankin Scale (mRS) score. Multivariable logistic regression was used to assess the association between patient characteristics and dichotomized mRS. Results: A total of 43 consecutive patients underwent EVT for BAO. The average age was 67 years with 61% male patients. Overall, 37% (16/43) of patients achieved good functional outcome. Successful reperfusion was achieved in 72% (31/43) of cases. The median (interquartile range) stroke onset to treatment time was 420 (270–639) minutes (7 hours) for all patients. The procedure-related complication rate was 9% (4/43). On multivariate analysis, posterior circulation Alberta stroke program early computed tomography score and Basilar Artery on Computed Tomography Angiography score were associated with improved functional outcome. Conclusion: EVT appears to be safe and feasible in patients with BAO. Our finding that time to treatment and successful reperfusion were not associated with improved outcome is likely due to including patients with established infarcts. Given the variability of collaterals in the posterior circulation, the paradigm of utilizing a tissue window may assist in patient selection for EVT. Magnetic resonance imaging may be a reasonable option to determine the extent of ischemia in certain situations.

2018

1. Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions

   Lawrence J. Hirsch, Nicolas Gaspard, Andreas Baalen, Rima Nabbout, Sophie Demeret, Tobias Loddenkemper, Vincent Navarro, Nicola Specchio, Lieven Lagae, Andrea O. Rossetti, Sara Hocker, Teneille E. Gofton, and 6 more authors

   Epilepsia, 2018

   Abs

   We convened an international group of experts to standardize definitions of New‐Onset Refractory Status Epilepticus (NORSE), Febrile Infection‐Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in‐person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion‐Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super‐refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.

2. A Survey of Knowledge and Attitudes of Nurses About Pain Management in End-Stage Liver Disease in a Geriatric Palliative Care Unit

   Giulia-Anna Perri, Herman Yeung, Yoel Green, Abby Bezant, Carman Lee, Anna Berall, Jurgis Karuza, and Houman Khosravani

   American Journal of Hospice and Palliative Medicine®, 2018

   Abs

   Palliative care is often initiated late for patients with end stage liver disease (ESLD) with pain being a common morbidity that is under-treated throughout the disease trajectory. When admitted to a palliative care unit (PCU), nurses play a pivotal role and must be highly informed to ensure effective pain management. The aim of this study is to determine the baseline level of knowledge and attitudes of PCU nurses regarding pain management in patients with ESLD. A descriptive, cross-sectional self-administered survey design was used for this study. The sample comprised 35 PCU nurses working at a continuing chronic care facility in Toronto, Ontario, Canada. Data on the knowledge and attitudes of the nurses regarding pain management in patients with ESLD, was obtained using a modified version of the “Nurses Knowledge and Attitudes Survey Regarding Pain” (NKASRP) tool. Thirty-one PCU nurses were included for the analysis, giving a response rate of 89%. The mean total percentage score for the nurses on the modified version of the NKASRP was 72%. Only 26% of the nurse participants obtained a passing score of 80% or greater. There were no significant differences in mean total scores by age, gender, years of nursing experience or education level. The findings of this study provide important information about the inadequate knowledge and attitude in nurses regarding pain management for patients with ESLD. It is suggested that targeted educational programs and quality improvement initiatives in pain management for patients with ESLD could improve knowledge and attitudes for PCU nurses.

2016

1. Complications of end-stage liver disease.

   Giulia-Anna Perri, and Houman Khosravani

   Canadian family physician Medecin de famille canadien, 2016
2. Attributes and outcomes of end stage liver disease as compared with other noncancer patients admitted to a geriatric palliative care unit

   Giulia-Anna Perri, Shannon Bunn, Yeon Ji Oh, Altaf Kassam, Anna Berall, Jurgis Karuza, and Houman Khosravani

   Annals of Palliative Medicine, 2016

   Abs

   Background: End stage liver disease (ESLD) is increasingly more prevalent as a noncancer disease to manage in palliative care. Because of the clear lack of a “terminal phase” in ESLD, palliative care is often initiated only when death is perceived as being imminent. Palliative care units (PCUs) serve as an option for continued care for patients living with ESLD and are a limited resource, often not able to accommodate longer patient admissions. Concerns have been raised that ESLD patients may be admitted late in their disease course, not allowing for equitable access to such a service because of a perceived longer length of stay (LOS). The aim of this study is to better characterize the illness experience of patients with ESLD on a geriatric PCU comparing ESLD patients and other noncancer patients in terms of admission PPS, estimated prognosis and LOS. Methods: This was a single-center retrospective chart review of all noncancer patients admitted to Baycrest Health Sciences Palliative Care Unit (PCU) in Toronto, Canada over a four-year period. We measured the association between demographic data, estimated prognosis, Palliative Performance Score (PPS), and LOS between patients with ESLD and other noncancer diagnoses. Results: There were 235 patients with noncancer diagnoses admitted to the PCU during the study period, of which 19% had ESLD. Patients with ESLD were both significantly younger (P Conclusions: Patients with ESLD were younger and had a higher PPS score with no significant difference in estimated prognosis, LOS, or disposition when compared to other noncancer patients. Our findings suggest that patients with ESLD have a short LOS on the PCU with a unique illness experience compared to other noncancer patients.

2013

1. Association of mortality in stage 3 chronic kidney disease with variability in estimated glomerular filtration rate

   Houman Khosravani, David M J Naimark, and Sunnybrook Nephrology Journal Club

   Kidney International, 2013

2009

1. Time–Frequency Phase Analysis of Ictal EEG Recordings With the S-Transform

   C Robert Pinnegar, Houman Khosravani, and Paolo Federico

   IEEE Transactions on Biomedical Engineering, 2009

   Abs

   The calculation and visualization of temporal and phase information in the brain, such as during cognitive processes and epileptiform activity, is an important tool in EEG-based studies of physiological brain activation. To this end, we present a technique that estimates the phase and time offsets between different channels in EEG recordings of seizure activity. The offset information is visually combined with amplitude information to emphasize the most significant signal features. The estimates of phase and time offset are derived from the S-transform, a time-frequency representation that is similar to a windowed Fourier transform, but with a wavelet-like, scalable window. The phase offsets are obtained from the differences between phase spectra of S-transforms of different traces, and the time offsets are then obtained from the frequency-domain gradients of the phase offsets. This is analogous to the link between frequency "phase ramping" and time translation in ordinary Fourier analysis. In this paper, we present a synthetic example to help describe the method, and then show ictal EEG recordings from two human subjects. The differences between the recording times of spike-wave discharges at different electrodes exhibit behavior that is strongly dependent on time and frequency.

2. Occurrence and adverse effect on outcome of hyperlactatemia in the critically ill.

   Houman Khosravani, Reza Shahpori, H Thomas Stelfox, Andrew W Kirkpatrick, and Kevin B Laupland

   Critical care (London, England), 2009

   Abs

   Hyperlactatemia is frequent in critically ill patients and is often used as a marker of adverse outcome. However, studies to date have focused on selected intensive care unit (ICU) populations. We sought to determine the occurrence and relation of hyperlactatemia with ICU mortality in all patients admitted to four ICUs in a large regional critical care system.

3. Spatial localization and time-dependant changes of electrographic high frequency oscillations in human temporal lobe epilepsy

   Houman Khosravani, Nikhil Mehrotra, Michael Rigby, Walter J Hader, C Robert Pinnegar, Neelan Pillay, Samuel Wiebe, and Paolo Federico

   Epilepsia, 2009

   Abs

   High frequency oscillations (HFOs) >200 Hz are believed to be associated with epileptic processes. The spatial distribution of HFOs and their evolution over time leading up to seizure onset is unknown. Also, recording HFOs through conventional intracranial electrodes is not well established. We therefore wished to determine whether HFOs could be recorded using commercially available depth macroelectrodes. We also examined the spatial distribution and temporal progression of HFOs during the transition to seizure activity.

4. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors

   Houman Khosravani, Yunfeng Zhang, Shigeki Tsutsui, Shahid Hameed, Christophe Altier, Jawed Hamid, Lina Chen, Michelle Villemaire, Zenobia Ali, Frank R. Jirik, and Gerald W. Zamponi

   Journal of Cell Biology, 2009

2008

1. Cellular prion protein null mice display normal AMPA receptor mediated long term depression

   Houman Khosravani, Yunfeng Zhang, and Gerald W Zamponi

   Prion, 2008

   Abs

   Cellular prion protein (PrP(C)) appears to be involved in numerous physiological processes. We have recently shown a novel modulation of NMDA receptors by PrP(C) that results in neuroprotection via silencing of NMDA receptors containing NR2D subunits, whereas no effects on AMPA receptor function could be observed (Khosravani, et al. J Cell Biol 2008; 181:551). Here we show that PrP-null mice show a normal response to long-term depression stimuli requiring AMPA receptor activity, thus further supporting our previous findings of a selective action on NMDA receptors among ionotropic glutamate receptors.

2. Specific Lipids Supply Critical Negative Spontaneous Curvature—An Essential Component of Native Ca2+-Triggered Membrane Fusion

   Matthew A Churchward, Tatiana Rogasevskaia, David M Brandman, Houman Khosravani, Phillip Nava, Jeffrey K Atkinson, and Jens R Coorssen

   Biophysical Journal, 2008

   Abs

   The Ca(2+)-triggered merger of two apposed membranes is the defining step of regulated exocytosis. CHOL is required at critical levels in secretory vesicle membranes to enable efficient, native membrane fusion: CHOL-sphingomyelin enriched microdomains organize the site and regulate fusion efficiency, and CHOL directly supports the capacity for membrane merger by virtue of its negative spontaneous curvature. Specific, structurally dissimilar lipids substitute for CHOL in supporting the ability of vesicles to fuse: diacylglycerol, alphaT, and phosphatidylethanolamine support triggered fusion in CHOL-depleted vesicles, and this correlates quantitatively with the amount of curvature each imparts to the membrane. Lipids of lesser negative curvature than cholesterol do not support fusion. The fundamental mechanism of regulated bilayer merger requires not only a defined amount of membrane-negative curvature, but this curvature must be provided by molecules having a specific, critical spontaneous curvature. Such a local lipid composition is energetically favorable, ensuring the necessary "spontaneous" lipid rearrangements that must occur during native membrane fusion-Ca(2+)-triggered fusion pore formation and expansion. Thus, different fusion sites or vesicle types can use specific alternate lipidic components, or combinations thereof, to facilitate and modulate the fusion pore.

3. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors.

   Houman Khosravani, Yunfeng Zhang, Shigeki Tsutsui, Shahid Hameed, Christophe Altier, Jawed Hamid, Lina Chen, Michelle Villemaire, Zenobia Ali, Frank R Jirik, and Gerald W Zamponi

   The Journal of cell biology, 2008

   Abs

   It is well established that misfolded forms of cellular prion protein (PrP [PrP(C)]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrP(C) remains incompletely understood. To determine the physiological role of PrP(C), we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N-methyl-d-aspartate (NMDA)-evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrP(C). The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrP(C) mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits.

2007

1. Modulation of NMDA receptors by prion proteins

   Houman Khosravani, Yunfeng Zhang, Shigeki Tsutsui, Shahid Hameed, Jawed Hamid, Christophe Altier, Frank R Jirik, and Gerald W Zamponi

   Clinical & Investigative Medicine, 2007
2. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants

   Sarah E Heron, Houman Khosravani, Diego Varela, Chris Bladen, Tristiana C Williams, Michelle R Newman, Ingrid E Scheffer, Samuel F Berkovic, John C Mulley, and Gerald W Zamponi

   Annals of Neurology, 2007

   Abs

   The relationship between genetic variation in the T‐type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single‐stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single‐stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site‐directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual’s susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome‐wide case–control study seeking a statistical association. Ann Neurol 2007

2006

1. The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks

   Alan W L Chiu, Shokrollah S Jahromi, Houman Khosravani, Peter L Carlen, and Berj L Bardakjian

   Journal of Neural Engineering, 2006

   Abs

   The existence of hippocampal high-frequency electrical activities (greater than 100 Hz) during the progression of seizure episodes in both human and animal experimental models of epilepsy has been well documented (Bragin A, Engel J, Wilson C L, Fried I and Buzsáki G 1999 Hippocampus 9 137–42; Khosravani H, Pinnegar C R, Mitchell J R, Bardakjian B L, Federico P and Carlen P L 2005 Epilepsia 46 1–10). However, this information has not been studied between successive seizure episodes or utilized in the application of seizure classification. In this study, we examine the dynamical changes of an in vitro low Mg2+ rat hippocampal slice model of epilepsy at different frequency bands using wavelet transforms and artificial neural networks. By dividing the time–frequency spectrum of each seizure-like event (SLE) into frequency bins, we can analyze their burst-to-burst variations within individual SLEs as well as between successive SLE episodes. Wavelet energy and wavelet entropy are estimated for intracellular and extracellular electrical recordings using sufficiently high sampling rates (10 kHz). We demonstrate that the activities of high-frequency oscillations in the 100–400 Hz range increase as the slice approaches SLE onsets and in later episodes of SLEs. Utilizing the time-dependent relationship between different frequency bands, we can achieve frequency-dependent state classification. We demonstrate that activities in the frequency range 100–400 Hz are critical for the accurate classification of the different states of electrographic seizure-like episodes (containing interictal, preictal and ictal states) in brain slices undergoing recurrent spontaneous SLEs. While preictal activities can be classified with an average accuracy of 77.4 ± 6.7% utilizing the frequency spectrum in the range 0–400 Hz, we can also achieve a similar level of accuracy by using a nonlinear relationship between 100–400 Hz and <4 Hz frequency bands only.

2. Voltage-Gated Calcium Channels and Idiopathic Generalized Epilepsies

   Houman Khosravani, and Gerald W. Zamponi

   Physiological Reviews, 2006

   Abs

   The idiopathic generalized epilepsies encompass a class of epileptic seizure types that exhibit a polygenic and heritable etiology. Advances in molecular biology and genetics have implicated defects in certain types of voltage-gated calcium channels and their ancillary subunits as important players in this form of epilepsy. Both T-type and P/Q-type channels appear to mediate important contributions to seizure genesis, modulation of network activity, and genetic seizure susceptibility. Here, we provide a comprehensive overview of the roles of these channels and associated subunits in normal and pathological brain activity within the context of idiopathic generalized epilepsy.

3. ORL1 receptor–mediated internalization of N-type calcium channels

   Christophe Altier, Houman Khosravani, Rhian M Evans, Shahid Hameed, Jean B Peloquin, Brian A Vartian, Lina Chen, Aaron M Beedle, Stephen S G Ferguson, Alexandre Mezghrani, Stefan J Dubel, Emmanuel Bourinet, and 2 more authors

   Nature Neuroscience, 2006

   Abs

   The inhibition of N-type calcium channels by opioid receptor like receptor 1 (ORL1) is a key mechanism for controlling the transmission of nociceptive signals. We recently reported that signaling complexes consisting of ORL1 receptors and N-type channels mediate a tonic inhibition of calcium entry. Here we show that prolonged (∼30 min) exposure of ORL1 receptors to their agonist nociceptin triggers an internalization of these signaling complexes into vesicular compartments. This effect is dependent on protein kinase C activation, occurs selectively for N-type channels and cannot be observed with μ-opioid or angiotensin receptors. In expression systems and in rat dorsal root ganglion neurons, the nociceptin-mediated internalization of the channels is accompanied by a significant downregulation of calcium entry, which parallels the selective removal of N-type calcium channels from the plasma membrane. This may provide a new means for long-term regulation of calcium entry in the pain pathway.

4. Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy.

   Jean B Peloquin, Houman Khosravani, Wendy Barr, Chris Bladen, Rhian Evans, Janette Mezeyova, David Parker, Terrance P Snutch, John E McRory, and Gerald W Zamponi

   Epilepsia, 2006

   Abs

   Childhood absence epilepsy (CAE) is an idiopathic form of seizure disorder that is believed to have a genetic basis.

5. Role of Angiotensin II Type 1A Receptor Phosphorylation, Phospholipase D, and Extracellular Calcium in Isoform-specific Protein Kinase C Membrane Translocation Responses*

   Aleksandra Policha, Noriko Daneshtalab, Lina Chen, Lianne B. Dale, Christophe Altier, Houman Khosravani, Walter G. Thomas, Gerald W. Zamponi, and Stephen S.G. Ferguson

   Journal of Biological Chemistry, 2006

   Abs

   The angiotensin II type 1A receptor (AT1AR) plays an important role in cardiovascular function and as such represents a primary target for therapeutic intervention. The AT1AR is coupled via Gq to the activation of phospholipase C, the hydrolysis of phosphoinositides, release of calcium from intracellular stores, and the activation of protein kinase C (PKC). We show here that PKCβI and PKCβII exhibit different membrane translocation patterns in response to AT1AR agonist activation. Whereas PKCβII translocation to the membrane is transient, PKCβI displays additional translocation responses: persistent membrane localization and oscillations between the membrane and cytosol following agonist removal. The initial translocation of PKCβI requires the release of calcium from intracellular stores and the activation of phospholipase C, but persistent membrane localization is dependent upon extracellular calcium influx. The mutation of any of the three PKC phosphorylation consensus sites (Ser-331, Ser-338, and Ser-348) localized within the AT1AR C-tail significantly increases the probability that persistent increases in diacylglycerol levels and PKCβI translocation responses will be observed. The persistent increase in AT1AR-mediated diacylglycerol formation is mediated by the activation of phospholipase D. Although the persistent PKCβI membrane translocation response is absolutely dependent upon the PKC activity-dependent recruitment of an extracellular calcium current, it does not require the activation of phospholipase D. Taken together, we show that the patterning of AT1AR second messenger response patterns is regulated by heterologous desensitization and PKC isoform substrate specificity.

6. Dynamics of epileptic phenomena determined from statistics of ictal transitions.

   Piotr Suffczynski, Fernando H Lopes da Silva, Jaime Parra, Demetrios N Velis, Brigitte M Bouwman, Clementina M van Rijn, Peter van Hese, Paul Boon, Houman Khosravani, Miron Derchansky, Peter Carlen, and Stiliyan Kalitzin

   IEEE transactions on bio-medical engineering, 2006

   Abs

   In this paper, we investigate the dynamical scenarios of transitions between normal and paroxysmal state in epilepsy. We assume that some epileptic neural network are bistable i.e., they feature two operational states, ictal and interictal that co-exist. The transitions between these two states may occur according to a Poisson process, a random walk process or as a result of deterministic time-dependent mechanisms. We analyze data from animal models of absence epilepsy, human epilepsies and in vitro models. The distributions of durations of ictal and interictal epochs are fitted with a gamma distribution. On the basis of qualitative features of the fits, we identify the dynamical processes that may have generated the underlying data. The analysis showed that the following hold. 1) The dynamics of ictal epochs differ from those of interictal states. 2) Seizure initiation can be accounted for by a random walk process while seizure termination is often mediated by deterministic mechanisms. 3) In certain cases, the transitions between ictal and interictal states can be modeled by a Poisson process operating in a bistable network. These results imply that exact prediction of seizure occurrence is not possible but termination of an ictal state by appropriate counter stimulation might be feasible.

2005

1. Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy

   Houman Khosravani, Christopher Bladen, David B Parker, Terrance P Snutch, John E McRory, and Gerald W Zamponi

   Annals of Neurology, 2005

   Abs

   Heron and colleagues (Ann Neurol 2004;55:595-596) identified three missense mutations in the Cav3.2 T-type calcium channel gene (CACNA1H) in patients with idiopathic generalized epilepsy. None of the variants were associated with a specific epilepsy phenotype and were not found in patients with juvenile absence epilepsy or childhood absence epilepsy. Here, we introduced and functionally characterized these three mutations using transiently expressed human Cav3.2 channels. Two of the mutations exhibited functional changes that are consistent with increased channel function. Taken together, these findings along with previous reports, strongly implicate CACNA1H as a susceptibility gene in complex idiopathic generalized epilepsy.

2. The Arg473Cys-neuroligin-1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons

   Houman Khosravani, Christophe Altier, Gerald W Zamponi, and Michael A Colicos

   FEBS Letters, 2005

   Abs

   Synapses mediate communication between neurons, thus playing a fundamental role in information processing in the CNS. Neuroligins form a family of heterophilic synaptic cell adhesion molecules, and neuroligin 1 (NL1) has been shown to be involved in the formation of excitatory synapses and have been suggested to associate indirectly with NMDA receptors by common binding to PSD95. A mutation in neuroligin 3 (Arg451Cys-NL3, human sequence numbering) identified in autistic patients is associated with altered spine density and has reduced binding capacity for its presynaptic partner beta-neurexin. Here, we investigated the role of NL1 and the homologous NL1 mutation Arg473Cys-NL1 (R473C-NL1) in excitatory synaptic transmission and NMDA receptor distribution. We demonstrate that R473C-NL1, when expressed in cultured hippocampal neurons, can induce a dramatic increase in NMDA current amplitude and that this change is accompanied by NMDA receptor clustering in the postsynaptic cell.

3. Increased High‐frequency Oscillations Precede in vitro Low‐Mg2+ Seizures

   Houman Khosravani, C. Robert Pinnegar, J. Ross Mitchell, Berj L. Bardakjian, Paolo Federico, and Peter L. Carlen

   Epilepsia, 2005

   Abs

   Summary: Purpose: High‐frequency oscillations (HFOs) in the range of ≥80 Hz have been recorded in neocortical and hippocampal brain structures in vitro and in vivo and have been associated with physiologic and epileptiform neuronal population activity. Frequencies in the fast‐ripple range (>200 Hz) are believed to be exclusive to epileptiform activity and have been recorded in vitro, in vivo, and in epilepsy patients. Although the presence of HFOs is well characterized, their temporal evolution in the context of transition to seizure activity is not well understood. Methods: With an in vitro low‐magnesium model of spontaneous seizures, we obtained extracellular field recordings (hippocampal regions CA1 and CA3) of interictal, preictal, and ictal activity. Recordings were subjected to power–frequency analysis, in time, by using a local multiscale Fourier transform. The power spectrum was computed continuously and was quantified for each epileptiform discharge into four frequency ranges spanning subripple, ripple, and two fast‐ripple frequency bands. Results: A statistically significant increasing trend was observed in the subripple (0–100 Hz), ripple (100–200 Hz), and fast‐ripple 1 (200–300 Hz) frequency bands during the epoch corresponding to the transition to seizure (preictal to ictal). Conclusions: Temporal patterns of HFOs during epileptiform activity are indicative of dynamic changes in network behavior, and their characterization may offer insights into pathophysiologic processes underlying seizure initiation.

4. Prediction of seizure onset in an in-vitro hippocampal slice model of epilepsy using Gaussian-based and wavelet-based artificial neural networks.

   Alan W L Chiu, Sarit Daniel, Houman Khosravani, Peter L Carlen, and Berj L Bardakjian

   Annals of biomedical engineering, 2005

   Abs

   We propose that artificial neural networks (ANNs) can be used to predict seizure onsets in an in-vitro hippocampal slice model capable of generating spontaneous seizure-like events (SLEs) in their extracellular field recordings. This paper assesses the effectiveness of two ANN prediction schemes: Gaussian-based artificial neural network (GANN) and wavelet-based artificial neural network (WANN). The GANN prediction system consists of a recurrent network having Gaussian radial basis function (RBF) nonlinearities capable of extracting the estimated manifold of the system. It is able to classify the underlying dynamics of spontaneous in-vitro activities into interictal, preictal and ictal modes. It is also able to successfully predict the onsets of SLEs as early as 60 s before. Improvements can be made to the overall seizure predictor design by incorporating time-varying frequency information. Consequently, the idea of WANN is considered. The WANN design entails the assumption that frequency variations in the extracellular field recordings can be used to compute the times at which onsets of SLEs are most likely to occur in the future. Progressions of different frequency components can be captured by the ANN using appropriate frequency band adjustments via pruning, after the initial wavelet transforms. In the off-line processing comprised of 102 spontaneous SLEs generated from 14 in-vitro rat hippocampal slices, with half of them used for training and the other half for testing, the WANN is able to predict the forecoming ictal onsets as early as 2 min prior to SLEs with over 75% accuracy within a 30 s precision window.

2004

1. A subharmonic dynamical bifurcation during in vitro epileptiform activity

   Jose L. Perez Velazquez, and Houman Khosravani

   Chaos: An Interdisciplinary Journal of Nonlinear Science, 2004

   Abs

   Epileptic seizures are considered to result from a sudden change in the synchronization of firing neurons in brain neural networks. We have used an in vitro model of status epilepticus (SE) to characterize dynamical regimes underlying the observed seizure-like activity. Time intervals between spikes or bursts were used as the variable to construct first-return interpeak or interburst interval plots, for studying neuronal population activity during the transition to seizure, as well as within seizures. Return maps constructed for a brief epoch before seizures were used for approximating the local system dynamics during that time window. Analysis of the first-return maps suggests that intermittency is a dynamical regime underlying the observed epileptic activity. This type of analysis may be useful for understanding the collective dynamics of neuronal populations in the normal and pathological brain.

2. Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy

   Houman Khosravani, Christophe Altier, Brett Simms, Kevin S Hamming, Terrance P Snutch, Janette Mezeyova, John E McRory, and Gerald W Zamponi

   Journal of Biological Chemistry, 2004

   Abs

   Childhood absence epilepsy (CAE) is a type of generalized epilepsy observed in 2-10% of epileptic children. In a recent study by Chen et al. (Chen, Y., Lu, J., Pan, H., Zhang, Y., Wu, H., Xu, K., Liu, X., Jiang, Y., Bao, X., Yao, Z., Ding, K., Lo, W. H., Qiang, B., Chan, P., Shen, Y., and Wu, X. (2003) Ann. Neurol. 54, 239-243) 12 missense mutations were identified in the CACNA1H (Ca(v)3.2) gene in 14 of 118 patients with CAE but not in 230 control individuals. We have functionally characterized five of these mutations (F161L, E282K, C456S, V831M, and D1463N) using rat Ca(v)3.2 and whole-cell patch clamp recordings in transfected HEK293 cells. Two of the mutations, F161L and E282K, mediated an approximately 10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a approximately 50% slowing of inactivation relative to control and shifted half-inactivation potential approximately 10 mV toward more depolarized potentials. Mean time to peak was significantly increased by mutation V831M but was unchanged for all others. No resolvable changes in the parameters of the IV relation or current kinetics were observed with the remaining mutations. The findings suggest that several of the Ca(v)3.2 mutants allow for greater calcium influx during physiological activation and in the case of F161L and E282K can result in channel openings at more hyperpolarized (close to resting) potentials. This may underlie the propensity for seizures in patients with CAE.

2003

1. Time response of interstitial fluid pressure measurements in cervix cancer.

   Houman Khosravani, Brige Chugh, Michael F Milosevic, and Kenneth H Norwich

   Microvascular research, 2003

   Abs

   Increased interstitial fluid pressure (IFP) is a common finding in malignant tumors as a result of the abnormal tumor vasculature and a lack of functional lymphatics. A recent clinical study by Milosevic et al. [Cancer Res. 61 (2001) 6400] reported a link between elevated IFP and survival in patients with cancer of the cervix. Patients with high IFP were more likely to have recurrence of tumors even after radiotherapy and were also more likely to die of progressive disease, independent of other prognostic factors. In this complementary study, using human data, we analyze 152 cervical tumor pressure IFP measurements from 42 patients with clinically diagnosed cancer of the cervix, randomly selected from the sample of 102 patients involved in the original study. We propose a simple biophysical model, based on flow through porous media, to explain the time response of the measured pressure curves in human cervical tumors. The response of IFP was governed by a time-constant tau(IFP) = 14 +/- 1 s averaged over multiple tumor sites. Interstitial hydraulic conductivity was computed to be approximately equal to 4.3 x 10(-6) cm(2)/mm Hgs.

2. Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic-clonic seizures.

   Leanne Casaubon, Bernd Pohlmann-Eden, Houman Khosravani, Peter L Carlen, and Richard Wennberg

   Epileptic disorders : international epilepsy journal with videotape, 2003

   Abs

   Whether cortical or subcortical structures, specifically the thalamus, play the dominant role in generating primary generalized seizures has been the subject of long debate. Most experimental data implicate a hyperexcitable cortical generator of spike-and-wave activity, with the thalamus quickly recruited to sustain the generalized oscillations through a reverberating thalamocortical network. However, there is little clinical evidence to support the cortical generator hypothesis. We present video-EEG recordings of generalized tonic-clonic seizures in three patients with proven primary generalized epilepsy (PGE), all of whom showed a consistent pattern of lateralized seizure onset compatible with a focal frontal lobe generator.

1999

1. Type III intermittency in human partial epilepsy

   J L Perez Velazquez, Houman Khosravani, Andres Lozano, Berj L Bardakjian, Peter L Carlen, and Richard Wennberg

   European Journal of Neuroscience, 1999

   Abs

   A rigorous characterization of the dynamic regimes underlying human seizures is needed to understand, and possibly control, the transition to seizure. Intra‐ or extracranial brain electrical activity was recorded in five patients with partial epilepsy, and the interictal and ictal activity analysed to determine the dynamics of seizures. We constructed first‐return one‐dimensional maps by fitting the scatter plots of interpeak intervals. The features of the mapping indicated that type III intermittency is the dynamic charateristic of the ictal events. This was confirmed using histograms of the durations of the regular phases during seizures. The intermittent regime explains the abrupt transitions observed during ictal events in terms of transient stabilization of the unstable steady state.

1998

1. CO₂ uptake mechanism in Eremosphaera viridis

   Jason S T Deveau, Houman Khosravani, Roger R Lew, and Brian Colman

   Canadian Journal of Botany, 1998