scholarly journals 4512 Allopregnanolone Dose Finding for Status Epilepticus Treatment by Pharmacokinetic-Pharmacodynamic Modeling using Quantitative EEG in Dogs

2020 ◽  
Vol 4 (s1) ◽  
pp. 1-2
Author(s):  
Edward “Ned” Patterson ◽  
Irene Vuu ◽  
Dorota Zolkowska ◽  
Chun-Yi Wu ◽  
Ilo Leppik ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Power Density ◽  
Frequency Band ◽  
Plasma Concentrations ◽  
Refractory Status Epilepticus ◽  
Dose Finding ◽  
Pharmacodynamic Modeling ◽  
Pkpd Model ◽  
Eeg Data ◽  
Beta Frequency

OBJECTIVES/GOALS: Allopregnanolone (ALLO), a modulator of GABAA receptors, may be useful as a treatment for human and canine benzodiazepine-refractory status epilepticus (SE). Our objective was to develop a phamacokinetic-pharmacodynamic (PKPD) model relating ALLO plasma concentrations to electroencephalographic (EEG) effects in dogs. METHODS/STUDY POPULATION: Four healthy dogs and one dog with epilepsy that had implanted intracranial electrodes were utilized. ALLO doses ranging from 1-6 mg/kg were administered IV over 5 min. EEG data were collected during four IM doses (1-2 mg/kg). Blood samples were collected up to 6 hr following dosing. ALLO concentrations were measured using HPLC-MS/MS. Power density was determined in EEG bands using a custom algorithm. A two-compartment link PKPD model was developed to describe the relation between ALLO plasma concentration and change in EEG power in the alpha, beta, delta and theta bands. RESULTS/ANTICIPATED RESULTS: ALLO caused a rapid increase in absolute power density in all EEG bands measured (1-4, >4 – 8, >8 – 12, >12 – 25, and >25 – 100 Hz). The onset of effect was rapid (1-3 min) and demonstrated by frequency band and dose analysis. Concentration-EEG data were best fit by a two-compartment PK model and sigmoidal Emax PD indirect link model. The beta frequency band was most sensitive, showing increases in power at the lowest ALLO concentrations. The EC50 concentration for the beta frequency was ~270 ng/mL. The EC50 values for effects on the other frequency bands were ~500-700 ng /mL. In conclusion, IV ALLO causes a rapid effect on EEG that can be used to determine minimal plasma concentrations associated with target engagement. DISCUSSION/SIGNIFICANCE OF IMPACT: Dose selection for future clinical trials will use the effective concentrations determined here in conjunction with studies in animal status epilepticus models. Studies are planned in client owned dogs with epilepsy to evaluate clinical efficacy in dogs and as nonclinical proof-of-concept evidence supporting translational studies in people. CONFLICT OF INTEREST DESCRIPTION: Michael Rogawski and Dorota Zolkowska are named as inventors on patent applications claiming use of neuroactive steroids including allopregnanolone and ganaxolone in the treatment of status epilepticus.

scholarly journals Beta-frequency electrophysiological bursts: BOLD correlates and relationships with psychotic illness

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S37-S38
Author(s):  
Paul M Briley ◽  
Elizabeth B Liddle ◽  
Karen J Mullinger ◽  
Molly Simmonite ◽  
Lena Palaniyappan ◽  
...  
Keyword(s):  
Working Memory ◽  
Frequency Band ◽  
Blood Oxygenation ◽  
Healthy Controls ◽  
Psychotic Illness ◽  
Beta Power ◽  
Eeg Data ◽  
Beta Frequency Band ◽  
Sensorimotor Information ◽  
Beta Frequency

AimsTo identify the BOLD (blood oxygenation level dependent) correlates of bursts of beta frequency band electrophysiological activity, and to compare BOLD responses between healthy controls and patients with psychotic illness.The post movement beta rebound (PMBR) is a transient increase in power in the beta frequency band (13-30 Hz), recorded with methods such as electroencephalography (EEG), following the completion of a movement. PMBR size is reduced in patients with schizophrenia and inversely correlated with severity of illness. PMBR size is inversely correlated with measures of schizotypy in non-clinical groups. Therefore, beta-band activity may reflect a fundamental neural process whose disruption plays an important role in the pathophysiology of schizophrenia. Recent work has found that changes in beta power reflect changes in the probability-of-occurrence of transient bursts of beta-frequency activity. Understanding the generators of beta bursts could help unravel the pathophysiology of psychotic illness and thus identify novel treatment targets.MethodEEG data were recorded simultaneously with BOLD data measured with 3T functional magnetic resonance imaging (fMRI), whilst participants performed an n-back working memory task. We included seventy-eight participants – 32 patients with schizophrenia, 16 with bipolar disorder and 30 healthy controls. Beta bursts were identified in the EEG data using a thresholding method and burst timings were used as markers in an event-related fMRI design convolved with a conventional haemodynamic response function. A region of interest analysis compared beta-event-related BOLD activity between patients and controls.ResultBeta bursts phasically activated brain regions implicated in coding task-relevant content (specifically, regions involved in the phonological representation of letter stimuli, as well as areas representing motor responses). Further, bursts were associated with suppression of tonically-active regions. In the EEG, PMBR was greater in controls than patients, and, in patients, PMBR size was positively correlated with Global Assessment of Functioning scores, and negatively correlated with persisting symptoms of disorganisation and performance on a digit symbol substition test. Despite this, patients showed greater, more extensive, burst-related BOLD activation than controls.ConclusionOur findings are consistent with a recent model in which beta bursts serve to reactivate latently-maintained, task-relevant, sensorimotor information. The increased BOLD response associated with bursts in patients, despite reduced PMBR, could reflect inefficiency of burst-mediated cortical synchrony, or it may suggest that the sensorimotor information reactivated by beta bursts is less precisely specified in psychosis. We propose that dysfunction of the mechanisms by which beta bursts reactivate task-relevant content can manifest as disorganisation and working memory deficits, and may contribute to persisting symptoms and impairment in psychosis.

scholarly journals How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries

2021 ◽  
pp. 153575972199832
Author(s):  
Karnig Kazazian ◽  
Marissa Kellogg ◽  
Nora Wong ◽  
Krista Eschbach ◽  
Raquel Farias Moeller ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Refractory Status Epilepticus ◽  
Epilepsy Syndrome ◽  
Neurologic Disorder ◽  
Mortality And Morbidity ◽  
Refractory Status ◽  
Rigorous Research ◽  
Active Epilepsy ◽  
New Onset

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES.

scholarly journals Resolution of cryptogenic new onset refractory status epilepticus with tocilizumab

2021 ◽  
Vol 15 ◽  
pp. 100431
Author(s):  
Jonathan P. Donnelly ◽  
Nidhi Kasatwar ◽  
Shaheryar Hafeez ◽  
Ali Seifi ◽  
Andrea Gilbert ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Refractory Status Epilepticus ◽  
Refractory Status ◽  
New Onset

Not all patients with convulsive status epilepticus intubated in pre-hospital settings meet the criteria for refractory status epilepticus

Seizure ◽  
2021 ◽  
Vol 88 ◽  
pp. 29-35
Author(s):  
Sinead Zeidan ◽  
Benjamin Rohaut ◽  
Hervé Outin ◽  
Francis Bolgert ◽  
Marion Houot ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Refractory Status Epilepticus ◽  
Convulsive Status Epilepticus ◽  
Refractory Status
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