Post-ictal Modulation of Baroreflex Sensitivity in Patients With Intractable Epilepsy

Objective: Seizure-related autonomic dysregulation occurs in epilepsy patients and may contribute to Sudden Unexpected Death in Epilepsy (SUDEP). We tested how different types of seizures affect baroreflex sensitivity (BRS) and heart rate variability (HRV). We hypothesized that BRS and HRV would be reduced after bilateral convulsive seizures (BCS).Methods: We recorded blood pressure (BP), electrocardiogram (ECG) and oxygen saturation continuously in patients (n = 18) with intractable epilepsy undergoing video-EEG monitoring. A total of 23 seizures, either focal seizures (FS, n = 14) or BCS (n = 9), were analyzed from these patients. We used 5 different HRV measurements in both the time and frequency domains to study HRV in pre- and post-ictal states. We used the average frequency domain gain, computed as the average of the magnitude ratio between the systolic BP (BPsys) and the RR-interval time series, in the low-frequency (LF) band as frequency domain index of BRS in addition to the instantaneous slope between systolic BP and RR-interval satisfying spontaneous BRS criteria as a time domain index of BRS.Results: Overall, the post-ictal modulation of HRV varied across the subjects but not specifically by the type of seizures. Comparing pre- to post-ictal epochs, the LF power of BRS decreased in 8 of 9 seizures for patients with BCS; whereas following 12 of 14 FS, BRS increased. Similarly, spontaneous BRS decreased following 7 of 9 BCS. The presence or absence of oxygen desaturation was not consistent with the changes in BRS following seizures, and the HRV does not appear to be correlated with the BRS changes. These data suggest that a transient decrease in BRS and temporary loss of cardiovascular homeostatic control can follow BCS but is unlikely following FS.Significance: These findings indicate significant post-ictal autonomic dysregulation in patients with epilepsy following BCS. Further, reduced BRS following BCS, if confirmed in future studies on SUDEP cases, may indicate one quantifiable risk marker of SUDEP

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Post-ictal Modulation of Baroreflex Sensitivity in Patients with Intractable Generalized Tonic Clonic Seizures versus Partial Seizures

Seizure-related autonomic dysregulation occurs in epilepsy patients and may contribute to Sudden Unexpected Death in Epilepsy (SUDEP). We tested how different types of seizures affect baroreflex sensitivity (BRS). We hypothesized that BRS would be reduced after generalized tonic-clonic seizures (GTCS). Our results showed significant post-ictal autonomic dysregulation in patients with epilepsy following GTCS. Further, the loss of BRS following GTCS may indicate a generalized post-ictal brainstem dysfunction following seizures, and BRS measurements in GTCS may provide one quantifiable risk marker of SUDEP