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Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures

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Abstract

Background

Pregabalin (PGB) is an effective adjunctive treatment for focal epilepsy and acts by binding to the alpha2-delta subunit of voltage-gated calcium channels to reduce excitatory neurotransmitter release. Limited data exist on its use in the neurocritical care setting, including cyclic seizures—a pattern of recurrent seizures occurring at nearly regular intervals. Although the mechanism underpinning cyclic seizures remains elusive, spreading excitation linked to spreading depolarizations may play a role in seizure recurrence and periodicity. PGB has been shown to increase spreading depolarization threshold; hence, we hypothesized that the magnitude of antiseizure effect from PGB is more pronounced in patients with cyclic versus noncyclic seizures in a critically ill cohort with recurrent seizures.

Methods

We conducted a retrospective case series of adults admitted to two academic neurointensive care units between January 2017 and March 2019 who received PGB for treatment of seizures. Data collected included demographics, etiology of brain injury, antiseizure medications, and outcome. Continuous electroencephalogram recordings 48 hours before and after PGB administration were reviewed by electroencephalographers blinded to the administration of antiseizure medications to obtain granular data on electrographic seizure burden. Cyclic seizures were determined quantitatively (i.e., < 50% variation of interseizure intervals for at least 50% of consecutive seizures). Coprimary outcomes were decrease in hourly seizure burden in minutes and decrease in seizure frequency in the 48 hours after PGB initiation. We used nonparametric tests for comparison of seizure frequency and burden and segmented linear regression to assess PGB effect.

Results

We included 16 patients; the median age was 69 years, 11 (68.7%) were women, three (18.8%) had undergone a neurosurgical procedure, and five (31%) had underlying epilepsy. All seizures had focal onset; ten patients (62.5%) had cyclic seizures. The median hourly seizure burden over the 48 hours prior to PGB initiation was 1.87 min/hour (interquartile range 1.49–8.53), and the median seizure frequency was 1.96 seizures/hour (interquartile range 1.06–3.41). In the 48 hours following PGB (median daily dose 300 mg, range 75–300 mg), the median number of seizures per hour was reduced by 0.80 seizures/hour (95% confidence interval 0.19–1.40), whereas the median hourly seizure burden decreased by 1.71 min/hour (95% confidence interval 0.38–3.04). When we compared patients with cyclic versus noncyclic seizures, there was a relative decrease in hourly seizure frequency (− 86.7% versus − 2%, p = 0.04) and hourly seizure burden (− 89% versus − 7.8%, p = 0.03) at 48 hours.

Conclusions

PGB was associated with a relative reduction in seizure burden in neurocritically ill patients with recurrent seizures, especially those with cyclic seizures, and may be considered in the therapeutic arsenal for refractory seizures. Whether this effect is mediated via modulation of spreading depolarization requires further study.

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Acknowledgements

Dr. Carolina B. Maciel has received the Claude D. Pepper Older Americans Independence Center Junior Scholar award, which supports preclinical studies of mechanisms of secondary brain injury in a rodent cardiac arrest model, and the American Heart Association Innovative Project award investigating the pharmacokinetics of vigabatrin absorption in the post-cardiac-arrest period.

Funding

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Authors and Affiliations

  1. Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA

    Katharina M. Busl, Mitesh Patel, Christine N. Smith, Sotiris Mitropanopoulos, Maria Bruzzone, Stephan Eisenschenk, Christopher P. Robinson, William H. Roth, Pouya Alexander Ameli, Marc-Alain Babi, Michael A. Pizzi & Carolina B. Maciel

  2. Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, USA

    Katharina M. Busl, Christopher P. Robinson, William H. Roth, Pouya Alexander Ameli, Marc-Alain Babi, Michael A. Pizzi & Carolina B. Maciel

  3. Westmead Comprehensive Epilepsy Unit, Westmead Hospital, University of Sydney, Sydney, Australia

    Michael W. K. Fong

  4. Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    Michael W. K. Fong, Rakesh Jadav, Emily J. Gilmore, Lawrence J. Hirsch & Carolina B. Maciel

  5. United States Air Force, Eglin Air Force Base, Florida, USA

    Zachary Newcomer

  6. Department of Emergency Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    Scott A. Cohen

  7. Baptist Neurology, Jacksonville, FL, USA

    Maria Hella

  8. Department of Neurology, University of Utah, Salt Lake City, UT, 81432, USA

    Carolina B. Maciel

  9. Neurocritical Care, McKnight Brain Institute, 1149 Newell Drive, L3-100, Gainesville, FL, 32610, USA

    Carolina B. Maciel

Authors
  1. Katharina M. Busl
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  4. Mitesh Patel
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Contributions

The authors contributed to this article as follows: Drs. Maciel, Hirsch, Jadav, and Fong conceptualized and designed the study, oversaw data acquisition, and intellectually revised the manuscript. Dr. Busl drafted the manuscript and intellectually revised it. Mr. Cohen provided initial data analysis and revised the manuscript. Drs. Patel, Bruzzone, Hella, and Newcomer were responsible for data acquisition and critically revised the manuscript. Drs. Gilmore, Maciel, and Hirsch critically assessed the EEGs in addition. Drs. Ameli, Babi, Eisenschenk, Mitropanopoulos, Roth, Pizzi, Robinson, Gilmore, and Smith revised the manuscript for intellectual content. The final manuscript was approved by all authors.

Corresponding author

Correspondence to Carolina B. Maciel.

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Conflict of interest

No author declared any conflict of interest pertaining to this article, and all reported items pertained to outside of this work. Drs. Ameli, Babi, Bruzzone, Cohen, Eisenschenk, Fong, Gilmore, Hella, Jadav, Mitropanopoulos, Newcomer, Patel, Roth, and Smith did not report any disclosures. Drs. Maciel, Robinson, and Pizzi report receiving honoraria for authoring chapters for the American Academy of Neurology. Dr. Busl reports personal consulting fees from Guidepoint Global, Techspert, and Health Advances as well as honoraria from the American Academy of Neurology for course directorship and guest editing. Dr. Robinson receives personal compensation for serving as a legal expert witness for traumatic brain injury. Dr. Gilmore receives personal fees from UCB and honoraria from Inova for speaking at a symposium. Dr. Hirsch reports research support to Yale University for investigator-initiated studies from the Daniel Raymond Wong Neurology Research Fund at Yale, royalties from Wiley and Wolters-Kluwer, personal fees from Ceribell, Monteris, Neuropace, Aquestive, Medtronic, UCB, Marinus, Accure, Natus, Neurelis, and Eisai, and speaking honoraria from Neuropace, Natus, and UCB.

Ethical approval/informed consent

This study adheres to ethical guidelines and has approval from the local institutional review board (University of Florida, IRB201901034; Yale, IRB HIC#111109342), including a waiver of consent.

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Busl, K.M., Fong, M.W.K., Newcomer, Z. et al. Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures. Neurocrit Care 37, 140–148 (2022). https://doi.org/10.1007/s12028-022-01459-6

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