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Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep

Departments of Clinical Neurophysiology (Drs. Hennessy and Binnie, and M.G. Tighe) and Neurology (Drs. Hennessy and Nashef), Kings College Hospital, London, UK.

Address correspondence and reprint requests to Dr. M.J. Hennessy, Department of Clinical Neurophysiology, Kings College Hospital, Denmark Hill, London SE5 9RS, UK; e-mail: Michael{at}hennessy72.fsnet.co.uk

Objective:— To evaluate the cardiac autonomic effects of abrupt withdrawal of carbamazepine (CBZ) during sleep in patients with epilepsy.

Background:— The pathophysiology of sudden unexpected death in epilepsy (SUDEP) is uncertain, with ictal or peri-ictal cardiorespiratory compromise appearing probable. Risk factors for SUDEP include multiple antiepileptic drugs (AED), poor compliance, and abrupt AED withdrawal. The spectral analysis of the beat-to-beat heart rate variability (HRV) displays two main components: low frequency (LF), representing sympathetic and parasympathetic influence and high frequency (HF), representing parasympathetic influence. The LF/HF ratio is commonly regarded as an indicator of sympathovagal balance.

Method:— Twelve patients with medically intractable seizures underwent abrupt withdrawal of CBZ to facilitate seizure recording during controlled circuit TV-EEG monitoring. Continuous EKG recording was begun 24 hours before CBZ reduction. Spectral analysis of the HRV was performed during selected samples of non-REM sleep before and after CBZ reduction. Analyses were made at least 6 hours after from (complex) partial and 12 hours from generalized seizures.

Results:— The mean LF/HF ratio before withdrawal of CBZ was 2.15 compared with a ratio of 2.65 on day 4 after withdrawal, an increase of 19% (geometric mean; 95% CI, 2% to 34%; Wilcoxon test, z = 2.36; p = 0.018). The ratio increased in 10 patients compared with a decrease in only one patient.

Conclusion:— Abrupt withdrawal of CBZ leads to enhanced sympathetic activity in sleep as evidenced by increased LF/HF ratios. Increased sympathetic activity in the setting of seizure-induced hypoxia could predispose to SUDEP.

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