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limbic structures, especially the amygdala and pyriform cortex, modulate hypothalamic
function, and stimulation of these foci can elicit both sympathetic and parasympathetic
visceromotor autonomic responses44.

Other than visual inspection of a standard 12-lead ECG, more sophisticated methods to
interrogate the cardiac autonomic system have been developed, for example, measures of
heart rate variability (HRV). In its simplest form this is measured in a time domain analysis
as the standard deviation of R-R wave intervals45,46. Frequency domain analysis permits the
calculation of high-frequency (HF) and low-frequency (LF) components which assess the
relative contribution of parasympathetic and sympathetic autonomic activity47.

Cardiac mechanisms

Structural cardiac pathology. The exclusion of cardiac pathology as a contributing factor in
SUDEP is challenging due to the presence of, for example, subtle abnormalities that only a
detailed microscopic examination of cardiac tissue can elucidate, such as conducting system
fibrosis or cardiomyopathy48, tissue decomposition precluding the acquisition of suitable
material for evaluation, lack of an appropriate control group for comparison, and the
possibility of a functional rather than a structural disorder, such as ion channelopathies or
pre-excitation syndromes, with normal macroscopic and microscopic examinations being
implicated49.

Increased cardiac weight has been observed in male SUDEP cases compared to control
subjects7 although more recent studies, using more convincing methodology, have failed to
replicate this earlier finding and cardiac weight is not considered to differ between SUDEP
and non-SUDEP cases50-52. Minor, non-specific pathological changes presumed to be non-
fatal, such as atherosclerosis, conducting system fibrosis and diffuse myocardial fibrosis have
been identified in SUDEP cases27,51,53. It has been postulated that neurogenic coronary
vasospasm may be implicated, and that if recurrent, this may eventually progress to
perivascular and interstitial fibrosis54. This may, in turn, predispose the heart to
arrhythmogenesis, particularly in the setting of considerable autonomic imbalance during
seizures55,56. The occurrence and significance of these pathological changes in SUDEP is not
universally agreed however50,57 and the full characterisation of the relationship between
myocardial pathology and acute and recurrent seizures remains unclear at the present time.

Inter-ictal. At the simplest level, inter-ictal cardiac function can be evaluated by visually
assessing a standard 12-lead ECG, primarily for evidence of conduction abnormalities,
although these are frequently normal58-60 or show only minor, non-significant changes61.
However, a recent preliminary study of 128 patients with severe refractory epilepsy and
learning disability revealed inter-ictal ECG abnormalities in approximately 60% of patients,
including first-degree atrio-ventricular block and poor R-wave progression62.

Early experimental studies demonstrated that inter-ictal epileptiform activity was associated
with sympathetic and parasympathetic autonomic dysfunction, in a time-locked synchronised
pattern63,64. In the first clinical reports, analysis of inter-ictal heart rate variability in 19
patients with refractory temporal lobe epilepsy revealed frequent, high-amplitude
fluctuations in heart rate which were most pronounced in poor surgical candidates65. More
recently, reduced sympathetic tone, demonstrated by decreased low-frequency power, has
been seen in both focal and, albeit less markedly, primary generalised epilepsy45,60,65,66.
Overall, there is some evidence for inter-ictal cardiac autonomic dysfunction in patients with
both focal and generalised epilepsy, possibly modulated by antiepileptic medication, in
particular carbamazepine. There are conflicting reports in the literature however, suggesting
that the relationship between inter-ictal epileptiform activity, antiepileptic medication and
autonomic function has not yet been fully characterised.