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combined28. Conversely, high seizure frequency was not an independent risk factor in a
number of other reports although a number of methodological issues exist8,20,25,27. For
example, in a retrospective case-control study of 42 patients with SUDEP there was no
reported difference in seizure frequency between the SUDEP and non-SUDEP control
groups. The study was undertaken at a tertiary referral centre, with both groups having
chronic refractory epilepsy and frequent seizures27. Other negative studies may have been
similarly influenced25. Intuitively, the severity of convulsive seizures may also be important
in SUDEP, but this is more challenging to quantify and hence has not been evaluated as a
risk factor.

Antiepileptic medication
The number of antiepileptic drugs (AEDs) taken concomitantly has been reported to be an
independent risk factor for SUDEP29, even after correction for seizure frequency21,28.This is
not universally reported however8,14,25-27, although small numbers of patients and a high
frequency of polytherapy in control subjects may be contributory in these negative studies. It
has been shown that the risk of SUDEP increases with the number of AEDs previously taken
despite correction for seizure frequency, perhaps a surrogate for epilepsy severity. Risk of
SUDEP is also increased in those whose treatment history was unclear, which may reflect the
risk associated with the lack of treatment and uncontrolled seizures, although the reason for
this was not objectively assessed22.

Despite several descriptive studies suggesting that subtherapeutic levels of AEDs are a risk
factor for SUDEP6,7,16,20, this has not been corroborated by the majority of case-control
studies25,31,32, most likely because this is difficult to study as an independent factor. Of note
is that postmortem levels of AEDs may not accurately reflect antemortem levels possibly due
to, for example, redistribution and continuing metabolism33. Compliance with AED treatment
was proposed as a risk factor for SUDEP in an uncontrolled study which found
‘subtherapeutic’ AED levels in 68% of SUDEP cases16. Therapeutic drug monitoring has
traditionally been considered a surrogate for medication adherence although, due to the
existence of a number of confounding factors, it is clear that the two terms are not
interchangeable. For example, in patients with uncontrolled seizures, changes of dose and
type of medication are commonplace and serum levels will not be stable and may frequently
be sub-therapeutic despite excellent compliance. The issue of variability of AED use was
recently addressed in a study comparing hair AED concentration variability in patients with
SUDEP, non-SUDEP epilepsy-related deaths, epilepsy outpatients and epilepsy inpatients.
The SUDEP group showed greater hair AED concentration variability than either the
outpatient or the inpatient groups, reflecting variable AED ingestion over time. However, this
cannot distinguish prescribed changes from poor compliance, or identify consistent non-
compliance over time. Secondly, it does not provide information on drug taking behaviour
immediately before death as it takes about five days for drug sequestrated into the follicle to
appear at the scalp; therefore short-term non-compliance immediately before death is not
assessed by this study and may have been overlooked34.

Despite a number of descriptive and controlled studies, no specific AED has been clearly
associated with an increased risk of SUDEP14,20,23,27,28,31,35, although a small number of studies
have implicated treatment with carbamazepine as an independent risk factor22,36,37. For
antiepileptic medication in general, proposed mechanisms include perturbed heart rate
variability, lengthening of the Q-T interval on the electrocardiogram combined with a mild
pro-arrhythmic effect of epileptic seizure discharges, or excessive post-seizure brainstem
inhibition producing a blunting or transient abolition of the central hypoxic and hypercarbic
respiratory drive, with consequent post-ictal respiratory arrest36-38. Elevated serum levels of
carbamazepine have been associated with an increased risk of SUDEP even after adjustments
for seizure frequency have been made. Frequent drug changes and multiple concomitant
AEDs, conventional markers of severe and unstable epilepsy, increased this risk