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synergistically32. On this basis, it is difficult to know whether a high carbamazepine level is
an independent risk factor or is merely representative of challenging epilepsy.

Perimortem features
There is evidence from both descriptive and controlled studies that a terminal convulsive
seizure7,10,16,18,20,25,27,39, being found alone in bed10,17-19,25,27 and in the prone position20,27 are
independent risk factors for SUDEP. Whereas a small number of descriptive studies have not
found an association, all case-control studies that have evaluated these factors have found a
positive relationship with the risk of SUDEP. In a published report of interviews with
bereaved relatives, evidence for a terminal seizure was found in 24 out of 26 cases but it is
of interest that only two were witnessed. The observation that, in most studies, unwitnessed
cases far outnumber those witnessed suggests that enhanced surveillance of patients with
epilepsy may be protective18. This is corroborated by a study of young patients with epilepsy
at a special residential school. All sudden deaths during the period of the study occurred when
the pupils were not under the close supervision of the school and most were unwitnessed11.
Similar findings of a protective effect of enhanced supervision at night were also found in a
large controlled study, where supervision was defined as the presence in the bedroom of an
individual of normal intelligence and at least 10 years old or the use of special precautions,
such as checks throughout the night or the use of a listening device22.

In some cases where a prone position was not observed, other factors which might
compromise breathing were identified. For example, in one study only five out of 26 people
were found face down in the pillow, and a sixth with the head in carpet pile. In total however,
there were 11 out of 26 cases in which an extrinsic or intrinsic positional obstruction to
breathing amenable to intervention may have contributed18. Moreover, it is possible that this
may be an underestimate as obstructive apnoea can occur in an apparently benign position40.

Other features
There is limited evidence for an independent relationship between learning disability and an
increased risk of SUDEP. Early descriptive and population-based studies, in which learning
disability was determined by observer impressions rather than by formal IQ examination,
provided only weak support for this association7,41. Most recent studies have found no clear
correlation18,25-27,30 although others have reported an IQ of less than 70 to be a risk factor for
SUDEP, even after accounting for seizure frequency28. It has been postulated that patients
with learning disability are more susceptible to central apneoa and positional asphyxia that
may cause SUDEP as a result of prolonged post-ictal encephalopathy42, decreased post-ictal
respiratory drive and impaired movement and righting reflexes28. Despite early reports of an
increased incidence of structural lesions in patients with SUDEP7,16,43, this has not been
confirmed by more recent, controlled studies21,27,28. While there is evidence that psychotropic
medication can influence the risk of sudden death in general, there is no convincing evidence
of this being particularly relevant in SUDEP.

Pathophysiology of SUDEP

Pathophysiological mechanisms of SUDEP are likely to be heterogeneous and may be
multifactorial. Theories propounded have focused on autonomic disturbance  particularly
cardiac arrhythmias and central and obstructive apnoea and neurogenic pulmonary oedema.
Additionally, the possibility of structural or functional cardiac pathology predisposing
patients with epilepsy to cardiac events has been proposed.

Cerebrogenic autonomic control
The components of the central autonomic network involved in the functional relationships
between cortical, subcortical and somatic regions have been elucidated from experimental
and human stimulation and lesional studies. For example, it has been demonstrated that