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Traumatic brain injury: Traumatic lesions
may be a cause of epilepsy but are also a
consequence. Patients with generalised
seizures have a higher risk of minor and
severe cerebral injuries, including cerebral
haemorrhage and contusions; the risk is
related to seizure frequency, type and
control10,11. Post mortem examinations
may identify old cystic cortical contusions,
particularly in the fronto-temporal regions,
present in 30% in one series, and may increase vulnerability to age-accelerated neurofibrillary
tangle pathology12.

Neurodegeneration. Epilepsy may form part of the clinical manifestations of various
neurodegenerative diseases and other common neurological conditions such as strokes and
inflammatory conditions including MS13. Patients with Alzheimer’s disease are at increased risk
for developing epilepsy; the underlying epileptogenic mechanism is unknown, but the toxic
effects of amyloid-β on synaptic transmission have been considered14.

Sudden death in epilepsy

Neuropathology: Post mortem examination is mandatory in sudden unexpected death in epilepsy
(SUDEP), primarily to exclude an anatomical (e.g. cardiac) or other cause of death. The
examination of the brain in SUDEP cases may show mild swelling or ‘fullness’ of the convexities
reflected in high-average brain weights but, by definition, significant swelling, shift or herniation
is absent15. It is perhaps a common misconception that the brain in SUDEP cases is normal in
the vast majority of cases. Analysis from the larger SUDEP series report macroscopic
abnormalities in half to two-thirds of cases16,17. More frequently reported macroscopic
abnormalities include old cerebral traumatic lesions (contusions, gliosis, previous craniotomy
sites), hippocampal or cortical atrophy, cerebellar atrophy, haemangiomas, low-grade tumours
and cortical malformations16. There is no accurate data regarding the relative risk or association
of any of these specific pathological lesions for SUDEP. Some lesions, including acquired old
injuries and cortical neuronal damage, however may give an indirect measure of the clinical
severity of the epilepsy. Histopathological examination is required in SUDEP cases for the
confirmation of any type of macroscopic lesion identified but also to investigate any unsuspected
pathology, e.g. meningo-encephalitis.

It is not possible or necessary for a neuropathologist to perform all autopsies on patients with
epilepsy. Ideally, a specialist neuropathologist should be involved in the interpretation of the
histological brain findings. The Royal College of Pathologists’ guidelines on autopsy practice in
epilepsy recommends that a case should be made to the Coroner and relatives for retention of the
whole brain for fixation. This allows optimal examination following 23 weeks’ fixation. If this
is not permissible, the next best practice is to fix coronal slices of the brain (taken 1.5 cm thick
just in front of the midbrain and just behind the midbrain) for a short period (23 days) followed
by photography and histopathology sampling. If even this is not permissible then small tissue
samples must be selected and trimmed for histopathological analysis and the brain immediately
returned to the body at time of autopsy. It has been shown in SUDEP series that if the brain is
cut and examined in fresh rather than a fixed state, pathology is more likely to be overlooked17.