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There is no single constant anatomical lesion of epilepsy. A sound autopsy answer separates an underlying brain lesion, changes associated with longstanding epilepsy, and the consequences of the final seizure or death.

The potentially causal group includes healed traumatic scars, old cerebral infarctions or intracranial haemorrhages, developmental abnormalities of the cerebral cortex, brain tumours, and inflammatory or infectious destruction of brain tissue. Such abnormalities can leave an enduring network capable of generating recurrent seizures. Their importance depends on location and the lifetime history; an incidental abnormality is not automatically the cause. A modern acute symptomatic seizure during a transient metabolic disturbance should also not automatically be called epilepsy.^[ref]

In longstanding cases one may find atrophy or scarring of particular brain regions. Hippocampal sclerosis is an important modern example: loss of neurons with gliosis in the hippocampus, associated especially with temporal-lobe epilepsy. Association does not settle whether a particular lesion preceded the first seizure, resulted from repeated seizures, or shares another cause with them. Conversely, genetically determined disturbances of neuronal excitability can produce recurrent seizures without a grossly visible destructive lesion.^[ref]

For the historical question, vascular redness or congestion and alterations around the medulla oblongata deserve mention as contemporary observations rather than established universal causes. A January 1864 report describes microscopic examination of fourteen longstanding cases, including dilated blood vessels and altered nervous material in that region. Its proposed localization of epilepsy to the medulla oblongata is a historical theory; modern epilepsy is not defined by that site or by those vascular appearances.^[ref]

The terminal group includes cerebral oedema, hypoxic-ischaemic brain injury, and pulmonary oedema or aspiration in some deaths. Congestion is nonspecific and may be terminal; injuries can result from a fall during a seizure. None of these alone establishes that epilepsy was the original cause. A modern autopsy study of sudden deaths in people with epilepsy found both structural abnormalities and nonspecific changes; exclusion of another anatomical or toxicological cause remains central to classifying sudden unexpected death in epilepsy.^[ref]

The appropriate investigation is therefore inspection followed by systematic histology, especially of the cerebral cortex and hippocampus on both sides, interpreted alongside the recorded seizure history and examination of other organs. A normal-looking brain does not exclude epilepsy, and a congested one does not prove it.

The chief physiological routes are abrupt failure of blood circulation, failure of pulmonary ventilation or gas exchange, or catastrophic failure of the central control of those functions. Historical clinical accounts used labels such as syncope, asphyxia and medical coma in explaining deaths; these terms describe broad physiological failures rather than identifying the underlying diseases.^[ref] A brief faint or ordinary medical coma is not itself necessarily fatal.

In primary circulatory failure, effective delivery of blood to the brain stops. Modern examples include ventricular fibrillation, pulseless ventricular tachycardia, severe bradyarrhythmia and asystole. They may arise in coronary artery disease, after myocardial infarction, in cardiomyopathy, or from inherited cardiac ion channel disorders. An electrical cause may leave little distinctive gross evidence at autopsy. These modern mechanisms refine the broad historical description of cardiac syncope.^[ref]

Mechanical interruption of blood circulation gives another group: massive haemorrhage, rupture of an aortic aneurysm, cardiac tamponade, and large pulmonary embolism. The immediate deficit differs in each. Haemorrhage removes circulating volume; cardiac tamponade prevents adequate filling; pulmonary embolism obstructs flow through the pulmonary circulation. All can end with critically low cardiac output even if some electrical activity persists.^[ref]

Respiratory failure includes obstruction of the airway by a foreign body, laryngeal oedema or aspiration; drowning; and depression of breathing by drugs or major brainstem injury. Oxygen delivery then fails and secondary cardiac arrest follows. Carbon monoxide poisoning and cyanide poisoning illustrate related failure of oxygen transport or use: not every hypoxic death is caused by physical obstruction of an airway.^{[ref][ref][ref]}

A major intracranial haemorrhage or rapidly developing brain herniation can destroy or compress the pathways maintaining consciousness and breathing. A severe disturbance of electrolytes, especially potassium, may instead act directly on the heart's electrical function. A fatal seizure can involve respiratory and circulatory mechanisms; sudden unexpected death in epilepsy remains a diagnosis requiring exclusion of other causes, not merely recognition of a history of epilepsy.^[ref]

The practical distinction is between mode, immediate mechanism and underlying cause. For example, rupture of an aneurysm can cause haemorrhage, then circulatory failure, then irreversible hypoxic-ischaemic brain injury. A complete explanation identifies that chain. Inspection, histology, examination of the airway and heart, and appropriately interpreted toxicology may establish it; an unexplained sudden death cannot be assigned a precise cause from its suddenness alone.