Post-mortem studies in epilepsy: use and curation of a unique UK resource
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Epilepsy is a common, important and serious group of conditions. Whilst seizures in most patients with epilepsy are well controlled with antiepileptic drugs, for about 30% of patients, these drugs fail to control seizures. Even for patients whose seizures are controlled with drugs, the drugs do not control all the problems of epilepsy and have side effects. New, rational treatments are required. Rational therapies demand better understanding of the causes and consequences of epilepsy and seizures. Some animal models can provide important information, but no animal model exactly mirrors human epilepsies.
The epilepsies are brain diseases: better understanding requires study of the brain. Some patients with epilepsy unresponsive to drugs have brain surgery as treatment: the part of the brain causing seizures is removed surgically. Usually, this stops seizures. It also provides an opportunity to examine the part of the brain causing seizures, using microscopy and sophisticated molecular tests. However, only one part of the brain can be studied, and it is usually impossible to say whether abnormalities found are the cause or the consequence of the epilepsy. Worse still, the part removed often is incomplete. Only brain tissue from some epilepsies can be studied, as only certain patients have surgery. So although we need to study brain tissue, most available tissue has some limitations in its usefulness ? though it has undoubtedly contributed to current understanding.
Before MRI and surgery became widespread, study of brain tissue from patients with epilepsy obtained after their death was the main source of information. Though unfashionable, post-mortem study offers major advantages: all of the brain can be studied, permitting comparisons in the same brain between parts causing epilepsy and those that do not; parts of the brain involved in epilepsy but unavailable from surgery can be studied; causes of epilepsy for which surgery is not undertaken can be studied. These, and other factors, mean that important questions can be answered using post-mortem tissue that cannot be answered in humans in any other way.
We have a large collection of post-mortem brains from patients with epilepsy, all consented for research, either in advance by the patients, or after death by next-of-kin. In each case, next-of-kin were consulted for permission. This tissue is invaluable in what it could reveal to us about epilepsy. We will use modern neuropathological methods to examine this precious resource and improve understanding of epilepsy for the benefit of patients with epilepsy.
The epilepsies are brain diseases: better understanding requires study of the brain. Some patients with epilepsy unresponsive to drugs have brain surgery as treatment: the part of the brain causing seizures is removed surgically. Usually, this stops seizures. It also provides an opportunity to examine the part of the brain causing seizures, using microscopy and sophisticated molecular tests. However, only one part of the brain can be studied, and it is usually impossible to say whether abnormalities found are the cause or the consequence of the epilepsy. Worse still, the part removed often is incomplete. Only brain tissue from some epilepsies can be studied, as only certain patients have surgery. So although we need to study brain tissue, most available tissue has some limitations in its usefulness ? though it has undoubtedly contributed to current understanding.
Before MRI and surgery became widespread, study of brain tissue from patients with epilepsy obtained after their death was the main source of information. Though unfashionable, post-mortem study offers major advantages: all of the brain can be studied, permitting comparisons in the same brain between parts causing epilepsy and those that do not; parts of the brain involved in epilepsy but unavailable from surgery can be studied; causes of epilepsy for which surgery is not undertaken can be studied. These, and other factors, mean that important questions can be answered using post-mortem tissue that cannot be answered in humans in any other way.
We have a large collection of post-mortem brains from patients with epilepsy, all consented for research, either in advance by the patients, or after death by next-of-kin. In each case, next-of-kin were consulted for permission. This tissue is invaluable in what it could reveal to us about epilepsy. We will use modern neuropathological methods to examine this precious resource and improve understanding of epilepsy for the benefit of patients with epilepsy.
Technical Summary
Many remaining key questions in epilepsy pathobiology can only be answered by examining human epileptogenic brain tissue. Whilst tissue resected therapeutically from patients with drug-resistant epilepsy allows detailed study at various levels, there are insurmountable limitations here: only certain pathologies can be studied; only one part of one side of the brain is usually available; often tissue is damaged or missing; ideal comparator control tissues (matched for age, sex, history including seizures, drugs, trauma; or matched for pathology but seizure-free) are almost always unavailable.
Post-mortem tissue examination underpinned epilepsy research for decades, becoming unfashionable as surgical resection material and MRI became common. Post-mortem histopathology remains the diagnostic gold standard, and the only research resource, for many neuropathologies, proving invaluable even now, as technology has enhanced its utility. In epilepsy, post-mortem tissue offers a complementary resource allowing: comparison between epileptogenic and distant regions, for example the contralateral non-diseased hippocampus, which in individual patients serves as the best possible control and should allow separation of primary and potentially epileptogenic changes (ipsilateral, sclerosed hippocampus) from secondary or adaptive phenomena (ipsilateral, sclerosed hippocampus and contralateral non-sclerosed hippocampus); study of entire hippocampal structure; examination of related limbic structures that may contribute to epilepsy; study of the ?post-epileptic? brain ? from individuals who had entered terminal remission pre-mortem; examination of other structural associations of epilepsy, including pathologies rarely available through surgical treatment; complementary neuropathological confirmation of results from genomic analyses.
We propose multilevel examination of our unique collection of 110 research-consented post-mortem brains from patients with epilepsy, who were residents at the National Society for Epilepsy, a charity established for care and treatment of people with epilepsy. Meticulous, detailed, medical, seizure, investigation and treatment records kept for clinical management are available for each case, with additional EEG, neuropsychometry and imaging data for many.
Interrogating this resource with advanced pathological methods, we will test a range of hypotheses including: processes of hippocampal neurogenesis and neurodegeneration cease with remission from seizures; upregulation of multidrug transporters is limited to the epileptogenic focus and putative seizure propagation pathways; upregulation occurs only in subjects with active drug-resistant epilepsy; there will be spatially-relevant expression of genes containing variation associated with specific epilepsy phenotypes; somatic mutation in candidate genes causes focal developmental malformations, such as focal cortical dysplasia.
We will also curate the collection to facilitate subsequent collaborations. We envisage the emergence of important information informing our understanding of epilepsy biology and its treatment.
Post-mortem tissue examination underpinned epilepsy research for decades, becoming unfashionable as surgical resection material and MRI became common. Post-mortem histopathology remains the diagnostic gold standard, and the only research resource, for many neuropathologies, proving invaluable even now, as technology has enhanced its utility. In epilepsy, post-mortem tissue offers a complementary resource allowing: comparison between epileptogenic and distant regions, for example the contralateral non-diseased hippocampus, which in individual patients serves as the best possible control and should allow separation of primary and potentially epileptogenic changes (ipsilateral, sclerosed hippocampus) from secondary or adaptive phenomena (ipsilateral, sclerosed hippocampus and contralateral non-sclerosed hippocampus); study of entire hippocampal structure; examination of related limbic structures that may contribute to epilepsy; study of the ?post-epileptic? brain ? from individuals who had entered terminal remission pre-mortem; examination of other structural associations of epilepsy, including pathologies rarely available through surgical treatment; complementary neuropathological confirmation of results from genomic analyses.
We propose multilevel examination of our unique collection of 110 research-consented post-mortem brains from patients with epilepsy, who were residents at the National Society for Epilepsy, a charity established for care and treatment of people with epilepsy. Meticulous, detailed, medical, seizure, investigation and treatment records kept for clinical management are available for each case, with additional EEG, neuropsychometry and imaging data for many.
Interrogating this resource with advanced pathological methods, we will test a range of hypotheses including: processes of hippocampal neurogenesis and neurodegeneration cease with remission from seizures; upregulation of multidrug transporters is limited to the epileptogenic focus and putative seizure propagation pathways; upregulation occurs only in subjects with active drug-resistant epilepsy; there will be spatially-relevant expression of genes containing variation associated with specific epilepsy phenotypes; somatic mutation in candidate genes causes focal developmental malformations, such as focal cortical dysplasia.
We will also curate the collection to facilitate subsequent collaborations. We envisage the emergence of important information informing our understanding of epilepsy biology and its treatment.