Cause Matters: A Neuropathological Challenge to Human Epilepsies

Epilepsy is the most common neurological disorder, affecting 1% of the population worldwide. However, epilepsy cannot be regarded as one specific disease entity as it includes many different etiologies, that is, single genetic point mutations, metabolic dysfunction or acquired brain lesions. Indeed, any brain can generate seizures and any lesion may lower a brain's seizure threshold. A major challenge is to identify reliable factors and biomarkers predicting a given patient's risk for epilepsy onset and progression, for cognitive and psychiatric comorbidities, and for response to available treatment. Hence, the clinicopathological spectrum of epilepsies is broad and it remains another challenging issue to understand how a genetic or acquired brain lesion will generate seizures by recruiting and synchronizing large epileptogenic networks. Indeed, the causality between a detectable brain lesion and the patient's epilepsy is difficult to prove. In order to promote joint efforts between basic and clinical research, the International League Against Epilepsy (ILAE) has proposed new concepts for the classification of seizure disorders in 2010 (2). This most recent classification system follows a long‐standing and often controversial dialog about the impact of etiology, dating back to the early work of Sir John Russel Reynolds (1861), John Hughlings Jackson (1870), William Gowers (1881), Henry Gastaud (1953) or William Lennox (1960; for review, see (7)). In all of these classification schemes, circumscribed brain lesions were recognized and classified as symptomatic (synonyms: organic or structural) epilepsy with a highly precipitating risk to develop spontaneous seizures. Our survey of 5392 surgical epilepsy brain tissue specimens collected at the European Epilepsy Brain Bank (founded by the European EpiCure consortium) confirms the broad spectrum of structural brain lesions resected in patients with drug‐resistant localized epilepsies (Table 1). Indeed, the list is similar to those categories of epilepsy‐associated brain lesions proposed by Walter Dandy early in 1932 (4). Nevertheless, our knowledge about underlying molecular and pathophysiological pathways of epileptogenesis remains largely unknown.

Table 1.

Neuropathologic categories of symptomatic human epilepsies. All data were retrieved from the European Epilepsy Brain Bank. Histopathological diagnosis and clinical findings are as following: Age OP = age of patients at surgery (in years); DUAL = dual pathologies; Duration = duration of seizure disorder before surgical treatment (in years); HS = hippocampal sclerosis; LEAT = long‐term epilepsy‐associated tumors; MCD = malformations of cortical development; Onset = age at onset of spontaneous seizure activity (in years).

Category	Numbers (%)	Age OP	Onset	Duration
HS	1816 (33.7%)	34.1 + 10.4	11.3 + 7.7	22.7 + 10.0
Dual	278 (5.2%)	26.0 + 12.8	9.9 + 7.8	15.8 + 9.9
LEAT	1354 (25.1%)	28.0 + 12.3	16.3 + 10.1	12.0 + 8.8
MCD	836 (15.5%)	18.2 + 12.0	5.8 + 5.7	12.5 + 9.1
Vascular	309 (5.7%)	36.2 + 12.3	23.2 + 11.4	13.0 + 9.0
Glial scars	266 (4.9%)	25.7 + 12.4	10.4 + 8.0	14.8 + 8.6
Encephalitis	87 (1.6%)	21.0 + 12.6	12.8 + 9.4	8.7 + 7.1
No lesion	433 (8%)	28.5 + 10.8	12.3 + 7.7	15.9 + 8.0
Total	5392	28.8 + 12.5	12.4 + 8.9	16.7 + 10.1

In the last few decades, neuropathology has not always been acknowledgeable as a leading discipline addressing the impact of etiology on seizure disorders. More recently, this notion has changed and evoked a “neuropathology renaissance.” The opportunity to specify clinicopathologic subtypes that allows prediction of the patient's risk of either favorable or unfavorable seizure control following surgery will make the difference, and many epilepsy surgery programs appreciate an advanced neuropathology workup of resected human brain tissue. A prominent example of such joint efforts promoting the notion that “cause matters” is the ILAE's first consensus classification system for focal cortical dysplasias (3). According to this proposal, neuropathology assessment of surgical epilepsy specimens and reports should apply consensus terminologies and should follow standardized protocols. These efforts will be highlighted by this Brain Pathology Mini‐Symposium reviewing the neuropathologic impact of brain lesions in the scenario of drug‐resistant, focal epilepsies. Each article will no only review the state‐of‐the‐art histopathological diagnosis, but also refer to most recent attempts to identify clinically relevant phenotypes and subtypes predicting etiology and/or differences in postsurgical outcome.

A survey of the European Epilepsy Brain Bank indicates hippocampal sclerosis as the single most frequent brain lesion. Blümcke, Coras, Miyata and Özkara will summarize histopathological findings in patients suffering from mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE‐HS), and characterize four distinct clinicopathological subtypes. Different patterns of pyramidal cell loss make a difference and correlative studies suggest unfavorable atypical variants with respect to postsurgical seizure control. Granule cell loss is another hallmark of the disease. It was shown, however, to relate with memory impairment rather than predicting postsurgical seizure control. This pattern recognition may present a basis for an international consensus classification system in the near future. It may also be translated into clinical perspectives if high‐field magnetic resonance imaging (MRI) or other imaging tools will be able to detect subfield specific hippocampal lesion patterns prior to surgery. Notwithstanding, we cannot prove causality between hippocampal sclerosis and mesial temporal lobe epilepsy as neuronal cell loss will secondarily be aggravated by chronic seizures and thus it remains a “chicken and the egg” dilemma of which comes first, the chronic seizure disorder or the neuronal loss. Synopsis of available data suggests, however, that precipitating factors during development and/or compromised postnatal maturation are likely to contribute to classic hippocampal sclerosis patterns, whereas atypical variants may result from later time points of disease onset.

Most epilepsy‐associated brain tumors that occur in the temporal lobe show low proliferative activity and consist of combined glial and neuronal components. Maria Thom, Eleonora Aronica and Ingmar Blümcke will review the broad, although specific spectrum of “long‐term epilepsy‐associated tumors (LEAT),” with particular emphasis on dysembryoplastic neuroepithelial tumors (DNT) and gangliogliomas as the most frequent entities in these patient cohorts. A major clinical concern addresses, however, the biological nature and risk for tumor relapse, which cannot be sufficiently predicted by the WHO 2007 classification scheme. Indeed, previous studies have used different reading of the WHO classification system of epilepsy‐associated brain tumors with either “lumping” or “splitting” of DNT and ganglioglioma variants. Hence, the propensity of a DNT to recur or even transform into malignancy remains controversial. It is the lack of any prospective clinical trial that makes this issue difficult to review. Another challenge in the field is the tumor's association with epilepsy, its extent of surrounding epileptogenic tissue and required surgical excision of adjacent brain structures. Consensus about the histopathologic assessment and translational molecular studies are urgently required to better guide tailored epilepsy surgery.

Malformations of cortical development (MCD) are the third major disease entity associated with drug‐resistant epilepsies. Among this diverse group, focal cortical dysplasias (FCD) constitute about 75% of cases and are, therefore, the clinically most challenging cohort. These lesions are highly epileptogenic, and present with different clinicopathological variants. A prominent example is the one described first by David Taylor and colleagues in 1971 (8). It is now recognized as FCD type IIa and IIb and is readily visible using optimized MRI techniques. Surgical resection usually offers long‐term seizure control, and molecular biological studies suggest an involvement of the tuberous sclerosis gene complex (TSG) (1), which is related to the mammalian target of rapamycin (mTOR) signaling pathway. Such coherent clinicopathological studies may open new treatment avenues using targeted antagonists, such as everolimus, already approved for treatment of TSC‐related brain tumors (5). On the contrary, FCD type I and III are still difficult to recognize clinically or radiographically and their diagnosis can only be confirmed by careful neuropathological investigation (6). In addition, postsurgical outcome is less successful in cases of FCD type I, which require joint efforts to clarify their etiology and to develop successful medical treatment strategies. In this respect, the ILAE has proposed a first consensus classification system for FCD (3), which will be reviewed by Eleonora Aronica, Albert Becker and Roberto Spreafico in this issue. They will also refer to the concept of an associated FCD III subtype, proposed by the new ILAE classification system. They are commonly recognized in combination with mTLE‐HS, glioneuronal tumors, vascular malformations or early brain injury. Unraveling neurodevelopmentally regulated molecular pathways will be a key issue to better understand these epileptogenic lesions commonly observed in human brain.

Central nervous system (CNS) disorders associated with antibodies to specific ion channels or neurotransmitter receptors represent a yet under‐recognized etiology of many adult onset seizure disorders. Pathomechanisms can be successfully studied in animal models and an increasing panel of auto‐antibodies can be identified in patients. Accordingly, these epilepsies have different clinical presentations such as limbic encephalitis or encephalopathies, and advanced antibody assays can help to confirm the diagnosis. This fascinating topic will be reviewed by Jan Bauer, Christian Bien and Annamaria Vezzani focusing also on the possibility of successful treatment with immunotherapies. On the other hand, increasing knowledge will require new disease classification systems defining the relationship between antibodies and specific clinical phenotypes, as well as predicting optimal treatment strategies.

Ten years ago, Brain Pathology published a first Symposium on “Pathogenesis and Pathophysiology of Focal Epilepsies” with six contributions focusing on temporal lobe epilepsies, neurophysiologic seizure mechanisms and animal models (2002, Volume 12, pp. 191–256). We believe it is now appropriate to update this rapidly growing field and hope to attract an audience of neuropathologists, as well as clinicians and basic researchers. Despite the remarkable discoveries of the last decade, successful treatment strategies in epilepsy patients with drug resistance are limited and will require interdisciplinary collaboration toward new diagnostic and therapeutic avenues. We hope this Mini‐Symposium will emphasize our strong conviction that a better understanding of clinicopathological causes will matter!

We declare no conflict of interest.