Familial mesial temporal lobe epilepsy and the borderland of déjà vu

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Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adulthood,1 and traditionally has been regarded as a predominantly acquired disorder. The identification of familial types of TLE, including mesial and lateral forms,2 led to revision of this historical view and to recognition of the important contribution of genetic factors to the etiology of TLE. Familial mesial TLE (FMTLE) was the first familial type of TLE to be identified, in the setting of a community‐based study in twins.2 FMTLE was originally described as a benign syndrome, with onset in adolescence or early adulthood and no antecedent febrile seizures. Seizures were mild and often subtle, consisting predominantly of focal aware seizures (formerly known as simple partial seizures)4 with prominent déjà vu and, less commonly, nausea, perceptual distortions, and fear. In many affected individuals, these symptoms were the only ictal manifestations and went completely unrecognized. When present, focal impaired awareness seizures and focal to bilateral tonic–clonic seizures (formerly known as complex partial seizures and secondarily generalized tonic–clonic seizures)4 were infrequent and rare, respectively, and were easily controlled with antiepileptic drug therapy. Electroencephalographic (EEG) recordings often did not reveal epileptiform abnormalities, and magnetic resonance imaging (MRI) investigations were normal. Similar characteristics were later appreciated in other cohorts, including nontwin families.5 In hospital‐based series, families with a heterogeneous clinical presentation, often associated with antecedent febrile seizures, hippocampal sclerosis (HS), and drug resistance, were also identified.9 FMTLE typically displays complex inheritance,7 but rare dominant families, with linkage to candidate loci13 or association with mutations in GATOR1 complex genes in small families,16 have been reported. In contrast to FMTLE, the rare syndrome of familial lateral TLE is due to mutations in LGI1 in 50% of families, with reelin mutations described in a few pedigrees.3
The epidemiology of FMTLE is unknown. Its assessment is hampered by the mild and often subtle nature of the symptoms, which may be perceived as “normal” phenomena by affected individuals. These individuals typically remain undiagnosed, unless a focal to bilateral tonic–clonic seizure occurs, which may prompt them to seek medical attention. In addition, FMTLE may not be recognized by clinicians if careful inquiries into specific symptoms are not made. Here, we addressed these methodological challenges within the framework of a case–control study by directly assessing relatives of patients presenting to a first seizure clinic with nonlesional mesial TLE (MTLE‐NL). We included cases with MRI evidence of HS in this group, but not those with structural lesions. We show that FMTLE accounts for a substantial proportion of new diagnoses of MTLE‐NL, and yet it is largely unrecognized. In addition, we highlight that, unlike matched controls, relatives of patients with MTLE‐NL may experience déjà vu phenomena, which clinically are in the “borderland” between physiological déjà vu and epileptic seizures of mesial temporal lobe origin.

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