Jan 25, 2011 - Introduction. Temporal lobe epilepsy (TLE) represents the most common type of partial epilepsy in adulthood.1 On the basis of seizure semiol-.
PERSPECTIVES OPINION
Benign mesial temporal lobe epilepsy Angelo Labate, Antonio Gambardella, Eva Andermann, Umberto Aguglia, Fernando Cendes, Samuel F. Berkovic and Frederick Andermann Abstract | Benign mesial temporal lobe epilepsy (bMTLE), which is defined as at least 24 months of seizure freedom with or without antiepileptic medication, has probably been under-recognized because of a literature bias toward refractory epilepsy cases. Seizure onset in bMTLE tends to be in adolescence or adulthood, and patients frequently have a family history of febrile seizures and epilepsy. Long-term seizure freedom is observed with or without antiepileptic medication. On brain MRI, nearly 40% of patients with long-standing bMTLE show evidence of hippocampal sclerosis, a feature usually associated with refractory temporal lobe epilepsy. Prospective studies are needed to determine the features that allow prediction of a benign course, and to clarify the significance of hippocampal MRI changes. Labate, A. et al. Nat. Rev. Neurol. 7, 237–240 (2011); published online 25 January 2011; doi:10.1038/nrneurol.2010.212
Introduction Temporal lobe epilepsy (TLE) represents the most common type of partial epilepsy in adulthood.1 On the basis of seizure semiology, TLE is divided into two main broad categories, a common form with mesial temporal lobe symptoms, and a rarer form with lateral temporal lobe symptoms. Traditionally, mesial TLE (MTLE) has been viewed exclusively as an acquired, severe, drug-resistant epilepsy—often associated with hippocampal sclerosis, as well as a history of prolonged febrile convulsions in many cases—in which surgical treatment may be considered. 2 Over the past few decades, the literature has been dominated by studies on clinical features, imaging, presurgical evaluation and outcomes of acquired refractory TLE. By contrast, little attention has been paid to morebenign forms of TLE, although these were recognized many years ago.3 More-recent studies aimed at establishing the clinical features, etiology and outcomes of MTLE in patients who were not selected for surgery confirmed the existence of a benign form of MTLE (bMTLE), which is operationally defined as at least 24 months of seizure freedom with or without antiepileptic medication. bMTLE seems to be Competing interests The authors declare no competing interests.
a common and often unrecognized clinical entity, in which genetic factors have a major etiological role.4–6 Moreover, the identification of MRI evidence of hippocampal sclerosis in many cases of bMTLE indicates that this feature per se does not necessarily signify intractable epilepsy with a poor outcome.7,8 Thus, the relationship between bMTLE and severe pharmacoresistant MTLE seems to be more complex than was previously thought, and these conditions might lie along a biological continuum.9 Here, we review the literature and emerging concepts on bMTLE, some of which were developed during an international workshop held in Catanzaro, Italy, 18–19 September 2008. We emphasize demographic, clinical, genetic and neuroimaging features, and treatment of this type of epilepsy.
Epidemiological aspects TLE is generally believed to carry a worse prognosis than other forms of epilepsy, although most studies of this type of epilepsy have not been concerned primarily with clini cal course and prognosis. Population-based epidemiological studies regarding outcomes in adult patients with well-defined TLE are lacking, in part due to methodological difficulties in studying prognosis of epilepsy in general and, specifically, to inconsistent definitions of TLE and complex partial seizures in most epidemiological studies.10 Indeed,
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the study of bMTLE poses challenges for prospective epidemiological studies, as the benign course can only be definitively documented after a long period of observation and, at least in younger patients, some cases of intractable TLE have long periods of early remission.11 Despite these limitations, however, some large community-based studies have provided evidence that many patients falling into the category of TLE may have bMTLE, as patients achieve at least 24 month seizure freedom and enter remission, with or without antiepileptic medication.10,12 In agreement with these findings, a study published in 1971 by Currie et al.,3 which was devised to establish the clinical features and outcome of an unselected hospital-based TLE series, found a good prognosis in about two-thirds of cases. The etiology could be inferred in only ≈25% of these patients—a finding that can be partly explained by the inability to image hippo campal sclerosis in that era. The mean age at onset was 28 years, which is much later than has been observed in surgical series. The average period of freedom from attacks was 4 years, which would be taken by many physicians as adequate grounds to consider cessation of drug therapy. More recently, in a long-term follow-up study of a nonsurgical series of 73 adult patients with nonlesional TLE that also included patients with hippocampal sclero sis, about two-thirds were found to have a mild course with good prognosis at very long follow-up.4 An updated prospective follow-up study has found that 56% (109) of 190 patients with nonlesional TLE had bMTLE, as they were seizure free for 3 years or more.13 Similarly, in childhood TLE, evidence exists for a subset of individuals with an excellent long-term outcome.14
Clinical features In bMTLE, seizures typically start in adolescence to mid-adult life,5,6 with a mean age at onset of 34.3 ± 15.3 years in the series of Aguglia et al.4 and 33.1 ± 19.8 years in the updated Italian series.13 In each patient, the diagnosis of TLE was made on the basis of the constellation of clinical, MRI and EEG criteria, which are considered to be reliable interictal indicators of TLE (Boxes 1 and 2).15 Past medical histories of patients VOLUME 7 | APRIL 2011 | 237
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PERSPECTIVES Box 1 | Clinical features of bMTLE ■■ Onset in late adolescence or adulthood ■■ Normal neurological examination ■■ Normal cognitive examination ■■ Unremarkable past medical history ■■ ≈30% have positive family history of febrile seizures or epilepsy ■■ ≈15% have personal antecedents of simple febrile seizures ■■ Viscerosensory auras are the predominant symptoms ■■ Easily controlled with a single antiepileptic drug ■■ Misdiagnosis of panic attacks or gastrointestinal disturbances is very common Abbreviation: bMTLE, benign mesial temporal lobe epilepsy.
with bMTLE are unremarkable with respect to head injury, cerebrovascular disease, and alcohol or drug abuse. About 30% have family histories of seizures or febrile seizures in one or more first-degree to thirddegree relatives.4,13 Among affected relatives, the most common epileptic phenotype was also bMTLE, and a detailed family history led to the discovery of a family with autosomal dominant bMTLE.16 Epileptic disorders other than bMTLE, however, were also found in the first-degree relatives of some patients.4 About 15% of patients with bMTLE also had personal histories of simple febrile seizures.13 Neurological examination was usually normal, with no evidence of cognitive impairment that might have repercussions in the patient’s daily life.5 Viscerosensory or experiential auras were the predominant ictal symptoms, occurring in the vast majority of patients,4,6,7 but other experiential phenomena such as fear, structured hallucinations, olfactory hallucina tions, déjà vu, jamais vu, dysphasia, dreamy state and vertigo, with or without oro alimentary, verbal or gestural automatisms, were also observed in some patients. Intriguingly, déjà vu experience is also common in healthy individuals and may be related to misfiring of the pattern-separation circuit within the parahippocampal gyrus and its neocortical connections, which are responsible for judgments of familiarity.17 So far, no one has offered a convincing explanation for this phenomenon. The striking similarity between déjà vu as an ictal phenomenon and déjà vu in healthy individuals, and the observation in patients with bMTLE that the déjà vu experience 238 | APRIL 2011 | VOLUME 7
often represents the only type of seizure for many years, raises the possibility that déjà vu might sometimes be an ictal phenomenon in apparently normal individuals, and could represent the mildest manifestation on the TLE spectrum. Before treatment, infrequent complex partial seizures occurred in about twothirds of patients,4,7 and were often preceded by the typical auras. Secondary generalized tonic seizures were rare events (fewer than four per year) and tended to occur during sleep. The majority of patients (61%) show normal interictal EEG recordings; however, interictal EEG abnormalities were found in ≈80% of patients with bMTLE who showed MRI signs of hippocampal sclerosis. 7 The abnormalities mainly occurred during non-rapid eye movement sleep, and were usually unil ateral and located over one temporal region. Owing to this peculiar, mild clinical picture, misdiagnosis of bMTLE as panic attacks or gastrointestinal disturbances has been common. Moreover, patients usually did not seek medical advice for a long time, until disabling seizures occurred. 4 Before receiving the correct diagnosis, many patients with bMTLE underwent several and repeated diagnostic procedures, including upper and lower gastrointestinal endos copies, abdominal ultrasonographies, barium enema, 24 h Holter electroc ardiography, and electrocardiographic stress tests, all of which were always normal.4
Neuroimaging A recent study aimed at evaluating the presence of hippocampal sclerosis in 101 consecutive patients with bMTLE found MRI evidence of hippocampal sclerosis in 39% of prevalent cases imaged after a mean of 16 years following onset.7 Analogous to these findings, in an Australian series of patients with long-standing TLE no differences in hippocampal volumes or T2 hyperi ntensities were observed between refractory and mild TLE. 18 A 2009 study aimed at identifying prognostic factors in patients with TLE showed that around one-third (9 of 28; 32%) of patients with bMTLE had evidence of hippoc ampal scleros is on MRI. 19 Evidence was also obtained that febrile seizures, hippocampal sclerosis, early age at seizure onset, and epileptiform interictal abnormalities are negative prognostic factors, and that febrile seizures are related to hippocampal sclerosis.20 Overall, such findings indicate that
Box 2 | EEG, MRI and genetics of bMTLE ■■ ≥60% have normal interictal EEG ■■ Almost 40% have MRI evidence of hippocampal sclerosis ■■ Genetic predisposition is known to exist ■■ Remarkable intrafamilial and interfamilial phenotypic heterogeneity ■■ Autosomal dominant inheritance is rare Abbreviation: bMTLE, benign mesial temporal lobe epilepsy.
patients with TLE can have MRI findings of hippocampal sclerosis regardless of their seizure control, and that other factors— both genetic and environmental—probably have important roles in the causation and severity of seizures.20,21 Similarly, a voxel-based morphometry (VBM) MRI study in patients with bMTLE22 demonstrated structural abnormalities located in the hippocampus and thalamus that were strikingly similar to previous findings in VBM studies of patients with refractory TLE.23 The severity and extent of volume loss seen on brain VBM was found to parallel the volume loss detected on routine MRI study, being more severe in patients with routine MRI evidence of hippocampal sclerosis.22 More importantly, even patients with normal MRI scans on visual inspection showed similar structural changes on VBM, albeit at lower thres hold, suggesting that the absence of visual hippocampal sclerosis does not signify a distinct type of epilepsy, and that these apparently variable phenotypes might lie along a biological continuum.22 Moreover, the structural abnormalities seen in patients with bMTLE further reinforce the belief that a temporolimbic pathway, which includes the thalamus, plays a major part in the pathogenesis of TLE even when the seizures are well controlled.
Genetics Notably, the clinical, EEG and imaging features—as well as seizure outcome—of unrelated cases with bMTLE are similar to those described in familial MTLE.5 Some studies of familial MTLE, however, show different features from series of bMTLE, such as low frequency of antecedent febrile seizures and absence of hippocampal sclerosis.5 The clinical features of familial MTLE included onset typically during the teenage years or early adult life, with no antecedent factors for epilepsy. Febrile seizures occurred in only 2.7% of family www.nature.com/nrneurol
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PERSPECTIVES members of individ uals with familial MTLE, a frequency similar to that reported in the general population (3–4%). 24 The nature of the aura suggested a mesial temporal origin, and déjà vu and jamais vu seemed to be overrepresented in this group of patients. Complex partial seizures and, especially, secondarily generalized seizures were infrequent, and the EEG recordings often showed no epileptiform abnormalities.5 Like sporadic bMTLE, this hereditary epilepsy might often go undiagnosed owing to its mild nature. Following the initial description of fami lial MTLE, similar families—some with possible overrepresentation of migraine— were reported by other authors.16 Although one cannot rule out the possibility that this association between familial MTLE and migraine is an artifact of ascertainment in some patients, a causal relationship may exist between the two conditions. In recent years, genetic studies have increasingly indicated a shared susceptibility to epilepsy and migraine.25 In some patients with familial MTLE, hippocampal sclerosis was later found on MRI,8 providing further evidence that this feature is not necessarily synonymous with medical intractability. Like sporadic TLE, familial MTLE seems to exhibit remarkable intrafamilial and interfamilial phenotypic heterogeneity with respect to history of febrile seizures, severity of the epilepsy, and presence of hippocampal sclerosis.8 Moreover, MRI evidence of hippocampal sclerosis has been observed in asympto matic family members, suggesting that in certain families the hippocampal abnormalities themselves might be inherited but do not necessarily lead to epilepsy.26 Overall, these findings indicate that genetic predisposition is an important causal factor for bMTLE, as many cases of bMTLE have similar electroclinical and neuroi maging features to familial cases. Large families with MTLE inherited in an autosomal dominant manner seem to be very rare. In one family with evidence of autosomal dominant inheritance, the genetic defect was mapped to chromosome 4q, but the causative gene has not been identified.27 By contrast, in familial lateral TLE (autosomal dominant partial epilepsy with auditory features), numerous fami lies with autosomal dominant inheritance and a benign course have been described, around half of which have mutations in the LGI1 (leucine-rich, glioma inactivated 1) gene.28 LGI1 codes for a protein that may
act as an accessory potassium channel subunit and might have a role in synaptogenesis.29,30 Interestingly, this protein has been identified as a target for antibodies in autoimmune limbic encephalitis.31,32 Recent clinical genetic evidence supports a model of complex inheritance for familial MTLE.33 Attempts to identify susceptibility alleles for TLE have not yet yielded reproducible findings, probably largely owing to methodological issues such as inadequate sample sizes.34
Treatment and evolution By definition, bMTLE is easily treated. In most patients (>90%) in the Italian series, seizures were easily controlled with a single antiepileptic drug (AED)—most commonly carbamazepine or oxcarbazepine at low dosage.4,13 Other AEDs, including phenytoin, valproate and barbiturates, also seem to be effective, although the effects of dif ferent AEDs have not been directly compared. 4 Some patients have refused medication because the mild ictal symptomatology has no major impact on their daily lives. This mild symptomat ology represents one of the main features of bMTLE. An important point to emphasize is that the follow-up period in patients with bMTLE in the Aguglia et al. study was usually many years (mean 5.3 ± 3.1 years),4 suggesting that later intractability was unlikely. This concept is of particular concern in young patients, as severe TLE is often preceded by an initial precipitating injury, of which a prolonged complex febrile seizure is the most common. 2,35 Thereafter, a latent period tends to ensue, followed by recurrent, spontaneous seizures, often characterized by periods of remission with relative seizure freedom. 35 On the other hand, adult-onset epilepsy might give us less reason to suspect delayed appearance of intractability.36 Importantly, in this series of patients with bMTLE, initial precipitating cerebral insults such as complex febrile seizures were absent, and spontaneous seizures tended to start during adulthood or old age. Indeed, when a series of variables that might predict a good prognosis for TLE was analyzed among 190 patients with bMTLE, univariate analyses revealed that patients in remission showed significantly higher ages at onset of epilepsy (33.5 ± 19.9 years versus 17.2 ± 14.4 years).13 On multivariate analysis, the only prognostic predictor strongly (P
