We systematically reviewed the literature to describe the “natural” history of medically treated temporal lobe epilepsy (TLE). No population-based studies recruiting incident cases of TLE irrespective of age exist. Prospective, population-based studies were limited to those recruiting only childhood-onset TLE or those reporting TLE as a subgroup of cohorts of focal epilepsies. Few studies have been performed in the “MRI era” limiting information on natural history secondary to specific pathologies. Available data suggests that TLE is highly variable, with unpredictable transient remissions and low rates of seizure freedom (30 to 50%). Etiology and failure of first and second drug seem to be the most important predictors for treatment prognosis. The role of initial precipitating injuries remains speculative, as imaging information of related events is either missing or conflicting. Prospective cohorts of new-onset TLE with long-term followup using advanced MRI techniques, timely EEG recordings, and assessments of psychiatric comorbidities are needed.
Temporal lobe epilepsy (TLE) is the most frequent medically refractory epilepsy syndrome seen in epilepsy outpatient clinics. It has received considerable attention in recent years owing to the remarkable rates of remission that can be achieved through surgical intervention [
To date, therapeutic advances in TLE have far outpaced our understanding of the natural history of the disorder. According to a recent International League Against Epilepsy (ILAE) commission report [
The ideal natural history study requires a large prospective cohort of patients with new-onset TLE undergoing extensive structural and functional testing with a followup of >10 years. We conducted a systematic review of the literature to identify prospective, population-based natural history studies of TLE and reviewed appropriate longitudinal and retrospective case series. We extracted critical information on initial precipitating injury, seizure outcome, silent periods, and long-term remission to describe the natural history of this condition. Natural history in its strictest sense means the course of a disorder from onset without intervention until the disorder resolves or death ensues [
We performed a comprehensive literature search of Medline and Embase using validated search terms (See the Appendix) on August 10th, 2011. We searched the bibliography of relevant reviews and articles to identify additional studies that may not have been retrieved by our search strategy. One of the authors (CBJ) independently applied the following study inclusion criteria: (i) unselected cohorts of epilepsy patients drawn from the general population; (ii) a minimal study population of ≥20 participants; (iii) quantitative report of patient demographics, initial precipitating injuries, the results of EEG and MRI, and seizure outcomes. Titles were screened and abstracts or full articles were reviewed when there was doubt concerning the article’s potential relevance. Questions concerning eligibility were resolved through consensus discussion between the two authors. All relevant articles were retrieved for full review. We abstracted data from the most recent publication if there were multiple articles identified from the same study population. Full-length English articles were selected without restriction on place or date of publication.
We accepted the authors’ diagnosis of TLE. One of the authors (CBJ) abstracted all data and priority was given to prospective, population-based cohorts of incident diagnoses of TLE. The primary outcome was seizure freedom at the end of followup. Age at onset, the frequency of risk factors such as a family history or initial precipitating injuries, frequency of abnormalities found on electrophysiological and neuroimaging studies, the existence of an intervening “silent” period between diagnosis and later seizure relapse, and the longest duration of remission were considered secondary outcomes of interest. Additional measures such as psychosocial and cognitive outcomes were not analyzed due to the limited scope of the paper.
We identified 1774 articles and reviewed titles and abstracts to retrieve 39 (2%) that were potentially relevant to the review. We performed a full review of all 39 articles and 5 (13%) were ultimately included in our analysis (Figure
Prospective population-based studies of sporadic and familial temporal lobe epilepsies.
Study | Country | Setting | Sample size | Follow-up duration | Age at onset | Silent period | History of IPI | Family history | EEG | Imaging | Rate of seizure freedom | Longest remission |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Hauser and Kurland 1975 [ | USA | Childhood and adult onset | ? | ? | ? | ? | ? | ? | ? | ? | 41% 2-year seizure freedom | ? |
Manford et al. 1992 [ | UK | Childhood and adult onset | 43 | 3 to 7 years | Mean 40 years-old (standard deviation 20 years) | ? | 6 (14%) | ? | 38/43 (89%); abnormality 4/38 (11%) | CT (30/43; 70%); abnormality (3/30; 10%) | 49% 2-year seizure freedom | ? |
Sillanpää and Schmidt 2006 [ | Finland | Childhood onset | 43 | Median 40 years | ? | 8/43 (19%) | ? | ? | ? | ? | 53% 5-year seizure freedom | ? |
Spooner et al. 2006 [ | Australia | Childhood onset | 62 | Median 13.7 years | Median 6.4 years old | 16/62 (26%) | 17 (27%) | 13 (21%) | vEEG temporal lobe seizure (31/62 (50%) | MRI 58/62 (94%); abnormality 28/58 (48%) | 31% 2-year seizure freedom | Median seizure-free duration 10 years (range 5–15 years) |
Morita et al. 2008 [ | Brazil | Familial mesial temporal sclerosis | 64 | Mean 7.8 years | ? | ? | ? | 100% | ? | ? | 50% 2-year seizure freedom | ? |
CT = computed tomography; EEG = electroencephalography; IPI = initial precipitating injury; MRI = magnetic resonance imaging; vEEG = video electroencephalography.
Search strategy and evidence base.
Only one population-based study dedicated solely to TLE was identified by our search. It enrolled incident and prevalent cases of TLE in the state of Victoria, Australia, (interval from seizure onset to enrollment was 1 week to 3.9 years) and found that 31% of individuals were able to achieve a minimum of two-year seizure freedom off antiepileptic drugs (AEDs) over a median follow-up period of 13.7 years. All other individuals in the cohort either continued to have seizures despite AED status or had progressed to surgery. Interestingly, all patients still taking AEDs at the end of followup had failed to achieve seizure remission. However, only two children who went greater than one-year seizure free had a recurrence of seizures before their terminal remission. The only predictor of seizure freedom according to a univariable analysis was the absence of a lesion on MRI [
Additional prospective, population-based studies of focal epilepsies have been informative. The National General Practice Study of Epilepsy (NGPSE) captured incident diagnoses of epileptic seizures across the United Kingdom over a three-year period from 1984–1987 [
There is little prospective information available for the prognosis of individual subtypes of TLE. A prospective study of incident and prevalent cases of familial mesial temporal lobe sclerosis suggested that its prognosis may not differ significantly from sporadic TLE. Patients were classified according to their degree of seizure freedom at the beginning of follow-up (seizure-free for two or more years, less than six complex partial seizures per year and no more than two secondarily generalized seizures per year, or six or greater complex partial seizures per year despite adequate AED therapy). At the end of a mean of 7.8 years followup (standard deviation of
Retrospective studies from tertiary care centres reported far more variable rates of seizure remission. Rates of seizure freedom of one year or more by last followup ranged from 11–63% in populations of patients with TLE [
Two studies reported on rates of potential precipitating injuries that may have contributed to the development of temporal lobe epilepsy. Common antecedent events considered risk factors for epilepsy included complicated febrile convulsions, prolonged afebrile seizures, infantile spasms, meningitis or encephalitis, hypertensive encephalopathy, apnea and respiratory arrest, tumours, congenital malformations, remote trauma, and vascular events including intracranial hemorrhage [
Two studies reported proportions of patients undergoing electrophysiological and neuroimaging studies. Electroencephalography (EEG) was performed in 89% of patients with temporal lobe epilepsy in one study and revealed evidence of a focal abnormality in 11% of those tested [
No studies reported the delay from the first seizure to the diagnosis of epilepsy. However, in one study of epilepsy in Rochester, MN, there were more cases of temporal lobe epilepsy in an undiagnosed subgroup whose epilepsy had developed but had not yet been localized to the temporal lobe on the dates from which cases were drawn to determine incidence and prevalence. A disproportionate number of these patients were eventually diagnosed with TLE suggesting a longer interval between initial seizure onset and ultimate epilepsy classification when compared to other types of epilepsy [
Few studies reported on periods of seizure remission followed by symptomatic relapse. One study of childhood-onset temporal lobe epilepsy, which included individual patient data, reported that 16 of 62 cases (26%) had periods of at least one year of seizure freedom before relapsing; some of which occurred between five to ten years after the onset of epilepsy [
Only one study reported on the duration of seizure freedom. Spooner et al. [
This systematic review of the literature highlights the relative dearth of information available on the natural course of medically treated TLE. It supports the notion that our knowledge of the “natural” history of medically treated TLE is very poor. Clinical impression of the benign or malign nature of TLE typically derives from what is often a highly selected surgical series with potentially nonrepresentative patient populations. Patient groups in these studies mainly consist of medically refractory cases of TLE and are often restricted to the subpopulation of mTLE. This is further complicated by the fact that within the mTLE group, the focus has primarily been on mTLE-HS, which is only one well-described disorder in what is otherwise a wide range of heterogeneous conditions that cause mTLE [
Not surprisingly, our systematic review of the literature revealed many deficiencies in our knowledge and raised several questions. We did not identify any population-based studies recruiting all incident cases of temporal lobe epilepsy over the whole life span. Our extracted information was limited to few studies, including a prospective, population-based study on childhood-onset temporal lobe epilepsy [
Prognosis in general, measured by seizure freedom, was worst in the most rigorous prospective study of childhood onset-TLE. Only 31% of individuals were able to achieve a minimum of two-year seizure freedom off AEDs over a median follow-up period of 13.7 years [
Initial precipitating injuries, including complicated febrile convulsions and nonspecific brain insults (meningitis or encephalitits), were found in 14% in the NGPSE study [
Sophisticated imaging is crucial to assess the potential causal role of associated temporal lobe pathology. While CT scans in the pre MRI-era NGPSE study only detected abnormalities in 10% (mainly extratemporal tumours), almost half of all patients (48%) in the Australian study [
Based on this systematic review of the literature, we currently cannot predict whether the course of new-onset TLE will be straightforward with rapid long-term seizure control, rapidly progress to drug resistance, or go into short-or long-term remission. Stuttering, relapsing, and silent periods may be a characteristic features of TLE. Over one-quarter (26%) of the prospective childhood-onset temporal lobe epilepsy had periods of at least one year of seizure freedom before relapsing [
Our systematic review confirmed that the course TLE could be highly variable with unpredictable phases of transient remissions and low rates of seizure freedom that range between 30 and 50% in prospective studies. Based on the limited available data, etiology and failure of first and second AED are the most important predictors for prognosis. The role of initial precipitating injuries remains speculative, as imaging information of related events is either missing or conflicting. Our understanding of the basic mechanisms of epileptogenesis remains limited.
Prospective, population based studies of new-onset epilepsies suggestive of TLE are needed to adequately address these questions in the context of a reliable, evidence-based framework. For instance, a rigorous approach to determining epilepsy syndromes upon evaluating the first seizure (including new-onset epilepsy) was adopted by King et al. (1998) [
There is now considerable interest in the role of advanced neuroimaging technology in early stages of epilepsy [
exp epilepsy, temporal lobe/
((epilepsy adj3 temporal) or TLE).tw.
exp incidence/
exp mortality/
exp prognosis/
exp quality of life/
exp survival analysis/
(incidence or mortality or prognos* or predict* or course or outcome or “quality of life” or memory or “survival analysis”).tw.
exp cohort study/
exp case-control study/
exp Randomized Controlled Trial/
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exp followup studies/
(1 or 2) and (3 or 4 or 5 or 6 or 7 or 8) and (9 or 10 or 11 or 12 or 13)
limit 14 to humans.
Dr. C. Josephson reports no disclosure. Dr. B. Pohlmann-Eden reports no disclosure.