N Forthoffer
email: n.forthoffer@chru-nancy.fr

H Brissart

L Tyvaert

L Maillard

Long-term cognitive outcomes in patient with epilepsy

Keywords:

In contrast to short-term cognitive outcomes, long-term cognitive outcomes (over 5 years) has been scarcely assessed so far. Yet, predicting long-term outcomes at any time point of the epilepsy, from initial diagnosis, to medically intractability is very important for therapeutic decision-making, patient information, and orientation. Assessing long-term cognitive outcomes in patients with epilepsy would ideally require longitudinal studies and a comparison with a healthy controls group. This issue has been addressed extensively, but with controversial results. However, there is a general consensus about the fact that cognitive outcome is not the same in all groups of patients with epilepsy. Possible prognostic factors include age at onset, duration of epilepsy, syndrome and etiology, seizure outcome and therapeutics. The multiplicity of factors makes it very difficult to assess their relative weight in individuals. Although longterm cognitive outcome studies are scarce, this issue has been specifically studied in newly diagnosed epilepsies and in focal drug-resistant epilepsies. In the first clinical setting, i.e. newly diagnosed epilepsy, it appears that cognitive deficits are already present at epilepsy onset in a significant proportion of patients but seem to remain stable over time. In focal drug-resistant epilepsies, cognitive deficits (mainly verbal memory) were generally shown to remain stable provided that seizures were controlled either by medication or by surgery. Beyond the possible correlation between seizure and cognitive outcome, no causal link however has been demonstrated between these two important outcomes.

Introduction

Epilepsy is one of the most common chronic neurological disorders. According to ILAE's definition, "epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition" [START_REF] Fisher | Epileptic Seizures and Epilepsy: Definitions Proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)[END_REF]. Cognitive impairment is often reported in patients with epilepsy (PWE). The prevalence of cognitive disorders is up to 70% of adult patients at disease onset [START_REF] Witt | Should cognition be screened in new-onset epilepsies? A study in 247 untreated patients[END_REF]. Several factors may have an impact on cognition such as characteristic features of the epilepsy (epilepsy syndrome, age of onset, disease duration, seizures/interictal activities), sleep quality, brain development in children, brain aging in adults, antiepileptic treatments (drugs, surgery) and etiology [START_REF] Maillard | Comprendre et prendre en charge les troubles cognitifs dans les épilepsies[END_REF].

Long-term cognitive outcomes have not been clearly assessed so far in PWE. In temporal lobe epilepsy (TLE) a cross-sectional study reported verbal memory scores with a large cohort of patients [START_REF] Helmstaedter | Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?[END_REF] ranging in age from 6 to 68 years (1156 patients). The results suggested a major impact of the initial neurodevelopmental disease as well as a negative effect of the interaction between memory impairment and cognitive aging, rather than a gradual decline towards dementia in patients with chronic TLE. During childhood, and even more so in the decade following puberty, the normal development of episodic memory is crucial. The occurrence of focal TLE during this period increases the risk of memory deficit later, even in the absence of an accelerated decline. This robust study reported crucial information but the design was not longitudinal. Longitudinal study of long-term cognitive outcomes in epilepsy is methodologically very challenging, due to missing data, the time course of epilepsy (number of seizures, antiepileptic drug, surgery) and controlled interval test-retest (with reliable change index or healthy controls sample). Moreover, the period of time covered by "long-term outcome" is not clearly defined. Thus, in literature there is wide variability in follow-up duration, ranging from 2 to 15 years. This article focuses on long-term cognitive outcomes in new-onset epilepsy and focal epilepsy in adult patients with over 5 years follow-up.

Newly diagnosed epileptic patients

Studying cognitive outcome in newly diagnosed epileptic patients is relevant because the baseline performance measured before antiepileptic drug (AED) introduction can be used as a reference. This allows differentiating the impact of the etiology (or initial hit) from the impact of seizure recurrence, for example, in the cognitive outcome. Indeed, several studies have shown that cognitive deficits are already observed in newly diagnosed epileptic patients [START_REF] Witt | Cognition in the early stages of adult epilepsy[END_REF].

Deficits at the very onset of epilepsy and before AED treatment are frequent and mostly affect the domains of attention, executive functions and memory [START_REF] Kälviäinen | Memory and attention in newly diagnosed epileptic seizure disorder[END_REF][START_REF] Aikiä | Verbal learning and memory in newly diagnosed partial epilepsy[END_REF][START_REF] Äikiä | Verbal Memory in Newly Diagnosed Patients and Patients with Chronic Left Temporal Lobe Epilepsy[END_REF]. To the best of our knowledge, there are only two papers that focused on the long-term cognitive outcome of this particular population [START_REF] Äikiä | Verbal Memory in Newly Diagnosed Patients and Patients with Chronic Left Temporal Lobe Epilepsy[END_REF][START_REF] Taylor | Newly diagnosed epilepsy: Cognitive outcome at 5years[END_REF] with a mean follow-up of 5 years. One study derived from the SANAD study on all types of epilepsies and the other one focused on left TLE. However, even in the first study, a great majority of patients had in fact focal-onset epilepsy (84%) and only 8% had generalized-onset epilepsy. The second advantage of this kind of study is to be more representative of the real population of epileptic patients with a majority being seizure free (58%) and under monotherapy (80%) at last follow-up. The cognitive evaluation was comprehensive and comprised psychomotor speed, memory, information processing, mental flexibility and mood [START_REF] Taylor | Newly diagnosed epilepsy: Cognitive outcome at 5years[END_REF]. At baseline, 53.5% of patients had at least one abnormal score (< at 2 standard deviation) compared to 20.7% of controls mainly in the same two cognitive domains (memory and psychomotor speed). "At the 5-year follow-up the majority of cognitive measures remained stable, although significant (but subtle: 10-15% from baseline) declines were noted for memory and psychomotor speed domains in 38% of people with epilepsy" [START_REF] Taylor | Newly diagnosed epilepsy: Cognitive outcome at 5years[END_REF]. The authors did not identify any predisposing factor that differentiated the decliner from the non-decliner.

The absence of a healthy paired control group does not allow differentiating the effect of normal aging from a specific effect of epilepsy. The second study was conducted with 20 patients and 46 healthy controls and was focused on verbal memory in newly diagnosed left TLE [START_REF] Äikiä | Verbal Memory in Newly Diagnosed Patients and Patients with Chronic Left Temporal Lobe Epilepsy[END_REF]. It did not show any deterioration over time in verbal memory performance whereas verbal memory impairment was in fact reported early in the course of the disease, at the first neuropsychological assessment. Although these two studies apparently yield slightly different findings their common message is the greater importance of the initial cognitive deficits that clearly exceeds the effect of treatment, seizure repetition, and psychosocial factors over a 5-year follow-up. Does this observation remain true after a much longer disease course?

Focal epilepsy

Twelve studies have been recorded on longitudinal neuropsychological follow-up in adult patients with focal epilepsy over 5 years [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF][START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF][START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF][START_REF] Grewe | Very long-term outcome in resected and non-resected patients with temporal lobe epilepsy with medial temporal lobe sclerosis: A multiple case-study[END_REF][START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF][START_REF] Engman | Serial cognitive change patterns across time after temporal lobe resection for epilepsy[END_REF][START_REF] Thompson | Cognitive Decline in Severe Intractable Epilepsy[END_REF][START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF][START_REF] Holmes | Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures[END_REF][START_REF] Kalska | Cognitive changes in epilepsy: a ten year follow up[END_REF]. Nine studies focused on TLE and the mean follow-up duration was 11 years. There are five retrospective studies and four prospective studies which included a total of 395 operated and 214 non-operated TLE patients (n=609).

Only one cohort included healthy controls [START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF]. Most studies focused on postoperative outcome but four studies explored long-term cognitive outcome of PWE who had not undergone surgery [START_REF] Thompson | Cognitive Decline in Severe Intractable Epilepsy[END_REF][START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF][START_REF] Holmes | Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures[END_REF][START_REF] Kalska | Cognitive changes in epilepsy: a ten year follow up[END_REF]. Normative data was the most common method used with group analyses in all studies but some studies used in addition reliable change index and carried out individual analyses [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF][START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF]. The main cognitive domain explored was episodic memory.

Other cognitive dimensions (intellectual efficiency, attention, executive functions, processing speed and language) have been less reported and differed according to the studies.

Memory

Cognitive outcomes after TLE surgery, mainly in memory and language, are a priority in medical care. Short-terms outcomes are well established, and reports have consistently shown that memory and language decline may be observed early after temporal lobectomy [START_REF] Sherman | Neuropsychological outcomes after epilepsy surgery: Systematic review and pooled estimates: Cognitive Change after Epilepsy Surgery[END_REF]. But very long-term cognitive outcomes (10 years and more) in memory are poorly detailed with less than 10 studies (see Table 1).

Verbal memory and non-verbal memory were assessed in all studies but methodological variability makes it difficult to summarize all data. The first study that assessed patients on a very long term was published in 2003 [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF]. The mean duration of follow-up was 12.8 years.

Authors reported a long-term continuous decline in memory, especially verbal memory, after temporal lobectomy in case of a healthy hippocampus on pre-surgical magnetic resonance imaging scan or a high early post-operative memory score. In other studies, the picture seems to be more complex. In a much larger longitudinal cohort study [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF], the authors reported a decline of memory in 60% of patients after temporal lobectomy compared to 50% in the nonoperated group of TLE in the long-term follow-up (4.8 years in average). This decline was anticipated on early post-operative assessment in the surgery group. It is however important to note that this decline was more severe in case of left temporal surgery and surgical failure (postoperative recurrence of seizures). In contrast, as compared to patients in the medical treatment group, patients free of seizure after surgery recovered non-mnesic functions one year postoperatively and mnesic functions on a longer follow-up. This is an important finding suggesting that the cognitive decline may be reversed in refractory focal epilepsy by a therapeutic intervention, provided that it is successful on seizures. Another study [START_REF] Engman | Serial cognitive change patterns across time after temporal lobe resection for epilepsy[END_REF] on a much smaller cohort (25 patients) supported this finding and emphasized the individual heterogeneity of cognitive outcome showing for example that at early (2.7 years) post-operative assessment 12-29% declined (according to the domain of memory) as compared to a control group whereas 8-21% actually improved and that the performance of the whole surgical group tended to evolve towards the pre-operative state at the late assessment (9.8 years in average) with 0-12% decliners and 0-16% improvers. Predictive factors of decline were normal pre-operative performance, pre-operative cognitive deficit consistent with a contralateral temporal dysfunction, lack of mental reserve, recurrence of seizure, healthy hippocampus and late surgery. The role of seizure persistence in the long-term cognitive decline has remained controversial so far, but with supporting evidence having the advantage (pros: [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF][START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF] for example; contras: [START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF]). In contrast, there is a general consensus about the following statements: i) memory decline is generally observed after dominant temporal lobe surgery; ii) when present, memory decline occurs early after surgery; iii) on a long-term basis, there is generally no additional and delayed decline; iv) and there is a general trend towards stability as compared to early post-operative assessment and even a possible recovery, especially in seizure-free patients [START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF].

These results however should be taken with caution according to some authors because many patients had a pre-existing impairment in verbal memory before surgery and neuropsychological testing could not provide evidence of postoperative decline due to the preexisting low scores [START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF]. Interestingly, the duration of epilepsy before the first pre-surgical assessment in these studies ranged between 16 and 22 years. It is impossible to determine from these studies whether the pre-operative verbal memory decline observed in left TLE is related to the etiology and is present at the onset of the epilepsy or results from the very long duration of refractory epilepsy before surgery.

Beyond the surgical context (see Table 2), two studies reported a relative stability of memory (verbal and nonverbal) after a decade of follow-up [START_REF] Holmes | Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures[END_REF][START_REF] Kalska | Cognitive changes in epilepsy: a ten year follow up[END_REF]. One study using group analysis reported a stability in verbal memory but a decline in nonverbal memory [START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF]. A study focusing on severe intractable epilepsy in patients living in specialized institutions or referred to a tertiary center reported a decline in verbal memory and identified several predicting factors such as the frequency of generalized tonic-clonic seizures and of complex partial seizures, as well as the occurrence of per-ictal head trauma [START_REF] Thompson | Cognitive Decline in Severe Intractable Epilepsy[END_REF]. In these studies, there was no differentiation by type of epilepsy or the laterality of the seizure focus. Thus, results are few and disparate in PWE who have not undergone surgery.

Non-memory functions

Long-term follow up in other cognitive domains in a context of surgery has been reported in six studies [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF][START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF][START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF][START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF][START_REF] Engman | Serial cognitive change patterns across time after temporal lobe resection for epilepsy[END_REF].

Cognitive performances remained globally stable after 13 years on executive function and attention (assessed by a mental control task and a trail making test) [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF]. An improvement is reported in two studies [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF] solely in seizure-free patients, with benefit being greater in operated than non-operated patients [START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF]. In these studies, executive function was assessed by a word fluency task [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF] and an inhibition task [START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF]. Attention was assessed by a cancellation task [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF]. These results are in accordance with a meta-analysis of short-term cognitive outcomes after TLE surgery which highlighted a decline or an improvement in these functions [START_REF] Sherman | Neuropsychological outcomes after epilepsy surgery: Systematic review and pooled estimates: Cognitive Change after Epilepsy Surgery[END_REF].

One study investigated long-term outcome in language with Wechsler subtests (Vocabulary and Similitudes) and did not observe any change [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF]. These tasks assessed semantic memory, but not naming. None of these selected studies assessed visual naming. This is surprising because in short-term outcomes the prevalence of decline in visual naming after TLE surgery has ranged from 25 to 60% [START_REF] Sherman | Neuropsychological outcomes after epilepsy surgery: Systematic review and pooled estimates: Cognitive Change after Epilepsy Surgery[END_REF].

Moreover, three studies investigated intellectual efficiency and reported less improvement of intellectual quotient in non-dominant but not in dominant TLE as compared to controls [START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF], improvement in seizure-free patients [START_REF] Engman | Serial cognitive change patterns across time after temporal lobe resection for epilepsy[END_REF] or stability [START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF].

Beyond the surgical context, cognitive performances of patients were stable [START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF][START_REF] Holmes | Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures[END_REF][START_REF] Kalska | Cognitive changes in epilepsy: a ten year follow up[END_REF] except for patients with severe intractable epilepsy who declined in all assessed cognitive domains [START_REF] Thompson | Cognitive Decline in Severe Intractable Epilepsy[END_REF]. Thus, very long-term non-memory function outcomes are poorly detailed and often not statistically analyzed but tend to be globally stable in seizure-free patients, especially after surgery.

Depression

Depressive symptoms are often assessed in the surgical context or in the progression of the disease in relation with seizure outcome [START_REF] Altalib | Presurgical depression and anxiety are not associated with worse epilepsy surgery outcome five years postoperatively[END_REF][START_REF] Hamid | Long-term association between seizure outcome and depression after resective epilepsy surgery[END_REF] but it is rarely studied in relation to cognition and even more in long-term outcomes [START_REF] Forthoffer | Depression could modulate neuropsychological status in epilepsy[END_REF]. In cognitive outcome studies, there is a tendency to exclude patients with mood disorders so it is difficult to know the impact of depression in longterm follow-up. This is surprising considering that the prevalence of depression in PWE ranges from 10 to 60% [START_REF] Bazil | Comprehensive Care of the Epilepsy Patient-Control, Comorbidity, and Cost[END_REF][START_REF] Mula | Epilepsy and depression: An update[END_REF]. Only one study reported depression in correlation with cognitive scores [START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF]. Authors suggested that patients could have better scores in memory tests after a decade of follow-up when mood status improves. In addition, seizure control after epilepsy surgery was associated with improvements in mood and anxiety symptoms [START_REF] Hamid | Long-term association between seizure outcome and depression after resective epilepsy surgery[END_REF]. Thus, at long-term followup, better cognitive and mood outcomes seem to be related to seizures freedom.

Limitations

So, studies of cognitive outcomes in a long-term follow-up are scarce. Here, we have focused on cognitive outcomes over 5 years.

Methods have differed across studies, comparing either operated patients to non-operated patients and/or patients operated on left versus right. The presence of a healthy control group is also quite rare in longitudinal follow-up [START_REF] Andersson-Roswall | Cognitive outcome 10 years after temporal lobe epilepsy surgery: A prospective controlled study[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF]. Group analysis is the most widely used method but some studies tend to use individual analysis and reliable change index [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF][START_REF] Andersson-Roswall | Verbal memory decline is less frequent at 10years than at 2years after temporal lobe surgery for epilepsy[END_REF][START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF]. This type of analysis should be definitively favored because of the individual heterogeneity of long-term cognitive outcome (ranging from decline to improvement).

The neuropsychological assessment has been performed with a wide range of tools which makes it difficult to extrapolate reported results in all patients. One study used story recall for memory assessment and another a word list recall which does not involve the same learning processes. Moreover, normative data differ for each test and authors choose the z-score they consider a cut-off for a pathological score. The reference was set at 1 standard deviation for some and 1.5 or 2 standard deviation for others. This issue is also present in the manner in which cognitive decline is defined (particularly post-operatively). Some studies did not fully describe their samples [START_REF] Rausch | Early and late cognitive changes following temporal lobe surgery for epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF][START_REF] Grewe | Very long-term outcome in resected and non-resected patients with temporal lobe epilepsy with medial temporal lobe sclerosis: A multiple case-study[END_REF] and others included acquired injury/tumor/other pathology in their samples (up to 45% of the sample in one study [START_REF] Helmstaedter | Chronic epilepsy and cognition: A longitudinal study in temporal lobe epilepsy[END_REF]; [START_REF] Baxendale | Neuropsychological function in patients who have had epilepsy surgery: A long-term follow-up[END_REF][START_REF] Thompson | Cognitive Decline in Severe Intractable Epilepsy[END_REF]). The other studies clearly mentioned that patients with other pathologies and/or severe disorders (postoperative complications for example) that could interfere with cognition were excluded [START_REF] Engman | Serial cognitive change patterns across time after temporal lobe resection for epilepsy[END_REF][START_REF] Mameniškienė | Cognitive changes in people with temporal lobe epilepsy over a 13-year period[END_REF][START_REF] Holmes | Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures[END_REF]. Tumor is an insidious pathology and we can assume that the mechanisms of epilepsy are different between these two populations so the follow-up cannot be the same.

All selected studies concerned young patients except one that conducted a descriptive analysis [START_REF] Grewe | Very long-term outcome in resected and non-resected patients with temporal lobe epilepsy with medial temporal lobe sclerosis: A multiple case-study[END_REF]. Median patient age was around 30 years at baseline and 40 years at long-term follow-up.

At the fifth decade, normal changes in memory are reported in the healthy population [START_REF] Albert | Nonlinear changes in cognition with age and their neuropsychologic correlates[END_REF][START_REF] Baxendale | IQ and Ability Across the Adult Life Span[END_REF] so it is important to conduct a longitudinal follow-up over 10 years. We already mentioned that there is no study with a follow-up longer than 5 years in PWE newly diagnosed and even less in older patients. This is unfortunate because new-onset epilepsy may be associated with cognitive decline leading to an incorrect diagnosis of dementia in these patients [START_REF] Giovagnoli | Epilepsy and Aging[END_REF]. No more than 10% of new-onset epilepsy cases in older patients involve neurodegenerative disorders [START_REF] Larner | Epileptic Seizures in AD Patients[END_REF].

Finally studies with a long-term follow-up on cognitive outcomes are methodologically difficult due to the great variability of etiologies, electro-clinical syndromes and therapeutics [START_REF] Helmstaedter | Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: Remarkable functional recovery when seizures are controlled[END_REF]. All these reasons, (heterogeneity of neuropsychological assessment, heterogeneity of methodological assessment regarding the presence of a healthy control group and statistical analysis, heterogeneity of timing at the onset of follow-up), make it difficult to extrapolate results of a particular cohort to a whole population. This helps us to understand why study designs are often retrospective in order to form large cohorts that have allowed us to monitor long-term cognitive outcomes in PWE.

Conclusion

Through the selected studies we notice that memory remains the most studied function, other cognitive functions are almost always ignored. It appears that shortly after surgery there may be a greater decline of memory performance in left than right TLE patients and a trend to stabilization or even recovery at very long-term outcomes. A possible recovery in seizure-free patients is a major point and patients shall be informed of this possibility. The results for nonmemory functions are too few to lead to a consensus. For all cognitive functions assessed, a cognitive baseline is essential to avoid misinterpreting changes in patient outcomes.

Although studies linking depression and cognition in epilepsy are rare and required, there appears to be a relationship with an improvement in memory in long-term outcomes after surgery when mood improves. Early assessment and treatment of depressive disorders in PWE is therefore essential.

Assessing long-term (over 5 years) cognitive outcomes in patients with epilepsy would ideally require longitudinal studies, a comparison to a healthy controls group and an individual analysis (integrating reliable change index) to take into account the great individual variability. This variability depends on multiple factors. Among these factors, the etiology and the repetition of refractory seizures have been emphasized. Three different models have been incompletely explored: in the first model, etiology (brain damage for example) causes both epilepsy and cognitive decline. In the second model, the repetition of seizures causes brain damage which results in cognitive decline (the best example is the status epilepticus). In the last model, the etiology causes seizures whose repetition when refractory causes cognitive decline. The complexity comes from the fact that these three distinct models may in fact co-exist in the same patient depending on the etiology. The best and most extensively studied example is medial TLE with hippocampal sclerosis: an initial status causes brain damage that in turn causes both seizures and cognitive deficit, which may then be aggravated on a long-term basis by the repetition of drug-resistant seizures.

none NF: this work was supported by UCB Pharma (research grant) LT: none LM: this work was supported by UCB Pharma (research grant)

Authors

No changes in verbal memory in 65% of patients but 71% of patients had impair performances preoperatively.

No changes in nonverbal memory in 79% of patients but 47% of patients had impair performances preoperatively.


MD Annacarmen Nilo

MD Philippe Gelisse
email: gelisse@chu-montpellier.fr

MD, PhD Arielle Crespel

Dr Gelisse Philippe

Genetic/Idiopathic Generalized Epilepsies: not so good as that!

Keywords: 86 Running Head Idiopathic generalized epilepsies and prognosis idiopathic/genetic generalized epilepsy, long-term prognosis, SUDEP, comorbidities, women of childbearing potential

Genetic or idiopathic generalized epilepsies (IGEs) account for 15-20% of all epilepsies. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long-time. Drug resistance is not uncommon (7-15%). Lifestyle remains essential and is an integral part of the treatment. Comorbidities such as obstructive sleep apnea syndrome must be considered and treated.

A highly underestimated condition is the risk of sudden unexpected death in epilepsy (SUDEP).

Very few data are available about the prevalence of SUDEP in IGE, but patients with generalized tonic-clonic seizures (GTCS) are exposed to this risk. IGEs are also characterized by a specific pharmalogical sensisitivity but may be aggravated by ASDs. Historically, the treatment of IGEs has relied mostly on valproate but this drug should be avoided in women of childbearing potential.

Women with IGE not treated with valproate are more likely to have unsatisfactory seizure control.

Female gender appears now as a new risk factor for drug-resistance. Finally, aside from the typical forms, there are epilepsies that fulfill most of the criteria of IGE, but that have an unusual history with GTCS, absences, falls, and drug resistance. Patients do not have psychomotor regression, brain magnetic resonance imaging is normal. EEG shows generalized fast rhythms during NREM sleep.

These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. These cases are considered "intermediary" between IGE and epileptic encephalopathies.

Introduction

Genetic or idiopathic generalized epilepsies (IGEs) are a group of epileptic syndromes that account for 15-20% of all epilepsies [START_REF] Jallon | Epidemiology of idiopathic generalized epilepsies[END_REF]. These syndromes are diagnosed by strict clinical and electroencephalographic (EEG) features: the combination of one or more of the generalized seizure triad (absences, myoclonic jerks (MJ), and tonic-clonic seizures) and the EEG hallmark of paroxysms of generalized spike-waves [START_REF] Koutroumanidis | The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1)[END_REF]. Controversy surrounds the use of the term idiopathic. In 2017, a new classification scheme of epileptic seizures and epilepsies was established [START_REF] Scheffer | ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology[END_REF].

Idiopathic officially became genetic, although the former term is still accepted due to its extensive use. Based on the predominant seizure type, the International League Against Epilepsy (ILAE) has recognized four main IGE syndromes with typical onset in childhood, adolescents or young adults: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures (GTCS) only [START_REF] Scheffer | ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology[END_REF]. Anyway, a number of distinctive electroclinical phenotypes, over the last few decades, have been well documented within the IGE spectrum [START_REF] Koutroumanidis | The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1)[END_REF]. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long time [START_REF] Wolf | Historical aspects of idiopathic generalized epilepsies[END_REF]. The interest in this topic reflects the need to discuss the evolution and long-term prognosis of IGE, highlighting the favorable and unfavorable aspects.

Material and methods

We carried out a literature search respecting the main theme of this review using PUBMED database up to November 2019. The search was performed with the following terms: "idiopathic generalized epilepsy", "genetic generalized epilepsy", "long-term prognosis", "refractory idiopathic generalized epilepsy", "predictor factors", "adult-onset of idiopathic generalized epilepsy", "mortality risk", "SUDEP", "comorbidity". All abstracts were screened by a reviewer in order to select those relevant. Full texts of pertinent articles written in English and French were checked, irrespective of publication date. We found 131 articles, but only 51 were selected (Fig. 1).

Prognosis factors

Factors related to the epileptic syndrome

Seizure outcome

Long-term seizure outcome and need for lifelong antiseizure treatment are highly relevant aspects of epilepsies. IGEs are genetically determined syndromes with a typically age-dependent seizure onset. They have always been considered to be highly responsive to ASDs [START_REF] Szaflarski | Seizure control in patients with idiopathic generalized epilepsies -EEG determinants of medication response[END_REF]. With the use of appropriate drugs, the reported remission rate of IGE, as a group, ranges from 64-82% [START_REF] Szaflarski | Seizure control in patients with idiopathic generalized epilepsies -EEG determinants of medication response[END_REF][START_REF] Mohanraj | Outcomes of newly diagnosed idiopathic generalized epilepsy syndromes in a non-pediatric setting[END_REF][START_REF] Seneviratne | The prognosis of idiopathic generalized epilepsy[END_REF]. In different studies [START_REF] Berg | Two-year remission and subsequent relapse in children with newly diagnosed epilepsy[END_REF][START_REF] Geerts | Onset of intractability and its course over time: the Dutch study of epilepsy in childhood[END_REF], patients with idiopathic epilepsy showed a significantly lower rate of refractoriness compared to cryptogenic and symptomatic forms [START_REF] Geerts | Onset of intractability and its course over time: the Dutch study of epilepsy in childhood[END_REF].

The remission rate varies across the different IGE syndromes. CAE usually carries an excellent prognosis and successful ASD withdrawal, with a remission rate ranged from 56-84% [START_REF] Trinka | Long-term prognosis for childhood and juvenile absence epilepsy[END_REF][START_REF] Vierck | Polyspike and waves do not predict generalized tonic-clonic seizures in childhood absence epilepsy[END_REF] with a possible development in JME. Limited data are available about JAE: the reported remission rates vary from 37% to 62% [START_REF] Seneviratne | The prognosis of idiopathic generalized epilepsy[END_REF][START_REF] Trinka | Long-term prognosis for childhood and juvenile absence epilepsy[END_REF]. The development of myoclonus [START_REF] Trinka | Long-term prognosis for childhood and juvenile absence epilepsy[END_REF][START_REF] Wirrell | Long-term prognosis of typical childhood absence epilepsy: remission or progression to juvenile myoclonic epilepsy[END_REF] and GTCS [START_REF] Grosso | Childhood absence epilepsy: evolution and prognostic factors[END_REF] is the most predictor factor of bad prognosis in absence syndromes. Other poor prognostic factors are absence status, a slowing EEG background, and atypical EEG features [START_REF] Seneviratne | The prognosis of idiopathic generalized epilepsy[END_REF]. JME is the most frequent form of IGE. It is strongly responsive to low doses of appropriate drugs, in particular valproate (VPA), but some patients need a higher dose, and their epilepsy remains difficult to treat. Complete seizure control is achieved in 80-90% of JME patients [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF].

However, true drug resistance is not uncommon (7-15%). The presence of all three seizure types (absences, MJ, and GTCS) seems to be a risk factor [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF]. Independently, the presence of psychiatric problems, including personality disorders, seems also to be a factor of drug resistance [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF].

Additionally, a significant association between the occurrence of a photoparoxysmal response and a worse seizure outcome is reported [START_REF] Podewils | Natural course and predictors of spontaneous seizure remission in idiopathic generalized epilepsy: 7-27 years of follow-up[END_REF]. It is important, however, to distinguish pseudo-resistant cases, in which seizures persistence is associated with inadequate lifestyle, poor compliance or suboptimal drug regimen, from truly pharmaco-resistance. Pseudo-resistant cases represent 9.7-16.7% of all resistant patients [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF][START_REF] Baykan | Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy[END_REF]. Fernando-Dongas et al. (2000) found that patients with VPA-refractory JME were more likely to have EEG asymmetry, atypical seizure characteristics, and intellectual difficulty (low intelligence quotient) [START_REF] Mc | Characteristics of valproic acid resistant juvenile myoclonic epilepsy[END_REF]. [START_REF] Voll | Predicting drug resistance in adult patients with generalized epilepsy: a case-control study[END_REF] showed that significant risk factors for the development of drug-resistant epilepsy were: epilepsy diagnosed before 12 years, previous history of status epilepticus, development delay, more than one seizure type [START_REF] Voll | Predicting drug resistance in adult patients with generalized epilepsy: a case-control study[END_REF].

Instead, protective factors were a good response to the first drug and a history of febrile seizures.

In JME and other juvenile IGEs, the overall prognosis remains good but these genetic epilepsies are considered a longlasting, potentially "lifetime" condition. Even after years of full seizure control, withdrawal of ASDs nearly always results in recurrence of seizures (80-90%) [START_REF] Healy | Relapse after treatment withdrawal of antiepileptic drugs for Juvenile Absence Epilepsy and Juvenile Myoclonic Epilepsy[END_REF].

Status epilepticus

The risk of status epilepticus (SE) and its true frequency in IGE patients is unclear. Clinical experience suggests that generalized convulsive status is rare, while nonconvulsive forms of SE are more common. Typical absence status (AS) (or petit mal) is probably the most common form of SE in IGE, but its frequency varies considerably between the different syndromes. Typical AS is a prolonged, generalized, and nonconvulsive seizure characterized by a variable clouding of consciousness. In 90% of cases, the confusional symptoms fluctuate. Subtle motor signs are present in half of patients, e.g. bilateral jerks of the eyelids.

Typical AS can occur in virtually all IGEs with typical absences. AS, which rarely occurs in the setting of CAE, can occur in 6.7% of patients with JME and more commonly (approximately in 20% of cases) in patients with JAE. AS occurs in 57.1% of patients with perioral myoclonia with absences and, in lower percentage (18.2%), in patients with eyelid myoclonia with absences or Jeavons syndrome [START_REF] Agathonikou | Typical absence status in adults: diagnostic and syndromic considerations[END_REF]. AS occurs in about 50% of patients with epilepsy with phantom absences.

AS can occur either spontaneously or as a consequence of drug withdrawal, or other external factors such as sleep deprivation, excessive alcohol intake, menstruation, or metabolic disturbances. Severe pharmacodynamic aggravation of seizures in IGE by inappropriate ASDs such as carbamazepine (CBZ) may also result in AS [21].

Myoclonic SE or mixed absence-myoclonic status is uncommon in JME, often precipitated by sleep deprivation, withdrawal of medication, or inadequate ASDs [START_REF] Thomas | Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy[END_REF][START_REF] Crespel | Management of juvenile myoclonic epilepsy[END_REF][START_REF] Gélisse | Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy[END_REF] (Fig. 2). Among 237 consecutive JME patients, [START_REF] Larch | Myoclonic status epilepticus in juvenile myoclonic epilepsy[END_REF] reported seven cases of myoclonic SE, including five associated GTCS cases. Triggering factors were present in six, including drug withdrawal in four, inappropriate treatment in two [START_REF] Larch | Myoclonic status epilepticus in juvenile myoclonic epilepsy[END_REF].

. Absence status epilepsy is a distinct entity of IGE proposed by [START_REF] Genton | Absence status epilepsy: delineation of a distinct idiopathic generalized epilepsy syndrome[END_REF], characterized by recurrent, unprovoked episodes of typical AS with onset after puberty or in early adulthood. These patients have infrequent GTCS, rarely typical absences, no family history of epilepsy, normal neurological evaluation, normal neuroimaging, interictal EEG showing generalized spike-and polyspike-wave discharges on a normal background, no photoparoxysmal response, variable response of AS to intravenous benzodiazepines, and usually good seizure control with VPA [START_REF] Genton | Absence status epilepsy: delineation of a distinct idiopathic generalized epilepsy syndrome[END_REF].

Cognitive, and behavioural outcome

Considering the definitions, IGEs are characterized by the absence of intellectual disability and/or focal neurological deficits. However, some patients can have temporary or permanent cognitive impairment. Relatively little is known about cognitive function in IGE. Its effects on cognition have always been considered benign, within normal range but lower than the general population [START_REF] Jeong | Neuropsychological status of children with newly diagnosed idiopathic childhood epilepsy[END_REF]. The cause of cognitive dysfunction in IGE is considered multifactorial and remains undetermined [START_REF] Hommet | Idiopathic epileptic syndromes and cognition[END_REF]. Possible causes include neurobiological factors, such as epilepsy duration, acute and cumulative effects of seizures, ASD side-effects, epileptiform discharges, and also psychopathology comorbidities [START_REF] Caplan | Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities[END_REF][START_REF] Loughman | A comprehensive assessment of cognitive function in the common genetic generalized epilepsy syndromes[END_REF]. In a 10-year follow-up study on patients with different types of intractable epilepsy, the frequency of GTCS recurrence was the strongest predictor of cognitive decline [START_REF] Thompson | Cognitive decline in severe intractable epilepsy[END_REF]. Nevertheless, the relationship between absence seizures, history of GTCS, and cognition remains a point of debate, given that other studies have not found a relationship between seizure types and cognitive function [START_REF] Loughman | A comprehensive assessment of cognitive function in the common genetic generalized epilepsy syndromes[END_REF].

Most publications assessing cognition in IGE concern JME, but there is also evidence of cognitive deficit in CAE. At least one-third of children with CAE tend to have deficits in verbal and non-verbal attention and to make more omission errors in the divided and sustained attention tasks [START_REF] Lee | Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder[END_REF]. Previously, these cognitive-attentive problems were connected only with the recurrence of absence seizures. But today, several studies support that selective attention deficit persists in both seizure-free subjects and those who continue to have seizures, representing a core neuropsychological symptom of CAE [START_REF] Lee | Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder[END_REF][START_REF] Glauser | Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absences epilepsy[END_REF]. About JME, several studies support the presence of an alteration of executive functions, such as visuospatial working memory, processing speed, cognitive strategy, and also acquired knowledge [START_REF] Loughman | A comprehensive assessment of cognitive function in the common genetic generalized epilepsy syndromes[END_REF][START_REF] Chowdhury | Impaired cognitive function in idiopathic generalized epilepsy and unaffected family members: an epilepsy endophenotype[END_REF][START_REF] Abarrategui | The cognitive phenotype of idiopathic generalized epilepsy[END_REF]]. An English study has shown a similar cognitive profile also in unaffected relatives of IGE patients, presuming a genetically determined cognitive endophenotype [START_REF] Caplan | Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities[END_REF]. It is difficult to identify a different cognitive profile between JME and absence epilepsies, due to the limited data. [START_REF] Loughman | Cognitive functioning in idiopathic generalized epilepsies: a systematic review and meta-analysis[END_REF], in their review, did not find a distinctive cognitive profile for either CAE or JME [START_REF] Loughman | Cognitive functioning in idiopathic generalized epilepsies: a systematic review and meta-analysis[END_REF]. It is also possible that the treatment with VPA plays a role in reduced performance on visuospatial span tests vai a dose-related mechanism [START_REF] Abarrategui | The cognitive phenotype of idiopathic generalized epilepsy[END_REF]. Moreover, imaging studies in patients with IGE have shown some alterations that could sustain cognitive deficits as an integral component of IGE syndrome. In particular, functional studies on JME patients have shown a thalamo-frontal network dysfunction [START_REF] Richardson | Current themes in neuroimaging of epilepsy: brain networks, dynamic phenomena, and clinical relevance[END_REF] and, fluorodeoxyglucose-positron emission tomography analyses have found a reduction of glucose metabolism in dorsolateral prefrontal cortex, premotor cortex and basal frontal regions [START_REF] Swartz | Visual working memory in primary generalized epilepsy: an 18FDG-PET study[END_REF], underlining a relationship with poorer performance in working memory task. Performance on visual recognition and verbal recall was found to correlate with magnetic resonance spectroscopy ratios of N-acetyl aspartate/choline and N-acetyl aspartate/creatine in temporal lobes of IGE patients [START_REF] Dickson | Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy[END_REF].

Mortality outcome

It is well known that patients with epilepsy have a higher risk of dying early (2 to 3 times) than the general population [START_REF] Laxer | The consequences of refractory epilepsy and its treatment[END_REF]. Both adults and children with epilepsy may die for many reasons including complication of a seizure, such as aspiration of stomach contents, suffocation, brain injury, drowning, SE, a related underlying condition (e.g. brain tumor), sudden unexpected death in epilepsy (SUDEP), but also, accidents, suicide and vascular disease [START_REF] Laxer | The consequences of refractory epilepsy and its treatment[END_REF].

IGEs have been considered as a "benign" form of epilepsy without an increase in the standardized mortality ratio (SMR) [START_REF] Jallon | Epidemiology of idiopathic generalized epilepsies[END_REF]. The following studies have shown an SMR increase in all epilepsy forms at 20-25 years after diagnosis, although with a greater increase in symptomatic groups (3.68 SMR for patients with symptomatic epilepsy vs 1.66 SMR for those with idiopathic epilepsy) [START_REF] Neligan | The long-term risk of premature mortality in people with epilepsy[END_REF]. As well as etiology of epilepsy (symptomatic vs idiopathic), the risk of mortality in epileptic patients depends on the seizure type, and its frequency: in fact, the presence of GTCS and a state of refractoriness increase the mortality rate [START_REF] Laxer | The consequences of refractory epilepsy and its treatment[END_REF][START_REF] Lhatoo | Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort[END_REF]. Patients with abnormal lifestyle, including excessive intake of alcohol or irregular sleep-wake schedules, are at risk of persisting GTCS. More than in other types of epilepsy, these patients with IGE must correct their lifestyle to avoid GTCS and the risk of SUDEP.

SUDEP is the leading cause of death in patients with uncontrolled GTCS.

In adults, SUDEP rates vary significantly between different studies and range from as high as 6/1000 person-years in refractory symptomatic epilepsy [START_REF] Annegers | Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death[END_REF] to as low as 0.35/1000 person-years in a population-based study [START_REF] Ficker | Population-based study of the incidence of sudden unexplained death in epilepsy[END_REF]. Very few data are available about the SUDEP incidence in IGE people, but different elements do not exclude a potential risk in these patients. Among three JME patients with premature death, two died suddenly and unexpectedly, probably in association with a major seizure during sleep [START_REF] Genton | Premature death in juvenile myoclonic epilepsy[END_REF]. [START_REF] Baykan | Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy[END_REF] also reported a morbidly obese, well-controlled patient with probable SUDEP [START_REF] Baykan | Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy[END_REF]. [START_REF] Brodie | Modern management of juvenile myoclonic epilepsy[END_REF] reported few female patients with uncontrolled JME, who died in bed of SUDEP during or following a seizure, having refused to consider treatment with lowdose VPA [START_REF] Brodie | Modern management of juvenile myoclonic epilepsy[END_REF].

SUDEP has not been associated with any drugs except CBZ and lamotrigine (LTG) [START_REF] Tomson | Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials[END_REF]. [START_REF] Aurlien | Lamotrigine in idiopathic epilepsy-increased risk of cardiac death?[END_REF] reported four consecutive SUDEP in young women with IGE on LTG [START_REF] Aurlien | Lamotrigine in idiopathic epilepsy-increased risk of cardiac death?[END_REF],

and the same team reported latter an increased risk of SUDEP in female patients treated with this drug. In a 10-year period (1995 to 2005), the incidence of definite and probable SUDEP in women treated with LTG was estimated as 2.5 per 1,000 patient-years and 0.5 per 1,000 patient-years in females who were not taking LTG (p = 0.007) [START_REF] Aurlien | Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study[END_REF]. However, in a pooled analysis of randomized controlled studies, there was no statistically significant difference in rate of SUDEP between LTG and placebo or another ASD [START_REF] Tomson | Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials[END_REF]. Other studies are necessary to confirm or refute this potential relationship.

Late-onset forms

IGEs have always been considered as age-related epileptic syndromes, with typical onset in childhood and adolescence. However, a late-onset is possible, although rare. Few different studies have reported a variable prevalence ranged from 8.5% to 28%, considering the total IGE population [START_REF] Cutting | Adult-onset idiopathic generalized epilepsy: clinical and behavioural features[END_REF][START_REF] Marini | Idiopathic generalised epilepsy of adult onset: clinical syndromes and genetics[END_REF]. It remains controversial if adult-onset IGE is a distinct syndrome or a continuum of a previous epileptic syndrome. It could occur as reactivation of IGE in adults and elderly individuals, in whom generalized epilepsy has remitted after puberty or juvenile age, or was unknown. This reactivation could be due or not, to triggering factors, as alcohol abuse, benzodiazepine withdrawal, emotional stress with sleep deprivation, obstructive sleep apnea [START_REF] Thomas | De novo' absence status of late onset: report of 11 cases[END_REF][START_REF] Chihorek | Obstructive sleep apnea is associated with seizure occurrence in older adults with epilepsy[END_REF]. But cases of late-onset IGE de novo, without any seizure history, have been described [START_REF] Brigo | De novo late-onset absence status epilepticus or late-onset idiopathic generalized epilepsy? A case report and systematic review of the literature[END_REF]. About the subsyndrome type, in some studies the JME is reported as the most common in adult age [START_REF] Asadi-Pooya | Age of onset in idiopathic (genetic) generalized epilepsies: clinical and EEG findings in various age groups[END_REF]; in others, epilepsy with GTCS only seems the most frequent [START_REF] Reichsoellner | Idiopathic generalised epilepsy of late onset: a separate nosological entity?[END_REF]. Few studies have no found differences of clinical and EEG features between the late-onset and early-onset forms [START_REF] Asadi-Pooya | Age of onset in idiopathic (genetic) generalized epilepsies: clinical and EEG findings in various age groups[END_REF][START_REF] Reichsoellner | Idiopathic generalised epilepsy of late onset: a separate nosological entity?[END_REF][START_REF] Yenjun | EEG in adult-onset idiopathic generalized epilepsy[END_REF]. All that supports the hypothesis that IGE syndromes at different ages share common biologic (and probably genetic) determinants and, consequently, also prognosis. A characteristic IGE with an adult-onset is the syndrome with phantom absences, rarely GTCS, and absence status [START_REF] Panayiotopoulos | Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic seizures, and frequent absence status[END_REF]. The phantom absences are typical absence seizures, which are so brief and inconspicuous to the patient and imperceptible to the observer, and they are usually discovered during video-EEG recordings [START_REF] Panayiotopoulos | Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic seizures, and frequent absence status[END_REF]. Finally, another form of rare adulthood absence is absence status epilepsy [START_REF] Genton | Absence status epilepsy: delineation of a distinct idiopathic generalized epilepsy syndrome[END_REF]. These IGE forms generate some diagnostic and therapeutic problems. The principal differential diagnosis is focal (frontal and/or temporal) seizure with impaired awareness.

Factors related to the patient

Psychiatric comorbidities and social outcomes

Closely associated with cognitive impairment is the presence of psychiatric disorders and poor psychosocial outcomes in IGE patients. Janz and Christian (1957), in one of the first JME descriptions, noted that some patients had an "attractive but immature" personality, which resulted in some difficulties of social integration, and abnormal lifestyle [START_REF] Gelisse | Psychiatric disorders in juvenile myoclonic epilepsy[END_REF]. This early observation was confirmed successively. Mild personality problems have been described in patients with IGE, in particular, JME. Gelisse et al. [START_REF] Gelisse | Psychiatric disorders in juvenile myoclonic epilepsy[END_REF] found a prevalence of psychiatric disorders of 26.5%, especially personality disorders (14%). A borderline personality, responsible for poor social integration, was the most frequent disorder (6.5%) [START_REF] Gelisse | Psychiatric disorders in juvenile myoclonic epilepsy[END_REF]. Similar data were reported by [START_REF] Loughman | A systematic review of psychiatric and psychosocial comorbidities of genetic generalised epilepsies (GGE)[END_REF] in a systematic review, with a mild difference between children-onset and adult-onset groups (55-61% vs 20-35%, respectively) [START_REF] Loughman | A systematic review of psychiatric and psychosocial comorbidities of genetic generalised epilepsies (GGE)[END_REF]. In the children group, attention deficit and oppositional defiance problems were the most common, followed by affective and anxiety disorders. However, in adult patients, depression and anxiety were the most common disorders, in contrast to impulse control or psychotic disorders [START_REF] Loughman | A systematic review of psychiatric and psychosocial comorbidities of genetic generalised epilepsies (GGE)[END_REF].

As expected, seizure burden and ASD number seem to be the most important factors predictive of the development of a psychiatric disorder [START_REF] Loughman | A systematic review of psychiatric and psychosocial comorbidities of genetic generalised epilepsies (GGE)[END_REF]. Moreover, it is reported that JME patients with praxis induction and photosensibility had indeed greater executive dysfunction and more frequent psychiatric comorbidities [START_REF] Carvalho | Cognitive performance in juvenile myoclonic epilepsy patients with specific endophenotypes[END_REF]. In Gelisse's series [START_REF] Gelisse | Psychiatric disorders in juvenile myoclonic epilepsy[END_REF], the presence of psychiatric disorders in JME, in particular personality disorders and generalized anxiety, was a strong factor for drug resistance, with a consequent negative impact on life quality [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF]. A relationship between psychological comorbidities and drug-resistance was also reported by [START_REF] Cutting | Adult-onset idiopathic generalized epilepsy: clinical and behavioural features[END_REF] [START_REF] Cutting | Adult-onset idiopathic generalized epilepsy: clinical and behavioural features[END_REF]. All this results in an unfavourable social outcome in 76% of patients without apparent differences between IGE subtypes [START_REF] Loughman | A systematic review of psychiatric and psychosocial comorbidities of genetic generalised epilepsies (GGE)[END_REF]. In a small population-based study of JME, Camfield and Camfield (2010) reported higher rates of unemployment, poorer quality of life, reduced educational attainment, and increased rates of unplanned pregnancy in IGE patients [START_REF] Camfield | Idiopathic generalized epilepsy with generalized tonic-clonic seizures (IGE-GTC): a population-based cohort with >20 year follow up for medical and social outcome[END_REF]. These data were confirmed by other teams [START_REF] Cutting | Adult-onset idiopathic generalized epilepsy: clinical and behavioural features[END_REF][START_REF] Schneider-Von Podewils | Clinical predictors of the long-term social outcome and quality of life in juvenile myoclonic epilepsy: 20-65 years of follow-up[END_REF]. These findings -alongside evidence of cognitive dysfunctionsuggest that despite relatively high rates of seizure remission, it is no longer appropriate to consider these syndromes as completely "benign" [START_REF] Seneviratne | The prognosis of idiopathic generalized epilepsy[END_REF][START_REF] Healy | Relapse after treatment withdrawal of antiepileptic drugs for Juvenile Absence Epilepsy and Juvenile Myoclonic Epilepsy[END_REF][START_REF] Loughman | Cognitive functioning in idiopathic generalized epilepsies: a systematic review and meta-analysis[END_REF].

Other medical comorbidities

Comorbid conditions are relatively common in people with epilepsy, and their presence has important implications for diagnosis but also for treatment and quality of life [START_REF] Gaitatzis | The epidemiology of the comorbidity of epilepsy in the general population[END_REF]. Six large-scale studies, surveying over 1.4 million subjects from different countries, reported that 26.8-84% of epileptic patients had at least one comorbid medical condition [START_REF] Seidenberg | Association of epilepsy and comorbid conditions[END_REF], particularly older people [START_REF] Jetter | Epilepsy in elderly[END_REF].

The comorbid condition could be due to epilepsy or its treatment, or it could be the epilepsy cause.

As extensively discussed in the preceeding section, epilepsy patients have a higher risk of developing a psychiatric condition. Mood disorders, in particular depression, are the most common [START_REF] Gaitatzis | The epidemiology of the comorbidity of epilepsy in the general population[END_REF]. Another important comorbidity to deal with is the development of low bone mineral density.

Long-term use of ASDs is commonly associated with bone health problems, particularly in women [START_REF] Fraser | Enzyme-inducing antiepileptic drug and fractures in people with epilepsy: a systematic review[END_REF]. The older ASDs, usually with an action of cytochrome P450 enzyme-induction, e.g. phenytoin (PHE), phenobarbital (PB) and CBZ, are associated with an adverse impact on vitamin D-calcium system profile, resulting in a deficit [START_REF] Brodie | Enzyme induction with antiepileptic drugs: cause for concern?[END_REF]. This increase the risk of bone fractures. Women have a higher risk of bone fractures, often under-investigated and undiagnosed [START_REF] Grzonka | Bone fractures from generalized convulsive seizures and status epilepticus -a systematic review[END_REF]. Among all fractures, bilateral posterior fracture-dislocations of the shoulders are the most frequently reported (33%), followed by thoracic and lumbar vertebral compression fractures (29%), skull and jaw fractures (8%), and bilateral femoral neck fractures (6%). In IGEs, CBZ and PHE are not the drugs of choice but PB at low dosage may be an acceptable choice in JME [START_REF] Serafini | Treatment of Juvenile Myoclonic Epilepsy in Patients of Child-Bearing Potential[END_REF], particularly if cost is an issue [START_REF] Brodie | Modern management of juvenile myoclonic epilepsy[END_REF].

The strong association between epilepsy in childhood/adolescence and subsequent development of attention deficit hyperactivity disorder (ADHD) is well known [START_REF] Bertelsen | Childhood Epilepsy, Febrile Seizures, and Subsequent Risk of ADHD[END_REF]. The prevalence of ADHD is reported to be 30-60% in CAE, which is much higher than in the normal population [START_REF] Lee | Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder[END_REF]. The comorbid ADHD contributes to further impairment of sustained attention and response inhibition, influencing the severity of cognitive disorders [START_REF] Lee | Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder[END_REF]. In a Danish population-based cohort, convulsion severity was correlated with the risk of developing ADHD, but a detailed analysis of subtypes of epilepsy was not performed [START_REF] Fanella | Ictal epileptic headache as "subtle" symptom in generalized idiopathic epilepsy[END_REF]. In contrast with this, one study demonstrated that ADHD onset antedates the diagnosis of epilepsy in the majority of children, supporting the hypothesis that it is due to previous neurodevelopmental abnormalities and not to seizure recurrences and ASD treatment [START_REF] Hermann | The frequency, complications and aetiology of ADHD in new onset paediatric epilepsy[END_REF]. In another recent study, JME was associated with the possible development of ADHD in particular in females (OR 15.5), but more evidence is necessary.

The association between headache/migraine and epilepsy is frequent. The most common headache is post-ictal (45%), and most frequently, it occurs after GTCS. Although rare, ictal headache is described in patients with IGEs as a symptom rather as a comorbidity [START_REF] Fanella | Ictal epileptic headache as "subtle" symptom in generalized idiopathic epilepsy[END_REF].

Finally, patients with epilepsy have a high prevalence of obstructive sleep apnea (OSA), compared to the general population, in particular in the elderly: 30% of women and 73% of men with epilepsy, aged 50 years and older [START_REF] Chihorek | Obstructive sleep apnea is associated with seizure occurrence in older adults with epilepsy[END_REF]. It has been described that OSA is a risk factor for seizure worsening [START_REF] Chihorek | Obstructive sleep apnea is associated with seizure occurrence in older adults with epilepsy[END_REF][START_REF] Hollinger | Epilepsy and obstructive sleep apnea[END_REF]. Several mechanisms associated with sleep-disordered breathing potentially facilitate seizure recurrence, in particular nocturnal seizures, which include sleep deprivation, sleep fragmentation, cerebral hypoxemia, decreased cardiac output and also cardiac arrhythmias [START_REF] Sivathamboo | Sleep-disordered breathing in epilepsy: epidemiology, mechanisms, and treatment[END_REF]. In patients with epilepsy, OSA is often underdiagnosed and undertreated.

Standardized questionnaires used for sleep and apneas appear to be useful. Some elements that could aggravate or trigger a sleep apnea syndrome must be sought such as being overweight and the use of ASDs with a respiratory depressor effect (benzodiazepines, PB) or inducing a weight gain such as VPA and perampanel [START_REF] Sivathamboo | Sleep-disordered breathing in epilepsy: epidemiology, mechanisms, and treatment[END_REF]. OSA may also increase cardiovascular risk, including potentially increased risk of cardiac arrhythmias and so SUDEP risk. But the real correlation between OSA and SUDEP needs to be established. Treatment with CPAP (continuous positive airway p ressure) seems to improve seizure control in some patients [START_REF] Malow | Treating obstructive sleep apnea in adults with epilepsy[END_REF].

Factors related to drug prescription

The risk of seizure aggravation has increased with the number of ASDs. IGE are primary candidates for a pharmacodynamics aggravation. Many antiepileptic drugs such as CBZ, oxcarbazepine (OXC), gabapentine (GBP), vigabatrin (VGB), tiagabine may aggravate absence epilepsies [START_REF] Thomas | Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy[END_REF][START_REF] Parker | Inappropriate use of carbamazepine and vigabatrin in typical absence seizures[END_REF][START_REF] Genton | When antiepileptic drugs aggravate epilepsy[END_REF][START_REF] Gelisse | Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies[END_REF]. PHE seems to be less aggravating for absences [START_REF] Genton | When antiepileptic drugs aggravate epilepsy[END_REF]. PB may have a dual effect (increasing absences at high doses, decreasing them at low dosages) [START_REF] Genton | When antiepileptic drugs aggravate epilepsy[END_REF]. In JME, [START_REF] Genton | When antiepileptic drugs aggravate epilepsy[END_REF] reported that PHE was not very efficient (38% aggravated, 12% improved, whereas 50% did not notice any change in seizure frequency). In this study, CBZ worsened symptoms in nearly 68% of patients exposed, whereas 14% of them were improved, with no effect in the remaining cases (18%) [START_REF] Genton | Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy?[END_REF]. OXC appears to have a significant potential for aggravation in juvenile IGE [START_REF] Gelisse | Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies[END_REF].

LTG is a therapeutic option in IGE, especially in absence epilepsies but in JME this drug can aggravate MJ [START_REF] Biraben | Exacerbation of juvenile myoclonic epilepsy with lamotrigine[END_REF] or GTCS [START_REF] Maiga | Exacerbation of tonicoclonic seizures in a juvenile myoclonic epileptic taking lamotrigine[END_REF]. [START_REF] Crespel | Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies[END_REF] reported de novo appearance of MJ in juvenile IGE in five women among 93 patients treated with LTG (5.4%) with a phenotype close to JME at the time of aggravation [START_REF] Crespel | Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies[END_REF]. Two distinct profiles of aggravation were observed: (1) a doserelated aggravation of MJ during or at the end of LTG titration that may respond to LTG dosage reduction by 25 to 50%; (2) a severe aggravation of MJ occurring several months after LTG titration and evolving into myoclonic status, requiring cessation of LTG. Finally, AS has been reported in IGE patients treated with inappropriate ASDs [START_REF] Thomas | Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy[END_REF]. Potential precipitating factors for AS were increase of CBZ or of CBZ and PHE; initiation of CBZ, VGB or GBP and decrease of PB.

VPA has historically been considered the ASD of first choice in juvenile IGE, especially in JME, with response rates of up to 80%. Given the high rate of malformation and cognitive side effects associated with prenatal exposure, the use of VPA is nowadays limited to women with persisting GTCS, including at least LTG and LEV or experiencing side effects with these drugs [START_REF] Serafini | Treatment of Juvenile Myoclonic Epilepsy in Patients of Child-Bearing Potential[END_REF]. In women of childbearing age with IGE, Cerulli Irelli et al. (2019) reported that VPA avoidance/switch could be linked to a poor seizure control [START_REF] Irelli | Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome[END_REF]. Seizure remission was observed in 78.7% patients taking VPA and in 51.7% not taking VPA. The authors conclude that "clinicians should thoroughly discuss with their patients about potential risks and benefits of VPA avoidance, especially in cases of specific syndromic contexts (e.g., JME)". Figure 3 presents a 15-year-old woman with JME and ineffective/inappropriate ASDs. At the time of the EEG, she had 2-3 GTCS per month, frequent MJ evolving to status epilepticus. She was treated at this time with LTG (200 mg/d) and OXC (600 mg/d), but previously she was treated with high-dose LTG, LEV, topiramate (TPM) followed by an association of TPM, clonazepam, LTG and OXC. Monitoring video-EEG showed in the awakening period bursts of generalized polyspikes-waves associated with a myoclonia followed by an atonia. There were also atypical absences. She had multifocal erratic myoclonus, especially during hyperventilation. The patient was unaware of these jerks and the atypical absences. She also had a photoparoxysmal response. The EEG and the clinical presentation were highly suggestive of paradoxical seizure aggravation. Indeed, myoclono-atonic seizures are not usually observed in JME but can happen in the context of paradoxical seizure aggravation by ASDs, but can also be observed in progressive myoclonic epilepsy. OXC was stopped. VPA and PB were started at the same time to control the seizures quickly. She became seizure-free. Three years later, with VPA (1,000 mg/d), PB (20 mg/d) and LTG (200 mg/d), the long-term video-EEG monitoring was subnormal with no photosensitivity and the patient passed her driver's license.

Discussion and Conclusions

The term "idiopathic" has always implied a benign nature of IGE syndromes. In different studies, idiopathic nature of epilepsy was found to be a significant predictor of good prognosis, with a significantly lower rate of refractoriness [START_REF] Geerts | Onset of intractability and its course over time: the Dutch study of epilepsy in childhood[END_REF]. Indeed, IGE patients achieve seizure control with a low dose of a single ASD, typically VPA. But literature studies and clinical experience highlight that long-term treatment allows adequate seizure control and the best quality of life. CAE is known to have an excellent evolution, with the possibility of spontaneous resolution once puberty is reached. The reported remission rate in CAE ranges from 56-84% [START_REF] Trinka | Long-term prognosis for childhood and juvenile absence epilepsy[END_REF][START_REF] Bartolomei | Prognostic factors for childhood and juvenile absence epilepsies[END_REF]. This wide range is probably due to the heterogeneity of the studies, not all made in tertiary centres and with variable inclusion criteria. Anyway, pharmaco-resistant forms of CAE exist. The principal negative prognostic factors are early onset and recurrence of GTCS and myoclonic jerks, the latter suggestive of a possible evolution to JME. Scarce data are available about JAE prognosis. JAE seems to be a lifelong condition with the necessity of long-term therapy, considering the 100% reported relapse rate after treatment withdrawal [START_REF] Healy | Relapse after treatment withdrawal of antiepileptic drugs for Juvenile Absence Epilepsy and Juvenile Myoclonic Epilepsy[END_REF]. JAE seems to share the same negative predictor factors with a higher incidence than CAE, in particular, the risk of GTCS development ranges between 81% and 95% (vs 38-69% of CAE) [START_REF] Trinka | Long-term prognosis for childhood and juvenile absence epilepsy[END_REF][START_REF] Bartolomei | Prognostic factors for childhood and juvenile absence epilepsies[END_REF]. More data are available about JME.

The remission rate is higher (80-90%) and, as well, an elevated relapse rate is reported after treatment withdrawal (80%) [START_REF] Healy | Relapse after treatment withdrawal of antiepileptic drugs for Juvenile Absence Epilepsy and Juvenile Myoclonic Epilepsy[END_REF]. Only 7-8% of patients achieve spontaneous remission without antiepileptic drugs [START_REF] Seneviratne | The prognosis of idiopathic generalized epilepsy[END_REF]. It is important to distinguish between true resistance and pseudo-resistance.

The latter is reported in 9.7-16.7% of patients with JME [START_REF] Gelisse | Clinical factors of drug resistance in juvenile myoclonic epilepsy[END_REF][START_REF] Baykan | Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy[END_REF], due to lifestyle and poor compliance to therapy, frequently found in adolescent patients. Therefore, results from prognosis studies on IGE are variable and, at the same time, contradictory, so difficult to compare.

The IGEs are a lifelong pathology, with an elevated risk of comorbidity. Several studies have underlined the cognitive aspects of IGEs. Specific personality traits and subtle neuropsychological deficits have long been attributed particularly to subjects with JME, but also with CAE/JAE. No evidence of a clear relationship between the main seizure type and cognitive dysfunction has been reported [START_REF] Loughman | A comprehensive assessment of cognitive function in the common genetic generalized epilepsy syndromes[END_REF]. On the contrary, there is evidence in favour of a possible genetically determined origin of this deficit [START_REF] Chowdhury | Impaired cognitive function in idiopathic generalized epilepsy and unaffected family members: an epilepsy endophenotype[END_REF], rather than comorbidity related to seizure persistence. Also, neuroimaging, both functional and metabolic studies, have shown some alterations that could sustain cognitive deficits as an integral component of IGE syndrome [START_REF] Richardson | Current themes in neuroimaging of epilepsy: brain networks, dynamic phenomena, and clinical relevance[END_REF][START_REF] Swartz | Visual working memory in primary generalized epilepsy: an 18FDG-PET study[END_REF][START_REF] Dickson | Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy[END_REF].

Although less than for a symptomatic form, IGE patients have an increase of SMR compared to healthy people [START_REF] Neligan | The long-term risk of premature mortality in people with epilepsy[END_REF]. Very interesting and not still well known, is the risk of SUDEP in this category of epilepsy. SUDEP is a probabilistic event, difficult to predict. The mechanisms that carry SUDEP are not well identified. SUDEP is correlated with reduced control of seizures, in particular with the number of GTCS per year. IGE patients with uncontrolled GTCS have an increased risk of SUDEP.

Still in open debate is the existence of a late-onset form of IGE. But several pieces of evidence are in favour of a common genetic origin with the childhood/adolescent forms [START_REF] Asadi-Pooya | Age of onset in idiopathic (genetic) generalized epilepsies: clinical and EEG findings in various age groups[END_REF][START_REF] Reichsoellner | Idiopathic generalised epilepsy of late onset: a separate nosological entity?[END_REF][START_REF] Yenjun | EEG in adult-onset idiopathic generalized epilepsy[END_REF]. In these cases, a detailed anamnestic collection is necessary to search for earlier symptoms, such as MJ or phantom absences, and to find eventual trigger factors, such as sleep deprivation, consumption of alcoholic beaverages, and comorbidities such as infectious or OSA. When adequately treated, these forms share the same prognosis of early-onset forms.

Finally, aside from the typical forms, there are epilepsies with mostly or only more or less typical absences, which occur in children or in adolescents but do not strictly have the same clinical and EEG characteristics. "Intermediate petit mal" has been described as borderline between CAE and more severe conditions, with slow spike-waves on the EEG during absences and a comparatively poor prognosis. The presence of atypical EEG findings in a case of absence epilepsy, especially polyspike discharges during sleep, is probably a predictor of poor prognosis with persisting seizures and drug resistance [START_REF] Michelucci | Electroclinical features of idiopathic generalised epilepsy with persisting absences in adult life[END_REF]. Some patients start this type of epilepsy at adolescence. They fulfill most of the criteria of IGE, but they have an unusual history with GTCS, absence seizures, falls, and drug resistance. They do not have a psychomotor regression, as observed in Lennox-Gastaut syndrome, because of a later age of onset after a normal development. Brain magnetic resonance imaging is always normal. The EEGs showed generalized fast rhythms during NREM sleep similar to Lennox-Gastaut syndrome (Figure 4). These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. For this reason, we considered such cases as "intermediary" between IGE and epileptic encephalopathies [START_REF] Gelisse | The Epilepsies[END_REF]. These patients are difficult to treat.

In conclusion, IGEs appear to be more favourable compared to other epilepsies. However, these epilepsies cannot be considered a truly benign condition, although they may remit at least partially, with age. Treatment of IGEs includes lifestyle interventions as well as ASDs. IGEs of adults are characterized by phamacodependency, and in a few patients, by the risk of complications, including SUDEP, and poor social adjustment. Women of childbearing age require additional counselling regarding the management of their condition. The use of VPA should be restricted because of the high rates of malformations and adverse cognitive effects associated with neonatal exposure. However, it is essential to keep in mind that some patients with IGEs might respond only to VPA.

Female gender now appears to be a risk factor for drug-resistance. Onset of epilepsy at age 14 with rare generalized tonic clonic seizures. From age 18 on, the patient also experienced rare absences with incomplete loss of contact. At age 32, epilepsy became drugresistant with series of absences over periods of two weeks, sometimes causing falls. A: The patient is awake, eyes open. There is a generalized discharge of symmetric and synchronous spikewaves predominating anteriorly, that lasts 8 seconds, and appears to be fragmented. The frequency of spike-waves is high, around 4.5 Hz (atypical absence), then slows down to 3 Hz. The patient seems to be far away but there is no complete loss of contact during the atypical absence. B and C: The patient is asleep in stage N2 sleep. Fast activities on both hemispheres followed by a period of flattening of the EEG.

Figure 1 .

 1 Figure 1. Flow of information regarding literature review.

Figure 2 .

 2 Figure 2. 24-year-old woman with Juvenile Myoclonic Epilepsy and bipolar disorder. Confusion five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor. A: Typical absence status with continuous bilateral rhythmic activity at 5-6 Hz. Catatonic state with subtle myoclonus of the arms. Note the eyes are open. B: The absence status stopped after IV injection of clonazepam (1 mg). Consciousness returned to normal. Nurses and doctors were making jokes and laughing.

Figure 3 .

 3 Figure 3. 15-year-old woman with Juvenile Myoclonic Epilepsy treated at the time of the EEG with lamotrigine (200 mg/d) and oxcarbazepine (600 mg/d). A: Awakening period. A burst of generalized polyspike-waves associated with a myoclonia followed by an atonia (arrow). B: Atypical absence with slow spike-waves predominating anteriorly. The patient was unaware of the absence. C: Hyperventilation triggers spike and polyspike-waves with multifocal erratic myoclonus (arrows). Downward eyelid blinking artifacts on the frontopolar leads.

Figure 4 .

 4 Figure 4. 40-year-old patient with absence epilepsy and an atypical evolution with drug resistance.Onset of epilepsy at age 14 with rare generalized tonic clonic seizures. From age 18 on, the patient also experienced rare absences with incomplete loss of contact. At age 32, epilepsy became drugresistant with series of absences over periods of two weeks, sometimes causing falls. A: The patient is awake, eyes open. There is a generalized discharge of symmetric and synchronous spikewaves predominating anteriorly, that lasts 8 seconds, and appears to be fragmented. The frequency of spike-waves is high, around 4.5 Hz (atypical absence), then slows down to 3 Hz. The patient seems to be far away but there is no complete loss of contact during the atypical absence. B and C: The patient is asleep in stage N2 sleep. Fast activities on both hemispheres followed by a period of flattening of the EEG.

7 •-

 7 Excluded based on language criteria: n = 40 -Impossible to access full text: n = 35 -Single case reports excluded because of insufficient data: n = 5

CONFLICT OF INTEREST DISCLOSURE

Dr. Nilo reports no conflicts of interest.

Dr. Gelisse received support for teaching programs from Sanofi, UCB, EISAI and Psicofarma. He received a research grant from Janssen-Cilag. He worked as a consultant for Eisai-France in 2011.

Dr. Crespel received support for teaching programs from Sanofi, UCB, GSK, Shire and is an advisory board member for Eisai-France.

All co-authors have been substantially involved in the study and preparation of the manuscript. No undisclosed persons have had a primary role in the study or manuscript preparation. All co-authors have approved the submitted version of the paper and accept responsibility for its content.