Stéphane Auvin
email: stephane.auvin@aphp.fr

Lennox-Gastaut syndrome: new treatments and treatments under investigation

Keywords: cannabidiol, carisbamate, fenfluramine, Lennox-Gastaut syndrome, perampanel

There are currently five compounds (clobazam, felbamate, lamotrigine, topiramate, rufinamide) available for prescription with a demonstrated efficacy on drop seizures for Lennox-Gastaut syndrome (LGS). There are also currently new and under-investigation compounds. This paper gives an overview on these novel developments for LGS based on the lecture given at the French Chapter meeting of the International League Against Epilepsy (ILAE) held in Paris in October 2019. Five compounds were discussed. Epidiolex (cannabidiol) has been approved recently based on positive randomized control trials in LGS patients. Four drugs are under investigation according to a search on the 'clinicaltrials.gov' database.

Perampanel and fenfluramine are both being studied in ongoing phase 3 studies. Two compounds are in an earlier stage of development with ongoing phase 1 and 2 studies: carisbamate and OV953. We summarized the publicly available data. Based on these drug development programs, we can expect that new compounds will become available for LGS in the next years, possibly resulting in new treatment paradigms.

Introduction:

Lennox-Gastaut syndrome (LGS) is a childhood epileptic encephalopathy (EE). The diagnosis is not always easy since the electroclinical characteristics appear progressively.

LGS, when fully developed, is defined by the association of many types of seizures including tonic seizures, cognitive impairment, and an interictal EEG pattern of diffuse, slow spike-wave complexes [START_REF] Arzimanoglou | Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology[END_REF]. The main seizure types are tonic seizures, atonic seizures and atypical absences. Tonic seizures remain the main feature, and will persist over time, even into adulthood [START_REF] Ferlazzo | Lennox-Gastaut syndrome in adulthood: Clinical and EEG features[END_REF]. The classic interictal EEG feature is the slow spike-wave pattern, consisting of slow spikes or slow spikes-and-waves organized in prolonged discharges at 1-2 Hz. Bilateral fast rhythm patterns (10 Hz or more) or "polyspikes" are typically recorded during slow sleep and, when EMG electrodes are used, it is not unusual to observe a concomitant tonic contraction [START_REF] Ferlazzo | Lennox-Gastaut syndrome in adulthood: Clinical and EEG features[END_REF].

Children with LGS usually experience cognitive regression around the time of diagnosis and established

LGS is almost always associated with moderate to severe cognitive impairment [START_REF] Ferlazzo | Lennox-Gastaut syndrome in adulthood: Clinical and EEG features[END_REF]. Cognitive impairment seems linked to the age of onset and persistence of seizures [START_REF] Arzimanoglou | Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology[END_REF]. There are currently six compounds (cannabidiol, clobazam, felbamate, lamotrigine, topiramate, rufinamide) that have demonstrated efficacy on drop seizures in LGS patients. Even if the primary endpoint used in the randomized controlled trial (RCT) is focused only on reliable and countable events (the drop seizure that is a mixed of tonic and atonic seizures), this design has enabled approvals from regulatory agencies making these compounds available for patients. Moreover, there are also effective non-pharmacologic treatments for LGS such as dietary treatment (ketogenic diet and modified Atkins diet), vagal nerve stimulation and palliative surgery with callosotomy. Recently, an algorithm of treatment has been proposed by European experts [START_REF] Cross | Expert Opinion on the Management of Lennox-Gastaut Syndrome: Treatment Algorithms and Practical Consideration[END_REF].

Despite this number of approved drugs for LGS, there are still unmet needs for treatment. These drugs provide an improvement, but usually not with sustained long-term effect, resulting in a need for a new treatment to stabilize the epileptic activity when a worsening occurs. Moreover to date, no disease-modifying treatment has come forward. Even if there are many underlying causes, personalized medicine should also be an area of investigation in this epilepsy syndrome [START_REF] Auvin | Current understanding and neurobiology of epileptic encephalopathies[END_REF].

The purpose of this paper, based on the lecture that was given at the 2019 epilepsy meeting of the French chapter of the International League Against Epilepsy (ILAE), is to describe new treatments for LGS. We focused on one drug (Epidiolex, cannabidiol) recently approved by the European Medicine Agency (EMA) and on compounds being tested in recruiting clinical trials according to the 'clinicaltrials.gov' database. There are four ongoing drug development programs: fenfluramine in phase 3 study, perampanel in phase 3 study, OV935 in phase 2 study and carisbamate in phase 1 study. Current knowledge about these compounds in LGS is summarized below.

Epidiolex, cannabidiol

The precise mechanism by which cannabidiol (CBD) exerts its antiepileptic effects is unknown and is under further investigation. However, it is known that CBD does not directly activate CB1 receptors, and is not reported to have psychoactive effects [START_REF] Gaston | Pharmacology of cannabinoids in the treatment of epilepsy[END_REF]. CDB is responsible for an increase in the active metabolite of clobazam. Two RCTs have been conducted in LGS with positive results. In the first RCT, CDB was tested at the daily dose of 20mg/kg. One hundred seventy-one patients (aged 2-55 years) with treatment-resistant LGS were included resulting in a significant reduction in monthly drop seizure in the CBD group compared to the placebo group [START_REF] Thiele | Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial[END_REF]. The second RCT evaluated two doses of CBD (10 and 20 mg/kg/day). Two hundred twenty-five LGS patients were included. A significant reduction in drop seizures was observed for both doses compared to placebo [START_REF] Devinsky | Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome[END_REF]. These data were published more than one year ago. The update for this product is the recent approval by the European medicine agency on September 23, 2019. The approval was given in conjunction with clobazam for uncontrolled seizure in Dravet syndrome and Lennox-Gasatut syndrome [8].

For now, prescription in France is available under an early access program (Autorization temporaire d'utilisation, ATU) approved by the French medicine agency.

Fenfluramine

Fenfluramine was used initially as an anti-obesity drug. Case reports suggested that fenfluramine could also be used in obsessive compulsive behavior associated with photosensitive seizures. Careful study of the patients who responded best to fenfluramine showed that they were patients with Dravet syndrome. Larger case studies followed by two RCTs confirmed that low-dose fenfluramine is indeed effective in Dravet syndrome [START_REF] Polster | Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome[END_REF]. Recent preclinical evidence suggests that fenfluramine does not act through the serotonin pathway alone but also via σ1 receptors [START_REF] Sourbron | Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish[END_REF].

A phase 2, open-label, dose-finding study of add-on ZX008 was conducted in 13 patients aged 3-18 years with LGS (NCT02655198). The included patients had at least four convulsive seizures in the four weeks prior to starting fenfluramine as adjunctive treatment twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every four weeks if no decrease of at least 50% of the convulsive seizure frequency, based on seizure diary, occurred. Ten (77%) patients completed the 20 weeks of fenfluramine treatment with a 53% median reduction in convulsive seizures (n = 13); the median reduction was 60% in the 10 completers. At 15 months in the extension study (n = 9), median reduction in convulsive seizures was 58%. The most common adverse events were decreased appetite in four patients. No adverse heart effects were recorded [START_REF] Lagae | A pilot, open-label study of the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut syndrome[END_REF].

Perampanel

Perampanel is a selective non-competitive antagonist of AMPA receptors. This drug is currently approved by the EMA for focal-onset seizure and generalized tonic-clonic seizure of idiopathic generalized epilepsy in addition to other drugs for patients aged 12 years and above [START_REF] Dozieres-Puyravel | An Evidence-Based Review On The Use Of Perampanel For The Treatment Of Focal-Onset Seizures In Pediatric Patients[END_REF]. Real-life studies reported few patients (n=11) but limited data on the efficacy are available from these papers reporting the use of perampanel in different epilepsy syndromes. Our group reported the use of perampanel in [START_REF] Dozieres-Puyravel | An Evidence-Based Review On The Use Of Perampanel For The Treatment Of Focal-Onset Seizures In Pediatric Patients[END_REF] LGS patients (seven male; mean age, 12.8 years). In this prospective data collection, perampanel was initiated at 2mg/day and titrated to a median maximum dose of 6mg/day. After a mean follow-up of 10.8 months (range, 1-24 months), nine patients (69.2%) were responders (≥50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as "much improved" or "very much improved". Four patients (30.8%) discontinued perampanel due to lack of efficacy (n=2) and seizure aggravation (n=2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n=3), behavior disturbance with agitation (n=2), and/or fatigue (n=2). All AEs became manageable after perampanel dosing was decreased. Introduction of perampanel allowed dose reduction and/or discontinuation of other treatments in seven patients (53.8%) [START_REF] Auvin | Use of perampanel in children and adolescents with Lennox-Gastaut Syndrome[END_REF].

A phase 3 RCT (NCT02834793) started in December 2016 and aims to include 142 patients. Completion of inclusion is expected for August 2020.

Soticlestat -OV953/TAK-953

Soticlestat has showed an anticonvulsant effect in various preclinical models. It is the first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) and is currently investigated as an antiseizure compound. CH24H is predominantly expressed in the brain, involved in cholesterol homeostasis. CH24H converts cholesterol to 24-hydroxycholesterol (24HC). The exact underlying mechanism is under investigation but it is currently believed that soticlestat acts through a modulation of the excitatory pathway. A first phase 1b/2a in adult patients with developmental and epileptic encephalopathies was positive [START_REF]Rare-Epilepsies[END_REF] A phase 2, prospective, interventional, open-label, multi-site, extension study to assess the long-term safety and tolerability of Soticlestat TAK-935 (OV935) as adjunctive therapy in patients with rare epilepsy (NCT03635073) aims to include 176 patients with various rare epilepsy syndromes including LGS (but also Dravet Syndrome, Dup15q Syndrome, CDKL5 Deficiency Disorder). The trial started July 2018 and is expected to be completed by 2023.

Carisbamate

Carisbamate possesses potent and broad-spectrum activity in a battery of wellcharacterized animal seizure models in which seizures are induced electrically, chemically or by kindling, with median effective dose (ED50) values ranging from 5 to 60 mg/kg. Inhibition of voltage-dependent brain-type sodium channels appears to be the major identified mechanism of the antiepileptic activity of carisbamate. The drug development has been modified after a negative phase 3 study [START_REF] Halford | A randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of adjunctive carisbamate treatment in patients with partial-onset seizures[END_REF].

On the clinicaltrials.gov database, we found an ongoing phase I, open-label, pharmacokinetic, dose escalation study of carisbamate in adult and pediatric subjects with

LGS. This study started in February 2019 (NCT03731715) aiming to include 24 participants by December 2019.

Conclusion

There are several ongoing research programs evaluating the efficacy and safety of new compounds as antiseizure drugs for LGS. This is an important opportunity for the future because there are still several unmet needs in LGS. First, all LGS patients still have pharmacoresistant epilepsy. Second, current evaluation of antiseizure drugs for LGS focuses only on drop seizure that is a mix of atonic and tonic seizures despite the fact that there are other seizure types in this syndrome. Finally, we definitely need a paradigm shift for the development of disease-modifying medicines capable of altering the course of the diseases rather than simply modifying epileptic symptoms.

Conflict of interest

Stéphane Auvin has served as consultant or received honoraria for lectures from Advicenne Pharma, Biocodex, Eisai, GW Pharma, Novartis, Nutricia, Shire, UCB Pharma, Ultragenyx, Zogenyx. He has been investigator for clinical trials for Advicenne Pharma, Eisai, UCB Pharma and Zogenyx.

A phase 3

 3 RCT (NCT03355209) started in November 2017 and aims to include 225 patients aged 2 to 35 years. Completion of inclusion is expected for December 2019 [12].


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

& Brissart

Depression could modulate neuropsychological status in epilepsy

Keywords:

While cognition and depression have often been studied in patients with epilepsy, only a few studies have so far attempted to link these two domains, and more specifically to investigate the specific impact of depression on cognition in epilepsy. In this review, we performed an extensive search of the literature database to provide a better understanding of this subject. Using several inclusion criteria (adult population, quantitative depression/neuropsychological assessment, statistical analyses of the impact of depression on cognitive scores, patients with epilepsy (PWE) and no other neurological disease, and studies including at least 20 patients), we identified 20 articles (out of 712 search results) that investigated both depression and cognition in PWE. Their results were summarized using a narrative and descriptive approach. This review highlights a variable impact of depression on cognition in PWE, depending on the laterality of the seizure onset zone, the type of epilepsy and the surgical context. We emphasize the need for a systematic depression assessment in these patients, especially since depressed PWE will benefit from prompt and appropriate care to help them avoid cognitive decline, particularly in a surgical context.

Epilepsy is one of the most common chronic neurological disorders, and is characterised by intermittent temporary brain dysfunctions (seizures). Epilepsy affects more than 600,000 people in France and 60 million people in the world. According to the definition from the International League against Epilepsy (ILAE), "epilepsy is a disorder of the brain characterised 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]. This definition enhances the fact that epilepsy cannot be considered independently of cognitive and psychological aspects. However, while both cognitive and psychological dimensions have been extensively studied in patients with epilepsy (PWE), they have mostly been investigated separately. Most strikingly, psychiatric comorbidities are often considered to be an exclusion criterion in studies investigating cognitive aspects of epilepsy. Considering the importance of these two dimensions in the care of PWE, it appears essential to understand their relationship to each other. The purpose of this narrative review is to highlight the link between cognitive and psychological aspects in PWE and to raise awareness of the importance of this link which is often underestimated.

Epilepsy and depression: a bidirectional relation

Psychiatric pathologies are frequent in PWE but often underestimated [START_REF] Hingray | Clinique et diagnostic des troubles psychiatriques dans les épilepsies[END_REF]. Depressive syndrome in PWE can be associated with a decreased quality of life (QoL) [START_REF] Mcgonigal | Syndrome dépressif et épilepsies : spécificité sémiologique et outil de dépistage validé[END_REF], an increased risk of suicidal behavior [START_REF] Jones | Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy[END_REF], difficulties in controlling seizures [START_REF] Thapar | Do depression symptoms predict seizure frequency-or vice versa?[END_REF], increased side effects of antiepileptics drugs (AED) [START_REF] Luoni | Determinants of health-related quality of life in pharmacoresistant epilepsy: Results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments: Quality of Life in Pharmacoresistant Epilepsy[END_REF], a poorer outcome of surgical treatment [START_REF] Kanner | A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy[END_REF], and increased health costs [START_REF] Cramer | The impact of comorbid depression on health resource utilization in a community sample of people with epilepsy[END_REF]. Strikingly, the main predictor of QoL in PWE is the presence of a depressive syndrome, rather than the frequency of seizures [START_REF] Boylan | Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy[END_REF].

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] Kanner | Comorbidités psychiatriques de l'épilepsie : données et controverses[END_REF][START_REF] Mula | Epilepsy and depression: An update[END_REF]. It is likely that this large variability in the prevalence of depression relies on the frequent confusion between symptoms of depression and symptoms of epilepsy. Many manifestations of epilepsy, whether interictal (dysphoric disorder) or postictal (depression or mania), can be mistaken for depressive symptoms. Depressive disorders in epilepsy are also likely to have atypical clinical manifestations in regard to the duration and types of symptoms, requiring the clinician to be particularly careful when associating these symptoms to depression or interictal, ictal or postictal manifestations of epilepsy [START_REF] Josephson | Psychiatric comorbidities in epilepsy[END_REF][START_REF] Fiest | Depression in epilepsy: A systematic review and meta-analysis[END_REF]. Moreover, diagnostic criteria for depression (DSM-V) are poorly suitable for PWE because insomnia, weight fluctuations and attention disorders, that are all symptoms characterizing depression, may also be related to side effects of AEDs. Additionally, the feeling of sadness, which is a key symptom of depression as identified by the DSM-V, is not always an explicit complaint of PWE. The major symptoms of interictal and postoperative depression in epilepsy are, respectively, dysthymic or dysphoric features and anhedonia, i.e., loss of desire to do things that used to bring satisfaction [START_REF] Koch-Stoecker | Treatment of postsurgical psychiatric complications[END_REF].

Interestingly, duration of epilepsy, location of epileptogenic zone and type of epileptic seizures do not appear to be risk factors of depression [START_REF] Babu | Co-morbidities in people living with epilepsy: Hospital based case-control study from a resource-poor setting[END_REF][START_REF] Rayner | Differential contributions of objective memory and mood to subjective memory complaints in refractory focal epilepsy[END_REF], but the prevalence of depressive symptoms is greater in patients with recurrent epilepsy than in those with controlled epilepsy [START_REF] Bazil | Comprehensive Care of the Epilepsy Patient-Control, Comorbidity, and Cost[END_REF].

The relation between epilepsy and psychiatric disorders is not a unidirectional causality in which psychiatric disorders would be reduced to psychosocial consequences of epilepsy [START_REF] Hingray | Comorbidités psychiatriques et épilepsie[END_REF].

The incidence of psychiatric disorders was examined 3 years before and 3 years after a diagnosis of epilepsy in 3 773 PWE and compared with 14 025 matched controls [START_REF] Hesdorffer | Epilepsy, suicidality, and psychiatric disorders: A bidirectional association[END_REF]. Controls were matched by year of birth, gender, general practice, and years of medical records before the diagnosis of a disease. Data recorded in UK between 1996 and 2005 were extracted from a medical database including several million people. The results indicated an increased incidence rate for depression in PWE even 3 years before diagnosis. Another study demonstrated that PWE have a 43% higher risk of developing depression than control subjects without epilepsy [START_REF] Fuller-Thomson | The association between depression and epilepsy in a nationally representative sample[END_REF]. Moreover, people with mood and anxiety disorders have up to sevenfold higher risk of developing epilepsy [START_REF] Josephson | Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis[END_REF][START_REF] Forsgren | An incident case-referent study of epileptic seizures in adults[END_REF][START_REF] Hesdorffer | Major depression is a risk factor for seizures in older adults[END_REF][START_REF] Hesdorffer | Depression and suicide attempt as risk factors for incident unprovoked seizures[END_REF][START_REF] Adelow | Hospitalization for psychiatric disorders before and after onset of unprovoked seizures/epilepsy[END_REF]. Thus, depressive patients have higher risks of developing epilepsy and depression can be a premorbid phase of epilepsy. These data underline a bidirectional relationship between epilepsy and mood disorders. The high prevalence rates of psychiatric disorders in PWE is explained by some authors by common mechanisms for psychiatric disorders and epilepsy [START_REF] Ribot | Neurobiologic properties of mood disorders may have an impact on epilepsy: Should this motivate neurologists to screen for this psychiatric comorbidity in these patients?[END_REF]. Moreover, treating depression often improves seizure control and therefore reduces the frequency of seizures [START_REF] Josephson | Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis[END_REF].

The existence of a psychiatric disorder associated with epilepsy also increases the risk of epilepsy becoming refractory to AED, thus increasing the likelihood that surgical treatment will be undertaken [START_REF] De Araújo Filho | Major depressive disorder as a predictor of a worse seizure outcome one year after surgery in patients with temporal lobe epilepsy and mesial temporal sclerosis[END_REF][START_REF] Hitiris | Predictors of pharmacoresistant epilepsy[END_REF]. Importantly, some AEDs known to induce depression should be avoided for PWE with depressive symptoms, particularly phenobarbital, vigabatrin, tiagabine and topiramate. It is particularly necessary to take in consideration the rapidity of the titration rate of topiramate since a rapid titration can increase the risk to develop depression, especially in PWE with a psychiatric history [START_REF] Mula | The role of titration schedule of topiramate for the development of depression in patients with epilepsy[END_REF]. To note, leviteracetam should also be avoided in a context of other psychiatric comorbidities such as psychosis, anxiety and behavioral disorders [START_REF] Hingray | Traitements des troubles psychiatriques dans les épilepsies[END_REF].

Lamotrigine should be favored in depressive patients [START_REF] Visseaux | ffets psychotropes des antiépileptiques : Risques et bénéfices[END_REF][START_REF] Mula | Epilepsy and mood disorders[END_REF].

Only recent studies have started to investigate the neurobiology of depression in epilepsy. While studies in depressed patients without epilepsy have shown a decrease in the volume of their bilateral hippocampi [START_REF] Sheline | Untreated Depression and Hippocampal Volume Loss[END_REF], a modification of cortical thickness and a reduction of neuronal cell density in the frontal lobe [START_REF] Cotter | Reduced Neuronal Size and Glial Cell Density in Area 9 of the Dorsolateral Prefrontal Cortex in Subjects with Major Depressive Disorder[END_REF][START_REF] Cotter | Glial cell abnormalities in major psychiatric disorders: the evidence and implications[END_REF], similar cerebral changes have recently been shown in PWE [START_REF] Stretton | Temporal lobe epilepsy and affective disorders: the role of the subgenual anterior cingulate cortex[END_REF][START_REF] Pope | Frontal lobe dysfunction as a predictor of depression and anxiety following temporal lobe epilepsy surgery[END_REF]. These results suggest common neurobiological changes in depression and in PWE and depression.

Altogether, these findings point to a bidirectional relation between epilepsy and depression.

Epilepsy and cognition

Cognitive disorders affect up to 70% of adult PWE as early as epilepsy onset and even before the start of antiepileptic treatment, and they have been shown to significantly impact QoL [START_REF] Engel | A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force on Classification and Terminology[END_REF][START_REF] Taylor | Predictors of health-related quality of life and costs in adults with epilepsy: A systematic review: Quality of Life and Costs in Epilepsy[END_REF][START_REF] Witt | Should cognition be screened in new-onset epilepsies? A study in 247 untreated patients[END_REF]. Cognitive disorders may increase as the disease progresses, and they constitute a major burden in work, social and family settings in addition to that caused by seizures. Various factors influence cognition, depending on the clinical and demographic characteristics of the patient: characteristics related to epilepsy (epilepsy syndrome, age at onset, duration of progression, seizures/interictal activities), quality of sleep, brain development in children and 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][START_REF] Elger | Chronic epilepsy and cognition[END_REF].

The expression and characteristics of cognitive impairments are also largely driven by the epileptogenic zone location and its repercussion on the whole neural network [START_REF] Samson | Épilepsie : place du bilan neuropsychologique[END_REF]. Partial epilepsies are a good example of the relationship between the epileptogenic zone location and the pattern of cognitive impairments. For example, the most common cognitive disorders observed in temporal lobe epilepsy (TLE) affects episodic memory and language, which is consistent with the important role of the temporal lobe in these two functions [START_REF] Witt | Cognition in the early stages of adult epilepsy[END_REF][START_REF] Lomlomdjian | The right hemisphere's contribution to discourse processing: A study in temporal lobe epilepsy[END_REF]. Thus, the frequency of objective memory disorders ranges from 70 to 99% in patients with drug-resistant epilepsy, with verbal impairments being more frequent than non-verbal ones [START_REF] Helmstaedter | Cognitive Outcomes in Patients with Chronic Temporal Lobe Epilepsy[END_REF][START_REF] Helmstaedter | Cognitive outcomes of different surgical approaches in temporal lobe epilepsy[END_REF][START_REF] Ravat | Surgical outcomes with non-invasive presurgical evaluation in MRI determined bilateral mesial temporal sclerosis: A retrospective cohort study[END_REF]. Objective language deficits are also frequent, affecting 17% to 33% of TLE patients, with a higher prevalence in patients with left TLE [START_REF] Bartha-Doering | The interictal language profile in adult epilepsy[END_REF]. In these patients, language disorders are characterized by difficulties in naming, comprehension, spontaneous speech and/or verbal fluency [START_REF] Bartha-Doering | The interictal language profile in adult epilepsy[END_REF].

Another example is the frequent impairment of executive functioning in frontal lobe epilepsy, which is in line with the role of frontal lobes in this cognitive function [START_REF] Patrikelis | Neurocognitive and behavioral functioning in frontal lobe epilepsy: A review[END_REF][START_REF] Benge | The Neuropsychology of Frontal Lobe Epilepsy: A Selective Review of 5 Years of Progress[END_REF]. Executive functioning includes shifting, mental inhibition, attention, verbal fluency, verbal abstraction, planning process and deduction.

The prevalence of cognitive disorders in PWE appears important and covers a wide range of cognitive domains. These disorders can be present from the beginning of the disease and should therefore be explored as early as possible even if no subjective complaints are found, especially because these patients tend to underestimate their cognitive difficulties [START_REF] Witt | Should cognition be screened in new-onset epilepsies? A study in 247 untreated patients[END_REF].

Neuropsychological assessment is therefore essential in the management of all PWE [START_REF] Brissart | Les troubles cognitifs des patients épileptiques[END_REF]. For this reason, a first neuropsychological assessment is recommended to provide a reference point for long-term follow-up of PWE and to track the changes in the cognitive status as the disease progresses. However, few studies in epilepsy have considered the involvement of mood disturbance on cognition. Taking psychiatric comorbidities into consideration could moderate the results of the studies mentioned above.

Epilepsy, cognitive impairment and depression: an interdependent relation?

Clinical facts

It is important to stress that depression is associated with cognitive impairment [START_REF] Snyder | Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review[END_REF][START_REF] Lee | A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder[END_REF].

Impairments in attention (sustained attention) and executive functioning (reasoning and working memory) are often reported in depressed patients even if the mood improves [START_REF] Douglas | Longitudinal Assessment of Neuropsychological Function in Major Depression[END_REF][START_REF] Rock | Cognitive impairment in depression: a systematic review and meta-analysis[END_REF].

Attention and executive function disorders seem to be a common feature in both current and remitted depressed patients [START_REF] Bora | Cognitive impairment in euthymic major depressive disorder: a meta-analysis[END_REF][START_REF] Bhalla | Persistence of Neuropsychologic Deficits in the Remitted State of Late-Life Depression[END_REF][START_REF] Hasselbalch | Cognitive impairment in the remitted state of unipolar depressive disorder: A systematic review[END_REF].

It would be logical then to expect that depression impacts cognitive outcomes in PWE too.

However, symptoms of depression and cognitive impairment are often studied separately in epilepsy and few studies have focused on the relation between depression and neuropsychological status in PWE. We conducted a review of these studies on PUBMED using the following search terms "Epilepsy" AND "Cognition", "Neuropsychology", "Neuropsychological", "Neurocognitive disorder", "Cognitive impairment", "Cognitive disorder" AND "Mood", "Depression", "Depressive disorder", "Depressed", "Psychiatry", "Psychiatric" AND "Adult". The search yielded 712 hits (appendix 1). All 712 abstracts were examined and articles were included in the review if they met the following criteria: (i) adult population, (ii) quantitative depression and neuropsychological assessment (only objective cognitive disorders), (iii) analyses of the impact of depression on cognitive scores, (iv) PWE and no other neurological disease, and (v) at least 20 patients included in the study. Search parameters' details and exclusion criteria are provided in supplementary data. Only 20 studies matched all these inclusion criteria, investigating both depression and neuropsychological status in PWE (only idiopathic/genetic and generalized epilepsy, excluding epileptic encephalopathy) (Table 1 &2). A narrative approach to synthesize the data was used. To note, 14 out of the 20 selected studies were published over the past 10 years, highlighting the recent interest in this matter.

Overall, the articles included 1968 PWE, 64% of whom have TLE. Two different designs could be distinguished: comparing patients according to the lateralization of their epilepsy (left TLE, LTLE, 53% or right TLE, RTLE, 47%), and/or comparing them according to the presence (35%) or absence of depression (65%). Seventeen of the 20 studies demonstrated an interaction between cognition and depression [START_REF] Pope | Frontal lobe dysfunction as a predictor of depression and anxiety following temporal lobe epilepsy surgery[END_REF][START_REF] Paradiso | Impact of depressed mood on neuropsychological status in temporal lobe epilepsy[END_REF][START_REF] Rösche | Memory deficits and depression in patients with chronic epilepsy[END_REF][START_REF] Galioto | Depressive Symptoms Contribute to Executive Deficits in Temporal Lobe Epilepsy[END_REF][START_REF] Hermann | Mood state in unilateral temporal lobe epilepsy[END_REF][START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization[END_REF][START_REF] Busch | Pre-Surgical Mood Predicts Memory Decline after Anterior Temporal Lobe Resection for Epilepsy[END_REF][START_REF] Dulay | Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy[END_REF][START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF][START_REF] Rayner | Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights[END_REF][START_REF] Tedrus | Major depressive episode, cognition, and epilepsy[END_REF][START_REF] Dulay | Memory, Emotional and Vocational Impairments before and after Anterior Temporal Lobectomy for Complex Partial Seizures[END_REF][START_REF] Liik | Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression[END_REF][START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF][START_REF] Rayner | Mechanisms of memory impairment in epilepsy depend on age at disease onset[END_REF][START_REF] Vaccaro | Neuropsychological profile of mild temporal lobe epilepsy[END_REF], and three failed to show a causal link [START_REF] Tracy | Are Depression and Cognitive Performance Related in Temporal Lobe Epilepsy?[END_REF][START_REF] Demin | Are mental distress and cognitive impairment related in temporal lobe epilepsy?[END_REF][START_REF] Shehata | Cognitive function, mood, behavioral aspects, and personality traits of adult males with idiopathic epilepsy[END_REF].

[Table 1 &2] Memory (verbal and non-verbal) and executive functions are the most common cognitive domains impaired by depression in epilepsy (Table 3). Depressed PWE have lower scores in immediate recall in verbal [START_REF] Rösche | Memory deficits and depression in patients with chronic epilepsy[END_REF][START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization[END_REF][START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF][START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF] and non-verbal memory [START_REF] Paradiso | Impact of depressed mood on neuropsychological status in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization[END_REF][START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF], and in delayed recall of verbal [START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF][START_REF] Busch | Pre-Surgical Mood Predicts Memory Decline after Anterior Temporal Lobe Resection for Epilepsy[END_REF][START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF][START_REF] Dulay | Memory, Emotional and Vocational Impairments before and after Anterior Temporal Lobectomy for Complex Partial Seizures[END_REF][START_REF] Liik | Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression[END_REF][START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF][START_REF] Vaccaro | Neuropsychological profile of mild temporal lobe epilepsy[END_REF] and non-verbal memory [START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF][START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF]. Depressed PWE seems to have more difficulties at encoding and storing verbal and non-verbal information than PWE without depression. In autobiographical memory, depressed PWE have poorer semantic memory and poorer recollection of episodic autobiographic memories than PWE without depression [START_REF] Rayner | Mechanisms of memory impairment in epilepsy depend on age at disease onset[END_REF]. These results can be related to neurobiological studies showing a reduction of hippocampal volume in depressed patients [START_REF] Baxendale | Epilepsy & depression: The effects of comorbidity on hippocampal volume-A pilot study[END_REF]. Concerning executive functioning, depressed PWE have lower scores in mental flexibility [START_REF] Paradiso | Impact of depressed mood on neuropsychological status in temporal lobe epilepsy[END_REF][START_REF] Dulay | Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy[END_REF][START_REF] Liik | Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression[END_REF], in verbal [START_REF] Paradiso | Impact of depressed mood on neuropsychological status in temporal lobe epilepsy[END_REF][START_REF] Galioto | Depressive Symptoms Contribute to Executive Deficits in Temporal Lobe Epilepsy[END_REF][START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF][START_REF] Tedrus | Major depressive episode, cognition, and epilepsy[END_REF][START_REF] Liik | Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression[END_REF] and design fluency [START_REF] Galioto | Depressive Symptoms Contribute to Executive Deficits in Temporal Lobe Epilepsy[END_REF], and present more perseverative response in a deduction task [START_REF] Pope | Frontal lobe dysfunction as a predictor of depression and anxiety following temporal lobe epilepsy surgery[END_REF][START_REF] Hermann | Mood state in unilateral temporal lobe epilepsy[END_REF] than PWE without depression. While disorders in executive functioning and memory are reported both in depressed patients without epilepsy and in depressed PWE, deficits in TLE may be distinct from those found in patients with idiopathic depression. Notably, while depression in patients with TLE has a significant effect on verbal fluency and on speed reading, motor speed and design fluency are more frequently affected in depressed patients without epilepsy [START_REF] Galioto | Depressive Symptoms Contribute to Executive Deficits in Temporal Lobe Epilepsy[END_REF].

[ Table 3] When it comes to the clinical characteristics of PWE, the laterality of the seizure onset zone needs to be considered. In TLE patients, the impact of laterality of the seizure onset zone has often been studied (LTLE vs. RTLE). Depressed LTLE patients have been shown to be more impaired in episodic verbal memory than depressed RTLE patients, both on learning and delayed recall [START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF][START_REF] Helmstaedter | Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization[END_REF][START_REF] Busch | Pre-Surgical Mood Predicts Memory Decline after Anterior Temporal Lobe Resection for Epilepsy[END_REF]. Some authors have also demonstrated that depressive symptoms are more important if memory impairment is severe in LTLE patients [START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF]. A similar effect of laterality of the seizure onset zone has also been demonstrated on executive functions.

Depressed LTLE patients are more impaired in deduction making and show more perseverative responses than depressed RTLE patients [START_REF] Hermann | Mood state in unilateral temporal lobe epilepsy[END_REF]. This effect of laterality was not showed in two others studies [START_REF] Tracy | Are Depression and Cognitive Performance Related in Temporal Lobe Epilepsy?[END_REF][START_REF] Demin | Are mental distress and cognitive impairment related in temporal lobe epilepsy?[END_REF]. From these findings, it seems that depression has a higher influence on cognitive scores in LTLE than in RTLE. An effect of laterality has also been found at the neurobiological level. Notably, PWE are more likely to develop postoperative depression when they have a reduced preoperative contralateral hippocampal volume [START_REF] Wrench | Hippocampal volume and depression: insights from epilepsy surgery[END_REF]. Altogether, these results indicate a laterality effect of epilepsy, even though evidence remains sparse.

The type of epilepsy is relevant to consider but has not been widely studied. One study reported correlation between Beck Depression Inventory (BDI) score and cognitive scores in partial and generalized epilepsy [START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF]. The authors considered different variables to explain this decrease in cognitive performance, such as the number of AED, school duration, etc. Only cognitive scores that are exclusively correlated with depression score will be mentioned here. In the partial epilepsy group (the exact type of epilepsy is not provided by the authors), correlations were found between depression score and cognitive performances on verbal memory delayed recall and motor speed. In the generalized epilepsy group, only one correlation was found, linking the depression score with the patient's score on verbal fluency (executive function). In details we can notice that encoding and storage in episodic verbal and nonverbal memory seems to be more impaired in depressed generalized epilepsy than in depressed partial epilepsy [START_REF] Liik | Cognitive profile and depressive symptoms in patients with epilepsy[END_REF]. Thus, cognitive functions are not influenced in the same way in patients with partial or generalized epilepsy but evidence is still lacking and more studies will be necessary to better understand the relationship between depression and the type of epilepsy.

Only one study aimed to compare the influence of depression on drug-responsive and drugresistant PWE [START_REF] Tang | Neurocognitive and psychological profiles of adult patients with epilepsy in Hong Kong[END_REF]. The same impact of depression on cognitive scores was found in the 2 groups on both verbal and nonverbal memory (immediate and delayed recall). However, these results cannot be generalized, especially as patient groups were of small and inequal size, with only 7 depressed patients in the drug-responsive group (7% of the total sample) and 25 depressed patients in the drug-resistant group (30% of the total sample).

When considering impact of surgery, it is important to point that the relation between depression and neuropsychological status has been reported postoperatively but rarely preoperatively. Mood disturbance before surgery in patients with frontal lobe epilepsy could be a risk factor for the emergence of impairment in mental flexibility after surgery [START_REF] Dulay | Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy[END_REF]. In TLE patients, the number of preoperative perseverative responses in a deduction test predicts postoperative BDI's scores [START_REF] Pope | Frontal lobe dysfunction as a predictor of depression and anxiety following temporal lobe epilepsy surgery[END_REF]. Elevated pre-surgical depressive scores is also a risk factor for postsurgical verbal memory decline in LTLE patients [START_REF] Busch | Pre-Surgical Mood Predicts Memory Decline after Anterior Temporal Lobe Resection for Epilepsy[END_REF]. These results are not explained by seizure outcome (there is depression even if the patients are seizure-free after surgery) and are unexpected since patients with seizure onset zone on the right hemisphere are more prone to suffer postoperatively from depression [START_REF] Bonelli | Preoperative amygdala fMRI in temporal lobe epilepsy: Imaging Amygdala Function in TLE[END_REF][START_REF] Quigg | Depression in Intractable Partial Epilepsy Varies by Laterality of Focus and Surgery[END_REF].

Neurobiological correlates

When investigating the specificity of depression's impact on cognitive performance in PWE, we found that different factors may be involved in both behavioural and neurobiological aspects. Depression can be due to a pathological imbalance between two brain networks: the autobiographic memory network (AMN) and the cognitive control network (CCN). On the neuroanatomical level, AMN includes orbitomedial prefrontal cortex (PFC), dorsomedial PFC/rostral anterior cingulate cortex (ACC), hippocampus, posterior cingulate and retrosplenial cortex, precuneus, ventral PFC, anterior temporal cortex, temporoparietal junction, as well as cerebellar and parietal regions important for mental imagery. CCN includes dorsolateral PFC and dorsal ACC, as well as regions in the medial temporal lobe and intraparietal sulci. The AMN is activated when performing social cognition tasks, or autobiographical memory and self-related processes, while the CCN is activated during executive functioning, working memory and attentional tasks. In depression, the balance between the 2 networks is impaired: the AMN is not enough inhibited to engage the CCN. In depressed PWE, the AMN is hyperactivated while the CCN is hypo-activated as in depressed patients without epilepsy.

Dysfunctions of cognitive networks (including the AMN and CCN) are more important in depressed epileptic patients than in depressed non-epileptic patients (see [START_REF] Rayner | Cognition-related brain networks underpin the symptoms of unipolar depression: Evidence from a systematic review[END_REF][START_REF] Rayner | The Contribution of Cognitive Networks to Depression in Epilepsy[END_REF] for a complete description). Rayner et al. suggest two phenotypes of depression according to the symptoms presented by patients, cognitive scores and changes in the activation of brain networks specific to depression [START_REF] Rayner | Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights[END_REF]. The two subtypes of depression are: (1) "Cognitive Depression" which is characterised by cognitive depressive symptoms (suicidal thoughts), lower scores in memory (verbal, non-verbal and autobiographical) and a higher rate of dysphoria; and (2) "Somatic Depression" which is characterised by vegetative features (sleep disturbance, appetite change) and a higher rate of anhedonia [START_REF] Rayner | Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights[END_REF]. Cognitive Depression seems to be more frequent in PWE, representing 71% of depressed patients in this study, and highlighting the relation between cognition, depression and epilepsy. The study also demonstrated the impact of depressive symptoms in PWE, and suggest that depression and neuropsychological status should be considered interdependently in PWE.

Limitations

The main limitation of this review is the small number of studies, the small sample sizes and the different methods used in the included studies. Further investigations are required to confirm the impact of depression on cognitive functions in PWE.

Depression was evaluated with the BDI scale in 14 out of 20 studies. Validity of this scale has been reported in PWE [START_REF] Jones | Screening for Major Depression in Epilepsy with Common Self-report Depression Inventories[END_REF][START_REF] Gill | Depression screening tools in persons with epilepsy: A systematic review of validated tools[END_REF], but, there are several forms (brief or full scale) with different norms. For other tools used in the selected studies (MMPI, CES-D and HAM-D), same biases are observed with the use of one tool but different cut-offs according to the chosen normative data.

The reported prevalence of depression ranged from 7% to 42% when considering all types of epilepsy (Table 2) and from 23 to 57% in TLE patients only (Table 1). This considerable variability could be due to the timing of the mood assessment. According to studies, depression and cognition were either assessed during the week of hospitalisation with continuous electroencephalogram monitoring [START_REF] Hermann | Mood state in unilateral temporal lobe epilepsy[END_REF], during intensive therapeutic drug monitoring while changing antiepileptic medication [START_REF] Rösche | Memory deficits and depression in patients with chronic epilepsy[END_REF], or while conducting in-patient characterisation of partial seizures in hospital [START_REF] Rayner | Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights[END_REF].

Another limitation is that the studies focused more on the incidence of major depressive disorders than mild to moderate depressive disorders in epilepsy, suggesting that the actual incidence of depression on cognition may be underreported.

Finally, cognitive outcomes should be interpreted with caution as the tests used vary widely from one study to another. Moreover, some studies only considered a single cognitive domain or used cognitive screening, which cannot be considered as a complete neuropsychological assessment.

Perspectives

According to the results reviewed here, a correlation seems to exist between objective cognitive impairments and depression in PWE with cognitive complaints [START_REF] Dulay | Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy[END_REF][START_REF] Feldman | Evaluating subjective cognitive impairment in the adult epilepsy clinic: Effects of depression, number of antiepileptic medications, and seizure frequency[END_REF]. Mood disturbance explains the variance from 17% to 58% in subjective memory complaints [START_REF] Hall | Memory complaints in epilepsy: An accurate reflection of memory impairment or an indicator of poor adjustment? A Review of the literature[END_REF] and depression is the main predictive factor of QoL [START_REF] Boylan | Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy[END_REF]. Patients should thus be carefully questioned at least by the neurologist about their daily life so as not to miss this point in addition to being monitored for depression. A screening tool -the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) -has recently emerged [START_REF] Barkate | One step closer to a global tool for rapid screening of major depression in epilepsy: Validation of the French NDDI-E[END_REF]. This tool is recommended by the ILAE for the management of depressive disorders in PWE. It is quick and easy to be administered and allows patients to express their thymic difficulties. Neuropsychologists should also systematically assess mood disorders of patients, especially if access to a psychiatrist is not available on site.

Patients with epilepsy and symptoms of mood disturbance should be referred to a psychiatrist as promptly as possible since an appropriate care of depression could help protect them against cognitive decline. This thymic evaluation is crucial because it can also influence AED's choice.

In the context of surgery, it seems even more important that patients who suffer from depression before surgery benefit of an adapted treatment and a psychiatric follow-up in relation to the higher risk of cognitive decline, and the lower efficacy of surgical treatment in the 3 months following surgery associated with depression [START_REF] Kanner | A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy[END_REF].

Prospective studies are required to know the best time to evaluate and treat mood disorders and avoid a negative impact of depression on cognition. This implies a longitudinal follow-up of cognition and depression, starting at the beginning of the epilepsy. Such studies could also provide us with a better understanding of the impact of depression on objective cognitive performance in epilepsy, given that the number of studies on this subject remains low. In addition, it will be necessary to assess the full range of cognitive domains, including attention, executive functions and language, which are surprisingly under-represented in the studies included in this review. At the neuroanatomical level, depression leads to a pathological disruption of cognitive brain networks, including the amygdala and hippocampi. Epilepsy seems to increase this disruption in some but not all patients, probably because of seizure activity. More studies are needed to understand this link with medical imaging associated to behavioural and cognitive assessment in PWE. At the neurobiological level, the relationship between epilepsy and depression could rely on the hypothalamic-pituitary-adrenal (HPA) axis, which is well known to be affected in depressed patients without epilepsy [START_REF] Salvat-Pujol | Hypothalamic-pituitary-adrenal axis activity and cognition in major depression: The role of remission status[END_REF]. This axis seems to modulate some cognitive functions like processing speed, non-verbal memory and executive functioning in patients without epilepsy and will have to be considered in future studies with PWE [START_REF] Salvat-Pujol | Hypothalamic-pituitary-adrenal axis activity and cognition in major depression: The role of remission status[END_REF].

Altogether, there seems to be a link between depression, epilepsy and cognition, which is necessary to assess at all levels (neurobiological, neuroanatomical and behavioural) as it may potentially lead to other treatments of depression specific to epilepsy.

Conclusion

To date, only a few studies have attempted to differentiate the specific impact of depression on cognition in epilepsy, and their results appear to be heterogeneous and difficult to generalize.

However, this review highlighted a variable impact of depression on cognition in PWE, according to the laterality of the seizure onset zone (depression has more impact in LTLE than in RTLE), the type of epilepsy (depression has a different impact in partial and generalized epilepsy) and the surgical context (preoperative depression can be a risk factor to postoperative verbal memory decline in LTLE). Due to this relation between depression and cognition in PWE, it is essential to evaluate and treat depression, and to inform patients about this interaction. Depression in epilepsy has important specificities that caregivers should be aware of.

Conflicts of interest:

HB: none NF: NF has received personal fees from UCB Pharma.

CK: none MB: none

Table 1 -Studies exploring the link between cognition, depression and epilepsy in TLE

 1 TLE=temporal lobe epilepsy; LTLE=left temporal lobe epilepsy; RTLE=right temporal lobe epilepsy; ATL=anterior temporal lobectomy.

	Authors	Year	Type of epilepsy	Number of depressed patients	Cognitive assessment	Mood assessment	Results
	Hermann et al.	1991	LTLE (N=26)		N=9 in LTLE (35%)	IQ: WAIS-R	CES-D (no cut-off)	LTLE produced more perseverative responses, with
			RTLE (N=38)		N=14 in RTLE (37%)	Executive function: WCST	BDI (cut-off >10)	increased self-report of depressive symptoms (correlation with CES-D r = 0.67; correlation with BDI r = 0.60).
	Paradiso et al.	2001	TLE candidates for ATL		IQ: WAIS-R	BDI (no cut-off)	Depressed patients had significantly poorer performance
			TLE-Depressed = 15 LTLE / 9 RTLE TLE-Non-depressed = 32 LTLE / 14 RTLE	N=24 depressed (34%) N=46 not depressed	Memory: WMS + WWR Executive function: TMT-B + WCST + COWA	MMPI	in IQ (p<0.006), language (p<0.006), non-verbal memory (immediate recall (p<0.001)), and executive function (COWA (p<0.05) and TMT-B (p<0.03)).
						Language: WRAT-R reading + MAE
						visual naming
						Visuospatial abilities: JLO + WFR
						Psychomotor / attention: TMT-A
	Dulay et al.	2004	Medically	intractable		Memory: WMS-III (subtests involved	MMPI (cut-off T>65)	Impact of depression in all memory tests except in
			epileptic seizures		in auditory immediate and delayed		recognition for LTLE (correlation between -0.34 and -
			LTLE = 46		N=23 in LTLE (50%)	index)		0.57).
			RTLE = 38		N=18 in RTLE (47%)	Working memory: Block design + Digit span (WAIS-R) Executive function: Similarities		Higher self-report levels of depression were associated with poorer performance on memory tasks. No impact of depression in RTLE.
						(WAIS-R)
						Language: Boston naming test
						Operating: Arithmetic (WAIS-R)
						Motor speed: Digit symbol (WAIS-R)
	Helmstaedter et	2004	Surgical patient		Memory: VLMT + DCS-R	BDI (cut-off >12)	Only correlation between mood and cognitive scores in
	al.		RTLE-mesial = 37	N=64 (42%)			LTLE-lateral group.
			RTLE-lateral = 31				Verbal learning (r = -0.41, p<0.01)
			LTLE-mesial=42				Verbal recognition (r = -0.34, p<0.05)
			LTLE-lateral=42				Figural learning (r = -0.45, p<0.01)
	Dulay et al.	2006	Patients who underwent	31 patients never had	IQ: WAIS-III	BDI (cut-off > 12)	Left ATL patients with emotional disturbance have lower
			ATL Right ATL (N=51) Left ATL (N=39)	depression 59 patients had at least one period of depression	Verbal memory: VSRT Nonverbal memory: NVRST	MMPI (T score >70)	scores on delayed recall in verbal memory than all other groups (no p available).
					(66%)
	Tracy et al.	2007	LTLE (N=33)		N=16 in LTLE (48%)	IQ: WAIS-R	BDI (cut-off 10)	No impact of depression on cognitive performance
			RTLE (N=26)		N=6 in RTLE (23%)	Memory: WMS-II + CVLT + Benton
						facial recognition
						Executive function: COWA + semantic
						fluency
						Language: Boston naming test +
						BDAE

Epilepsy:

Table 2 -Studies exploring the link between cognition, depression and epilepsy in PWE (excluding TLE)

 2 Patients with cognitive depression have more deficits in memory than patients with somatic depression and are more likely to have semantic autobiographic, episodic autobiographic memory deficits, as well as deficits in immediate and delayed verbal and non-verbal recall.Poor semantic memory in late-onset epilepsy is associated with higher depression scores on the NDDI-E (p=0.007). Poor recollection of episodic autobiographic memories in the late-onset group is also associated with higher NDDI-E scores (p=0.003).

	Authors	Year	Epilepsy type	Depressed patients	Cognitive assessment	Mood assessment	Results
	Liik et al.	2009	Partial epilepsy (n=35,	BDI<11 (n=32)	Verbal memory: BSRT	BDI (cut-off 11)		Patients with higher scores on the BDI have lower scores
			included 10 TLE) Generalized (n=27)	epilepsy	BDI>11 (n=24, 39%)	Nonverbal memory: 10/36 Executive function: TMT + Word list generation + Verbal fluency test				in the SDMT (p<0.05), the Word List Generation (p<0.05), TMT (p<0.05), and the delayed recall of the BSRT (p<0.05).
							Speed accuracy: SDMT
	Shehata et al.	2009	Idiopathic epilepsy (n=71)	Information	not	Stanford-Binet test (fourth edition):	BDI (no cut-off)		No correlation was found between depression and
			Healthy controls (n=58)	mentioned		Vocabulary + Comprehension +				cognitive scores.
							Absurdities
							+ Verbal Relations + Memory for
							Objects +
							Bead Memory + Memory for Digits
							(Forward
							and Backward) + Memory for
							Sentences
	Rösche et al.	2012	Partial and generalized	Without	depression	Memory: Memo-test + Benton test	SDS	(<50	no	Patients with moderate to severe depression's scores have
			epilepsy (all types)	(N=56)			depression;	50-59	lower performance in immediate recall in verbal memory
					Minor depression (N=47,		minor depression; >60	than patients without depression's scores and patients with
					34%)			moderate to major	minor depression's scores (p=0.038).
					Moderate to severe		depression)
					depression (N=36, 26%)
	Dulay et al.	2013	Frontal lobe epilepsy	Non-depressed patients =	Executive function: TMT-B + WCST +	BDI-II (>13)		The depression score before surgery predicts the TMT-B
			surgery		48		letter fluency				score after surgery with only influence of presurgical
					Depressed patients = 16					depression status (p<0.05).
					(25%)
	Liik et al.	2013	Focal epilepsy (N=36)	Focal epilepsy = 10	Memory: BSRT + 10/36	BDI (cut-off 12)		No significant difference between groups in BDI scores.
			Generalized (N=26) Controls (N=53)	epilepsy	(28%) Generalized epilepsy = 11 (42%)	Attention: SDMT Executive function: verbal fluency + TMT				Correlation between BDI score and motor speed in focal epilepsy (r=-0.57, p<0.05) and GE (r=-0.55, p<0.05); nonverbal memory (delayed recall) in FE (r=-0.57, p<0.05) and GE (r=-0.59, p<0.05).
											Correlation between BDI score and encoding and storage
											in verbal memory in GE (p<0.05).
											No impact of depression in control group.
	Tang et al.	2013	Drug-responsive (n=102,	Drug-responsive = 7	IQ: WAIS-III	BDI-II (cut-off > 13)	Scores of BDI-II had significant correlations with most
			including 59 generalized onset epilepsy, 43 partial onset epilepsy and 28	(7%)		Verbal memory: CAVLT Nonverbal memory: ROCF				cognitive scores. A strong relation was found between BDI scores and immediate and delayed memory recall (rs between -.188 and-.300, p=0.05).
			TLE)				Language: Boston naming test				No group difference when analyzing the impact of mood
			Drug-resistant including 55 generalized (n=84, onset epilepsy and 39 onset epilepsy, 29 partial	Drug-resistant = 25 (30%)	digit span + Chinese Stroop test Executive function: category fluency + Visuospatial function: HVOT				on cognitive scores.
			TLE)

Epilepsy: LTLE=left temporal lobe epilepsy; RTLE=right temporal lobe epilepsy; TLE=temporal lobe epilepsy. Neuropsychological tests: AMI= autobiographical memory interview; BCB=brief cognitive battery; BSRT=Buschke selective reminding test; CAVLT=chinese auditory verbal learning test; HVOT= Hooper visual organization test; IQ=intellectual quotient; ROCF=Rey osterrieth complex figure; SDMT=symbol digit modalities test; TMT=trail-making test; WAIS=Wechsler adult intelligence scale; WCST=Wisconsin card sorting test; WMS=Wechsler memory scale. Depression assessment: BDI=Beck depression inventory; NDDI-E=N=neurological disorders depression inventory for epilepsy; SCID=depression structured clinical interview for DSM-IV A=axis I disorders, clinician version; SDS= self-rating depression scale. 1

Table 3 -Summary of the impact of depression on cognitive performance in PWE across studies mentioned in Tables 1 & 2

 3

	Authors	Epilepsy	Intellectual quotient	Memory	Executive function	Attention	Language	Psychomotor speed
	Hermann et al. (1991)	TLE
					(only in
					LTLE)
	Paradiso et al. (2001)	TLE
				(only non-
				verbal)
	Helmstaedter et al.	TLE
	(2004)			(only in
				LTLE-
				lateral)
	Dulay et al. (2004)	TLE
				(only in
				LTLE)
	Dulay et al. (2006)	TLE
				(only in left
				ATL)
	Tracy et al. (2007)	TLE
	Busch et al. (2011)	TLE
				(only in
				LTLE)
	Galioto et al. (2017)	TLE
	Demin et al. (2018)	TLE
	Vaccaro et al. (2018)	TLE
	Pope et al. (2019)	TLE
	Liik et al. (2009)	PE/GE
	Shehata et al. (2009)	IE
	Rösche et al. (2012)	PWE
				(only verbal,
				in PWE-
				MSD)
	Liik et al. (2013)	PE/GE
					(only in GE)
	Dulay et al. (2013)	FLE
	Tang et al. (2013)	PWE
	Rayner et al. (2016) 64	PWE
	Rayner et al. (2016) 69	PWE
	Tedrus et al. (2016)	PWE

FLE=frontal lobe epilepsy; GE=generalized epilepsy; IE=idiopathic epilepsy; LTLE-lateral=left temporal lobe epilepsy with left lateral epileptic foci; PE=partial epilepsy; PWE=patient with epilepsy; PWE-MSD=patient with epilepsy and moderate to severe depression; no impact of depression on cognition;

negative impact of depression on cognition.