Dr Luc Valton
email: valton.l@chu-toulouse.fr

M Benaiteau

M Denuelle

F Rulquin

C Hachon Lecamus

C Hein

A Viguier

J Curot

Etiological assessment of Status Epilepticus

Keywords: Apparent diffusion coefficient AED: Antiepileptic drug Convulsive status epilepticus CSF: Cerebrospinal fluid CSWS: Continuous spike and wave during sleep CT: Computerized tomography Febrile infection epilepsy-related syndrome FLAIR: Fluid-attenuated inversion recovery GPD: Generalized periodic discharges HIV: Human immunodeficiency virus ICU: Intensive care unit LED: Lateralized epileptiform discharges LFT: Liver function tests MRI: Magnetic resonance imaging NCSE: Non-convulsive status epilepticus Periodic lateralized epileptiform discharges PRES: Posterior reversible encephalopathy syndrome Reversible cerebral vasoconstriction syndrome REM sleep: Rapid eye movement sleep RSE: Refractory status epilepticus seizure, NORSE (New onset refractory status epilepticus), autoimmune encephalitis, FIRES (Febrile infection epilepsy-related syndrome), nonconvulsive

Status Epilepticus (SE) is a potentially serious condition that can affect vital and functional prognosis and requires urgent treatment. Etiology is a determining factor in the patient's functional outcome and in almost half of all cases justifies specific treatment to stop progression. Therefore, identifying and addressing the cause of SE is a key priority in SE management.

However, the etiology can be difficult to identify among acute and remote causes, which can also be multiple and interrelated. The most common etiologies are the discontinuation of antiepileptic medication in patients with a prior history of epilepsy, and acute brain aggression in cases of new onset SE (cerebrovascular pathologies are the most common). The list of remaining possible etiologies includes heterogeneous pathological contexts. Refractory SE and especially NORSE (New-Onset Refractory Status Epilepticus) lead to an extension of the etiological assessment in the search for encephalitis of autoimmune or infectious origin in adults and in children, as well as a genetic pathology in children in particular. This is an overview of current knowledge of SE etiologies and a pragmatic approach for carrying out an etiological assessment based on the following steps:

-Which etiological orientation is identified according to the field and clinical presentation? -Which etiologies to look for in an inaugural SE? -Which first-line assessment should be carried out? The place of the biological, EEG and imaging assessment is discussed.

-Which etiologies to look for in case of refractory SE?

Introduction

Status epilepticus (SE) is a potentially serious condition that can affect life and functional prognosis.

Mortality is between 8% and 33% one month after SE, 25% after one year and between 40 and 55% after two years [START_REF] Coeytaux | Incidence of status epilepticus in Frenchspeaking Switzerland: EPISTAR[END_REF][START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Logroscino | Longterm mortality after a first episode of status epilepticus[END_REF][START_REF] Vignatelli | Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy[END_REF][START_REF] Towne | Determinants of Mortality in Status Epilepticus[END_REF][START_REF] Treiman | A comparison of four treatments for generalized convulsive status epilepticus[END_REF]. Therefore, each SE requires urgent treatment and represents a substantial proportion of the patients admitted to intensive care units (ICUs). Approximately half of the SE episodes occur in patients with epilepsy whereas the other half are inaugural and known as "de novo" or new-onset SE (NOSE) [START_REF] Coeytaux | Incidence of status epilepticus in Frenchspeaking Switzerland: EPISTAR[END_REF][START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF][START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF]. In addition to the intrinsic gravity of the SE, etiology has a major influence on the prognosis [START_REF] Logroscino | Prognosis after a first episode of status epilepticus[END_REF]. Considering all known prognostic factors, etiology is the key factor that determines the patient's vital prognosis (etiology accounts for nearly 80% of mortality among all SEs [START_REF] Rossetti | Treatment deviating from guidelines does not influence status epilepticus prognosis[END_REF]) and functional outcome (cognitive sequelae and chronic epilepsy) [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Rossetti | Treatment deviating from guidelines does not influence status epilepticus prognosis[END_REF][START_REF] Neligan | Frequency and prognosis of convulsive status epilepticus of different causes: A systematic review[END_REF][START_REF] Rossetti | Prognosis of status epilepticus: Role of etiology, age, and consciousness impairment at presentation[END_REF]. Etiology can interfere with the symptomatic control of SE with standard antiepileptic and anesthetic drugs, and 45% of all SEs require specific etiological treatment to stop their progression [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF]. Conversely, the persistence of SE is likely to trigger a vicious cycle by worsening the lesions induced by the cause.

Therefore, a rapid etiological diagnosis is routinely required [START_REF] Young | Do nonconvulsive seizures damage the brain? -No[END_REF]. Functional deterioration is observed in between 28% and 54% of patients with SE [START_REF] Rossetti | Refractory Status Epilepticus[END_REF]. More than 40% of patients will develop chronic epilepsy within the next ten years following NOSE [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF]. The risk of chronic epilepsy secondary to SE varies according to the etiology. For instance, this risk increases to 3.6 in case of a metabolic cause and to 7.1 in case of a structural cause [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF].

Consequently, as reported in the latest formalized recommendations of French experts from the French Intensive Care and Emergency Medicine Societies, identifying and treating the cause of SE is an essential and urgent part of management, with a view to facilitating the resolution of SE and improving patient outcomes [START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF]. However, etiological diagnosis is often difficult. On one hand, semiology (e.g., motor symptoms) and intensive care management can limit the use and quality of the most pertinent paraclinical procedures (such as EEG or MRI). On the other hand, aside from the most common etiological causes, such as anti-epileptic treatment withdrawal and cerebrovascular lesions, the list of possible etiologies comprises diverse pathological contexts. SE should not be considered as a disease in itself but rather as a symptom with an assortment of etiologies [START_REF] Trinka | A definition and classification of status epilepticus -Report of the ILAE Task Force on Classification of Status Epilepticus[END_REF]. Many newly defined entities such as New Onset Refractory Status Epilepticus (NORSE) and the broad spectrum of autoimmune encephalitis represent a substantial part of SEs [START_REF] Davis | Autoimmunity, seizures, and status epilepticus[END_REF][START_REF] Holzer | Antibody-mediated status epilepticus: A retrospective multicenter survey[END_REF]. Unfortunately, their recent isolation and their phenotypic polymorphism may cause considerable delays in the diagnosis. Moreover, causes can overlap. Hence, a swift diagnosis is even more challenging since the assessment is at times extremely thorough, especially in the case of NOSE [START_REF] Rossetti | Refractory Status Epilepticus[END_REF].

Within this context, this document chiefly aims to elucidate the latest developments in current knowledge on SE etiologies. A review of recent literature emphasizes that the historical dichotomous classification opposing partial vs generalized SE and acute vs chronic causes in the approach to an etiological diagnosis is no longer sufficient. The diagnosis of SE also requires foreground reflection about the patient's background (Figure 1) and the addition of new recently defined entities (e.g., NOSE, NORSE, autoimmune encephalitis). It is hoped that an updated and comprehensive listing of all etiologies and their epidemiology, as well as the proposal of guidelines for pragmatic etiological assessment will help clinicians with the specific, early and targeted management of SE. To allow for the optimal tracing of the etiology in parallel to the usual treatment of SE, a review of the available answers to 6 major target questions that are part of the reflection algorithm for each clinician is suggested (Box1).

Box 1: Target questions for the etiological diagnosis of SE

1. How can the clinical pattern of onset help trace etiology? 2. How can the clinical background help trace etiology? 3. Which etiologies should be systematically addressed in case of new-onset SE? 4. Which etiologies should be systematically addressed in refractory SE? 5. Which rare etiologies should be considered after a negative initial screening? 6. How should etiological assessment be managed?

1-How can the clinical pattern of onset help trace etiology?

Acute vs non-acute etiologies

The clinical pattern of onset includes multimodal information (temporal -acute vs chronic SE, and semiological -generalized vs partial SE), traditionally considered as the major factor for linking SE to its cause. The initial classification separated acute etiologies from non-induced SE [START_REF] Hauser | Prevalence of Epilepsy in Rochester, Minnesota: 1940-1980[END_REF]. Based on Hauser's criteria, subsequent trials provided a breakdown of non-induced SE into three categories [START_REF] Logroscino | Longterm mortality after a first episode of status epilepticus[END_REF][START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Holtkamp | Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit[END_REF]: sequelae (remote symptomatic, when SE is associated with a fixed brain injury), progressive etiologies (progressive symptomatic, in the context of a progressive or neurodegenerative pathology) and cryptogenic/idiopathic SE. In the 2009 French guidelines, the classification was still arranged into 3 main groups according to this temporal onset dichotomy: acute etiologies, non-acute etiologies and unknown/unidentified causes [START_REF] Santoli | Recherche étiologique lors d'un état de mal épileptique[END_REF]. More recent guidelines from the ILAE taskforce (2015) identified etiology as one of the four major axes (with clinical semiology, EEG correlates and age) for characterizing SE [START_REF] Trinka | Which EEG patterns in coma are nonconvulsive status epilepticus?[END_REF]. These guidelines divided etiologies in two main groups: identified causes (or symptomatic) and unidentified causes (or cryptogenic). The identified causes were sub-classified in terms of onset mode: acute, remote or progressive etiologies and a parallel category linked to SE in specific electro-clinical syndromes.

The Rochester cohort provides an exhaustive description including the prevalence of SE etiologies in the first ever 199 cases of SE occurring between 1965 and 1984 (no age selection) [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF]. SEs were acute symptomatic in 50% of cases, with fever in 8% and non-induced in 42%. In acute symptomatic SE, the main etiologies were anoxic encephalopathy (20%), central nervous system (CNS) infections (17%) and cerebrovascular diseases (CVDs) (17%). Among the cases of non-induced SE, 20% were considered to be progressive and symptomatic, 47% were sequelae (= remote symptomatic) and 33% had no identified cause (Table 1). Nonetheless, according to trials and contrary to the Rochester cohort, the epidemiologic data may concern only sub-groups and/or be limited to a specific age group and/or a particular semiological type of SE (e.g., convulsive (CSE) vs non convulsive SE (NCSE)) and/or a particular onset (e.g., new-onset SE (NOSE)) or evolution (refractory SE (RSE)).

SE is considered to be acute symptomatic [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Santoli | Recherche étiologique lors d'un état de mal épileptique[END_REF][START_REF] Trinka | Which EEG patterns in coma are nonconvulsive status epilepticus?[END_REF] when it occurs in the acute phase (in the first seven days) of the onset of the following pathologies (Tables 1 and Appendix 1): head traumas, CNS infections, systemic infections with fever without any direct CNS lesion, CVDs, toxic encephalopathies, alcohol or drug withdrawal, and metabolic encephalopathies. The most frequently reported metabolic causes are blood glucose disorders (hypoglycemia, diabetic hyperglycemic hyperosmolar syndrome), electrolyte disorders (hypo or hypernatremia, hypo or hypercalcemia, hyperammonemia, hypoxemia, hyperhomocysteinemia, etc.) [START_REF] Ferlisi | Seizure precipitants (triggering factors) in patients with epilepsy[END_REF][START_REF] Frucht | Distribution of seizure precipitants among epilepsy syndromes[END_REF][START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF]. Febrile SEs have been included in this category [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF], especially SEs with fever without any other identified acute cause in children.

However, as it is mainly a pediatric etiology, some authors recommend classifying it separately [START_REF] Chin | Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study[END_REF]. In addition, SE linked to cerebral anoxia, initially classified as acute symptomatic, should be isolated and studied separately.

Non-acute etiologies are defined by a delay taking place between cerebral insult and SE greater than 7 days. Nevertheless, this delay is usually between several months and several years. Three categories are proposed in the most recent ILAE classification [START_REF] Trinka | A definition and classification of status epilepticus -Report of the ILAE Task Force on Classification of Status Epilepticus[END_REF]: remote symptomatic, progressive symptomatic and SE in the context of defined electro-clinical syndromes.

A substantial proportion of SE remains of unidentified or of unknown cause (sometimes referred to as cryptogenic or idiopathic) [START_REF] Logroscino | Longterm mortality after a first episode of status epilepticus[END_REF][START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Hauser | Prevalence of Epilepsy in Rochester, Minnesota: 1940-1980[END_REF]. This category includes all SEs without the identification of any acute precipitating factor or any prior neurological insult [START_REF] Santoli | Recherche étiologique lors d'un état de mal épileptique[END_REF].

Convulsive vs non-convulsive SE

In most studies, CSE was included, presenting disparate etiologies (Table 1): CVDs, CNS infections, cerebral tumors (primitive or secondary, benign or malignant), head trauma, consequences of alcohol consumption (intoxication or withdrawal), withdrawal or insufficient doses of anti-epileptic drugs (AED), metabolic disorders (electrolyte or blood glucose disorders, acidosis, hepatic or renal failure), hypoxic or anoxic coma [START_REF] Coeytaux | Incidence of status epilepticus in Frenchspeaking Switzerland: EPISTAR[END_REF][START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Vignatelli | Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy[END_REF][START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF][START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF][START_REF] Wu | Incidence and mortality of generalized convulsive status epilepticus in California[END_REF][START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF].

Data concerning etiologies more prevalent in NCSE are limited. Trinka et al. reviewed the literature for causes associated with NCSE, in case of absence status (AS), focal NCSE and comatose NCSE [START_REF] Trinka | Causes of status epilepticus[END_REF].

Many cases of AS have been related to nonspecific precipitating factors. The most important are AED withdrawal or poor compliance, alcohol, sleep deprivation, and sleep-wake cycle disturbances. Other nonspecific factors include stress, fatigue, fever, mild head trauma and metabolic derangement after surgery [START_REF] Thomas | États De Mal Épileptiques Non Convulsifs[END_REF][START_REF] Thomas | Frontal lobe nonconvulsive status epilepticus[END_REF]. Several idiopathic generalized epilepsy syndromes may worsen with inappropriate AEDs (e.g., carbamazepine, phenytoin, vigabatrin or other GABAergic medicinal products [START_REF] Thomas | Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy[END_REF]). Many other medicinal products (e.g., baclofen, theophylline, cimetidine, metformin, the addition or withdrawal of other psychotropic medication) may worsen absences, especially in lateonset AS [START_REF] Trinka | Causes of status epilepticus[END_REF][START_REF] Thomas | Absence status epilepticus[END_REF]. Metabolic and toxic factors have also been reported in many cases of AS, such as hyponatremia, hypoglycemia, decompensated chronic renal failure, hepatic failure, hypocalcemia and the use of contrast-enhancing products [START_REF] Trinka | Causes of status epilepticus[END_REF]. AS is more likely to occur in some electro-clinical syndromes, such as childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy or other syndromes associated with absences [START_REF] Yang | Absence status epilepticus in monozygotic twins with Jeavons syndrome[END_REF][START_REF] Panayiotopoulos | Idiopathic generalised epilepsy with phantom absences and absence status in a child[END_REF][START_REF] Agathonikou | Typical absence status in adults: Diagnostic and syndromic considerations[END_REF][START_REF] Genton | Absence status epilepsy: Delineation of a distinct idiopathic generalized epilepsy syndrome[END_REF]. AS is also associated with more severe syndromes, such as Angelman syndrome or ring chromosome 20 syndrome [START_REF] Jacobs | Refractory and severe status epilepticus in a patient with ring chromosome 20 syndrome[END_REF].

Focal NCSE occurs more often without any specific trigger. In a review of 70 patients presenting with focal NCSE of frontal origin, more than one fourth had no history of epilepsy and 45% had a focal frontal lesion (brain tumor, post-traumatic or post-surgical lesion) [START_REF] Thomas | Frontal lobe nonconvulsive status epilepticus[END_REF]. Mesial temporal lobe focal NCSEs could be the presenting symptom of viral or autoimmune encephalitis, especially those targeting limbic structures [START_REF] Spatola | Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis[END_REF][START_REF] Gaspard | Unusual Causes of Status Epilepticus[END_REF][START_REF] Dalmau | Status epilepticus due to paraneoplastic and nonparaneoplastic encephalitides[END_REF][START_REF] Vogrig | Seizure specificities in patients with antibody-mediated autoimmune encephalitis[END_REF]. These include encephalitis related to antibodies against voltage-gated potassium channel (VGKC) complex (especially LGI1, but also CASPR2) [START_REF] Navarro | Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis[END_REF], NMDA receptors [START_REF] Titulaer | Seizures as first symptom of anti-NMDA receptor encephalitis are more common in men[END_REF][START_REF] Viaccoz | Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis[END_REF][START_REF] Johnson | Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus[END_REF]; (Figure 2A), glutamic acid decarboxylase [START_REF] Malter | Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis[END_REF] or intracellular antigens. Despite scarcity of data, seizures and encephalitis have also been described with other types of antibodies [START_REF] Vogrig | Seizure specificities in patients with antibody-mediated autoimmune encephalitis[END_REF] (see Appendix 1 for more details). More infrequently, intravenous contrast media or various medicinal products trigger focal NCSE [START_REF] Thomas | Simple and Complex Partial Status Epilepticus[END_REF] (Appendix 1).

Lastly, the etiology in patients with comatose NCSE is almost always acute symptomatic, encompassing a wide variety of systemic diseases or CNS disorders [START_REF] Trinka | Causes of status epilepticus[END_REF].

Porous borders across categories and overlapping etiologies

The historical dichotomy for the nosology of SE, which is mainly based on the temporal onset of SE (e.g., acute onset or development that is more chronic), undoubtedly remains a major factor in the etiological diagnosis process. However, it is nonexclusive and sometimes confusing. SE can be induced by a combination of etiologies belonging to several categories (multiple "diagnoses" for one patient are listed in published cohorts [START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF]) and therefore requires great caution in diagnostic observation based only on the onset mode. In all trials, the total frequency of the different etiologies exceeded 100% (Table 1). In the study conducted by Knake et al., the etiological analysis identified up to 4 mixed causes for one SE and more than one cause was identified in the majority of SEs [START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF]. An acute cause may hide a chronic one and vice-versa. In such complex cases, one etiology might be at the foreground according to the patient's history. Resultantly, focusing on the history and separating SEs occurring in epileptic patients from those occurring "de novo" (NOSEs) could provide more pertinent clues.

2-How can the clinical background help trace etiology?

Despite its absence at the forefront of traditional classifications, clinical history is a highly valuable criterion in the etiological diagnosis algorithm. This criterion allows more specific etiologies to emerge; in particular, more recently defined syndromes such as NORSE, Status Epilepticus and Seizures in Alcoholic patients (SESA) or Febrile Infection Epilepsy-Related Syndrome (FIRES).

Incidentally and systematically, it allows clinicians to identify SE in epileptic patients and NOSE (Figure 1). A combination of two dimensions should be taken into account: (1) whether or not a history of epilepsy exists, (2) the patient's general medical history (e.g. age, non-epileptic chronic conditions). Specificities can be identified for children, elderly patients, pregnant women, obvious infectious context or chronic disease (cerebrovascular profile, metabolic disease, brain tumors). In addition, isolating NOSE from other categories makes it possible to target very specific causes in each individual case.

2-1 Etiological profiles according to the patient's general history

Etiological specificities in children

In a prospective cohort of CSE in 226 children under the age of 15, SE occurred in children without prior epilepsy or neurological deficit in 56% of the 176 first ever episodes [START_REF] Chin | Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study[END_REF]. The diagnosis of prolonged febrile seizure was the main etiology under the age of one (36%) and between the ages of 1 and 5 (43%) (Table 1). The etiology was acute symptomatic in 17% (metabolic disorders and CNS infections: 10%), acute in remote symptomatic affections in 16% and remote symptomatic in 17% (more frequent, the older the child) of the entire population .The etiology was related to prior epilepsy in almost 12% of children, mostly over the age of 5, and etiology could not be classified in 7%.

Therefore, in accordance with other cohorts [START_REF] Kravljanac | New-onset seizure presenting as status epilepticus: Etiology and clinical characteristics in a cohort of 236 children[END_REF], the prevalence of causes of CSE in childhood differs from those in adulthood. What also emerges from clinical experience is a major difference in etiologies under and over the age of one. Under the age of one, CNS infections, post-traumatic brain lesions (shaken baby syndrome) and Dravet syndrome prevail. As a result, the diagnosis of non-accidental head injury should be systematically mentioned whenever there is non-febrile SE [START_REF] Bourgeois | Epilepsy associated with shaken baby syndrome[END_REF]. Furthermore, a recent study emphasized the involvement of genetic etiologies in CSE in children, especially in younger children [START_REF] Guerrini | What is the role of next generation sequencing in status epilepticus?[END_REF], making the detection of a genetic disorder (specifically, Dravet syndrome) an essential aspect of etiological assessment due to major therapeutic implications.

Etiological specificities in elderly subjects

The prevalence and incidence of SE are higher in populations over the age of 60 than in younger adults [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF]. Incidence increases with age, from 15.5/100,000 for 60-69 year-old subjects to 25.9/100,000 for those over the age of 80 [START_REF] Rosenow | The epidemiology of convulsive and nonconvulsive status epilepticus[END_REF]. In older adults, most SEs are NOSEs, whereas SEs in epileptic patients are less frequent [START_REF] Meierkord | Non-convulsive status epilepticus in adults: clinical forms and treatment[END_REF]. The clinical presentation of SE in older patients is often confusing, which explains frequent diagnostic meandering and delayed management. NCSEs, which are harder to identify, are more frequent with cognitive and behavioral disorders. In a one-year retrospective series of older subjects with delirium admitted to an emergency room for whom first-line investigations was negative, almost 16% finally met the criteria for NCSE, in part uncovered by the EEG [START_REF] Veran | De novo epileptic confusion in the elderly: A 1-year prospective study[END_REF]. Moreover, an array of differential diagnoses share common semiological features: iatrogenic causes, systemic infections with chills, sleeping disorders (e.g., motor manifestations in rapid eye movements (REM) sleep), attacks of akinesia or dyskinesia in Parkinson's disease and psychobehavioral disorders typical of neuro-cognitive pathologies. They can interfere with the feasibility of an EEG, and delay diagnosis and therapeutic management alike.

Elderly patients often suffer from a number of comorbidities and are treated with multiple medicinal products. The frequent combination of factors, such as metabolic disorders, renal failure and systemic infection complicates the etiological context. Therefore, SE generally occurs in a multifactorial context, triggered by one or more acute cause(s) in patients with a predisposing condition (non-acute brain pathology and/or associated comorbidities). SE is often classified as acute or remote symptomatic (Table 1).

Among acute etiologies, iatrogenic causes represent more than a third of total cases [START_REF] Malter | New onset status epilepticus in older patients: Clinical characteristics and outcome[END_REF].

Medications with an epileptogenic potential (Appendix 1) are more likely to trigger SE when the subject is older and/or has brain damage, especially in the case of intricately linked factors.

Benzodiazepine withdrawal may also cause SEs, especially NCSEs [START_REF] Thomas | États De Mal Épileptiques Non Convulsifs[END_REF]. These occurred more often in women over the age of 75 presenting with unexplained delirium. In France, 38.5% of women over the age of 80 take benzodiazepines [START_REF] Benard | État des lieux de la consommation des benzodiazépines en France[END_REF]. The EEG generally highlights NCSE and allows for testing via an intravenous injection of benzodiazepines. However, even at this stage, additional causes should be systematically excluded. SE may be triggered by other acute medical conditions (cardiac, respiratory or hepatic), dysnatremia, whereas CVDs account for nearly half of the cases [START_REF] Canouï-Poitrine | Risk and prognostic factors of status epilepticus in the elderly: A case-control study[END_REF]. Although rare, AS may occur in older adults with either a personal or a family history of idiopathic generalized epilepsy [START_REF] Bauer | Absence status in the elderly as a late complication of idiopathic generalized epilepsies[END_REF][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].

The two main remote causes are sequelae of stroke and dementia, but mainly Alzheimer's disease. Epilepsy is a frequent complication of Alzheimer's disease; new onset NCSE may even be a determining factor for the latter [START_REF] Hommet | Epilepsy and dementia in the elderly[END_REF][START_REF] Cretin | Do we know how to diagnose epilepsy early in Alzheimer's disease?[END_REF][START_REF] Iyer | Status of memory loss[END_REF]. A rare differential diagnosis with Creutzfeldt-Jakob disease or metabolic encephalopathy can sometimes prove difficult because of nonspecific EEG patterns (see paragraph 6) [START_REF] Marquetand | Periodic EEG patterns in sporadic Creutzfeld-Jakob-Disease can be benzodiazepine-responsive and interpreted as non-convulsive status epilepticus[END_REF].

In conclusion, very few studies have made it possible to specifically analyze the different etiologies of SE in elderly subjects [START_REF] Legriel | Managing Status Epilepticus in the Older Adult[END_REF]. A substantial part of the information relating to this age group is only available with reference to comprehensive adult cohorts, where a subgroup of patients older than 65 is isolated [START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF][START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF][START_REF] Canouï-Poitrine | Risk and prognostic factors of status epilepticus in the elderly: A case-control study[END_REF][START_REF] Aminoff | Status Epilepticus. Causes, Clinical Features and Consequences in 98 patients[END_REF][START_REF] Legriel | Outcomes in 140 critically ill patients with status epilepticus[END_REF][START_REF] Sung | Status epilepticus in the elderly: etiology, seizure type and outcome[END_REF][START_REF] Delorenzo | Epidemiology of status epilepticus[END_REF] (Table 1). Combining these different sources of information [START_REF] Legriel | Managing Status Epilepticus in the Older Adult[END_REF],

the main causes identified in elderly subjects are predominantly strokes (acute or remote symptomatic: 52.3%), miscellaneous metabolic causes (21%), AED withdrawal (9.6%), dementia (9.3%), brain injuries (9.3%), infections (systemic: 6.3% or CNS: 2.3%), alcohol-related (8.6%), hypoxemia (5.3%) and undetermined in 4.6%.

Etiological specificities during pregnancy

In a retrospective study of 366 consecutive SE patients hospitalized at a neurology ICU, there were only 7 cases of pregnancy-associated SE [START_REF] Lu | Status epilepticus associated with pregnancy: A cohort study[END_REF], and in a prospective collection of SEs, 17 in 138 women presented with SE related to pregnancy [START_REF] Rajiv | Status epilepticus in pregnancy: Etiology, management, and clinical outcomes[END_REF]. Underdosing of AED is the main cause of SE occurring in pregnant epileptic patients (due to either inobservance or hemodilution because of a higher distribution volume and renal clearance). However, most SEs during pregnancy are NOSEs [START_REF] Lu | Status epilepticus associated with pregnancy: A cohort study[END_REF][START_REF] Rajiv | Status epilepticus in pregnancy: Etiology, management, and clinical outcomes[END_REF]. Further, the most common causes (38%) are posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) [START_REF] Rajiv | Status epilepticus in pregnancy -Can we frame a uniform treatment protocol?[END_REF] (Table 1). Among these patients, 45% suffered from eclampsia. Therefore, in every SE occurring in the second trimester of pregnancy, eclampsia should be investigated owing to severity, poor outcomes and the need for the prompt administration of a magnesium sulfate injection. It is a priority to check blood pressure and urine protein levels (proteinuria is present 80% of the times in eclampsia). Other main etiologies are central venous thrombosis (17%) and autoimmune encephalitis (17%) [START_REF] Rajiv | Status epilepticus in pregnancy -Can we frame a uniform treatment protocol?[END_REF] (Table 1). Rarer causes include subarachnoid or brain hemorrhage (3%), which risk increases during pregnancy (especially in the presence of cerebral vascular malformation).

Obvious infectious context

CNS infections (meningitis, encephalitis, cerebral abscesses of bacterial, viral, parasitic or fungal origin) induce between 3% and 6% of NOSEs [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF]. SE is also a highly frequent complication of the acute phase of CNS infections (10-20% of cases). The prevalence of SE is estimated to be approximately 20% in the acute phase of viral encephalitis (herpes simplex virus, HHV6, etc.) [START_REF] Sonneville | Early-onset status epilepticus in patients with acute encephalitis[END_REF], and about 15% in the acute phase of bacterial meningitis [START_REF] Zoons | Seizures in adults with bacterial meningitis[END_REF] (especially pneumococcus, and in children), (Appendix 1). Other prevalent causes are toxoplasmosis, cerebral tuberculosis and neurocysticercosis.

CNS infections increase the risk of RSE and excess mortality in hospital. In this context, SE is favored not only by the infection itself but also by fever or the side effects of medication. Some antibiotics are pro-convulsing (e.g., penicillins, cephalosporins, quinolones, etc.), and/or cause interactions with medicinal products that can reduce the effectiveness of AED (e.g., meropenem) and/or induce precipitating factors such as metabolic disorders or the decompensation of comorbidities (Appendix 1). Immunosuppressed subjects are more likely to be exposed because of higher risks of CNS and non-CNS infections and the toxic effects of medications.

Herpes simplex encephalitis, one of the most dreaded causes of SE, justifies the urgent initiation of aciclovir to avoid severe progression (Figure 2B). Clinicians should systematically consider this diagnosis in the presence of a temporal NCSE with fever, especially in cases of NOSE, SE without an identified cause following initial screening and RSE. Cerebrospinal fluid (CSF) samples confirm meningitis in 95% of the cases although they may be normal initially [START_REF] Steiner | The neurotropic herpes viruses: herpes simplex and varicella-zoster[END_REF]. Only positive herpes simplex PCR confirms the diagnosis [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Steiner | The neurotropic herpes viruses: herpes simplex and varicella-zoster[END_REF][START_REF] Mook-Kanamori | Herpes simplex encephalitis with normal initial cerebrospinal fluid examination[END_REF].

HIV infection is also associated with an increased risk of SE (seizures in 32% of HIV patients [START_REF] Sonneville | Neurological complications of HIV infection in critically ill patients : Clinical features and outcomes[END_REF] and SE in between 8% and 14% of HIV patients with new-onset seizures [START_REF] Van Paesschen | Metabolic Abnormalities and New-Onset Seizures in Human Immunodeficiency Virus-Seropositive Patients[END_REF]), most often related to a secondary infection (e.g., cerebral toxoplasmosis, etc.), medications (interactions engendering a pro-convulsive effect or reducing the effect of AEDs) or metabolic disorders [START_REF] Lee | Clinical features of status epilepticus in patients with HIV n[END_REF] (Appendix 1).

A history of cerebrovascular disorders (CVD)

Among the various CVDs (Appendix 1), the main pathologies are cerebral infarction (Figure 3) and primitive cerebral hemorrhage. The overall prevalence of SE is rare and is estimated at less than 1% [START_REF] Rumbach | Status epilepticus in stroke: Report on a hospital-based stroke cohort[END_REF]. Nevertheless, the very high frequency of CVDs indicates that they constitute a major etiology in adult SE. The characteristics of strokes inducing SE seem to be the same as those resulting in isolated epileptic seizures: cortical lesions, cerebral hemorrhage or the hemorrhagic transformation of ischemic lesions and large lesions.

Among patients suffering from severe stroke (those hospitalized in ICUs), the prevalence is higher and some NCSEs are probably underdiagnosed [START_REF] Bateman | Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: Frequency, predictors, and impact on outcome in a large administrative dataset[END_REF]. The combination of SE and stroke is more life-threatening and is associated with a worse functional outcome [START_REF] Lahiri | Mechanical Ventilation for Acute Stroke: A Multi-state Population-Based Study[END_REF]. Other CVDs, which share an extensive suffering of the cortex and a hemorrhagic component (e.g., subarachnoid hemorrhage due to ruptured aneurysm, venous thrombosis or PRES), are more infrequent but are associated with an even higher risk of SE. For instance, SE complicates approximately 10% of cases of cerebral venous thrombosis [START_REF] Kalita | Significance of seizure in cerebral venous sinus thrombosis[END_REF] and between 5% and 15% of PRES [START_REF] Fugate | Posterior reversible encephalopathy syndrome: Clinical and radiological manifestations, pathophysiology, and outstanding questions[END_REF]. The prevalence of SE in patients presenting with remote neurovascular pathology (Figure 3) is at least as high as in the acute phase of strokes.

Therefore, it is crucial to appraise any associated precipitating factors, in particular metabolic disorders or medication.

It is pointed out that SE can be mistaken for a stroke (stroke mimic) due to the absence of abnormal movements at the time of examination and/or its radiological appearance in MRI (diffusion, FLAIR sequences) (Figure 3A-B). It is even more confusing in patients with a history of stroke [START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Hand | Distinguishing between stroke and mimic at the bedside: The brain attack study[END_REF].

Conversely, an occlusion of the basilar trunk responsible for disorders of consciousness and abnormal movements correlated to damaged pyramidal pathways can be erroneously treated as SE or seizures (stroke chameleon) [START_REF] Fernandes | Strokes : mimics and chameleons 2013[END_REF]. Whenever clinicians have the slightest doubt, brain imagery (MRI, preferentially) comprising the analysis of the cerebral vessels (magnetic resonance angiography and venography) should be urgently performed [START_REF] Masterson | Postictal deficit mimicking stroke: Role of perfusion CT[END_REF].

Lastly, the inflammatory form of cerebral amyloid angiopathy is an unusual cause of SE which, however, should be mentioned when NOSE is associated with cortical petechial hemorrhage and pseudo-tumor lesion(s) in older adults [START_REF] Tolchin | Status epilepticus caused by cerebral amyloid angiopathy-related inflammation[END_REF].

Brain tumors

Between 3% and 12% of adult SEs are directly related to a brain tumor, in particular gliomas [START_REF] Delorenzo | Epidemiology of status epilepticus[END_REF][START_REF] Towne | Prevalence of nonconvulsive status epilepticus in comatose patients[END_REF][START_REF] Claassen | Predictors of functional disability and mortality after status epilepticus[END_REF] (Table 1). Indeed, in one recent (2013-2019) prospective cohort of 440 adults with SE (median age: 63), the cause was a glioma in 6% of cases [START_REF] Giovannini | Tumorr-associated status epilepticus in patients with glioma: Clinical characteristics and outcomes[END_REF]. 85% presented with high-grade glioma. SE was the first manifestation of tumor in 54% (suggesting that this etiology must be screened for NOSE) and appears to be treatment-responsive as SE in patients without glioma. NCSEs are frequent.

Unlike seizures unrelated to SEs and associated with brain tumors, SE risk is higher later in the course of the tumor progression and is directly proportional to the tumor grade (especially high-grade gliomas) [START_REF] Goonawardena | Brain tumour-Associated status epilepticus[END_REF]. It is preferentially linked to tumor changes: mostly progression [START_REF] Giovannini | Tumorr-associated status epilepticus in patients with glioma: Clinical characteristics and outcomes[END_REF], edema or hemorrhage. However, biopsy or surgical resection may also trigger SE. Besides, knowledge about SE and tumors has been confounded by several biases: the retrospective nature of most studies, small sample size, differences in tumor grade and histological tumor types across studies, epidemiological factors (especially age) and heterogeneous definitions of SE. Despite the consensus about the supratentorial location of brain tumors, the influence of the lobar location triggering SE remains equivocal: 77% were located in the temporal lobe in one cohort [START_REF] Giovannini | Tumorr-associated status epilepticus in patients with glioma: Clinical characteristics and outcomes[END_REF], whereas they were mostly frontal in other publications [START_REF] Goonawardena | Brain tumour-Associated status epilepticus[END_REF]. Information is too scarce to specify if an AED tailored to histological type would improve its management.

Chronic metabolic or digestive diseases

Patients presenting with kidney or hepatic failure [START_REF] Eleftheriadis | Status epilepticus as a manifestation of hepatic encephalopathy[END_REF] have a higher risk of metabolic encephalopathy and SE induced by an overdose of medication. It is stressed that kidney failureremote or acute -is a major factor contributing to SE in conjunction with medication or other agents of toxic origin.

SE in epileptic patients

Approximately half SEs in the adult population occurs in epileptic patients taking AED [START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF], mostly (15-35%) triggered by the withdrawal of AED(s), and is correlated to poor medication compliance or an unexpected event (digestive disorders, interactions with medicinal products) [START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF][START_REF] Wu | Incidence and mortality of generalized convulsive status epilepticus in California[END_REF][START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF][START_REF] Delorenzo | Epidemiology of status epilepticus[END_REF][START_REF] Betjemann | Status epilepticus in adults[END_REF] (Figure 1). SE correlated to a sudden low AED level has a good prognosis, with a low mortality equal to 4.0%-8.6% [START_REF] Towne | Determinants of Mortality in Status Epilepticus[END_REF]. However, other frequent causes in epileptic patients overlap with etiologies listed in NOSE [START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF](Appendix 1).

In addition, factors inducing seizures in any chronic epilepsy should be considered such as sleep deprivation, intense stress, fever, acute metabolic disorder, toxic intake or acute metabolic disorder (hypoglycemia, hyponatremia) [START_REF] Ferlisi | Seizure precipitants (triggering factors) in patients with epilepsy[END_REF][START_REF] Frucht | Distribution of seizure precipitants among epilepsy syndromes[END_REF]. The interruption or commencement of any other medication or any toxic intake [START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF] can favor seizures and trigger SE (Appendix 1) [START_REF] Tan | The uncommon causes of status epilepticus: A Systematic Review[END_REF]. The introduction of an AED can also precipitate the occurrence of SE via different mechanisms: toxic or paradoxical effect, encephalopathy or inappropriate AED for a specific epileptic syndrome (Appendix 1) [START_REF] Thomas | Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy[END_REF]. Lastly, approximately 25% of SEs in epileptic patients are unrelated to any other identified causal factor [START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF].

-Which etiologies should be systematically addressed in case of new-onset SE (NOSE)?

In adults, approximately half of SEs occur without any prior epilepsy (e.g. ,NOSE) [START_REF] Aranda | Generalized convulsive status epilepticus management in adults: A cohort study with evaluation of professional practice[END_REF][START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF][START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF].

Their incidence can vary from 16.3 to 18.3/100,000 inhabitants [START_REF] Coeytaux | Incidence of status epilepticus in Frenchspeaking Switzerland: EPISTAR[END_REF][START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF]. The prognosis is severe, with an acute mortality between 20% and 61% [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF][START_REF] Veran | De novo epileptic confusion in the elderly: A 1-year prospective study[END_REF][START_REF] Santamarina | Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy[END_REF][START_REF] Aukland | Predictive value of the Status Epilepticus Severity Score (STESS) and its components for long-term survival[END_REF][START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF]. The inaugural nature of SE multiplies the risk of death in patients over the age of 60 by 15 [START_REF] Canouï-Poitrine | Risk and prognostic factors of status epilepticus in the elderly: A case-control study[END_REF]. Poor prognostic factors are patient age, duration of SE and the etiologies [START_REF] Hesdorffer | Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in Germany: A prospective, population-based study[END_REF][START_REF] Veran | De novo epileptic confusion in the elderly: A 1-year prospective study[END_REF][START_REF] Santamarina | Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy[END_REF][START_REF] Aukland | Predictive value of the Status Epilepticus Severity Score (STESS) and its components for long-term survival[END_REF][START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF]. Thus, despite very few available prospective trials, identifying the cause for a specific treatment is vital.

In a prospective trial including 46 consecutive NOSEs [START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF], the etiology was acute symptomatic in 41%, remote symptomatic in 33% (including 80% vascular sequelae), progressive symptomatic in 15% and not identified in 8.7% of patients. Acute symptomatic cases gathered acute brain lesions with vascular etiology or of infectious or traumatic origin (20%), and alcohol withdrawal in alcoholic patients (10%), including 2 cases of SESA [START_REF] Laroche | Subacute encephalopathy and seizures in alcoholics (SESA) presenting with non-convulsive status epilepticus[END_REF][START_REF] Kaplan | Subacute Encephalopathy With Seizures in Alcoholics (SESA) Presenting as Focal Nonconvulsive Status Epilepticus[END_REF]. Half of remote symptomatic cases were associated with acute factors triggering seizures (as in the patients with prior epilepsy detailed above) [START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF]. In another prospective trial conducted in 89 consecutive NOSEs [START_REF] Santamarina | Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy[END_REF], etiologies were acute symptomatic in 59 patients (66%; brain lesions in 41, toxic or metabolic disorders in 18), remote or progressive symptomatic in 17 and cryptogenic in 13. Etiologies of NOSE in the main trials are summarized in Appendix 1 and Figure 1 [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF][START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF][START_REF] Aminoff | Status Epilepticus. Causes, Clinical Features and Consequences in 98 patients[END_REF][START_REF] Betjemann | Status epilepticus in adults[END_REF][START_REF] Gaspard | New-onset refractory status epilepticus: Etiology, clinical features, and outcome[END_REF][START_REF] Hirsch | Status epilepticus[END_REF][START_REF] Chakraborty | The Clinical Spectrum of New-Onset Status Epilepticus[END_REF]. Most are linked to an acute etiology, either isolated or associated with a non-acute cause.

4-Which etiologies should be systematically addressed in cases of refractory SE (RSE)?

The occurrence of a plethora of cases of early de novo RSE resulted in the definition of a contextual entity: NORSE. However, this acronym conceals various meanings and components according to the studies, leading experts to propose a more consensual and precise definition [START_REF] Hirsch | Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions[END_REF].

NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or any other relevant pre-existing neurological disorder, with the new onset of RSE, without any clear acute or active structural, toxic or metabolic cause (Figure 2C). The determination of NORSE requires the combination of imaging, CSF analysis, toxicology assessment and other blood tests, as generally recommended for the evaluation of SE [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Trinka | A definition and classification of status epilepticus -Report of the ILAE Task Force on Classification of Status Epilepticus[END_REF][START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF] (Appendix 2). In children, as it shares many similarities with NORSE, FIRES has recently been defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 hours prior to the onset of RSE, without any age criteria [START_REF] Gaspard | Newonset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives[END_REF] (Figure 4B). NORSE and FIRES often present as super-RSE. In the absence of a specific diagnostic test, their diagnosis is based on clinical factors after the initial workup has ruled out obvious causes of RSE, which usually takes 48-72 hours. RSE (particularly NORSE) should lead clinicians to investigate etiologies usually reported within this context, even if another etiology has already been identified (Appendix 2). This is especially true when this primarily suspected etiology has a good prognosis, which is illogical and does not match a refractory epileptic process. The most common etiologies of RSE are listed in Appendix 2 [START_REF] Gaspard | New-onset refractory status epilepticus: Etiology, clinical features, and outcome[END_REF][START_REF] Chakraborty | The Clinical Spectrum of New-Onset Status Epilepticus[END_REF][START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF].

Despite an extensive, albeit variable, workup, the cause remains unknown in half of the adult cases of NORSE [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF]. The clinical features do not greatly differ from autoimmune cases, which suggests similar etiology and physiopathological processes [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF]. Some cryptogenic cases may correspond to autoimmune encephalitis with antibodies not yet identified. In particular, the prevalence of CSF abnormalities has been reported to be significant in cryptogenic cases as in situations with an autoimmune or infectious etiology [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF]. Moreover, preliminary evidence suggests that early immunotherapy may be beneficial even when a definite immune etiology has not yet been identified, especially in adults [START_REF] Mikaeloff | Devastating epileptic encephalopathy in school-aged children (DESC): A pseudo encephalitis[END_REF][START_REF] Iizuka | Cryptogenic NORSE[END_REF][START_REF] Van Baalen | Febrile infection-related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood[END_REF][START_REF] Sakuma | Acute encephalitis with refractory, repetitive partial seizures (AERRPS): A peculiar form of childhood encephalitis[END_REF]. Unfortunately, prospective controlled studies are found wanting. Nevertheless, a ketogenic diet may prove particularly effective in children with FIRES [START_REF] Nabbout | Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES)[END_REF].

Regrettably, a wealth of other aspects relating to the etiology and therapeutic management of these patients remain understudied and uncertain.

Which rare etiologies should be considered after a negative initial screening?

An exhaustive review of the literature (from 1990 to 2008) relative to the rare causes of SE that do not belong to the main categories listed above was published in 2010 [START_REF] Tan | The uncommon causes of status epilepticus: A Systematic Review[END_REF]. It was recently updated and extended to a total amount of more than 200 etiologies [START_REF] Gaspard | Unusual Causes of Status Epilepticus[END_REF]. These represent less than 1% of all SEs according to the epidemiological studies conducted. The different etiologies were classified into 5 major groups: immunological disorders, mitochondriopathies, infectious diseases, genetic disorders and toxic/medicinal product related SE. The remaining causes were placed in a sixth group. In an update (Appendix 1), we also integrated the rare etiologies to be found in a recent detailed but non-exhaustive classification, developed by the ILAE task force [START_REF] Trinka | A definition and classification of status epilepticus -Report of the ILAE Task Force on Classification of Status Epilepticus[END_REF]. In the group of autoimmune encephalitis, the most frequent were encephalitis with antibodies targeting intracellular antigens, followed by encephalitis with antibodies targeting membrane antigens. Among the mitochondriopathies, mutations in POLG (like in Alpers disease or mitochondrial spinocerebellar ataxia and epilepsy) are recognized as the cause of refractory occipital lobe epilepsy and SE [START_REF] Tzoulis | The spectrum of clinical disease caused by the A467T and W748S POLG mutations: A study of 26 cases[END_REF][START_REF] Engelsen | POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection[END_REF] (Figure 4A). The list of genetic disorders (broken down into five categories: chromosomal aberrations, inborn errors of metabolism, malformations of cortical development, neurocutaneous syndromes and other disorders such as Dravet syndrome) is also very long. The sixth group included iatrogenic causes, unusual complications of frequent neurological or systemic diseases (such as multiple sclerosis, high blood pressure through PRES) and a compilation of unique case-reports.

-How should the etiological assessment be managed?

Discovering and addressing the cause(s) of SE should be a concern from the beginning of care, also given that SE can be caused by several intermixed etiologies. The etiological investigation process should be swift, pragmatic, structured (Figure 5, Appendix 2) and should not delay therapeutic management, as suggested in several reference articles [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF][START_REF] Santoli | Recherche étiologique lors d'un état de mal épileptique[END_REF][START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF][START_REF] Outin | Emergency and intensive care unit management of status epilepticus in adult patients and children (new-born excluded). Société de réanimation de langue française experts recommendations[END_REF]. Naturally, the preliminary step is always to establish the diagnosis of SE, and to discard the differential diagnoses.

Box 2: Key questions for a pragmatic management of the etiological assessment and for drawing its algorithm.

1. Are there any clinical symptoms specific to particular etiologies that should be investigated? 2. Which systematic vs tailored biological assessment (blood analyzes, lumbar puncture) should be carried out in practice?

3. Are there MRI patterns specific to one or more etiologies? 4. Are there EEG patterns specific to one or more etiologies?

Clinical investigation

The anamnesis must be thorough. It should first determine the general medical history (neurological history, treatments and comorbidities, as well as a description of the circumstances and seizure semiology), whether or not the patient has already suffered from epilepsy in order to swiftly glean whether or not it is inaugural in nature. A complete neurological examination is essential. A focal deficit and seizure semiology in favor of a partial SE are points of departure for investigating a structural brain injury. Temperature, vital signs and a general (especially cutaneous) examination can be informative in revealing signs of infection, indirect signs of drug intoxication, venipuncture sites (related to toxic intake) or purpura.

In case of SE in an epileptic patient, AED-related disorders should be investigated first, whereas in case of NOSE, clinicians should focus on identifying an acute etiology, particularly a brain pathology. Several symptoms (oral dyskinesia, subacute deterioration of the general state of health, subacute psychiatric or cognitive disorders or sleep disturbances in the weeks prior to the onset of SE, recently diagnosed neoplasia or tonic and dystonic seizures) suggest the possibility of autoimmune encephalitis [START_REF] Spatola | Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis[END_REF][START_REF] Graus | A clinical approach to diagnosis of autoimmune encephalitis[END_REF].

Blood tests

In patients of all ages, blood sugar levels should be promptly analyzed (with fingerstick) and a more complete biological assessment should ensue (Appendix 2). Serum dosage of the patient's AED is informative, since non-adherence to AED is a common cause of SE. Systematically testing blood alcohol levels is also justified. Toxic or other drug dosages can be requested on a case-by-case basis. Other more specific biological examinations (Appendix 2) may be requested depending on the context (suspected infection or intoxication) or the results of the etiological investigation (RSE or NORSE).

In children, American and international guidelines, have been published to conduct the etiological assessment of SE [START_REF] Guerrini | What is the role of next generation sequencing in status epilepticus?[END_REF][START_REF] Smith | Emergency management of status epilepticus in children[END_REF]: within the first minutes, capillary blood glucose levels should be tested and a cell blood count should be performed, followed by the testing of blood gases, blood ionogram, calcium, magnesium and the dosage of any AED taken by the child. The assessment should be completed according to the clinical context by liver function and coagulation tests, blood and urine toxicity tests and metabolic screening. A rapid genetic screening should be carried out when the etiological assessment remains negative, especially in children with CSE [START_REF] Guerrini | What is the role of next generation sequencing in status epilepticus?[END_REF], since several etiologies such as Dravet or Alpers syndromes [START_REF] Wolf | Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features[END_REF] require specific management and provide for the contraindication of certain AEDs. In very specific phenotypes such as Dravet syndrome, where the involvement of the SCN1A gene is major, progress in the analysis of this gene makes it possible to identify its involvement in most cases. NGS-type (next generation sequencing) genetic analysis should be part of the standard exploration of a pediatric SE if no etiology is identified in first-line tests [START_REF] Guerrini | What is the role of next generation sequencing in status epilepticus?[END_REF]. Furthermore, trio exome analysis centered on genes known to be involved in CSE would be the strategy of choice in future.

Lumbar puncture

In adults, a lumbar puncture should be systematically performed after brain imagery and in the absence of any contraindication under three main circumstances: (1) in all cases where a CNS infection is suspected (fever, highly evocative context) or in patients with immunodeficiency (genetic origin or acquired by HIV, neoplasia, chemotherapy); (2) if no etiology has been identified after standard evaluation based on clinical examination, blood samples and brain MRI; (3) if an association of symptoms strongly suggests an autoimmune origin [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF][START_REF] Graus | A clinical approach to diagnosis of autoimmune encephalitis[END_REF].

In children, a lumbar puncture should be performed in every case of febrile CSE, including cytological, biochemical, bacteriological and herpes PCR analysis. More specific analyzes such as parasite, fungal or autoimmune tests can be requested initially or at a later stage, depending on the clinical context [START_REF] Smith | Emergency management of status epilepticus in children[END_REF].

It should be noted that the lumbar puncture should be repeated in three situations. Firstly, when it has been performed at a very early stage. Indeed, the CSF collected very precociously can be normal when the cause is infectious (viral encephalitis as herpes in particular, even more so in patients presenting with immunosuppression) [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF][START_REF] Mook-Kanamori | Herpes simplex encephalitis with normal initial cerebrospinal fluid examination[END_REF], neoplastic, paraneoplastic or autoimmune in nature [START_REF] Graus | A clinical approach to diagnosis of autoimmune encephalitis[END_REF][START_REF] De Montmollin | Anti-Nmethyl-D-aspartate receptor encephalitis in adult patients requiring intensive care[END_REF]. Secondly, a lumbar puncture should be repeated when isolated and moderate pleocytosis has been observed on an initial CSF sample (< 25 cells.μl-1). Pleocytosis is not influenced by the duration and type of seizures [START_REF] Tumani | Effect of epileptic seizures on the cerebrospinal fluid -A systematic retrospective analysis[END_REF] but is observed in 6% of patients in the post-ictal phase, although there is no obvious infectious or vascular process. Lactate concentration and the "CSF/serum albumin" ratio may also increase. However, it was recently shown that non-infectious SE does not usually lead to CSF pleocytosis, which strongly suggests that its detection should urge clinicians to investigate an infectious or autoimmune process [START_REF] Graus | A clinical approach to diagnosis of autoimmune encephalitis[END_REF][START_REF] Malter | Cerebrospinal fluid findings in non-infectious status epilepticus[END_REF]. Thirdly, the lumbar puncture needs to be repeated in case of RSE, specifically by screening anti-neuronal antibodies [START_REF] Vogrig | Seizure specificities in patients with antibody-mediated autoimmune encephalitis[END_REF] and oligoclonal bands.

Despite being a rare cause of SE [START_REF] Spatola | Status epilepticus of inflammatory etiology: A cohort study[END_REF] (Appendix 1 and 2), autoimmune encephalitis must be immediately mentioned when first-line assessment fails to provide any answers [START_REF] Gaspard | New-onset refractory status epilepticus: Etiology, clinical features, and outcome[END_REF].

Brain imagery

Rapid brain imaging should be performed instantly in case of NOSE, as soon as the patient's condition is stabilized. It is required if a lumbar puncture is indicated. It is essential in all situations where the presence of a potentially progressive lesion or when specific treatment might be required (Appendix 2). Brain imaging is also indicated in known epileptic patients in cases of unexplained febrile condition, head injury, new abnormality upon clinical examination or a known brain pathology that may have evolved [START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF][START_REF] Santoli | Recherche étiologique lors d'un état de mal épileptique[END_REF][START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF].

The reference procedure is magnetic resonance imaging (MRI), as it is more sensitive than a computerized tomography (CT) scan and can improve the etiological diagnosis in almost one third of the patients [START_REF] Goyal | Role of MR imaging in the evaluation of etiology of status epilepticus[END_REF]. Regrettably, in many cases, a CT scan is much more accessible and rapid than MRI, which is more suitable for an emergency context. In such cases a CT scan must be performed with and without injection, including artery and venous sequences, as well as a delayed acquisition phase for brain tissue enhancement. It is also crucial to follow up with a brain MRI when the clinical investigation and CT scan fail to identify the etiology. Imaging can be delayed or even deemed unnecessary only if the clinical condition has strictly reverted to the previous state, if the etiological diagnosis is certain (e.g., indisputable metabolic cause or immediate generalized SE) and if the SE trigger is apparent in a known epileptic patient [START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF].

In some cases, MRI may show signs of peri-or post-ictal neuronal suffering in the form of signal abnormalities referred to as peri-ictal MRI abnormalities [START_REF] Szabo | Diffusionweighted and perfusion MRI demonstrates parenchymal changes in complex partial status epilepticus[END_REF][START_REF] Cartagena | Reversible and irreversible cranial MRI findings associated with status epilepticus[END_REF][START_REF] Mendes | Brain magnetic resonance in status epilepticus: A focused review[END_REF]. The anatomical structures affected are usually the homolateral cortex, the thalamus (in particular, the pulvinar) and the hippocampus. Peri-ictal MRI abnormalities are defined by a hypersignal upon diffusion and FLAIR sequences with moderate ADC restriction. They can be associated with cortical focal hyperperfusion (Figures 2B,3B,). Their prevalence is still not very well known: it ranges from 27.5% to 42.5% in two retrospective studies [START_REF] Rennebaum | Status epilepticus: Clinical characteristics and EEG patterns associated with and without MRI diffusion restriction in 69 patients[END_REF][START_REF] Nakae | Relationship between cortex and pulvinar abnormalities on diffusion-weighted imaging in status epilepticus[END_REF] and is equal to 37% in one prospective study [START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF]. A high correlation exists between clinical symptoms and EEG abnormalities. These are not always reversible, nevertheless, they are likely [START_REF] Benaiteau | Valeur pronostique des anomalies IRM à la phase aiguë de l'état de mal épileptique inaugural de l'adulte[END_REF]. However, peri-ictal MRI abnormalities are not specific to one given etiology. As they are directly linked to ictal activity, they complete a positive diagnosis of SE and must be clearly distinguished from the lesions that can help trace the SE etiology.

In children, imaging is indicated in every context where etiology is not apparent, and is urgent in trauma or oncological contexts. Under the age of one, brain imaging should be urgently performed in the presence of any non-febrile SE so as to systematically investigate the diagnosis of non-accidental head injury [START_REF] Smith | Emergency management of status epilepticus in children[END_REF]. A CT scan is often the first-line procedure in that it is more readily available and does not require sedation in young children. When CT scan is not informative, MRI must complete it.

Electroencephalogram (EEG)

An EEG is essential in any SE to confirm the diagnosis in combination with clinical semiology [START_REF] Lowenstein | Clinical and EEG features of status epilepticus in comatose patients[END_REF], to rule out anoxic coma or any other causes of coma [START_REF] Outin | Prise en charge des états 32 de mal épileptiques en préhospitalier, en structure d'urgence et en réanimation dans les 48 premières heures[END_REF] and to follow the progression.

Continuous EEG monitoring should always be conducted to significantly improve the possibility of detecting subclinical seizures, particularly NCSE in adults [START_REF] Dhakar | Continuous EEG Monitoring for Status Epilepticus[END_REF] and in children [START_REF] Smith | Emergency management of status epilepticus in children[END_REF]. Literature is primarily focused on the EEG patterns that allow for the confirmation of SE (e.g., repetitive electrographic seizures, continuous spike-and-wave activity [START_REF] Lowenstein | Clinical and EEG features of status epilepticus in comatose patients[END_REF]), especially in non-convulsive conditions or subclinical seizures (for a census and glossaries, see reviews [START_REF] Trinka | Which EEG patterns in coma are nonconvulsive status epilepticus?[END_REF][START_REF] Gelisse | Electroencéphalographie dans les états de mal épileptiques: Glossaire, protocole et interprétation[END_REF][START_REF] Kaplan | The EEG of status epilepticus[END_REF]). There are limited data on the existence or non-existence of scalp EEG biomarkers that can point to a specific cause, partly due to difficulties in performing high quality EEGs in ICUs, to achieve perfect interrater reliability and to establish a homogenous nomenclature shared by all clinicians [START_REF] Hirsch | Classification of EEG patterns in patients with impaired consciousness[END_REF]. However, a few EEG patterns can be relevant in the etiological investigation. These should be broken down into 2 categories: (1) EEG patterns that have been described in literature in a single etiology or that are undoubtedly syndrome-related; (2) EEG patterns with low specificity but suggestive of a "limited" set of etiologies that must be screened.

EEG patterns related to a single etiology or syndrome-related

Extreme delta brush activities (rhythmic high amplitude delta waves superimposed with beta frequency activity) best illustrate EEG patterns described in a single etiology. They have been essentially reported in anti-NMDA receptor encephalitis [START_REF] Schmitt | Extreme delta brush receptor encephalitis[END_REF][START_REF] Veciana | EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis[END_REF] (Figure 2A). Some EEG patterns during SE are considered as syndrome-related such as: the synchronous bilateral 3Hz spike and wave pattern of an absence seizure in idiopathic generalized epilepsy, the 1.5 to 2.0 Hz generalized spikes and waves during non REM sleep in continuous spike and wave during sleep syndrome (CSWS), the generalized spikes and wave activity from 1 to 2.5 Hz, associated with 10 Hz rhythms in atypical AS of Lennox-Gastaut syndrome. However, these patterns are not entirely specific. For instance, the CSWS pattern is encountered in more heterogeneous conditions as compared to a pure CSWS syndrome [START_REF] Veggiotti | Continuous spike-and-wave activity during slow-wave sleep: Syndrome or EEG pattern?[END_REF].

Less specific EEG patterns suggestive of a "limited" set of etiologies

Other EEG patterns suggestive of a "limited" set of etiologies provide some indirect clues in this sense through their morphological features, spatial distribution and temporal dynamics. The features of paroxysmal activities and their spatio-temporal dynamics (rhythmic vs periodic, or not) can, in some cases, provide information about the underlying epileptic process and contribute to characterizing the SE as partial or generalized. This first step helps in targeting etiological categories in the classifications listed above, especially for recognizing whether or not the SE is associated with a cerebral lesion or an epileptic syndrome.

In comatose NCSE, Bauer and Trinka proposed a distinction between coma with generalized periodic discharges (GPD) and coma with lateralized epileptiform discharges (LED) [START_REF] Bauer | Nonconvulsive status epilepticus and coma[END_REF]. GPDs include continuous generalized spiking, periodic spiking, burst suppression or bilateral triphasic waves. GPDs are mainly associated with diffuse brain disturbances (including infectious, toxic, metabolic and degenerative etiologies) and space-occupying lesions with brain stem compression. LEDs include continuous focal spiking, unilateral burst suppression, unilateral triphasic waves or periodic lateralized discharges. They are chiefly related to acute focal brain lesions, but they can be recorded in rare cases of diffuse disorders such as diabetic coma.

In comatose or non-comatose SE, periodic lateralized discharges are encountered in a broad spectrum of etiologies [START_REF] Grossman | Periodic EEG Patterns[END_REF] (Figure 2B-C). The ictal or pure lesional value of these paroxysms [START_REF] Garzon | Serial EEG during human status epilepticus: Evidence for PLED as an ictal pattern[END_REF], their inscription in an ictal-interictal continuum [START_REF] Rodríguez | Ictal-interictal continuum: A proposed treatment algorithm[END_REF] and even their definition (e.g., avoiding "epileptiform" in the acronym PLED) are still the subject of much debate. Their major common denominator is the frequent combination with peri-ictal MRI abnormalities [START_REF] Rennebaum | Status epilepticus: Clinical characteristics and EEG patterns associated with and without MRI diffusion restriction in 69 patients[END_REF] and the existence of a focal lesion, which must be investigated if not visible in primary scans (cerebrovascular, tumors, infectious diseases such as viral encephalitis, autoimmune encephalitis, dysplasia, prions, etc.).

Nevertheless, such lateralized and periodic activities have also been described in metabolic or electrolyte disorders (hypo/hyperglycemia, hypo/hypercalcemia, hypo/hypernatremia, hypo/hyperkaliemia and hypomagnesemia) and alcohol-related seizures [START_REF] Grossman | Periodic EEG Patterns[END_REF].

Caution is also required with triphasic waves, which should be more appropriately referred to as continuous from 1 to 3 Hz GPDs with triphasic morphology, as they can be found in comas of any origin [START_REF] Trinka | Which EEG patterns in coma are nonconvulsive status epilepticus?[END_REF]. Although commonly associated with toxic or metabolic encephalopathy, half of the triphasic waves recorded are associated with any type of metabolic disturbance [START_REF] Foreman | Generalized periodic discharges and "triphasic waves": A blinded evaluation of inter-rater agreement and clinical significance[END_REF].

Notwithstanding the foregoing, myriad criteria have been explored for their differentiation [START_REF] Boulanger | Triphasic waves versus nonconvulsive status epilepticus: EEG distinction[END_REF][START_REF] Kaplan | Proposition: Limbic encephalitis may represent limbic status epilepticus. A review of clinical and EEG characteristics[END_REF],

however, no criterion is specific enough for rendering them etiological biomarkers [START_REF] Oya | Mapping effective connectivity in the human brain with concurrent intracranial electrical stimulation and BOLD-fMRI[END_REF][START_REF] Husain | Generalized periodic epileptiform discharges: Etiologies, relationship to status epilepticus, and prognosis[END_REF][START_REF] Sutter | The neurophysiologic types of nonconvulsive status epilepticus: EEG patterns of different phenotypes[END_REF].

Rhythmic delta activity resembling frontal intermittent delta activity (occasional frontally predominant brief 2Hz generalized rhythmic delta activity) has been reported in confirmed or suspected autoimmune encephalitis [START_REF] Kaplan | Proposition: Limbic encephalitis may represent limbic status epilepticus. A review of clinical and EEG characteristics[END_REF]. However, frontal intermittent delta activity remains unspecific. For instance, it has also been recorded in the early stages of Creutzfeldt-Jakob disease before the periodic sharp wave complexes [START_REF] Hansen | Clinical changes and EEG patterns preceding the onset of periodic sharp complexes in Creutzfeldt -Jakob disease[END_REF] and in highly heterogeneous causes of brain lesions in ICUs with or without SE [START_REF] Mina | Clinical correlates and electroencephalographic features of FIRDA in a tertiary center[END_REF].

Algorithm for the rapid identification of SE etiologies

Given the diversity of SE etiologies and the need to treat them as early as possible, the use of a diagnostic algorithm is recommended. 5) [START_REF] Alvarez | Evaluation of a clinical tool for early etiology identification in status epilepticus[END_REF]. This questionnaire was tested on a cohort of 212 adults presenting with SE, based solely on the information available at the emergency room. It correctly identified the underlying etiology in 188 patients (88.7%). Therefore, the SEEIT should be considered as an invaluable tool for non-specialist physicians in promptly orienting their identification of the SE etiology. The 24 cases where etiology was not correctly identified were related to 4 main causes:

missing information in the initial MRI (30%) or in the anamnesis (12.5%), misinterpretation of the CSF results (20%) and situations considered as too complex to be diagnosed in the emergency room (12.5%, including autoimmune encephalitis, cerebral toxoplasmosis, etc.).

Conclusion

Etiology is one of the most important determinants of SE outcomes. Above all, mortality and morbidity are chiefly consequences of the underlying pathology and its complications, much more than a direct effect of the continuous epileptic activity itself. Moreover, SE may respond better to the treatment of the underlying cause than to the symptomatic treatment of SE. An "etiology-tailored" treatment should be initiated as early as possible, particularly in CNS infection, sepsis, metabolic disturbances, acute CVD and autoimmune processes.

It follows that etiological assessment is a cardinal axis for effective SE management. The first clinical step guides the etiological strategy according to age, medical history and SE type (especially when inaugural or non-inaugural in nature). The second step is based on an urgent standard biological assessment and brain imaging (MRI, whenever possible). If the etiology has not been identified, especially in the event of RSE, the workup should be completed by a spectrum of specific blood and CSF tests, and by a repeated or more detailed cerebral MRI, to identify etiologies that are more infrequent but more often associated with refractoriness (autoimmune or infectious encephalitis in patients of all ages, several genetic diseases in children). sometimes limited to graphs and must be analyzed cautiously (e.g., [START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF]152]). Columns colored in grey correspond to review articles. * Several patients had more than one etiology. Moreover, etiologies can overlap depending on authors' classification, as "Acute encephalitis with unidentified pathogen" which may correspond to CNS infection or to autoimmune encephalitis (with unidentified antibodies). Such overlap may explain total percentages different from 100%. When an etiology is not explicitly listed in authors' classification (e.g., autoimmune encephalitis), it may be classified in the "other" category. ** This systematic review includes data from various studies [START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF][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][START_REF] Sung | Status epilepticus in the elderly: etiology, seizure type and outcome[END_REF] on groups or subgroups of elderly patients and other younger adult patients [START_REF] Legriel | Functional outcome after convulsive status epilepticus[END_REF][START_REF] Delorenzo | A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia[END_REF][START_REF] Aminoff | Status Epilepticus. Causes, Clinical Features and Consequences in 98 patients[END_REF][START_REF] Legriel | Outcomes in 140 critically ill patients with status epilepticus[END_REF]

Figure 1 :

 1 Figure 1: Schematic representation of main SE etiologies in epileptic patients and new-onset SE. Approximate proportions are represented and partly inspired by a study conducted by Legriel et al. [27].

Figure 2 :

 2 Figure 2: Examples of SE with various etiologies in adults.

Figure 3 :

 3 Figure 3: Etiology, peri-ictal MRI abnormalities and ictal perfusion revealed by MRI in the acute

Figure 4 :

 4 Figure 4: Examples of SE with various etiologies in children.A: Convulsive SE induced by POL-G1 mutation in a 3 year-old child without any medical history. He developed a refractory right clonic SE, which progressively responded to a ketogenic diet. In the left panel, peri-ictal MRI abnormalities are visible in the left parieto-occipital area and thalamus (MRI diffusion and FLAIR, axial). Upon EEG, periodic lateralized discharges are visible mainly in the left posterior areas. B -Convulsive SE related to FIRES in a 6 year-old child, in a "viral context". However, no etiology was identified and SE became refractory. In the left panel, peri-ictal MRI abnormalities are visible in the left hemisphere (MRI diffusion and FLAIR, axial). Periodic lateralized activities are predominant in the left hemisphere upon EEG.

Figure 5 :

 5 Figure 5: Diagnostic workup. Adapted from Brophy et al. (2012) [96] (step 1), the SEEIT [7] (step 1 to 6) and Sculier and Gaspard (2019) [108] (step 7). It is pointed out that the SEEIT tool has been designed to guide SE etiology assessment in the emergency room and that step 7 must be conducted in a multidisciplinary effort between anesthetists and neurologists. The diagnostic workup should be completed as soon as possible. It should be used simultaneously and in parallel with the anti-seizure drug protocol. Specific screenings are outlined in Appendix 2.

1 .

 1 Preliminary check-up 2. Verify the diagnosis of the SE 3. Search for a known brain pathology: -prior epilepsy or seizures -history of brain damage -known progressive brain pathology (tumor, dementia, etc.) 4. New Onset SE: Absence of a known brain pathology Finger stick, vital signs monitoring Brain imaging Systematic biological assessment: blood glucose, ionogram (calcium, magnesium), CBC, renal function, LFT, AED levels if appropriate) + Specific biological elements according to the context EEG It is not a psychogenic non-epileptic seizure It is not epileptic seizures that do not meet the SE criteria Disturbance in the anti-epileptic treatment Systemic infection Intoxication or withdrawal (alcohol, drugs, treatments, etc.) Metabolic disorders Progression or modification of the underlying neurological condition, clinically or radiologically (new symptoms, tumor progression, bleeding, biopsy, recent surgery, etc.) Look for a brain pathology, acute, or previously asymptomatic EEG anomalies in favor of an idiopathic generalized epilepsy Intoxication or withdrawal (alcohol, drugs, medication, etc.) Metabolic disorders Severe systemic infection There is no acute etiology and antiepileptic treatment must be adapted SE is possibly cryptogenic (of unknown cause) Brain MRI (especially in case of normal CT scan & if any clinical or EEG focal signs) Normal screening Good evolution with AED + None of these etiologies identified 5. Refractory SE without a clear explanation -fever or systemic inflammatory response without clear systemic explanation -meningeal stiffness -unusual headache -new neurological abnormalities or recent behavioral changes 6. Record of suspected etiology 7. Cryptogenic RSE after 48 hours or NORSE (screenings details in table 3) Look for meningo-encephalitis Consider empirical anti-infective treatment Blood cultures Lumbar puncture (in the absence of contraindication) At the end of the initial assessment, after each point has been appraised Complete investigations 1. Standard biological assessment 2. Brain MRI with angiography and venography 3. Lumbar puncture 4. Infectious screening 5. Autoimmune screening 6. Toxicological screening Consider further investigations 7. Oncological screening 8. Screening for inborn error of metabolism & mitochondrial disorder 9. Genetic screening (consider it earlier in children)

  Alvarez et al. developed a questionnaire (SEEIT -Status Epilepticus Etiology Identification Tool) contributing to a rapid etiological diagnosis of SE, which can be used at the bedside in the emergency department or in the ICU, and comprising a few successive steps (summarized in Figure

10 .

 10 Consider brain biopsy

	Autoimmune encephalitis	NS	NS	NS	NS	NS	Anti-NMDAr encephalitis : 0.4%	2.5%	NS	17%	NS	patients with prolonged febrile seizures) NS (But a total of 32% with seizure) febrile prolonged	Ventriculitis: <1% Abscess: <1% HSV encephalitis: 2% Mycoplasma 2.5% Acute encephalitis pathogen: 9% unidentified with	NS	NS	NS
							Neuro-						peumoniae: 1%
	Brain/CNS tumors Other (neurodegene rative diseases, genetic disorders, systemic diseases, etc.) Number of patients Design Antiepileptic medication-related (withdrawal/n onadherence/r ecent change/low level) Alcohol related Medication-related CNS infection (Encephalitis/ meningitis) metabolic disorders Acute Post-anoxic Traumatic brain injury resistant epilepsy Pharmaco-withdrawal) (intoxication/ Acute stroke or vascular sequelae (cerebrovasc ular diseases) Unknown	6% 2% 154 Retrospect. 25 % 9% 8% 4% 4% 5% 5% 25% 4% 5%	Acute (primary/me tastatic): 7% Remote: 2% NS 204 (including children) Prospective Multicentric 34% 3% (drug overdose) 3% 15% 5% Hypoxia:13% Anoxia: NS NS 13% Acute CVD (vascular occlusion, embolism, or hemorrhagic infarct): 22% Remote CVD: 22% Acute intracerebral or subarachnoid hemorrhage: 1% Remote hemorrhage: 3% 3%	12% Other remote symptomatic (NS): 26.7% 150 Prospective Multicentric 8.7% 10.7% NS 8.7% NS Remote: 7.3% NS 8.7% Remote stroke: 36% Binswanger disease:16.7% Acute stroke (ischemic and hemorrhage): 14% 8.7%	11% 13% 111 Prospective Monocentric 23% 9% 6% 9% Excluded 17% 13% 17% 34% NS	8.1% 6.9% 248 Prospective Multicentric 17.3% 5.2% 8.1% 14% Excluded 3.2% NS 17.7% 19% 16.9%	With acute changes (bleeding/incr ease/biopsy/e dema): 2.36% No acute change: 13.2% degenerative diseases: 0.9% Systemic infection/sepsis: 4.7% Multiple sclerosis: 1.4% Neuro-sarcoidosis:0.4% Tumoral meningitis: 0.9% Micro-angiopathic hemolytic 212 Prospective Multicentric 16% withdrawal: 1.9%. See acute 5.66% metabolic) 4.72% (toxic-Excluded Remote: 2.8% Acute: 3.3% disorders. factors: 7.55% metabolic provocative structural without epilepsy non-Benzodiazpine Known bleeding: 0.4% 2.8% Acute hemorrhagic: 9.9% Remote vascular event: ischemic event: 2.36% Remote hemorrhagic: 3.77% without malformation Arteriovenous 0.4% Eclampsia: PRES: 1.4% Acute 6.6% anemia: 0.4% 5.2%	NS NS 570 Retrospective NS 3.3% NS Excluded NS NS NS NS NS NS	5.5% 4.3% 486 Systematic review 20.3% 6.2% 11.3% Excluded 2.3% 6.2% NS 14.2% 17.7% 21.8%	0% Porphyria: 3% Pyridoxine deficiency: 3% 29 Systematic review 10% 3% (HSV) 0% NS 0% 0% NS 0% angioma: 3% Cavernous 3% hemorrhage: Subarachnoid other causes: 55%) Cortical venous thrombosis: 17% related to PRES/RCV: 38% (including eclampsia: 45%, PRES 0%	1% Remote symptomatic: 39% (prior history of CVD, CNS infection, congenital malformation , genetic disease, trauma, hemorrhage, or tumor). 204 (including adults) Prospective Multicentric 21% 52% 7% Hypoxia: 4% Anoxia:1% 1% 3% (drug overdose) (See Other) NS 1% 9% 5%	Initiate or continue empirical anti-infectious treatment Abnormal CSF Acute encephalitis with unidentified pathogen: 9% NS, see Other (remote and acute on remote symptomatic) 3.5% Neuro-degenerative encephalopathy: 5% Remote 16% Acute on remote symptomatic 16% Mitochondrial disease/ Neurocutaneous syndrome: 2% Acute systemic, gastrointestinal or respiratory disease: 2% Consider diagnosis of autoimmune encephalitis No infection identified factorial:11 Normal CSF SE is cryptogenic 8% 4.8% Dementia 8.6% Multi-% : 9.3%% Nonvascu Hypoxem lar ia: 5.3% dementia: Systemic 44.4% infection: 6.3% Autoimmune encephalitis should be investigated Do not forget that CSF can be normal in the acute phase of viral encephalitis Still cryptogenic No etiological diagnosis despite extensive workup 226 (176 first ever SE) 236 342 63 302 Prospective Multicentric Prospective Multicentric Retrospect. Monocentric Case control study Syste-matic review See medication-related NA NS Alcohol intoxication or withdrawal, drugs: 17.4% 9.6% Bacterial meningitis: 6% Viral meningitis: 4% Bacterial meningitis pneumoniae: 1.5%, Neisseria meningitides: <1%, Escherichia coli <1%) 2% Infectious disease with fever: 30.2% 3% 6% 10% 64% 20.9% 2.9% <1% 2.5% NS 1.6% Excluded (Streptococcus vascular causes 2% symptomatic in 21% 7.9% 9.3% See remote <1% <1% NS NS NS NA NS NS NS 0% 0% NS 5.4% <1% abnormalitie: Vascular CNS 1.5% 1% Cerebral palsy: 44.4% <1% Chronic: hemorrhage: 35% 52.3% Intracranial 15.9% symptomatic Acute: Remote ar insult': <1% "Idiopathic": Acute ''Cerebrovascul 2% PRES: <1% 10% "Cryptogenic": 10% 13% NS 4.6%
												(among a total	Tuberculosis:
												of 32%	1%

Table 1

 1 legends: Approximate proportions are listed and more details are available in cited articles. Extracting approximate percentages was

  . CVD: Cerebrovascular disease. NA: Not applicable. NS: Not specified. PRES: Posterior reversible encephalopathy

syndrome; RCVS: Reversible vasoconstriction syndrome; Retrospectiv.: Retrospective trial; yo: year(s) old. Some trials (e.g.,

[153]

) were not included in the Table because of insufficient details concerning SE etiologies for classification.

Acknowledgements

We would like to express our gratitude to our colleagues from the departments of Neurology, Neuropediatrics, Neuroradiology, Neurosurgery and Neurological ICU for their help in SE management, and especially to: Jean-François Albucher, Blandine Acket, Agnès Annick, Fabrice Bonneville, Lionel Calvière, Claude Cancès, Pascal Cintas, Rachel Debs, Vincent Fabry, Thomas Geeraerts, Béatrice Guyard-Boileau, Muriel Kany, Delphine Larrieu-Ciron, Jean-Albert Lotterie, Jérémie Pariente, Nicolas Raposo, Annick Sevely, Jean Christophe Sol and Michel Tiberge.

Funding/conflicts of interest: None.