Julia Jacobs

Jagarlapudi M Murthy

Marie Benaiteau
email: marie.benaiteau@chu-lyon.fr

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

Ludovic Gardy

Marie Denuelle

Rachel Debs

Valentin Wucher

Florence Rulquin

Emmanuel J Barbeau

Fabrice Bonneville

Jérémie Pariente

Jonathan Curot
email: curotjonathan.curot@cnrs.fr

Specific profiles of new-onset vs. non-inaugural status epilepticus: From diagnosis to -year outcome

Keywords: status epilepticus, new-onset status epilepticus, new-onset refractory status epilepticus (NORSE), peri-ictal MRI abnormalities, outcome, epilepsy, refractory status epilepticus (RSE)

While new-onset status epilepticus (NOSE) is a harbinger of chronic epilepsy, prospective medical data are sparse in terms of specifying whether the evolution of status epilepticus (SE) and seizure expression in NOSE resembles what occurs in patients who have already been diagnosed with epilepsy [non-inaugural SE (NISE)] in all aspects apart from its inaugural nature. The aim of this study was to compare the clinical, MRI, and EEG features that could distinguish NOSE from NISE. We conducted a prospective monocentric study in which all patients ≥ years admitted for SE over a -month period were included. A total of patients ( NISE and NOSE cases) were included. Despite similar modified Rankin scores before SE, several aspects of the clinical history distinguished NOSE from NISE patients. NOSE patients were older and frequently had neurological comorbidity and preexisting cognitive decline, but they had a similar prevalence of alcohol consumption to NISE patients. NOSE and NISE evolve in the same proportions as refractory SE ( . % NOSE, % NISE) and share common features such as the same incidence ( % NOSE, % NISE, and p = . ) and volumes of peri-ictal abnormalities on MRI. However, in NOSE patients, we observed greater non-convulsive semiology ( . % NOSE, % NISE, and p = . ), more periodic lateral discharges on EEG (p = .

), later diagnosis, and higher severity according to the STESS and EMSE scales (p < .

). Mortality occurred in . % of NOSE patients and % of NISE patients at year (p = . ), but with di erent causes of death occurring at di erent time points: more early deaths directly linked to SE at month occurred in the NOSE group, while there were more remote deaths linked to causal brain lesions in the NISE group at final follow-up. In survivors, . % of the NOSE cases developed into epilepsy. Despite acute causal brain lesions, the novelty related to its inaugural nature is still too often associated with a delay in diagnosing SE and a poorer outcome, which justifies the need to more clearly specify the various types of SE to constantly raise awareness among clinicians. These results highlight the relevance of including novelty-related criteria, clinical history, and temporality of occurrence in the nosology of SE.

. Introduction

It is interesting to note that recent acronyms and definitions of status epilepticus (SE) include the following references to time and the novelty of occurrence: new-onset status epileptic (NOSE) [START_REF] Jafarpour | New-onset status epilepticus in pediatric patients: causes, characteristics, and outcomes[END_REF], new-onset refractory SE (NORSE) [START_REF] Hirsch | Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions[END_REF][START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF], late-onset absence SE (4), and subacute encephalopathy syndrome in alcoholics (SESA) [START_REF] Fernández-Torre | Subacute encephalopathy with seizures in alcoholics (SESA syndrome) revisited[END_REF]. Could the mode of onset, novelty, and temporal context be key to understanding SE? What makes NOSE a specific clinically relevant pathological entity that is distinguishable from other types of SE, i.e., non-inaugural SE that occurs in patients with epilepsy (NISE)?

Only recently have the temporality of onset and novelty become an integral part of the definitions of SE. Since the pioneer definitions of SE (4), many "mechanistic" or "operational" definitions of SE have been proposed [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] Gastaut | The significance of certain epileptic fugues; concerning a clinical and electrical observation of temporal status epilepticus[END_REF][START_REF] Gastaut | Clinical and electroencephalographical classification of epileptic seizures[END_REF][START_REF] Berg | Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009[END_REF][START_REF] Lowenstein | Status epilepticus: an overview of the clinical problem[END_REF][START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF]. Until now, they have been exclusively based on semiology (convulsive or non-convulsive, generalized or focal, etc.). The temporal dimension has long been considered regarding the duration of SE but not in the context of its onset. Operationally, NOSE is defined as "prolonged seizures lasting more than 5 min or the presence of recurrent seizures without return to baseline in between in patients with no previous history of epilepsy" [START_REF] Chakraborty | The clinical spectrum of new-onset status epilepticus[END_REF]. However, this definition remains non-consensual. SE nosology is constantly evolving due to the clinical heterogeneity of its semiology, a complex poorly understood pathophysiology [START_REF] Wasterlain | Pathophysiological mechanisms of brain damage from status epilepticus[END_REF][START_REF] Chen | Status epilepticus: pathophysiology and management in adults[END_REF], multiple etiologies [START_REF] Valton | Etiological assessment of status epilepticus[END_REF], and difficulties conducting prospective studies.

Clarifying the definition of NOSE is essential as the incidence is significant. Approximately half of all adult cases of SE (up to 59%) are inaugural in non-epileptic patients [START_REF] Hesdorffer | Incidence of status epilepticus in Rochester, Minnesota, 1965-1984[END_REF][START_REF] Coeytaux | Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR)[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in germany: a prospective, population-based study[END_REF][START_REF] Vignatelli | Epidemiology of status epilepticus in a rural area of northern Italy: a 2-year population-based study[END_REF][START_REF] Sutter | Mortality and recovery from refractory status epilepticus in the intensive care unit: a 7-year observational study[END_REF][START_REF] Malter | New onset status epilepticus in older patients: clinical characteristics and outcome[END_REF]. The incidence of NOSE was found to be 16.3/100,000 to 36/100,000 adults per year depending on the cohort and whether or not the new ILAE 2015 definition and classification of SE was taken into account [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] Leitinger | Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes[END_REF]. However, despite the incidence, knowledge of the clinical, EEG, and MRI spectrum of NOSE in adults is mostly based on retrospective data [START_REF] Chakraborty | The clinical spectrum of new-onset status epilepticus[END_REF][START_REF] Malter | New onset status epilepticus in older patients: clinical characteristics and outcome[END_REF][START_REF] Deng | The clinical analysis of new-onset status epilepticus[END_REF][START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF][START_REF] Rennebaum | Status epilepticus: clinical characteristics and EEG patterns associated with and without MRI diffusion restriction in 69 patients[END_REF].

One of the few consensual elements concerning NOSE is a poor prognosis and a possible progression to refractory SE (i.e., NORSE) [START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF][START_REF] Treiman | A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group[END_REF][START_REF] Santamarina | Prognosis of status epilepticus (SE): relationship between SE duration and subsequent development of epilepsy[END_REF][START_REF] Gaspard | New-onset refractory status epilepticus: etiology, clinical features, and outcome[END_REF]. Mortality in 1 month is 20-61% depending on the cohort. Factors of poor prognosis are the age of the patient [especially over 65 years [START_REF] Chakraborty | The clinical spectrum of new-onset status epilepticus[END_REF]], etiology, and the duration of the SE (15-17, 23, 24, 29, 30). Tracheal intubation and co-infections are additional factors of adverse outcomes [START_REF] Deng | The clinical analysis of new-onset status epilepticus[END_REF].

In survivors, a poor prognosis for NOSE also suggests the onset of a chronic illness. More than 58% of survivors may experience seizures, mainly related to acute or progressive brain injury, the duration of SE (significant threshold at 24 h) being the only independent predictor of the development of chronic epilepsy after SE [START_REF] Santamarina | Prognosis of status epilepticus (SE): relationship between SE duration and subsequent development of epilepsy[END_REF]. Paradoxically, some series also showed that progression to NORSE had no influence on functional outcome or mortality at the last follow-up, while SE semiology (non-convulsive vs. convulsive and loss of consciousness) or age above or equal to 65 did not predict progression to NORSE [START_REF] Chakraborty | The clinical spectrum of new-onset status epilepticus[END_REF].

If NOSE is a precursor to chronic epilepsy, it could be hypothesized that its presentation resembles NISE in all aspects apart from its inaugural nature. However, the medical literature is unable to demonstrate this. None of the studies cited above investigated the discriminating features between NOSE and NISE. In addition, little information is available on the paraclinical aspects associated with NOSE, and the most recent publications frequently focused on the refractory subtype of these de novo SE [START_REF] Hirsch | Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions[END_REF][START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF][START_REF] Werbaneth | A retrospective cohort study of new-onset refractory status epilepticus (NORSE): clinical features, timing of immunotherapy and outcomes[END_REF].

Although it is now well-established that NOSE can develop into epilepsy, to our knowledge, there is no prospective trial that compares the clinical, MRI, and EEG patterns that may distinguish NOSE from NISE. Does the mechanism that leads to epilepsy result in a specific clinical pattern of SE? Are there imaging and electrophysiological criteria that distinguish NOSE from NISE? Do NOSE and NISE progress similarly and have the same prognosis?

To clarify these questions, we conducted a prospective monocentric study to multimodally compare NOSE and NISE at baseline (before SE), during SE, and at follow-up in 1, 3, and 12 months. The aims of this study were [START_REF] Jafarpour | New-onset status epilepticus in pediatric patients: causes, characteristics, and outcomes[END_REF] to compare clinical and paraclinical (brain imagery and electrophysiological recordings) features of NOSE (including NORSE) and NISE; [START_REF] Hirsch | Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions[END_REF] to study the outcome of SE at 1, 3, and 12 months as well as the prognostic factors; and (3) more specifically to analyze peri-ictal MRI abnormalities. We hypothesized that NOSE and NISE each have their own specificities, particularly in terms of outcomes. We hoped to identify new markers for positive diagnosis and the prognosis of inaugural SE.

. Methods

. . Design and population

Our work is a prospective, observational, descriptive, singlecenter study (Figure 1). We collected clinical, neuroradiological, and electrophysiological data for each patient admitted consecutively to Toulouse University Hospital from December 2015 to June 2016 [START_REF] Jafarpour | New-onset status epilepticus in pediatric patients: causes, characteristics, and outcomes[END_REF] for SE and (2) SE not clinically diagnosed immediately on admission but subsequent to the first EEG. To select these patients, all EEGs performed during this period and all requests for EEGs for SE were screened. The inclusion criteria were a diagnosis of SE confirmed by a neurologist, exclusion of post-anoxic SE, age of 18 years and older, and non-refusal to participate in the study. The use of the data in our study was approved by the Regional Ethics Committee at Toulouse University Hospital (CPP Sud-Ouest no. 04-1215).

. . SE definitions and classifications

Epilepsy is defined as a lasting predisposition to generate seizures and the cognitive, behavioral, psychological, and social consequences of this condition [START_REF] Fisher | ILAE official report: a practical clinical definition of epilepsy[END_REF]. NOSE was defined as the occurrence in patients without a history of SE or uncured epilepsy (cured epilepsy is the absence of seizures in the absence of treatment for more than 5 years). The following functional and semiological definitions were used for either NOSE or NISE.

NOSE

ACUTE PHASE

Drug resistance

FIGURE

Study design, selection of patients, and SE classification. Five patients were secondarily excluded from the NOSE group ( with myoclonus of the left upper limb secondary to spinal cord ischemia, with vigilance fluctuations due to a post-traumatic brainstem lesion, with a reactive coma and abnormal movements secondary to severe intra-parenchymal hemorrhage, with psychomotor agitation and vagal discomfort with the loss of consciousness due to pain, and with a first psychogenic non-epileptic status). A total of patients were secondarily excluded from the NISE group ( with a psychogenic non-epileptic status, with serial seizures but complete clinical recovery between seizures, with a prolonged post-ictal deficit and/or post-ictal agitation, and with chronic meningitis on ventriculoperitoneal shunt, abnormal eye movements, and intracranial hypertension with no argument for seizures).

The definitions used for generalized and focal convulsive SE were [START_REF] Brophy | Guidelines for the evaluation and management of 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] Outin | le groupe d'experts. 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] the occurrence of at least two epileptic seizures in a short interval without complete recovery of a stable neurological status between seizures; ictal clinical or electrical activity lasting 5 min or more for generalized seizures and 10 min or more for focal seizures; serial seizures; and seizures followed by a coma or persistent confusion.

The definition used for non-convulsive SE (NCSE) was based on the Salzburg consensus criteria [START_REF] Leitinger | Salzburg consensus criteria for non-convulsive status epilepticus-approach to clinical application[END_REF][START_REF] Leitinger | Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study[END_REF]. We considered that an NCSE was certain if there was an association with an acute qualitative or quantitative alteration of consciousness without prominent motor symptoms or persistent after a clinical seizure with motor manifestation, not otherwise explained, and electrical confirmation by EEG (pattern of epileptiform discharges at a frequency >2.5 Hz present for more than 10 recorded seconds). When epileptiform discharges were present <2.5 Hz in the worst 10s epoch or there was no epileptiform discharge but only continuous rhythmic delta-theta activity >0.5 Hz, the following secondary criteria were fulfilled: (a) typical spatio-temporal evolution or (b) subtle clinical ictal phenomena were present during the patterns, or (c) a clear clinical and EEG improvement after intravenous administration of an appropriately chosen anti-seizure medication (ASM) was documented.

. . Clinical data

In the acute phase, we collected the following data: age, gender, personal history, modified Rankin score (mRS) before SE (at baseline), medications, clinical symptoms of the seizures observed during SE, and post-ictal deficit. Severe and lifethreatening complications were specified: respiratory distress, including infectious pneumonia, hemodynamic instability (systolic blood pressure <90 mmHg; the need for vasoamines), and traumatic complications.

SE duration was calculated or estimated through a combination of clinical and EEG data. SE was considered refractory if it persisted 30 min after the introduction of a first-and second-line ASM [START_REF] Lowenstein | Status epilepticus: an overview of the clinical problem[END_REF][START_REF] Mayer | Refractory status epilepticus: frequency, risk factors, and impact on outcome[END_REF] and super-refractory if it persisted at least 24 h after the start of general anesthesia [START_REF] Ferlisi | The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy[END_REF][START_REF] Kantanen | Incidence and mortality of super-refractory status epilepticus in adults[END_REF].

The etiologies and/or contributing factors of SE were classified according to the ILAE Task Force definition: acute etiologies, sequelae or old structural abnormalities, progressive etiologies, known epileptic syndromes, and unknown etiologies [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] Trinka | 25 years of advances in the definition, classification and treatment of status epilepticus[END_REF]. SE severity was rated by two scales, namely, the Status Epilepticus Severity Score (STESS) [START_REF] Rossetti | Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy[END_REF] and the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) [START_REF] Leitinger | Epidemiology-based mortality score in status epilepticus (EMSE)[END_REF].

The cognitive status of non-epileptic patients before SE was estimated using the long version (a 26-item questionnaire) of the IQ CODE [START_REF] Jorm | The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms[END_REF]. In the literature, the threshold chosen for diagnosing dementia is 3.4/5 [START_REF] Jorm | The Informant Questionnaire on cognitive decline in the elderly (IQCODE): a review[END_REF].

The chronology of follow-up was 1, 3, and 12 months to detect early, medium-term, and late complications, respectively (mRS, onset of recurrent epileptic seizures or new SE, and death). Cognitive complaint and focal neurological deficit were specified at 3 months.

. . Electrophysiological data

Scalp-EEGs (9-21 surface electrodes, 256 Hz sampling rate) combined with video and ECG were recorded with the Deltamed system (Natus Medical Incorporated). At least 20 min were recorded for each patient (12 patients were monitored for several hours). The time period between the first EEG and the onset of symptoms was noted. EEG recordings were analyzed by clinical electrophysiologists (JC, MB, MD, RD, and LV). EEGs were classified as "normal, " "sedation EEG, " "ictal, " or "post-ictal" EEG. Epileptic activities were divided into "periodic discharges, " "rhythmic delta discharges, " and "paroxysmal abnormalities" (i.e., spikes, polyspikes, and spikes-andwaves) [START_REF] Trinka | A definition and classification of status epilepticus-Report of the ILAE Task Force on Classification of Status Epilepticus[END_REF].

. . MRI

We used two 3T imagers (Magnetom Skyra, Siemens Healthcare and Achieva, Philips Medical System) in the clinical neuroradiology department. An MRI was performed urgently as soon as the patient's condition allowed, ideally within 72 h of the diagnosis of NOSE and if considered necessary for the care of patients with NISE. A minimum of the following sequences was performed: DWI, ADC mapping, fluid-attenuated inversion recovery (FLAIR), T1 with gadolinium, and gradient-recalled echo T2 * . The presence of PMAs in DWI and FLAIR sequences, the volume of PMAs in DWI, the presence and type of old cerebral lesions, and SE etiology were analyzed by a trained neuroradiologist and neurologist (FB and MB). When other lesions (peritumoral edema, gliosis, acute stroke, etc.) could explain the abnormalities in DWI and FLAIR, these were not considered as PMAs.

We semi-automatically quantified the PMA volume in DWI using OLEA software in a one-shot analysis with manual correction [Olea Sphere R version 2.3, cutting thickness of 3 or 4 mm, technique validated for ischemic stroke [START_REF] Nicoli | The combination of baseline magnetic resonance perfusion-weighted imaging-derived tissue volume with severely prolonged arterial-tissue delay and diffusion-weighted imaging lesion volume is predictive of MCA-M1 recanalization in patients treated with endovascular thrombectomy[END_REF]]. The PMA volume was estimated using the average of three different segmentations for each patient. The standard zones of the magnetic susceptibility artifact were systematically trimmed.

If an MRI control was required, it was scheduled on the same 3T machines within 3 months of the SE.

. . Statistical analyses

To compare the NOSE and NISE groups, we used the chisquare test for qualitative variables, except when the theoretical numbers were <5, in which case, Fisher's test was used. To compare quantitative variables, we used the Wilcoxon test. To limit the risk of type-1 errors associated with multiple comparisons, we corrected the alpha values using the Bonferroni method. The alpha values to be considered are indicated below the figures or tables (in general, the alpha value = 0.05/90). Due to the inherent heterogeneity of clinical data and the multiple comparisons made, we considered "tendencies" for p < 0.05 but above the corrected threshold. We only considered significant p-values below the corrected alpha values. For post-hoc analyses, Tukey's test was used (p-values automatically adjusted for multiple comparisons).

To study the impact on outcome (mRS) at different timestamps for predictive factors such as the presence or absence of PMA, drug resistance, or status epilepticus, we performed multiple linear regressions. We used linear mixed-effects models in which the variable "patient" was considered a random effect. The variables "measurement time" (baseline, first month, third month, and twelfth month), drug resistance (1/0), with or without PMA (1/0), and new-onset status epilepticus (1/0) were considered as fixed effects. Finally, Pearson correlations were performed. The corrected p-value was considered for the significance threshold for linear mixed-effect models, and the Pearson correlation was 0.017 (0.05/3).

. /fneur. .

. Results

. . A large prospective cohort of SE including NOSE and NISE

During the 6 months, 2,305 EEGs were performed, allowing the inclusion of 127 patients who had been treated for SE. A total of 18 patients initially considered as having SE were excluded after revision of the diagnosis a posteriori: five patients from the NOSE group and 13 epileptic patients from the NISE group. Therefore, 109 patients (46 NOSE and 63 NISE cases) were finally included (Figure 1).

. . Clinical history distinguishing NOSE and NISE patients

Clinical data are presented in Table 1. Despite a similar level of autonomy on the mRS before SE, patients experiencing NOSE tended to be older (p < 0.01, alpha = 0.0006). The same proportion of excessive alcohol consumption, psychiatric history, and use of psychotropic drugs was found in both groups. Alcohol abuse or dependence was directly involved in 5 NOSE patients and 6 NISE patients. The IQ code before SE was obtained for the NOSE group only: 28/46 (61%) patients had a score of ≥3.4/5, which is above the threshold indicating significant cognitive impairment that affects autonomy in daily life. All patients in the NISE group had been on ASM (median = 1, min = 1, max = 5). In total, 24 of 57 NISE patients (42%) had a history of SE (data are lacking for six subjects). Epilepsy was considered stabilized (seizure-free patients) for 38 of 59 patients before the onset of SE (data are lacking for four patients).

. . A higher frequency of acute brain lesions on imagery in NOSE

Acute brain lesions on imagery were significantly more frequent in the NOSE group (n = 10, p < 0.0001, and alpha = 0.0006). This included three severe traumatic brain injuries, three infectious diseases (pneumococcal meningitis, HSV1 herpes meningoencephalitis, and empyema with extensive cerebral venous thrombosis), 1 posterior reversible encephalopathy syndrome, 1 inflammatory cerebral amyloid angiopathy, 1 junctional ischemic stroke (M1 stenosis), and 1 undetermined meningoencephalitis leading to NORSE. Cases of acute brain etiologies in NISE patients were 2 severe head traumas (one of which was due to acute alcohol intoxication) and 1 ischemic stroke during meningioma surgery.

Progressive etiologies were all already known before SE in the NISE group and included a large majority of brain tumors (5 glioblastomas, 3 meningiomas, 2 brain metastases, and 1 cerebral lymphoma) and 1 patient with Alzheimer's disease and cerebral amyloid angiopathy, whereas 5 of 7 were discovered during SE evaluation in the NOSE group (2 glioblastomas, 1 brain metastases due to small cell lung cancer, 1 brain lymphoma recurrence, 1 cerebral cavernoma, and 2 cases of Alzheimer's disease).

Remote brain lesions were mainly post-traumatic and of a vascular, ischemic, or hemorrhagic nature.

. . Other heterogeneous acute factors that trigger NOSE and NISE

Other acute triggers could be associated and included forgetting ASM for 13 NISE patients (20.6%), sleep deprivation (4 NISE patients), stress (2 NISE patients), fever/sepsis (5 NOSE and 8 NISE patients), and drugs that lower the epileptic threshold (4 NOSE and 6 NISE patients). Among the 4 patients in the NOSE group with no etiology found at the time of SE, two were chronically heavy consumers of cannabis.

. . Beyond novelty or a history of epilepsy, a di erent expression of NOSE and NISE NOSE tended to be diagnosed later, with a maximal delay in the diagnosis of 15 days (vs. 30 h for NISE, p = 0.06, alpha = 0.0006) and a median of 60 min for NOSE vs. 10 min for NISE, resulting in diagnostic and therapeutic delays (p = 0.006 and p = 0.09, respectively, alpha = 0.0006) (Table 1). SE duration was heterogeneous: on average 62 h for NOSE vs. 23 h for NISE (p = 0.33). In both groups, SE lasted ≥24 h in one-third of the patients and if associated with severe complications required resuscitation management in 35% of the cases. The mean duration of hospitalization was 13 days for the NOSE group [min = 4, max = 96, median = 10 days] and 10 days for the NISE group [min = 1, max = 117, median = 7 days]. Progression to refractory SE was not significantly different between the groups (p = 0.93).

The following heterogeneous types of SE were encountered in both NOSE and NISE: generalized convulsive, focal convulsive, initially non-convulsive, or secondary generalized convulsive in similar proportions (Table 1). However, secondary non-convulsive SE tended to be more prevalent in NOSE than in NISE (21.7% in NOSE, 6% in NISE, p = 0.02, alpha = 0.0006). NOSE patients tended to have more post-ictal focal neurological deficits and a greater number of severe complications, especially hemodynamic complications (p = 0.04 and alpha = 0.0006).

SE severity was significantly higher in NOSE than in NISE. STESS and EMSE scores were above the poor prognosis threshold in 78% of NOSE vs. [START_REF] Mayer | Refractory status epilepticus: frequency, risk factors, and impact on outcome[END_REF]

. . Di erent proportions of poor outcomes between baseline and the last follow-up in NOSE and NISE

There was no global effect of the inaugural or non-inaugural nature of SE on the outcome (p = 0.373) according to a mixed-effects model. Nevertheless, there was an interaction between the type of SE and the mRS at baseline, and in 1, 3, and 12 months (p < 0.017). This suggests that mRS between baseline and 12 months changes at a different speed between the two groups of patients (Figures 2,3). For NISE patients, mRS at baseline was only different from the mRS at 12 months (Tukey's HSD test, diff = 1.05, and p = 0.0005). For NOSE patients, the mRS at baseline was different from the mRS at 1 month (Tukey's HSD test; diff = 1.28; and p = 0.0033), 3 months (Tukey's HSD test, diff = 1.46, and p = 0.0006), and 12 months (Tukey's HSD test, diff = 1.76; and p = 0). Finally, in NOSE and NISE combined, we observed positive correlations between outcomes at the final follow-up (mRS at 12 months) and in descending order on both the STESS (Pearson correlations, r = 0.455, p = 1 -06 , and alpha < 0.017) and EMSE scores (Pearson correlations, r = 0.326, p = 0.0006, and alpha < 0.017) as well as the duration of SE (Pearson correlations, r = 0.217, p = 0.002, and alpha < 0.017).

There was a recurrence of SE in 13 patients with NOSE (28.2%) and in 15 patients with NISE (23.8%) at 1 year but at different times: there was a recurrence in the first month in 7 cases of NOSE but only in 1 case of NISE (Fisher test, p = 0.01). For patients who did not die during the acute phase of SE, 17 of 39 patients with NOSE developed epilepsy (43.6%) and 29 of 52 patients with NISE had a recurrence of seizures in the year following SE (55.7%, data lacking for 11 patients). In survivors at 3 months, there was a cognitive complaint in 57% of the NOSE patients (57%) vs. 71% of the NISE patients and a focal (motor of language) deficit in 26% of NOSE and 43% of NISE cases.

. . Di erent causes of death at di erent time points in NOSE and NISE

At the final follow-up, mortality was observed in 32.6% of NOSE vs. 20.6% of NISE patients (p = 0.19). However, rates of death varied according to time points (Figure 3). This occurred within the first month in 15% of NOSE patients and 6% of NISE patients. The cumulated rate increased to 24% and 8% at 3 months (p = 0.02 and alpha = 0.0006; Table 1). The patients who died in 1 year all had refractory SE except for 1 NOSE and 2 NISE cases (25 refractory SE/28 deaths, 89%). The causes of death were diverse and variable according to the time. in the PMA group, r = . in the non-PMA group). Alpha = . / = . .

In the NISE group, at 1 month, death was related to the direct consequence of a refractory SE (1 patient), to the causal lesion induced by SE (2 patients with glioblastomas), and to a probable SUDEP (1 patient); at 3 months to invalidity (one 90-year-old patient); and at 1 year, to brain tumors (3 patients with glioblastomas and 2 patients with brain metastases), and to invalidity (3 patients with multiple pathologies).

In the NOSE group, at 1 month, death was related to the direct consequence of SE (five 54-to 95-year-old patients with organ failure after NORSE), at 3 months, to organ failure in super-refractory SE (one 56-year-old man) and to invalidity after SE in a context of multiple pathologies (three 72-to 91-year-old patients), and at 1 year, to glioblastoma (1 patient) and to progressive invalidity (three 62-to 101-year-old patients).

. . The same proportion of refractory NOSE and NISE

We observed similar numbers of pharmacoresistant NOSE and NISE cases (62% and 61%, respectively). According to the mixedeffects model, there was no global effect of refractoriness on the outcome, but there was an interaction between refractoriness and the time of the mRS assessment. This indicates that between baseline and 12 months, mRS changed in different proportions in refractory and non-refractory SE (considering both NOSE and NISE). Refractory SE had an average mRS of 2.01 at baseline, 3.08 at 1 month, 3.24 at 3 months, and 3.60 at 12 months. Non-refractory SE had an average mRS of 2.01 at baseline, 3.08 at 1 month, 2.58 at 3 months, and 2.97 at 12 months. Considering that the time of mRS assessment had a different effect on refractory and non-refractory SE, we analyzed these two groups independently. For refractory SE, baseline mRS was different from the mRS at 1 month (diff = 1.06, p = 0.003), 3 months (diff = 1.24, p = 0.0004), and 12 months (diff = 1.6, p = 0). For non-refractory SE, mRS after SE was different from baseline only at 12 months (diff = 0.95, p = 0.002).

. . No discriminating value for peri-ictal MRI abnormalities

A total of 54 patients (30 NOSE and 24 NISE cases) had a 3T MRI during the initial hospitalization for SE (MRI performed within the first 72 h of admission in 35 patients). MRI revealed an acute brain etiology in 9 patients with NOSE (30%), none in NISE patients, and old brain lesions in 18 patients in each group (66%).

PMAs were demonstrated in 20 patients (incidence of 37%, 10 patients in each group; Figures 1,4,5A). PMAs were present in 5 NOSE patients who responded to ASM, 5 NORSE, 6 refractory NISE, and 4 non-refractory NISE patients who experienced prolonged SE (180, 240, 700, and 2,000 min, respectively). The distribution of PMA and their aspect on the different MRI sequences were comparable in the 2 groups (Figure 4, Table 2). We noted the following two exceptions: a temporal punctiform gadolinium enhancement in two patients with non-refractory NOSE and a hyperintensity of the claustrum in one NOSE patient corresponding to SESA (Figure 4). There was no significant difference in PMA volume (Figure 5B, p = 0.36) between the 2 groups, but there was an outlier in the NISE group with a much higher volume than the others at 290 cc.

. . Relationship between PMA and outcome

According to the mixed-effects model for NOSE and NISE combined, there was no global effect of the occurrence of PMA on the outcome (p = 0.22). Nevertheless, there was an interaction between the occurrence of PMA and the moment of mRS assessment (baseline, at 1, 3, and 12 months; p = 0.000), which suggests that between baseline and 12 months, mRS changed in different proportions in the two groups of patients (Figure 5C). We analyzed PMA and non-PMA groups independently using Tukey's HSD tests. For patients with PMA, the mRS at baseline was different from the mRS at 1 month (diff = 1.55 and p = 0.02) and at 12 months (diff = 2.1 and p = 0.001). In patients without PMA, mRS at baseline was different from mRS at 1 month (diff = 0.73 and p = 0.01), 3 months (diff = 0.89 and p = 0.001), and 12 months (diff = 1.18 and p = 0) (Figure 5D). Concerning PMA changes during follow-up (7 of 10 patients with PMA in each group had an MRI control at 3 months), we noted a complete regression of PMA in only 5 patients (2 NOSE and 3 NISE cases) despite systematic normalization of the DWI due to the persistence of FLAIR hyperintensity in 8 patients (4 NOSE and 4 NISE cases) and the appearance of focal atrophy in 7 patients (5 NOSE and 2 NISE cases).

. . EEG patterns of periodic lateral discharges are more prevalent in NOSE

The median time before the first EEG was similar in both groups (∼17 h). Different types of ictal abnormalities recorded on EEG are summarized in Table 3, and examples are provided in Figure 6. We analyzed spikes, spike-and-wave patterns, rhythmic delta discharges, and periodic epileptiform activities without identifying any specific type of epileptic activity that could be related to either NOSE or NISE. However, periodic lateralized activities tended to be more frequent in NOSE (p = 0.004 and alpha = 0.0006). .

Discussion

Our study reveals a paradox: NOSE was more severe with more patients experiencing a poor outcome at the last follow-up but was not more refractory than NISE. Causes of death also differed at different time points of follow-up, with more early deaths directly linked to SE at 1 month in the NOSE group and more remote deaths related to causal brain lesions at the final follow-up in the NISE group.

We are aware of the limitations of our study: the clinical heterogeneity of the patients, heterogeneous types of SE and etiologies, outliers, MRI performed only in approximately half of the patients, and the difficulty assessing the kinetics of PMA. However, such limits are inherent in this type of prospective research precisely because of the severity of SE that can limit inclusion. Including more than 100 patients is rare and we were able to provide longitudinal data, without any patients lost to follow-up. Moreover, when available, MRI was always performed at a high resolution (3T) and within relatively homogeneous time frames.

. . NOSE patients are older than NISE patients at the onset

There is an undeniable fragility in NOSE patients at the onset: 61% had a preexisting cognitive decline (IQ Code ≥ 3.4). This fragility was not limited to the NOSE group: two-thirds of the patients had a significant disability (mRS ≥ 2) in both groups. The mean age of the patients in our study was 60 years, similar to the ages in previous cohorts: 60-65 years according to the cohort [START_REF] Hesdorffer | Incidence of status epilepticus in Rochester, Minnesota, 1965-1984[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in germany: a prospective, population-based study[END_REF][START_REF] Deng | The clinical analysis of new-onset status epilepticus[END_REF][START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF][START_REF] Tsetsou | Recurrence of status epilepticus: prognostic role and outcome predictors[END_REF][START_REF] Pan | Timing matters: there are significant differences in short-term outcomes between two time points of status epilepticus[END_REF][START_REF] Roberg | Prediction of long-term survival after status epilepticus using the ACD score[END_REF]. However, NOSE generally occurs in older subjects (65 years vs. 56 years in NISE patients). Therefore, it is interesting to note that epileptic and non-epileptic patients were comparable in the literature for neurological and psychiatric history, previous psychotropic drug use, and alcohol abuse or dependence [START_REF] Coeytaux | Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR)[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in germany: a prospective, population-based study[END_REF][START_REF] Tsai | Factors predictive of outcome in patients with de novo status epilepticus[END_REF][START_REF] Aukland | Predictive value of the Status Epilepticus Severity Score (STESS) and its components for long-term survival[END_REF]. In particular, SESA was not overrepresented in NOSE.

. . NOSE is not more refractory than NISE but tends to be more severe In both groups, SE was long, lasting ≥24 h in one-third of our patients, and if associated with severe complications required resuscitation management in 35% of the cases. This is consistent with previous studies in which the duration of SE was ≥ 24 h in 24-33% of the cases [START_REF] Hesdorffer | Incidence of status epilepticus in Rochester, Minnesota, 1965-1984[END_REF][START_REF] Coeytaux | Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR)[END_REF] and only 7% of SE lasted <30 min [START_REF] Tsetsou | Recurrence of status epilepticus: prognostic role and outcome predictors[END_REF].

In our study, the proportions of pharmacoresistance in SE (more than 60% of the cases in both groups) contrast with the 20-40% of refractoriness reported in the literature [START_REF] Coeytaux | Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR)[END_REF][START_REF] Knake | Incidence of status epilepticus in adults in germany: a prospective, population-based study[END_REF][START_REF] Tsetsou | Recurrence of status epilepticus: prognostic role and outcome predictors[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] Kantanen | Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus: a population-based study[END_REF], although we used the same definitions of drug resistance and clinical management according to the national recommendations for therapeutic escalation [START_REF] Outin | le groupe d'experts. 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].

However, as in the literature, NOSE was more severe than NISE. Indeed, the severity scales of NOSE were higher (p < 0.001), the duration was longer (62 vs. 23 h on average), and the diagnostic ); note that there was an outlier in the NISE group with a much higher volume than the others at ml, with a hypersignal in DWI of the majority of the left hemisphere cortex, the thalamus and at days a right cerebellar diaschisis of partial NCSE secondarily generalized in a -year-old man institutionalized for encephalopathy evolving since childhood. (C) Individual mRS in patients with PMA and those without PMA. Patients with PMA had an average mRS of . at baseline, . at month, . at months, and . at months. Patients without PMA had an average mRS of . at baseline, . at month, . at months, and . at months. (D) Correlations between PMA evolution and outcome (mRS) at di erent time points (Pearson correlations, r = .

in the PMA group, r = . in the non-PMA group). Alpha = . / = . . tardiness was greater (60 vs. 10 min) resulting in a therapeutic delay. NOSE patients had more post-ictal focal neurological deficits (80% vs. 62% in NISE) and more serious complications (50% vs. 30% in NISE), especially hemodynamic complications. The length of hospital stay was also longer for NOSE patients than for NISE patients, on average 3 days. This is in line with the previously identified prognostic factors of SE, such as the age of the patient, the rapidity of the diagnosis and suitable therapeutic management, and the duration and etiology of SE (15-17, 19, 24, 47, 50, 51).

. . NOSE becomes secondarily non-convulsive more often than NISE

In our cohort, 36.7% of the SE were non-convulsive (NCSE), whereas NCSE accounts for 25% of the SE in the literature [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] Leitinger | Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes[END_REF][START_REF] Cascino | Nonconvulsive status epilepticus in adults and children[END_REF]. NCSE is frequent (up to 47% of the SE managed in the Intensive Care Unit [START_REF] Rudin | High prevalence of nonconvulsive and subtle status epilepticus in an ICU of a tertiary care center: a three-year observational cohort study[END_REF][START_REF] Laccheo | Nonconvulsive status epilepticus and non-convulsive seizures in neurological ICU patients[END_REF] but is underestimated due to the misleading and non-specific clinical features. In fact, the diagnosis is mainly based on the EEG, and quite frequently there is a diagnostic delay and high pharmacoresistance in nearly one-third of the cases [START_REF] Kaplan | Assessing the outcomes in patients with nonconvulsive status epilepticus: nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity[END_REF][START_REF] Sutter | The neurophysiologic types of nonconvulsive status epilepticus: EEG patterns of different phenotypes[END_REF][START_REF] Sutter | Nonconvulsive status epilepticus in adults -insights into the invisible[END_REF][START_REF] Baysal-Kirac | Electroclinical patterns in patients with nonconvulsive status epilepticus: etiology, treatment, and outcome[END_REF]. NCSE has been associated with a longer duration and a worse prognosis than the other subtypes of SE, especially when it is inaugural because of its frequent refractoriness [START_REF] Power | Adult nonconvulsive status epilepticus in a clinical setting: semiology, aetiology, treatment and outcome[END_REF]. The mortality rate of the inaugural NCSE [nearly 69% of NCSE in some cohorts [START_REF] Baysal-Kirac | Electroclinical patterns in patients with nonconvulsive status epilepticus: etiology, treatment, and outcome[END_REF]] can be as high as 40%, whereas it is ∼10% for the other SE (59).

. . In line with novelty, more acute brain lesions occur in NOSE

In a recent retrospective cohort including 85 NOSE patients, the main etiologies were acute symptomatic NOSE in 53.9%, unknown in 25.9%, progressive in 11.8%, and remote in 9.4%. For adults below the age of 60 years, the main etiology remained unknown (36.3%) followed by autoimmune-related SE (16.4%), while in the elderly (≥60 years), the primary etiology was central nervous system If the etiologies overlap with these references, we emphasize different proportions according to these causes in our cohort (perhaps related to the fact that our NOSE cohort was smaller). The etiology of NOSE was acute in 43.5% of the cases vs. 8% in NISE (p < 0.0001), including an acute cerebral etiology in 21.7% of NOSE vs. 4.8% of NISE cases (p = 0.01). The etiology remained unknown in only 8.7% of the NOSE cases. However, by systematically comparing them to NISE, our results highlight the etiologies shared by both types of SE. For instance, we observed no autoimmune encephalitis, whereas this was the etiology for epilepsy in two NISE patients. We also noted 3 cases of non-convulsive NOSE that met the subacute encephalopathy and seizures in alcoholics (SESA) criteria [START_REF] Fernández-Torre | Subacute encephalopathy with seizures in alcoholics (SESA syndrome) revisited[END_REF][START_REF] Fernández-Torre | Subacute encephalopathy with seizures in alcoholics syndrome: a subtype of nonconvulsive status epilepticus[END_REF][START_REF] Laroche | Subacute encephalopathy and seizures in alcoholics (SESA) presenting with non-convulsive status epilepticus[END_REF], all with PMA on ictal MRI.

. . Poor outcome between baseline and last follow-up is more frequent in NOSE

To the best of our knowledge, the only study that has prospectively compared NOSE and NISE was restricted to 122 patients >60 years old with convulsive SE. It showed that comorbidities, a low Glasgow scale score, and an inaugural nature were poor prognostic factors [START_REF] Verma | Comparison of clinical profile and outcome of de novo convulsive status epilepticus with those with a past history of epilepsy in the elderly populace[END_REF]. By including younger subjects and all types of SE, we were able to demonstrate the frailty and older age of NOSE subjects.

We also observed that the mRS increased at each assessment time in both groups. However, after post-hoc analyses, baseline mRS (before SE) for NOSE was statistically different from mRS at 1, 3, and 12 months, while for NISE, it was only different from mRS at 12 months.

In our cohort, 43.6% of the NOSE patients who survived developed epilepsy in the ensuing months. For Santamarina et al., it was close to 58.7% [START_REF] Santamarina | Prognosis of status epilepticus (SE): relationship between SE duration and subsequent development of epilepsy[END_REF], which highlights the relevance of long-term maintenance of an ASM after SE. A total of 25.7% of patients had We noted a high frequency of focal neurological deficits (34.4%) and cognitive complaints (70%) in both groups at 3 months but which were higher for NISE. Cognitive consequences are frequently reported in the literature and have a significant impact on quality of life [START_REF] Power | Adult nonconvulsive status epilepticus in a clinical setting: semiology, aetiology, treatment and outcome[END_REF][START_REF] Adachi | Intellectual prognosis of status epilepticus in adult epilepsy patients: analysis with Wechsler Adult Intelligence Scale-revised[END_REF][START_REF] Sheppard | Cognitive outcome of status epilepticus in children[END_REF]. Therefore, in the clinical management of any SE, it would be relevant to conduct psychometric and standardized cognitive assessment some distance in time after NOSE and NISE to propose cognitive remediation adapted to these fragile patients.

. . Di erent causes of remote and early deaths in NOSE and NISE

The overall mortality of our population was high: 10%, 17%, and 26% at 1, 3, and 12 months, respectively. These rates are comparable to the mortality found in cohorts with any type of SE (NOSE and NISE, excluding post-anoxic encephalopathies) [START_REF] Knake | Incidence of status epilepticus in adults in germany: a prospective, population-based study[END_REF][START_REF] Aukland | Predictive value of the Status Epilepticus Severity Score (STESS) and its components for long-term survival[END_REF] or even studies including only refractory SE with 24.5-25.4% mortality at 1 year [START_REF] Kantanen | Incidence and mortality of super-refractory status epilepticus in adults[END_REF][START_REF] Delaj | Refractory and super-refractory status epilepticus in adults: a 9-year cohort study[END_REF]. Similarities to these rates can probably be explained by the high drug resistance in our cohort. In specific NORSE cohorts, mortality reached 22% [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF][START_REF] Gaspard | New-onset refractory status epilepticus: etiology, clinical features, and outcome[END_REF].

In our study, a higher global proportion of death was observed in NOSE than in NISE. The absence of statistical difference at the final follow-up does not exclude differences at distant time points and may reflect different mechanisms: more early deaths in the NOSE group directly linked to SE at 1 month and more remote deaths linked to causal brain lesions in the NISE group at final follow-up. In addition, it has been previously shown that NOSE is associated with a 15-fold increase in the risk of death in those older than 60 years (66).

. . For all SE in general, patients with PMA have a poorer prognosis at the last follow-up

The description and location of PMA in our cohort were comparable to previously published data (67-71): DWI hyperintensity with a moderate ADC restriction and FLAIR Here on the left hemisphere. (A) NOSE in a -year-old man (chronic psychiatric disorders and alcoholism with decompensated cirrhosis, left cerebral middle artery ischemic sequelae) who presented with a generalized convulsive SE, which became secondarily non-convulsive and super-refractory (SE lasted days until death). PMAs were observed on MRI on the left hemisphere. (B) NISE in a -year-old man who presented with refractory non-convulsive SE (SE lasted days). A context of stroke sequelae in the left middle cerebral artery region due to atheroma, alcoholism, and urinary tract infection. PMA was observed on MRI. After an initial stay of days, there was an SE recurrence in days leading to death in months.

hyperintensity, preferentially in the hippocampus, the cortex, the amygdala, and the thalamus. In our cohort, both NOSE and NISE had PMAs that were comparable in appearance, location, and volume. These results are important because contrary to common belief, PMAs are not exclusive to NORSE and in general and are not exclusive to NOSE. The overall incidence of PMAs (37%) is close to the incidences found in studies that did not consider only abnormal MRI: 27.5% [START_REF] Rennebaum | Status epilepticus: clinical characteristics and EEG patterns associated with and without MRI diffusion restriction in 69 patients[END_REF], 28% (72), and 42.5% [START_REF] Nakae | Relationship between cortex and pulvinar abnormalities on diffusion-weighted imaging in status epilepticus[END_REF]. The incidence of PMAs was somewhat higher in the NISE group (42% vs. 33%) but their MRIs were performed later than those for NOSE patients. This difference could be due to the kinetics of the occurrence of PMAs. A significant correlation has already been described between the presence of PMAs and the presence of PLDs on EEG with vigilance in the acute phase of SE, but no association was found with patient age, comorbidity, or mortality [START_REF] Rennebaum | Status epilepticus: clinical characteristics and EEG patterns associated with and without MRI diffusion restriction in 69 patients[END_REF]. Our clinical experience suggests that there is a very good anatomical correlation between the clinical symptoms of SE, the site of EEG abnormalities, and the location of PMA when present. Post-ictal motor deficits have also been more frequently associated with PMAs (53.3%) than with normal MRI (34.4%) [START_REF] Nakae | Relationship between cortex and pulvinar abnormalities on diffusion-weighted imaging in status epilepticus[END_REF]. In our data, the outcome at the last follow-up changed in different proportions in the patients with PMA and those without PMA, while no correlation exists between PMA volume and mRS during follow-up. There does not appear to be any specific feature (volume, locations, and change) of PMAs that can distinguish a periictal from a post-ictal state. Rapid brain imagery is recommended in the etiological assessment of any SE [START_REF] Brophy | Guidelines for the evaluation and management of status epilepticus[END_REF][START_REF] Outin | le groupe d'experts. 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]. Our results highlight that in addition to the diagnostic potential and the identification of acute lesions, MRI provides prognostic information that may prove valuable in long-term patient management.

In the neuroimaging studies cited above, MRI monitoring was not systematic and completion time was extremely variable (interval of up to 1 year between the two MRIs) [START_REF] Cianfoni | Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities[END_REF][START_REF] Ohe | MRI abnormality of the pulvinar in patients with status epilepticus[END_REF][START_REF] Szabo | Diffusion-weighted and perfusion MRI demonstrates parenchymal changes in complex partial status epilepticus[END_REF]. In our study, MRI time was more homogeneous at ∼3 months and complete reversibility of PMA was noted in 36% of patients. Although diffusion was normalized, FLAIR hyperintensity was found in 57% of patients and focal atrophy in 50% of patients, predominantly in the temporalhippocampal regions. These sequelae raise questions about the epileptogenic value and the clinical consequences of these permanent structural abnormalities.

. . Periodic lateral discharges are more frequent in NOSE than in NISE

We observed a tendency for more periodic lateral discharges (PLDs) in NOSE, while the median time before the first EEG was similar in both groups. Despite a later diagnosis in NOSE, accessibility to EEG was not different for NOSE and NISE, which is a crucial point to remember in clinical practice. PLDs were indicative of the presence of a cortical brain lesion and associated with more frequent vigilance disorders as previously described [START_REF] Dunand | Pseudoperiodic and paroxysmal electroencephalographic activities[END_REF]. PLDs were also associated with high morbidity and mortality in studies conducted in the eighties or nineties [START_REF] Snodgrass | Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus[END_REF][START_REF] Treiman | A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus[END_REF][START_REF] Jaitly | Prognostic value of EEG monitoring after status epilepticus: a prospective adult study[END_REF]. We were unable to determine whether there is a PLD pattern (morphology, periodicity, and amplitude) specific to each type of SE. Further studies that analyze the appearance of PLDs according to the etiology, lesion, and type of SE are warranted.

. . NORSE vs. non-inaugural refractory SE NOSE was not more refractory than NISE. Unfortunately, our data were not sufficient to highlight specificities between the particular cases of NORSE and non-inaugural refractory SE (NIRSE).

Are there certain etiologies that are particularly represented in refractory SE? In other series that focused specifically on the NORSE subgroup, the most common etiology was autoimmune encephalitis, while 52% of the cases of NORSE remained cryptogenic [START_REF] Sculier | New onset refractory status epilepticus (NORSE)[END_REF][START_REF] Gaspard | New-onset refractory status epilepticus: etiology, clinical features, and outcome[END_REF][START_REF] Werbaneth | A retrospective cohort study of new-onset refractory status epilepticus (NORSE): clinical features, timing of immunotherapy and outcomes[END_REF][START_REF] Lattanzi | Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies[END_REF]. No autoimmune encephalitis was identified in our NOSE cohort although this etiology was repeatedly suspected and sought, while two cases of autoimmune encephalitis were included in our NISE group with a refractory SE. Two patients in our cohort met the criteria for cryptogenic NORSE: the first died within a few days despite appropriate resuscitative management while the second patient had severe cognitive impairment and loss of autonomy at 3 months.

Moreover, our data were not sufficient to isolate specific patterns of PMA between NOSE and NORSE. However, particularities in three patients should be noted: a case of claustrum hyperintensity in the NOSE group corresponding to SESA with non-refractory NCSE. In a recent study, claustral changes were reported as infrequent, occurring in 9.1% of NORSE patients [START_REF] Kim | The timelines of MRI findings related to outcomes in adult patients with new-onset refractory status epilepticus[END_REF] although the etiology for NORSE patients with claustrum involvement has not yet been elucidated. The claustrum sign has been associated with an aggressive refractory form of SE in particular cases of FIRES with cryptogenic etiology [START_REF] Kim | The timelines of MRI findings related to outcomes in adult patients with new-onset refractory status epilepticus[END_REF][START_REF] Meletti | Newonset refractory status epilepticus with claustrum damage: definition of the clinical and neuroimaging features[END_REF] but never with SESA as far as we know. Two NISE patients presented with crossed cerebellar diaschisis with involvement of the cortex and the pulvinar ipsilateral to the refractory SE. Some identical cases have been described in the literature with reversible damage or the appearance of cerebellar atrophy associated with an unfavorable clinical course [START_REF] Massaro | Teaching neuroimages: crossed cerebellar diaschisis in hemispheric status epilepticus[END_REF][START_REF] Bn | Magnetic resonance imaging of crossed cerebellar diaschisis and bright pulvinar in status epilepticus[END_REF][START_REF] Ahn | Two cases of crossed cerebellar diaschisis with or without thalamic lesion on brain MRI in status epilepticus[END_REF][START_REF] Graffeo | Prognostic and mechanistic factors characterizing seizure-associated crossed cerebellar diaschisis[END_REF][START_REF] Samaniego | Crossed cerebellar diaschisis in status epilepticus[END_REF].

. Conclusion

NOSE and NISE evolved in the same proportions as refractory SE and shared common patterns, such as the same types of PMAs on MRI. However, NOSE was distinguishable by the severity, a more fragile and older population at onset, and a frequent nonconvulsive semiology. The causes of death differed in the early and late stages (at 1 year) in NOSE and NISE. Despite acute causal brain lesions, the inaugural character was still too often associated with a delay in diagnosis in SE, which justifies the need to more clearly specify the types of SE to constantly raise awareness among clinicians. These results also highlight the relevance of including novelty-related criteria, clinical history, and the temporality of occurrence in the nosology of status epilepticus.

  Abbreviations: ASM, Anti-seizure medication; CSF, Cerebrospinal fluid; EEG, Electroencephalogram; EMSE, Epidemiology-based mortality score in status epilepticus; FLAIR, Fluid-attenuated inversion recovery; GPDs, Generalized periodic discharges; MRI, Magnetic resonance imaging; mRS, Modified Rankin Scale; NCSE, Non-convulsive status epilepticus; NOSE, New-onset status epilepticus; NORSE, New-onset refractory status epilepticus; NIRSE, Noninaugural refractory status epilepticus; NISE, Non-inaugural status epilepticus; PLDs, Periodic lateralized discharges; PMAs, Peri-ictal MRI abnormalities; SE, Status epilepticus; SESA, Subacute encephalopathy with seizures in alcoholics; STESS, Status epilepticus severity score.

FIGURE

  FIGUREOutcome assessed by mRS between baseline and months changes in di erent proportions in NOSE and NISE. (A) Individual mRS at each time point in NOSE and NISE groups. NISE patients had an average mRS of . at baseline, . at month, . at months, and . at months. In contrast, NOSE patients had an average mRS of . at baseline, . at month, . at months, and . at months. Therefore, we performed post-hoc analyses on these two groups independently. (B) Correlations between time after SE and outcome (Pearson correlations, r = .in the PMA group, r = . in the non-PMA group). Alpha = . / = ..

FIGURE

  FIGURE Generally similar patterns of PMA in NOSE and NISE. Examples of axial DWI views in patients. (A) Right medial temporal hyperintensity in an -year-old woman with focal convulsive refractory NOSE. (B) Left thalamic, caudate nucleus, and frontal cortex hyperintensities in a -year-old man with generalized convulsive secondary non-convulsive super-refractory NOSE. (C) Right temporo-parietal cortex hyperintensity in a -year-old man with refractory generalized convulsive secondary non-convulsive NOSE. (D) Claustrum hyperintensity in the left hemisphere associated with a homolateral pulvinar and hippocampal hyperintensity in a -year-old alcoholic male with pharmacosensitive non-convulsive NOSE (SESA). (E) Left medial temporal hyperintensity in a -year-old man with pharmacosensitive focal non-convulsive NISE. (F) Left pulvinar hyperintensity in a -year-old man with pharmacosensitive focal non-convulsive NISE. (G, H) Right cerebellum hyperintensity and contralateral cortical hyperintensity in a -year-old man with a non-convulsive super-refractory NISE.

FIGURE

  FIGUREPMA volumes are similar in NOSE and NISE patients and PMA is related to prognosis. (A) PMA volumetry in DWI sequences. Semi-automatic quantification in one-shot analysis by OLEA (PMA is circumscribed in purple; colors were changed for purposes concerning the figure). Right mesial temporal hypersignal including the hippocampus (upper panel) and left posterior thalamic hypersignal (bottom panel). (B) Mean PMA volumes in each group. The two groups had a similar PMA volume (p = . ); note that there was an outlier in the NISE group with a much higher volume than the others at ml, with a hypersignal in DWI of the majority of the left hemisphere cortex, the thalamus and at days a right cerebellar diaschisis of partial NCSE secondarily generalized in a -year-old man institutionalized for encephalopathy evolving since childhood. (C) Individual mRS in patients with PMA and those without PMA. Patients with PMA had an average mRS of . at baseline, . at month, . at months, and . at months. Patients without PMA had an average mRS of . at baseline, . at month, . at months, and . at months. (D) Correlations between PMA evolution and outcome (mRS) at di erent time points (Pearson correlations, r = .in the PMA group, r = . in the non-PMA group). Alpha = . / = . .

FIGURE

  FIGURETwo examples of EEG patterns that can be observed in NOSE and NISE. PLDs could be observed in the two types of SE but were more prevalent in NOSE. Here on the left hemisphere. (A) NOSE in a -year-old man (chronic psychiatric disorders and alcoholism with decompensated cirrhosis, left cerebral middle artery ischemic sequelae) who presented with a generalized convulsive SE, which became secondarily non-convulsive and super-refractory (SE lasted days until death). PMAs were observed on MRI on the left hemisphere. (B) NISE in a -year-old man who presented with refractory non-convulsive SE (SE lasted days). A context of stroke sequelae in the left middle cerebral artery region due to atheroma, alcoholism, and urinary tract infection. PMA was observed on MRI. After an initial stay of days, there was an SE recurrence in days leading to death in months.

, 3, 12 months

	SELECTION SELECTION		Patients 18 years old Toulouse University Hospital
		Neurophysiological Explorations
		All EEGs from December 2015 to June 2016
			2305 EEGs
		Non postanoxic status epilepticus
			127 patients
			initially treated as SE
	ACUTE PHASE
	Clinical data, baseline mRS Clinical data, baseline mRS	non epileptic patients	18 non SE a posteriori	NISE epileptic patients
	SE semiology SE semiology	mean age: 65 yo		mean age: 56 yo
	STESS, EMSE STESS, EMSE	46 patients		63 patients
	3T MRI FOLLOW UP 1, 3, 12 months FOLLOW UP 1Drug resistance 3T MRI	30 patients (65%) (PMAs in 33%) as soon as possible NORSE 28 patients (61%)	if seemed necessary 24 patients (38%) (PMAs in 42%) Refractory SE 40 patients (62%)
	mRS & outcome mRS & outcome
	death death	15 patients (32.6%)		13 patients (20.6%)

  .5% of NISE patients (36/46 ≥ 3/6 vs. 23/63; p < 0.0001; alpha = 0.0006) and 63% vs. 28.5% (29/46 ≥ 64/255 vs. 18/63; p < 0.0001; and alpha = 0.0006), respectively.

  TABLE Clinical characteristics of NOSE and NISE patients.

		Total SE	NOSE	NISE	p
		n =	n =	n =
	Female gender	52 (47.7%)	21 (45%)	31 (49%)	0.71
	Age (years)	60	65.7 (22-101)	56.3 (15-90)	0.01 ∧
	Neurologic history	65 (60%)	24 (52%)	41 (65%)	0.49
	Cured epilepsy	3	3 (6.5%)	0	0.14
	Severe cranial trauma	29	7 (15%)	12 (19%)	0.58
	Stroke	23	15 (32.6%)	8 (12.7%)	0.01
	Cerebral hemorrhage	11	2 (4.3%)	9 (14 %)	0.11 #
	Cerebral tumors	14	2 (4.3%)	12 (19%)	0.02
	CNS infections	3	0	3 (4.7%)	0.26 #
	Psychiatric history	24 (22%)	10 (21.7%)	14 (22%)	0.95
	Alcohol abuse	24 (22%)	8 (17.4%)	16 (25%)	0.32
	Daily use of psychotropic drugs	44 (40%)	17 (37%)	27 (43%)	0.54
	IQ code ≥ 3.4/5	-	28 (60.9%)	-
	Modified Rankin Scale before SE
	0-1	38	18 (39%)	20 (31.7%)	0.55
	2-3	61	22 (47.8)	39 (62%)	0.2
	4-5	10	6 (13%)	4 (6.3%)	0.39
	SE type
	Generalized convulsive	39 (35.5%)	16 (34.7%)	23 (36.5%)	0.85
	Focal convulsive	44 (40%)	20 (43.5%)	24 (38%)	0.57
	Non-convulsive	26 (24%)	10 (21.7%)	16 (25.5%)	0.66
	Secondary non-convulsive	14 (12.8%)	10 (21.7%)	4 (6%)	0.02
	Secondary generalized convulsive	29 (26.6%)	14 (30.4%)	15 (24%)	0.44
	Median time between SE and diagnosis (min-max)	30 min (0-15 d)	60 min (0-15 d)	10 min (0-30 h)	0.006 ∧
	Median time between SE and therapeutic care (min-max)	90 min (0-15 d)	90 min (10 min-15 d)	60 min (5 min-30 h)	0.09 ∧
	Average number of ASMs needed to stop SE (min-max)	3 (1-7)	3 (1-7)	2.7 (1-6)	0.24 ∧
	ASMs used for SE
	Benzodiazepines	95 (87%)	41 (89%)	54 (85.7%)	0.81
	Phosphenytoin	45 (41%)	25 (54%)	20 (31.7%)	0.03
	Broad spectrum ASM	68 (62%)	27 (59%)	41 (65%)	0.63
	Narcotics	34 (32%)	19 (41.3%)	15 (23.8%)	0.08
	Severe complications	42 (38.5%)	23 (50%)	19 (30%)	0.057
	Respiratory	30 (27.5%)	15 (32.6%)	15 (24%)	0.42
	Hemodynamic	20 (18%)	13 (28.2%)	7 (11%)	0.04
	Trauma-related	13 (12%)	6 (13%)	7 (11%)	0.99
	Intensive care	39 (35.5%)	16 (35%)	23 (36%)	0.85
	Ventilated-intubated	26 (24%)	13 (28%)	13 (20%)	0.49
					(Continued)
	Frontiers in Neurology				frontiersin.org

TABLE (

 ( Psychotropic drugs included benzodiazepines and hypnotics, serotonin reuptake inhibitors, and neuroleptics. ASM include levetiracetam, sodium valproate, lacosamide, lamotrigine, carbamazepine, oxcarbazepine, eslicarbazepine, topiramate, phenobarbital, ethosuximide, gabapentine, zonisamide, phenytoin, stiripentol, clobazam, and clonazepam. Broad spectrum ASM used for SE treatment were levetiracetam, lacosamide, and sodium valproate in the majority of the cases and perampanel and oxcarbazepine occasionally. Cured epilepsy is the absence of seizures in the absence of any treatment for over 5 years. Alpha = 0.05/90 = 0.0006.

	Continued)
		Total SE	NOSE	NISE	p
		n =	n =	n =
	Post-ictal vigilance disorders	72 (66%)	34 (73.9%)	38 (60%)	0.2
	Focal post-ictal neurological deficit	76 (70%)	37 (80.4%)	39 (62%)	0.06
	STESS median	3/6	4/6	2/6	<0.0001
	Poor outcome threshold ≥ 3/6	59 (54 %)	36 (78%)	23 (36.5%)
	EMSE median	58/255	67/255	50/255	<0.0001
	Poor outcome threshold ≥ 64/255	47 (43 %)	29 (63%)	18 (28.5%)
	Average SE duration (min-max)	40 h (15 min-41 d)	62 h (15 min-41 d)	23 h (30 min-8 d)	0.33
	Pharmacoresistance
	Refractory SE	68 (62%)	28 (61%)	40 (62.5%)	0.93
	Super-refractory SE	9 (8%)	5 (11%)	4 (6%)	0.49 #
	SE etiologies
	Acute etiologies	25 (23%)	20 (43.5%)	5 (7.9%)	<0.0001
	Acute cerebral injury on MRI	13 (12%)	10 (21.7%)	3 (4.8%)	0.01
	Remote etiologies	41 (37.7%)	14 (30.4%)	27 (42.9%)
	Without acute trigger	16 (14.7%)	7 (15.2%)	9 (14.3%)	0.73
	Remote with acute trigger	25 (23 %)	7 (15.2%)	18 (28.6%)	0.09
	Progressive etiologies	17 (15.6%)	7 (15.2%)	10 (15.8%)	0.93
	Defined electroclinical syndromes	22 (20%)	1 (2.1%)	21 (33.3%)	<0.0001
	With acute trigger	12 (11%)	1 (2.1%)	11 (17.4%)	0.01
	Unknown/cryptogenic	4 (3.7%)	4 (8.7%)	0	0.029 #
	Mortality
	At 1 month	11 (10%)	7 (15.2%)	4 (6.4)	0.20 #
	At 3 months	16 (14.7%)	11 (24%)	5 (8%)	0.02
	At 1 year	28 (25.7%)	15 (32.6)	13 (20.6%)	0.19

#

Fisher's test, ∧ Wilcoxon test, or otherwise chi-square test.

  TABLE MRI results in NOSE and NISE groups.

		NOSE	NISE	p
		n =	( %)	n =	( %)	Chi 2 test
	Time of MRI in relation to SE
	Peri-ictal	11		9		1
	Postictal	15		12		0.82
	Remission of epileptic symptoms	5		3		1 #
	Within 72 h after admission	23 (77%)	11 (46%)	0.04
	Acute lesions (related to SE) visible on MRI, other than PMA	9 (30%)	0		0.01
	Old brain lesions (anterior to SE) visible on MRI, other than PMA	18 (56%)	18 (75%)	0.38
	PMA visible on MRI	10 (33%)	10 (42%)	0.53
	MRI sequences allowing PMA visualization
	Diffusion hyperintensity	9		10		1 #
	ADC restriction	8		7		1 #
	FLAIR hyperintensity	8		8		1 #
	Gadolinium contrast enhancement	2		0		0.47 #
	Perfusion increase	3/12 (2 without PMA)	4/18 (1 without PMA)	1 #
	PMA location
	Cortex	9		4		0.057 #
	Hippocampus	8		6		0.63 #
	Amygdala	7		3		0.18 #
	Thalamus	3		4		1 #
	Pulvinar	3		3		1 #
	Claustrum	1		0		1 #
	Crossed cerebellar diaschisis	0		2		0.47 #
	Average PMA volume in cc (min-max)	20 (3.2-47.6)	31.4 (1.9-290)	0.36 ∧
	PMA, peri-ictal MRI abnormalities.
	# Fisher's test; ∧ Wilcoxon test, or otherwise chi-square test. Alpha = 0.05/90 = 0.0006.
	infection (23.3%) followed by cerebrovascular disease (20%) and
	intracranial tumors (20%) (23). In the 89 patients reported by
	Santamarina et al. (mean age of 69 years), NOSE had an acute
	etiology for 66.3% of the patients (46.1% brain lesions and 20.2%
	toxic/metabolic causes), a remote or progressive etiology for 19.1% of
	the patients, and remained cryptogenic for 14.6% of the patients (27).

  TABLE EEG patterns during NOSE and NISE.

		NOSE	NISE	p
		n =	n =
	Median time before 1st EEG	17 h	17 h	0.89 ∧
	Average time before 1st EEG (min-max)	39 h (3 h-384 h)	29 h (2 h-360 h)
	1st EEG conclusions
	Ictal	17 (37%)	25 (40%)	0.77
	Postictal	22 (48%)	29 (47%)	0.85
	Neurosedation	6 (13%)	4 (6.5%)	0.32 #
	Normal	1 (2%)	4 (6.5%)	0.39 #
	Epileptic and other pathological activities
	Epileptic discharges	14 (30%)	21 (34%)	0.74
	Paroxysmal abnormalities	18 (39.1%)	23 (37%)	0.94
	Spikes	15	14	0.23
	Spike-and-wave patterns	5	16	0.06
	Rhythmic delta discharges	10 (21.8%)	14 (22.6%)	0.96
	Periodic activities	18 (39.1%)	8 (13%)	0.003
	PLD	17	8	0.004
	GPD		0	0.43 #
	Burst suppressions	0	2 (3.2%)	0.51 #
	EEG leading to SE diagnosis
	Generalized convulsive	0	1 (1.6%)	0.87 #
	Focal convulsive	5 (10.8%)	3 (4.8%)	0.40
	Non-convulsive	12 (26%)	8 (13%)	0.12
	Mean number of EEGs after the 1st one (median; min-max)	2 (1; 0-10)	2 (3; 0-16)	0.85
	Long-term EEG monitoring	6 (13%)	6 (9.7%)	0.79
	# Fisher's test; ∧ Wilcoxon test, otherwise chi-square test. PLD, periodic lateralized discharges; GPD, generalized periodic discharges.
	Alpha = 0.05/90 = 0.0006.
	a recurrence of SE during follow-up, including 28.2% NOSE cases
	[twice the rate found in a previous prospective cohort (45)]. There
	were more early recurrences of SE in NOSE patients (p = 0.01),
	probably associated with difficulty in controlling the initial SE and
	the underlying etiology.

Frontiers in Neurology frontiersin.org

Hospital (CPP Sud-Ouest no. 04-1215). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Acknowledgments

The authors acknowledge Vanessa Rousseau, Jean-Marc Olivot, and the Neurological Intensive Care Unit Team at Toulouse University Hospital; the Neuroradiologists at Toulouse University Hospital; and Neuropsychologist, Hélène Mirabel, for all their help in acquiring data or methodology-related advice.

Funding

MB received a Grant for Young Researchers from Toulouse University Hospital in 2015-2016.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by Regional Ethics Committee at Toulouse University

Author contributions

MB and JC: writing of the manuscript, major role in data acquisition and study design, data analysis and interpretation, and expert analysis of EEG. LV: revision of the manuscript, expert analysis of EEG, data analysis and interpretation, major role in the study design, and help with data acquisition. MD, FR, and RD: expert analysis of EEG and revision of the manuscript. EB: revision of the manuscript, data analysis, and interpretation. FB: expert analysis of MRI, major role in study design, and help with data acquisition. LG: statistical analyses and revision of the manuscript. VW: support for figures and statistical analyses. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


M François

Y Berthaud
email: berthaud@lmt.ens-cachan.fr

S Caré

F Foct

Mechanical properties of an iron oxide formed by corrosion in reinforced concrete structures

The paper deals with elastic properties of iron oxides formed in reinforced concrete structures. Due to the difficulty to perform mechanical tests on the real oxides presented in the form of (multiple) laminated stratums, the elastic modulus of iron oxides remains unknown. Young's moduli of porous compact "synthetic oxides" in powder form, obtained in laboratory conditions, were measured from both acoustic measurements and oedometric tests. The elastic modulus of the compact polycrystalline iron oxide is deduced with respect to two models, a micromechanical one and a Hertz' theory. The full method is validated on a well-known material, the alumina.

INTRODUCTION

The degradation of concrete structures due to the corrosion of the reinforcements is a crucial problem for both the safety and the economical point of view. By nature, the high alkalinity of the concrete pore solution (pH13) provides protection to the reinforcing steel but the penetration of carbon dioxide CO2 decreases the pH from 13 to 9, causing general corrosion. Moreover, chlorides ions can as well break down the passive layer and cause the mix of general and pitting corrosion. Usually, the layer of corrosion products consists of liquid water and hydrated iron oxides. Due to volume expansion of the oxides (with a coefficient between 2.2 and 3, depending on oxide/hydroxide nature), the cracking of concrete lead to dangerous fall of concrete parts and to unprotected steel. Numerical simulations of mechanical behaviour of concrete structures with corroded rebars need the knowledge of the mechanical behaviour of the iron oxide. Unfortunately, these data are available for the crystal only. As rust in concrete is mixed with the pore solution oome authors [START_REF] Molina | Cover cracking as a function of bar corrosion: Part 2 -Numerical model[END_REF] simply use the moduli of water K=2 GPa, nu=0.5 for the iron oxide. The elastic properties of iron oxide crystal can be found in "The Oxide Handbook" [START_REF] Samsonov | The oxide handbook[END_REF]. The Young's modulus of Fe2O3 or Fe3O4 ranges from 214 to 350 GPa and cannot be retained for the observed structure, which consists of a powder grain aggregate, more or less laminated. Due to grain-to-grain punctual contacts, these structures exhibit much lower elastic properties on which we have very few knowledge. Experimental difficulty is linked in one hand to the slowness of the reaction that leads to very few materials to make a specimen. The retained strategy has been to make both ultrasonic and oedometric measurements on synthetic oxide under different compressive loads. It has been verified that the chemical structure of synthetic oxide was relevant to the naturally formed 40 years old one. The elastic properties of the oxide crystal (not the powder, but the grain itself) can be of interest if it helps us to model more precisely the real oxide (or mix of oxide and water) behaviour in its different possible structure. The Young's modulus of the crystal will be recovered using various inverse analysis based on (i) a simple Hertz's model, (ii) a classical micromechanical approach Hashin Strikman bounds [START_REF] Zohdi | Extraction of elastic moduli from granular compacts[END_REF][START_REF] Hashin | On some variational principles in anisotropic and nonhomogeneous elasticity[END_REF] and (iii) a Self Consistent model [START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF][START_REF] Christensen | A critical evolution for a class of micro-mechanics models[END_REF] ((ii) and (iii) are not shown in this paper). Of course, the anisotropy of the crystal will not be taken into account as the available data are the mechanical properties of the powder structure which is supposed to be isotropic: the Young's modulus of the crystal has to be considered as the average one. In order to validate the present approach, experimental tests and numerical modelling has been performed on alumina powder whose mechanical properties are well known [START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF].

IRON OXIDE MANUFACTURING

To simulate the real conditions of oxides formation in carbonated reinforced concrete structure, iron oxides were obtained from low alloy steel samples exposed in an aerated solution containing 100 ppm of Cl-which pH was fixed to 9 by NaOH addition. A half of the oxides was dried in an oven at 50°C during 24 hours and the other one during 48 hours (the temperature was chosen to avoid modification of the chemical composition of the oxide). The weight loss between the oxides dried during 24 hours and those dried during 48 hours is 3.4 %. The oxides were in a powder state. The chemical composition of the produced oxides was studied by X ray diffraction. The analysis was also performed on the oxides obtained from a real reinforced concrete structure that was attacked by carbonation and chlorides ions during forty years. The chemical composition of these oxides is given in Table 1. A comparison of the chemical compositions shows that the laboratory grown oxides consist of lepidocrocite (γFeO(OH)) and the real oxides consist of goethite, lepidocrocite (quite majority) and maghemite. Note, that in both cases, the presence of lepidocrocite is the main observed phase. The density of both oxides was measured using a micro ultrapycnometer, P/N 02112-1 (Table 1). These results show that the density of the laboratory grown oxides (4049 kg/m3) is close to the one of the real oxides (4345 kg/m3). To study the distribution of particles size, the lepidocrocite dried during 48 hours was examined by a scanning electron microscope (SEM) (Figure 1). The size of forty particles was measured and the principal results are given in Table 1. Their size varies from 0.4 µm to 8.7 µm with an average value of 3.6 µm. The particles of alumina, the reference material, are 3 µm in mean diameter.

OEDOMETERIC MEASUREMENTS

Being a granular material, the iron oxide mechanical properties are supposed to depend strongly on the confinement. Moreover, around the corroded rebar, the oxide is confined between concrete and steel: this state can be assimilated to an oedometric one where the tangential and axial expansions are blocked by the symmetry of the problem. The strain tensor writes e e e e i i

) ( ⊗ = (1)
in which the ei direction corresponds the radial direction of both the rebar and the axis of the oedometer and ε a loading parameter. The diameter of the oedometer is determined with respect to the diameter of the ultrasonic transducer and its length has the same order of magnitude to insure a good transmission of the wave. The retained material is mild steel for both machinery and wave transmission. Once the oxide in the oedometer, the system has been compressed respect to a MTS hydraulic device. The load has been released to perform ultrasonic measurements as the oedometer had to be removed from the machine; at these steps, the load and displacements were recorded. The stress is obtained from the ratio between the applied force and the section of the oedometer and the strain is deduced from head displacement while neglecting the deformation of the oedometer (reasonable as soon as the mild steel has a Young's modulus of 220 GPa, much greater than the few GPa of the oxide powder as it will shown later on). In linear elasticity, for such oedometric testing, the stress to strain relationship writes:

( )( ) ( ) ν ν ν σ ε - - + = 1 2 1 1 E (2)
in which the function of ν varies very few when v varies from 0 to 0.2 that are common values of ν for such materials. For the 24h-dried lepidocrocite, a full mechanical testing has been performed with a unique unloading path at the end of the test: it exhibits the apparition of permanent strain, revealing the classical behaviour of a powder material and confirming the observations of Lungrend [START_REF] Lundgren | A model for 3D-analyses of bon between corroded reinforcement and concrete, Creep Shrinkage and Durability Mechanics of Concrete and other Quasi-Brittle Materials[END_REF] on the iron oxide (Figure 2). We can observe: (i) That from point O to point A, a strong non linear behaviour (with intense stick and slip phenomena) that can be associated to particles re-arrangement. (ii) From point A to B a linear curve is observed but does not correspond to linear elasticity as shown by the unloading response from point B to point C. (iii) The last path B-C is probably a non-linear elastic regime as observed on granular materials. Indeed, for granular materials we commonly observe unloading-reloading responses that are superimposed (see in Mitchell [START_REF] Mitchell | Fundamentals of soil behaviour[END_REF], Bardet [START_REF] Bardet | Experimental soil mechanics[END_REF]). Even if it is not the case, i.e. a small hysteresis exists, it will be of no practical importance in our case because the non linearity is not important. The tangent modulus for the 24 hours dried lepidocrocite has been measured (using the curve) for different stress states on the branch B-C supposed to be linear elastic and a 6 GPa secant modulus is obtained from Figure 2. A similar global behaviour has been observed in case of lepidocrocite dried during 48h and alumina (Figure 3).

ULTRASONIC MEASUREMENTS OF THE OXIDE IN POWDER FORM

Zohdi [START_REF] Zohdi | Extraction of elastic moduli from granular compacts[END_REF] used successfully the ultrasonic method on ettringite which is also a granular material. The ultrasonic measurements (Figure 3) have been performed respect to a homemade 220V pulse emitter, two 1MHz Panametrics longitudinal transducers and a 200MHz Tektronics numeric oscilloscope. The wavelength to grain size ratio is about 100 leading us to use the continuum approximation for propagation equation. The retained method was the transmission one, the emitter was stuck on one end of the oedometer with some silicon grease and the receiver at the other end. This method insures only one fly across the oxide, in order to keep some power at the receiver (such materials dissipate quickly the mechanical waves, especially at the loose sates). The flying time across the oxide is the difference between measured flying time and the one obtained for the empty oedometer: this eliminates the time origin incertitude relative to the direct contact method. The wave speed is simply the ratio between oxide thickness (oedometer is measured with a slide calliper) and the flying time. The ultrasonic theory [START_REF] Dieulesaint | Ondes élastiques dans les solides[END_REF] gives the following formula for the propagation of a longitudinal wave in an isotropic medium:

( )       - - - = 2 2 1 2 1 1 ν ν ν ρ E V (3)
in which E is the Young's modulus and ν the Poisson's ratio of the medium. The missing Poisson's ratio could be determined with shear waves; unfortunately, these ones propagate very poorly in such medium. However, the fraction in ν varies only from 1 to 1.11 when ν varies from 0 to 0.2. As a common Poisson's ratio for granular materials is around 0.2, it has been decided to keep that value for the present study. We suppose that the procedures in which the load unload sequences are prescribed to ensure the acoustical measurements are of no effect on the state of the material (that is true in the case of an elastic behaviour). During measurement, a 2.5 kg mass was applied onto the transducers in order to ensure a good contact. This load is equivalent to a very small stress around 0.1MPa. Even if this stress is indeed in the strongly non-linear part of the load strain curve, it permits the transmission of the wave and allows the measurement of the velocity. Of course, no measurement of the real elastic modulus of the granular material can be made from the mechanical data as this part of the behaviour is strongly non-linear and include friction, gliding, … It should be mentioned that the compacted powder seemed to be cohesive enough to permits the propagation of waves under a very small stress. A future extension of this work can be to perform in situ ultrasonic measurements.

The oedometric compression has been stopped for ultrasonic measurements five times for the 24h dried lepidocrocite and seven times for the 48h dried. As the actual oedometer length gives its volume V and the pycnometer oxide measurements give the oxide volume f V the oxide volume fraction f was deduced. We can observe in figure 4 that the measured Young modulus of 2 GPa is consistent with the value of 1.26 GPa given by the tangent modulus for a low (-5 MPa) applied stress as the ultrasonic modulus is often higher than the mechanical value for a large range of materials. For the reference alumina, five measurement points were performed. Without any surprise the Young's modulus increases as the compaction increases, with a typical non-linear behaviour for granular materials. A volume fraction of 1, for pure crystal, leads to several hundred GPa: from 215 to 350 GPa for maghemite Fe2O3 [START_REF] Samsonov | The oxide handbook[END_REF] and 390 GPa for alumina [START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF]. This point should be added to the measured modulus on Figure 4 and exhibits very high non linearity which can be explained from a micromechanical point of view by the increasing number of contact points when the load increases and from a purely elastic point of view by the non linearity of the Hertz equations for the elastic contact between two ellipsoidal domains. The measured Young's modulus is around some GPa, making the Lundgren [START_REF] Lundgren | A model for 3D-analyses of bon between corroded reinforcement and concrete, Creep Shrinkage and Durability Mechanics of Concrete and other Quasi-Brittle Materials[END_REF] assumption of 6 GPa a "reasonable" value.

HERTZ' CONTACT MODEL

Grain to grain contact seems to lead to the non-linear elasticity of the powder material. In order to model it, it has been chosen to use the Hertz' elastic contact theory. In such materials, a force network develops, with grain-to-grain transmission by contact forces. Considering a concentrated load, the network develops as a cone whose angle can vary from quite wide in the case of spherical particles without friction [START_REF] Oron | Exact calculation of force networks in granular piles[END_REF] to some straight line in the case of square grains [START_REF] Rajchenbach | Stress transmission through a cohesionless material[END_REF]. Friction tends also to diminish the angle of this cone, as in the Mohr-Coulomb approach. For the sake of simplicity, we chose to model the limit case of the transmission of the load by grain columns, as shown on Figure 5. The oedometric stress lead to grain forces whose intensity is given respect to the average surface Sg of the grain:

g g S F σ = (4)
Then it was supposed a spherical contact between grains. The load applied to particle surface can be presented as:

horizontal g N F F π = (5)
where Fg is the load applied on the surface of a particle; Nhorizontal is the particles number along the horizontal direction (the diameter of the specimen is equal to 20 mm) and F is the load measured during the manufacturing of a specimen of known porosity. When a mechanical load, F, acts along the z-axis on the surfaces of elastic particles 1 and 2 (Figure 5), the displacement δ, with increasing load can be obtained by:

vertical N L ∆ = δ (6)
where ∆L is the measured displacement (the vertical displacement of the piston) and Nvertical is the number of particles calculated with the initial height along the vertical direction. This displacement can be also given by:

3 1 2 * 2 16 9         = E R F g δ (7)
where ( ) ( )

2 1 * 1 1 1 R R R + =
is the relative curvature and E is the combined Young's modulus which is defined as:

1 2 2 2 1 2 1 1 1 -         - + - = E E E ν ν (8)
The subscripts 1 and 2 denote the particle 1 and particle 2, respectively. In case of the tested oxides, all the particles are assumed to have the same radius (R=R1=R2) and the same mechanical properties (E1=E2=E). The Young's modulus of an oxide particle -supposed to be isotropic -can be found:

( ) 3 4 2 2 1 9 δ ν R F E g - = (9)
In our case we intend to find the Young's modulus of the particle that matches the Young's modulus of the powder. The Figure 6 give the obtained values for lepidocrocite. The results for oxides are much more convenient to bibliography [START_REF] Samsonov | The oxide handbook[END_REF][START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF]. For the lepidcrocite of interest the Figure 6 suggests an average value of 400 GPa for the 48h dried lepidocrocite, with grain max size 8.7 µm, very close to the 390 GPa of the reference [START_REF] Samsonov | The oxide handbook[END_REF]. For the 3.63 µm grain average size we obtain a higher average value of 600 GPa. The order of magnitude is still correct but this simple model is probably no more applicable to this situation.

CONCLUSIONS

Based on the observations made during the experimental investigation and the results of theoretical calculations, the following conclusions can be made: Mechanical testing performed on iron oxide (lepidocrocite), in a powder state, shows a non-linear behaviour with important permanent strain, revealing the classical behaviour of a powder material and confirming the observations of Lungrend [START_REF] Lundgren | A model for 3D-analyses of bon between corroded reinforcement and concrete, Creep Shrinkage and Durability Mechanics of Concrete and other Quasi-Brittle Materials[END_REF]. To avoid any dissipative phenomena the Young's modulus of some GPa has been deduced from elastic discharge branch of stress-strain curve. The Young's modulus values obtained during mechanical testing were confirmed by ultrasonic measurements. The elastic modulus increases with the compaction and shows also a typical non-linear behaviour for granular material. For oxide volume fraction equal to 1 (pure crystal) the Young's modulus can reach several hundred GPa: from 215 to 350 GPa for maghemite Fe2O3 [START_REF] Samsonov | The oxide handbook[END_REF] and 390 GPa for alumina [START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF]. The ultrasonic measurements showed that the oxide dehydration increases the elastic modulus from 1.8 (drying 24 hours) to 3.6 (drying 48 hours) for 0.65 % of oxide volume fraction.

The Hertz contact model leads to results very convenient with results found in bibliography [START_REF] Samsonov | The oxide handbook[END_REF][START_REF] Schmitt | Micromechanics applied to the thermal shock behavior of refractory ceramics[END_REF]. An average value of 400 GPa for the 48 h dried lepidocrocite with grain max size 8.7 µm is very close to the 390 GPa of the reference [START_REF] Samsonov | The oxide handbook[END_REF]. Despite the influence of the friction contact on the estimation of the Young's modulus, it should be advised to use the Young's modulus obtained by ultrasonic measurements to perform a simulation of degradation processes in concrete structures under the expansion of corrosion products. This choice can be justified by the fact that these measurements were carried out on micrometric particles of oxides which is close to the real oxides.

Table 1 :Figure 1 .

 11 Figure 1. SEM observation of lepidocrocite particles dried during 48 hours at 50°C.

Figure 2 .

 2 Figure 2. Results of compression test on lepidocrocite dried during 24 hours.

Figure 3 .

 3 Figure 3. Scheme of the ultrasonic measurement system.

Figure 4 .

 4 Figure 4. Evolution of the Young modulus derived from the US measurements.

Figure 5 .

 5 Figure 5. Principle of the Hertz model.

Figure 6 .

 6 Figure 6. Young modulus derived from the Hertz theory.