Refractory status epilepticus – a major problem for the practitioners

Introduction: Status epilepticus (SE) is a life-threatening neurological emergency requiring immediate medical intervention and is associated with high mortality and morbidity. The aim of this research was evaluation of clinical and etiological profile of refractory status epilepticus (RSE) among children aged between 1 month and 18 years. Material and methods: The study was done between January 1, 2017 and December 24, 2019. All children with the age limits mentioned above, who presented convulsive SE, subsequently with development in refractory status epileptic (RSE), were included in the study. Patients were investigated and evaluated according to a standard protocol. Subsequently, the characteristics of children with RSE and those without an evolution in RSE were compared. Results: 55 children, out of whom 32 boys with SE were enrolled in the study, of which 20 children (36%) developed RSE. Central nervous system (CNS) infections were the most common causes of SE and development of RSE (51% in SE and 53% in RSE, p > 0.05). Noncompliance of antiepileptic medication served as the second cause for evolution of RSE. The overall mortality rate was 10.9%, the chances of death in RSE (20%) being higher than in SE (5.7%). The unfavorable prognosis was seven times higher in children with RSE, compared to children who developed SE. Conclusions: In the management of CNS infections, pediatricians should be aware of the high risk of developing RSE. In addition, the possibility of developing RSE should be considered and promptly managed in an intensive care unit in order to reduce the risk of mortality and morbidity of this severe neurological condition.


Introduction
Status epilepticus (SE) is a life-threatening neurological emergency requiring immediate medical intervention and is associated with high mortality and morbidity. The incidence of SE in children is reported to be of 10-40 children per 100000 people. SE is the most common pediatric neurological emergency [1,2], being a condition resulting from the loss of the mechanisms responsible for ending of convulsive access or by initiating mechanisms that cause an abnormal convulsive response (after Time 1) [3,4]. SE is a condition that can lead to long-term consequences (after Time 2), including neuronal death, neuronal injury, alterations of neural networks depending on the type and duration of the attacks [4]. The practical approach suggests that any seizure or series of seizures, lasting more than five minutes, could be considered as SE, most children requiring pharmacotherapy for control of seizures [3,4].
Recently, Tinka et al. proposed a new definition for focal SE: a duration of 10 minutes of seizures (without the return of consciousness between seizures) and 60 minutes for possible long-term consequences [4]. At the same time, and experimental data support the idea that prolonged seizures cause neuronal damage, therefore the drug intervention is considered critical in such cases [5,6].
In children, the incidence is higher compared to that in adults; however, the mortality rate of adult patients is higher, around 20%, and in children under 10 years of age, it can be up to 2.6% [7,8]. Early diagnosis and prompt treatment significantly reduce mortality and are key steps in SE management [9]. After initial supportive treatment (ABC via intravenous [I/V] access), seizure control with Lorazepam I/V is recommended as a first-line treatment [10,11]. Alternatives to Lorazepam include intravenous administration of Midazolam or Diazepam. If I/V access is not achieved, Midazolam may be administered orally, intranasally or intramuscularly. Diazepam may also be administered rectally [12,13]. First-line drugs control the seizures and they are obtained in 80% of children in the first 30 minutes [14]. If the patients continue to have seizures, additional treatment should be given rapidly [15]. Most experts recommend fosphenytoin as a secondline therapy, although there are supporters in favor of the use of other alternative antiepileptic drugs (AED), such as phenobarbital, valproic acid or levetiracetam [16]. While most of the causes of SE are due to epilepsy, in case of SE in children primary causes can be considered atypical febrile seizures, neuroinfections, cerebral hypoxia and innate errors of metabolism [17].
Refractory epileptic status (RSE) is a more severe variant of SE. Currently, the accepted definition of RSE is the persistence of seizures despite the administration of two adequate anticonvulsants in acceptable doses and is estimated in approximately 10-40% of patients with SE. RSE has been shown to be associated with a higher mortality rate and more long-term neurological consequences. Based on the fact that RSE is a major emergency and on the fact that there are no studies on RSE in the Republic of Moldova, this research was carried out with the aim of improving knowledge on the etiology and evolution of RSE among children with SE, to prevent unfavorable prognosis, including mortality.

Material and methods
This study is a part of a larger research, carried out within the project "Integration of epileptogenic mechanisms in order of creating a network of multimodal diagnosis and treatment of epilepsy". The study is retrospective and descriptive (preliminary data attributed to the project). The group of patients included in the study was selected from children admitted to the Departments of Neurology of the Institute of Mother and Child Health Care during the years 2017-2019. SE was defined as a continuous seizure lasting more than five minutes and/or multiple seizures between which the state of consciousness was not regained within at least 30 minutes. The age of the patients included in the study ranged from one month to 18 years. Newborns and children with undocumented SE were excluded from the research. The medical records were reviewed to make an analysis of the data, type of seizures (focal versus generalized), data on epilepsy, as a precursor disease to the installation of SE, analyzed antiepileptic drags (AED) used daily by patients, serum levels of AED at the time of admission (therapeutic or sub-therapeutic), neuroimaging examinations performed, EEG data, possible etiological causes, mortality rate. Continuous data is presented as a median interval; some is presented as a percentage. A p value of less than 0.05 was considered significant.
RSE was defined as SE, in which seizures persisted despite the administration of two adequate anticonvulsants at acceptable doses. Unfavorable prognosis included death of the patient, persistent vegetative state or severe disability. In subjects with previously diagnosed epilepsy were collected data about the type of seizures, duration of disease, especially drawing attention to non-compliance and / or other changes in the dosage of drugs. The standard management of SE consisted of two doses of Diazepam, followed sequentially by intravenous phenytoin and intravenous phenobarbital. In severe cases, Propofol infusion was done. After seizure control, neuroimaging and EEG examinations were performed. In the case, if the child had fever, the lumbar puncture was performed (Glasgow Scale > 7 points). The children were monitored daily with appropriate examinations. All data were analyzed using Epi Info software. Different characteristics and results obtained in children with SE and children with RSE were compared.

Results
Of the 55 children (32 boys) with SE, the evolution of SE to RSE was recorded in 20 children (36%). The average age of patients was 6.5 years. There have been documented 6 (10.9%) cases of children who developed a recurrent SE. At the time of admission, the number of children with preexisting seizures who did not receive routine AED was 9% (5 cases), and 32 children (58.1%) received two or more AED daily. The results of serum AED were evaluated in 77.3% of children, of whom 51.6% children had subtherapeutic levels of AED.
Diazepam was the most common medication given as emergency therapy, used both in children with preexisting seizures and in those with "de novo" SE (62.5% vs 51.1%; p >0.05). The second-line anticonvulsant therapy was phenytoin (45.2% vs 51.1%; p >0.05). Phenobarbital infusion was used in 7.3% of children with pre-existing seizures and in none of the children with "de novo" SE. In 36.3% of cases, endotracheal intubation was required, mainly in the children with RSE (28.5% vs. 60%, p >0.05).

Fig. 1. Etiological factors for convulsive SE in children (n=35 ), (%)
The gender and type of seizures did not differ significantly between these 2 groups (tab. 1). Electroencephalography (EEG) was performed in 82% of all children admitted with SE. Of these, 72% showed changes on the EEG route. Among children with RSE, EEG was performed in 98% of cases, an abnormal route of EEG was recorded in 85% of cases.
Being admitted to the hospital, children were analyzed for possible causes for the onset of SE. Thus, CNS infection was considered an etiological cause for both SE and RSE (51% in SE and 53% in RSE, respectively) ( fig. 2).

Discussion
In this observational study based on the hospitalization of 55 children with convulsive SE (including 20 with RSE) at the Hospital of Mother and Child Health Care, we found out that CNS infections were the most common etiological cause in both groups of patients. Most studies in developing countries report CNS infections as the most common etiology of SE. Among pediatric studies, CNS infections are also the most common RSE etiologies [18].
The unfavorable prognosis was seven times higher in children with RSE, compared to children who developed SE. The proportion of generalized seizures varies from 63% to 96% in pediatric studies, similar to our conclusions (85%) [19].
About 1/4 of the subjects in the study had a previously established diagnosis of epilepsy, the conclusion corresponds to similar studies on RSE (16-29%) [20]. In the same way, we were able to perform the EEG exam only in 82% of patients with SE and in 98% of RSE. Neuroimaging was performed in 62.6% of patients with SE and 85.2% with RSE, with pathological changes in 43.4% of patients with SE and 62.6 with RSE, data correlate with previous studies [20].
Non-compliance with AED dosing regimens was an important cause of SE in this study (13%), subtherapeutic levels constituting 51.6%, similar to previous reports in adults (20-27%) [21]. A meta-analysis of paediatric RSE reported a mortality rate of 16%; more recent studies report rates up to 3.7% [22]. Studies in the adult population report mortality rates of 5-35% in RSE [23]. Our study reported a mortality rate of 10.9%, predominantly in the case of RSE.

Conclusions
1. The high proportion of RSE in patients with CNS infections, high rate of mortality in children with RSE and high rates of remote unfavorable prognosis are the highlights in the management of these cases. 2. Early identification of RSE in intensive care unit and emergency care service could reduce mortality in this group of children.

Since most patients with RSE have various CNS infections
as an etiologic cause, antibacterial treatment should be initiated from the very first minutes of RSE. 4. During the management of children with CNS infections, treating physicians should be aware of the high risk of developing of RSE, and this risk should be managed in an intensive care unit in order to reduce mortality and morbidity due to this severe neurological condition. 5. In addition to infections, another important etiologic cause of RSE was noncompliance with the AED; a situation that could be avoided by improving physician-patient compliance.