Istore: a project on innovative statistical methodologies to improve rare diseases clinical trials in limited populations.

BACKGROUND: The conduct of rare disease clinical trials is still hampered by methodological problems. The number of patients suffering from a rare condition is variable, but may be very small and unfortunately statistical problems for small and finite populations have received less consideration. This paper describes the outline of the iSTORE project, its ambitions, and its methodological approaches. METHODS: In very small populations, methodological challenges exacerbate. iSTORE's ambition is to develop a comprehensive perspective on natural history course modelling through multiple endpoint methodologies, subgroup similarity identification, and improving level of evidence. RESULTS: The methodological approaches cover methods for sound scientific modeling of natural history course data, showing similarity between subgroups, defining, and analyzing multiple endpoints and quantifying the level of evidence in multiple endpoint trials that are often hampered by bias. CONCLUSION: Through its expected results, iSTORE will contribute to the rare diseases research field by providing an approach to better inform about and thus being able to plan a clinical trial. The methodological derivations can be synchronized and transferability will be outlined.

Composite endpoints, including patient reported outcomes, in rare diseases.

BACKGROUND: When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value. RESULTS: Recently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic. CONCLUSIONS: Generalized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.

Bilateral Reappearance of the N20 Potential in a Normothermic Young Woman Post-Anoxic Brain Injury.

SUMMARY: Hypoxic-ischemic brain injury is a well-known consequence of cardiac arrest and providing an accurate prognostication remains a challenge, especially in decisions related to withdrawal of care. Bilateral absence of the cortical response (N20 potential) on median somatosensory evoked potentials, on days 1 to 3 after the return of spontaneous circulation, is widely considered as the most reliable predictor of poor outcome with a high specificity and a low false-positive rate. The authors describe the case of a young comatose woman after hypoxic injury because of cardiac arrest whose initial median somatosensory evoked potentials revealed bilateral absence of the N20 response associated with evidence of selective injury to both perirolandic cortices and basal ganglia on brain MRI. This patient made a substantial recovery associated with bilateral reappearance of the N20 potential and resolution of the neuroimaging abnormalities.This case revealed that an acute selective and reversible hypoxic injury to both perirolandic cortices may lead to a temporary loss of the N20 responses and an inaccurate prediction of poor outcome after cardiac arrest. It emphasizes on the importance of adopting a multimodal approach in the prognostic assessment of survivors of cardiac arrest.

New-onset refractory status epilepticus as an early manifestation of multisystem inflammatory syndrome in adults after COVID-19.

Multisystem inflammatory syndrome in adults (MIS-A) is a rare hyperinflammatory complication with multi-organ involvement that manifests a few weeks after recovering from a typically mild coronavirus disease 2019 (COVID-19) infection. Although encephalopathy and seizures can occur in the acute phase of COVID-19, the nervous system is infrequently involved in patients with MIS-A. Herein, we describe the case of a young woman who presented with new-onset refractory status epilepticus (NORSE) following a mild COVID-19 infection associated with symptoms, signs, and laboratory findings that satisfy the updated Centers for Disease Control and Prevention (CDC) definition of MIS-A. Magnetic resonance imaging of the brain revealed symmetric T2-signal increase involving both orbitofrontal lobes, insulae, and hippocampi. One of the notable findings in our patient was the quick response and significant clinical recovery that occurred following initiation of treatment with intravenous methylprednisolone and intravenous immunoglobulin. Our case expands the clinical spectrum of MIS-A and documents the occurrence of NORSE as one of its early clinical manifestations. A routine comprehensive clinical and laboratory assessment is needed to screen for this underdiagnosed condition, especially in patients with post-COVID-19 inflammatory complications.

Predicting the occurrence of thrombocytopenia from free valproate levels: A prospective study.

PURPOSE: The likelihood of valproate (VPA) induced thrombocytopenia increases with higher VPA levels. In critically ill patients, the biological active free VPA level cannot be predicted from the total serum level. In this study, we evaluated the relationship between trough free VPA serum levels and concomitant platelet counts and assessed risk factors for the development of thrombocytopenia with the aim of generating a formula specifying the probabilities of developing thrombocytopenia based on trough free serum VPA levels. METHODS: Trough free VPA levels and concomitant platelet counts were collected from a large cohort of patients who participated in a prospective VPA monotherapy trial. Significant variables associated with thrombocytopenia in a univariate analysis were evaluated in a multivariate model. A receiver operator curve was performed to compute the trough free VPA levels with the greatest discriminating power in predicting thrombocytopenia. RESULTS: 844 trough free VPA levels and concomitant platelet counts obtained from 264 patients were analyzed. In a multivariate analysis, trough free VPA levels, gender, and baseline platelet counts were significantly associated with thrombocytopenia. Using stepwise regression and multivariate logistic regression analyses, we generated gender-specific formulas for predicting platelet counts and probabilities of developing thrombocytopenia. The trough free VPA with the greatest discriminating power to predict platelet values ≤ 100,000/µL was 16.65 µg/mL. CONCLUSIONS: The generated model was based on trough free VPA levels and achieved high sensitivity and specificity. Our results are therefore generalizable and can be applied to estimate the probability of developing thrombocytopenia in critically ill patients.

The importance of acknowledging diagnostic uncertainty in patients with new-onset paroxysmal spells.

OBJECTIVE: The aims of this study were to evaluate the frequency of paroxysmal spells of indeterminate nature (PSIN) in a large cohort of children and adults with suspected new-onset seizures, to evaluate the reasons for including patients in this category, and to calculate the rate of erroneous diagnoses if the epileptologists were compelled to label those events as epileptic seizures or nonepileptic paroxysmal spells. METHODS: Patients identified for this study participated in a prospective study evaluating patients with suspected new-onset unprovoked seizures. The workup included a detailed history and a thorough description of the spells, a 3-hour video EEG recording, and an epilepsy protocol brain MRI. Based exclusively on a detailed description of the ictal events, two epileptologists were asked to independently classify each patient into those with a definite diagnosis of unprovoked seizures or a definite diagnosis of a nonepileptic paroxysmal spells (group 1) and those with PSIN (group 2). RESULTS: A total of 1880 consecutive patients were enrolled with 255 (13.6%) included in the PSIN group. Patients with PSIN were significantly younger than those with a definite diagnosis, and PSIN were significantly more frequent in children with developmental delay. The most common reason for including patients in the PSIN group was the inability to categorically discriminate between a seizure and a nonepileptic mimicker. When the raters were compelled to classify the spells in the PSIN group, the frequencies of erroneous diagnoses ranged between 32% and 38%. The final diagnoses on those patients were made based on the results of the EEG, MRI, and follow-up visits. SIGNIFICANCE: Our data indicate that a diagnostic category of PSIN should be recognized and ought to be used in clinical practice. Acknowledging this uncertainty will result in lower frequencies of erroneous diagnoses, possible stigma, and potential exposure to unnecessary antiseizure medications.

Depression and anxiety in patients from Lebanon with new onset functional seizures.

OBJECTIVES: To prospectively compare the frequencies of depression and anxiety in patients with new onset functional seizures versus two age and gender-matched control groups consisting of patients with new onset epileptic seizures and normal individuals. METHODS: Consecutive patients, 16 years and older, enrolled in a prospective study for suspected new onset epileptic seizures and diagnosed with documented functional seizures were included. We compared the depression and state and trait anxiety scores using the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI) between patients with functional seizures and the other two control groups. RESULTS: The 33 patients with functional seizures had significantly higher depression and anxiety scores compared to those with epileptic seizures and normal controls. Twenty patients (60.6%) in the functional seizures group scored in the "depression" range compared to 5/33 (15.2%) in the epileptic seizures and 1/33 (3%) in the control groups. In the functional seizures group, 14/33 (42.4%) had scores in the "state anxiety" range compared to 6/33 (18.2%) and 2/33 (6.1%) in the epileptic seizures and normal control groups, respectively. Similarly, 15/33 (51.5%) of patients in the functional seizures group had scores in the "trait anxiety" range compared to 4/33 (12.1%) and 1/33 (3%) in the epileptic seizures and normal control groups, respectively. CONCLUSIONS: Our results indicate that patients with new onset functional seizures frequently suffer from depression and anxiety at the time of their initial evaluation. These findings underscore the importance of screening for depression and anxiety in that patient population.

A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.

Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.

Case Report: Distinctive EEG Patterns in SCARB-2 Related Progressive Myoclonus Epilepsy.

Action myoclonus-renal failure syndrome (AMRF) is a rare, recessively inherited form of progressive myoclonus epilepsy (PME) caused by mutations in the SCARB2 gene and associated with end-stage renal failure. In addition to severe progressive myoclonus, the neurological manifestations of this syndrome are characterized by progressive ataxia and dysarthria with preserved intellectual capacity. Since its original description, an increasing number of "AMRF-like" cases without renal failure have been reported. We describe the case of a 29-year-old woman with progressive disabling myoclonus associated with dysarthria and ataxia who was found to have a novel homozygous frameshift mutation in the SCARB2 gene. In addition, this report emphasizes the presence of two EEG patterns, fixation-off phenomenon, and bursts of parasagittal spikes exclusively seen during REM sleep that appear to be characteristic of this condition.

FARS2 Mutations: More Than Two Phenotypes? A Case Report.

FARS2, a nuclear gene, encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS). Previous reports have described two distinct phenotypes linked to FARS2 gene mutation: an early onset epileptic encephalopathy and spastic paraplegia. This report describes a distinctive phenotype of FARS2-linked, juvenile onset refractory epilepsy, caused by a hemizygous mutation in a compound heterozygous state (p.V197M and exon 2 microdeletion). A 17-year- old woman with normal development presented with a super refractory focal motor status epilepticus. Only an emergency life-saving surgery aborted her status after all therapeutic interventions, including anesthesia, failed to control her seizures. Pathological and biochemical activities on muscle biopsy showed mitochondrial proliferation with enhanced isolated activities of complexes II and IV, suggestive of a compensatory mechanism for the bioenergetic deficiency. Postoperatively, the patient started experiencing focal aware motor seizures originating from the contralateral hemisphere after being seizure free for a few months. This report suggests a third phenotypic manifestation of FARS2 gene mutation.

Ictal blinking in focal seizures: Insights from SEEG recordings.

PURPOSE: Ictal blinking may be observed in various forms of epilepsies. In the context of presurgical assessment of drug-resistant focal epilepsies, its semiological value is poorly understood. Our aims were to determine the prevalence and localizing value of ictal blinking. METHODS: We reviewed our cohort of more than 300 patients explored by SEEG, searching for ictal blinking. We defined seizure onset zone (SOZ) using visual analysis complemented by a quantified method (epileptogenicity index). We analysed the features of ictal blinking and the associated signs. We tested for statistically significant associations with the underlying SOZ. RESULTS: We found that about 8% of our patients exhibited ictal blinking, mostly bilateral. Ictal blinking was seen mostly in four types of SOZ: occipital, occipito-temporal, temporal mesial, and insulo-opercular. It was significantly over-represented in occipito-temporal and occipital SOZ. Eye blinking was fastest in insulo-opercular SOZ and slowest in temporal mesial SOZ. Nystagmus and tonic eye deviation were associated with SOZ involving the occipital lobe. CONCLUSION: Ictal blinking is not uncommon in the population of patients with drug-resistant focal epilepsies. It is mostly associated with four types of SOZ: occipital, occipito-temporal, temporal mesial, and insulo-opercular. Some features of ictal blinking, as well as the analysis of the associated signs, allow to orient clinical hypotheses toward some specific SOZ.

Efficacy and tolerability of treatment with lacosamide in children: Postmarketing experience from the Middle East.

PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in Lebanese children with focal-onset seizures and to determine if specific variables are predictive of better effectiveness. METHODS: This is a retrospective analysis from three medical centers on consecutive children diagnosed with focal onset seizures and initiated on LCM. The seizure frequencies following the introduction of LCM were recorded and compared to the baseline monthly frequency at 3, 6, 12, 18, and 24 months. The primary efficacy variables were the 50% responder and seizure-free rates. The secondary outcome variables included the terminal 6-month seizure remission and percentages of discontinuation due to lack of efficacy or tolerability. RESULTS: 58 patients with a mean age of 10 years experiencing a mean of 36.2 seizures per month during baseline were included. The seizure-free rates were 32.8%, 29.7%, and 12.5% at 6, 12 and 24 months follow up, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve a terminal 6-month seizure remission while the early introduction of LCM resulted in a significantly higher likelihood of attaining such a remission. 74.1% of patients were still maintained on LCM at the last follow-up. The most common adverse events consisted of dizziness, somnolence, nausea, vomiting, and rarely double vision. CONCLUSIONS: LCM is efficacious and overall well tolerated in children with focal-onset seizures and exhibits higher efficacy with early introduction and when added to a non-sodium channel blocker.

Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers.

BACKGROUND: The aim of this study was to understand the impact of Dravet syndrome (DS) on patients with Dravet syndrome and their families, with a focus on the social and economic impact on both mothers and fathers. METHODS: A French language on-line survey was distributed (October 2014-January 2015) for completion by caregivers of patients aged <18 years with DS. The survey was hosted on the French Dravet Syndrome Alliance website, and the survey link was provided to patients and caregivers during clinics at the Necker Hospital (Paris, France). RESULTS: Survey responses were available for 91 patients (median age 7.6 years; 81.6% SCN1A mutation positive). Total seizure frequency was >2 per week for 16.1% of patients, 1-8 per month for 55.2% and < 1 per month for 28.7%; tonic-clonic and myoclonic were the most frequent seizure types. Patients showed various degrees of intellectual disability and DS had a high impact on concentration and school learning in 70.1% and 80.5%. In addition, patients showed appetite disorders in 73.6%, sleep disorders in 72.4% and behavior disorders in 62.1%. Most parents were married (80.5%) with higher rates than the French general population (53.5%). Educational achievement and socio-professional categories for the parents were higher than observed in the French general population, while monthly net income was similar. Preparation of medication was generally done by the mother and father (46.0% of patients) or the mother only (37.9%). Most caregivers reported very low or no difficulty with treatment preparation and low or no risk of error. Parents typically spent <30 min per day on treatment preparation and administration and around 4 h per week for attending therapy appointments. Although most patients and parents were perceived to have good general health, mothers had a worse perception of their own general health than fathers. Compared with fathers, mothers reported a greater impact of caring for a child with DS on their social life, relationships with family and friends, time and energy, and professional life. CONCLUSION: Families caring for a child with DS experience considerable social and economic impact, with an apparent greater burden of care on the mother than the father.

Frequency and Stratification of Epileptogenic Lesions in Elderly With New Onset Seizures.

Objective: To evaluate prospectively the frequency of epileptogenic lesions in a consecutive cohort of elderly patients presenting with new onset unprovoked seizures, and who underwent a complete evaluation including dedicated epilepsy protocol MRI. Methods and materials: We included all consecutive patients 60 years or older who participated in a prospective study on new onset epilepsy. The work-up included the acquisition of a dedicated epilepsy protocol MRI and a 3 h video/EEG recording. We evaluated the frequency and types of epileptogenic lesions in the whole cohort and stratified those variables by age, gender, types and number of seizures at presentation. We also correlated the EEG findings with the clinical characteristics and neuroimaging results. Results: Of the 101 patients enrolled in the study and who underwent an epilepsy protocol MRI, an epileptogenic lesion was identified in 67% of cases. The most common etiologies were vascular events, followed by tumoral causes and traumatic brain injuries. Epileptogenic lesions were more likely to be identified in patients who presented with only focal aware and impaired awareness seizures. In addition, patients with tumoral epilepsy were significantly more likely to only experience those seizure types compared to patients with other pathological substrates. Interictal/ictal discharges were detected in the EEG of 21% of patients. Epileptiform discharges were significantly more frequent in patients with an epileptogenic lesion on brain MRI, especially in those with a brain tumor. Conclusions: Our results stress the importance of obtaining a dedicated epilepsy protocol MRI in elderly patients with new onset seizures. An epileptogenic lesion will be identified in approximately two thirds of patients with important implications regarding initiation of treatment. In addition, the data underscore the value of distinguishing the types of seizures experienced at presentation as this will apprise the treating physician on the likelihood of identifying an epileptogenic lesion and on the probable etiologies.

Efficacy and tolerability of treatment with lacosamide: Postmarketing experience from the Middle East region.

PURPOSE: Lacosamide (LCM) was recently introduced in the Middle East. The aim of this study was to evaluate the safety, tolerability, and efficacy of LCM in patients with focal onset seizures and determine if our results are comparable with those derived from Western countries. METHODS: This is a retrospective analysis from two medical centers on consecutive patients diagnosed as having focal onset seizures and treated with add-on LCM. The primary efficacy variables were the 50% responder and seizure-free rates, and the secondary outcome variables included the percentages of patients who achieved seizure remission during the last 6-month follow-up period and the percentages of discontinuation due to lack of efficacy or tolerability. RESULTS: One hundred four patients with a mean age of 30.9 years and experiencing a mean of 9.4 seizures per month during baseline were included. The 50% responder rates were 69% and 70% at 6- and 24-month follow-ups, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve seizure remission during the last 6-month follow-up period while the early introduction of LCM resulted in a significantly higher likelihood of achieving such a remission. Eighty-eight percent of patients were still maintained on LCM at the last follow-up, and the most common adverse events consisted of dizziness and somnolence, double vision, and nausea/vomiting. CONCLUSIONS: Our data show similar efficacy and tolerability to those reported from Western countries. Our results also substantiate the early introduction of LCM and support the dose reduction of baseline AED especially that of sodium channel blockers to minimize adverse events.

Determinants of free serum valproate concentration: A prospective study in patients on divalproex sodium monotherapy.

PURPOSE: To evaluate variables affecting the valproate (VPA) free fraction and develop an equation for computing free VPA concentration from total VPA concentration. METHODS: Trough total and free VPA concentrations were collected from patients who participated in a prospective VPA monotherapy trial. All available paired data of trough total and free VPA concentrations were included. Significant variables from the univariate analysis were evaluated in a multivariate model. RESULTS: A total of 902 concomitant total and free VPA concentrations were available. Multivariate analysis showed that total VPA concentration, age and gender were significantly associated with VPA free fraction. However, the effect size of total VPA concentration was substantially higher than that of gender and age. VPA free fraction remained stable at around 10% for total VPA concentration between 20 and 60 µg/mL with subsequent linear increases for higher concentration. A scatter plot correlating total and free VPA concentrations showed that a quadratic equation best fitted the data, accounting for 88% of the free VPA concentration variance. CONCLUSIONS: An increase in the total VPA concentration results in corresponding linear and non-linear rise in the VPA free fraction and free VPA concentration, respectively. The total daily dose of VPA should be increased in smaller increments whenever a total VPA concentration of 60 µg/mL is reached. When drug monitoring is needed, we recommend measuring the free VPA concentration. If this test is unavailable, and for patients with normal albumin levels, it can be predicted from the total VPA concentration using the generated equation.

Efficacy of the Sequential Administration of Melatonin, Hydroxyzine, and Chloral Hydrate for Recording Sleep EEGs in Children.

Sedation of children for electroencephalography (EEG) recordings is often required. Chloral hydrate (CH) requires medical clearance and continuous monitoring. To try to reduce personnel and time resources associated with CH administration, a new sedation policy was formulated. This study included all children who underwent an EEG during a consecutive 3-month period following the implementation of the new sedation policy, which consists of the sequential administration of melatonin, hydroxyzine (if needed), and CH (if needed). The comparator group included all children with a recorded EEG during a consecutive 3-month period when the sedation policy consisted of the sole administration of CH. A total of 803 children with a mean age of 7.9 years (SD = 5.1, range = 0.5-17.7 years) were included. Sleep EEG recordings were obtained in 364 of 385 children (94.6%) using the old sedation policy and in 409 of 418 children (97.9%) using the new one. With the new sedation policy, the percentage of children requiring CH dropped from 37.1% to 6.7% (P < .001). Time to sleep onset and duration of sleep were not significantly different between the 2 policies. The new sedation policy was very well tolerated. The new sedation policy is very safe, is highly efficacious in obtaining sleep EEG recordings, and will result in substantial saving of time and personnel resources.

Unilateral Mu Rhythm and Associated Cortical Lesions on Brain MRI.

PURPOSE: The purpose of this study was to assess the frequency of occurrence of a unilateral mu rhythm and the associated neuroimaging findings on dedicated epilepsy protocol brain MRI. METHODS: We retrospectively reviewed the EEG reports database at the American University of Beirut Medical Center between 2011 and 2014 searching for the presence of a unilateral mu rhythm. For patients with a unilateral mu rhythm, we recorded the patients' demographics, number of EEGs performed, characteristics of the mu activity, and the findings on the epilepsy protocol brain MRIs. RESULTS: A total of 7986 patients underwent 9,509 EEG between 2011 and 2014. Four patients (0.05%) aged between 19 and 55 years had evidence of a unilateral mu rhythm. Three patients were diagnosed with localization-related epilepsy and one with syncope. The brain MRIs showed cortical lesions involving the parietal cortex, ipsilateral to the unilateral mu rhythm in the three patients with epilepsy. CONCLUSIONS: A unilateral mu rhythm is a rare phenomenon on the scalp EEG that should prompt a search for an ipsilateral lesion, even in the absence of additional EEG abnormalities.

Panayiotopoulos syndrome presenting with respiratory arrest: A case report and literature review.

We describe a child with Panayiotopoulos syndrome (PS) who presented with autonomic status epilepticus and developed respiratory arrest requiring intubation and mechanical ventilation. Because of that life-threatening episode and the risk of developing a similar event in subsequent seizures, we decided to initiate our patient on AED treatment. Such life-threatening complications were previously reported in only four children with PS. Although PS is considered to be a benign childhood epilepsy syndrome usually not requiring treatment with antiepileptic drugs, our case and the small number of similar cases in the literature show it is important to realize that it can rarely be associated with life-threatening complications. It is our opinion that children with PS who develop an episode of autonomic status epilepticus and those living in remote areas with no quick access to emergency departments should be initiated on AED therapy to minimize the risk of experiencing a subsequent potentially fatal seizure. We further suggest that the use of benzodiazepines in this syndrome should only be administered during the early stage of the seizure, since administration of this class of drugs during an established autonomic status epilepticus can result in further respiratory depression.