[Patient safety culture in neonatal intensive care units as seen by nurses]. / La culture de sécurité des patients dans les unités de soins intensifsnéonatals vue par les équipes.

Neonatal intensive care units (NICUs) are critical environments in terms of safety of care, with a high risk of adverse events. Measuring the patient safety culture of the professionals working there should help to improve the care offered. A descriptive cross-sectional study, conducted among 141 nurses and childcare workers in 2020 in 5 Tunisian hospitals, examined this question.

Hypericum Humifusum Leaves Attenuates Hepatic Ischemia-Reperfusion Injury in a Rat Model.

INTRODUCTION: Effective prevention strategies require specific actions during the different phases of ischemia-reperfusion (I-R) injury. The objective of our study is to evaluate the effect of aqueous extract of Hypericum humifusum leaves (HHL) on liver I-R model in Rat. MATERIAL AND METHODS: Animals were subjected to 90 min of hepatic ischemia followed by reperfusion (120 min). HHL extract (25 mg/mL/kg) was injected 15 min before reperfusion. To evaluate the effect of HHL extract on I-R, we have monitored transaminases levels, Malondialdehyde (MDA) concentration, histological lesions (apoptosis and necrosis) and compared the results to a reference oxidant vitamin E. RESULTS: The determination of total phenol extracts of HHL was 59.91 ± 0.35 mg of Gallic Acid/g dry plant material with higher antioxidant activity (91.73% ± 1.67) compared to vitamin E (87.42%). Using aqueous extract of HHL, we noted a significant decrease of AST and ALT [1129 UI (585/1995) and 768 UI (335/1375)] compared to no-treated group [5,585.5 UI (5,035/12,070) and 8,099.5 UI (5,040/12,326)] as a decrease in MDA content [85.7% protection (50.9/91.5)]. HHL extract reduce the damage induced by I-R of 48.7% (27/48.7) and 96.1% (95.7/96.5) for necrosis and apoptosis lesions respectively. CONCLUSION: HHL aqueous extract have potential to protect liver from the damage effect induced by I-R better than vitamin E solution.

[Antiepileptic drugs administration by nasogastric tube in comatose patients]. / Modalités d'administration des antiépileptiques par sonde nasogastrique chez des patients comateux : étude des connaissances, attitudes et pratiques.

AIM: To evaluate the modalities of administration of antiepileptic drugs (AED) with nasogastric tube (NGT) by nurses and to draw up recommendations. METHODS: Our study consisted on investigating the modalities of administration of AED's with NGT by nurses during four months. We prepared 10 questions including demographic information. Participation was voluntary and anonymous. The questionnaire was distributed in seven intensive care departments after authorization of each head of the department. Thus, 45 nurses were included. RESULTS: Nurses sex ratio was 1.5 and mean age was 31 years (25 to 37 years). Among the nurses, 60% mentioned that the NGT were silicone made and 4% that they were PVC made. The mean duration before replacing the NGT was thought to be 5±3 days. Among the nurses, 91% affirmed to clear the NGT after each use. All the nurses had agreed that the solid form is the most commonly used pharmaceutical form in the NGT. AED were associated with the enteral feeding solution in 56%. The AED should be crushed before administration for 98% of the nurses even in case of polymedication. Among them, 62% recommended to crush all of the associated drugs together. Before introducing the AED into the NGT, 93% of the nurses reported mixing with tap water. We have noticed that 62% of nurses felt the need to improve their knowledge AED administration with NGT. CONCLUSION: To optimize AED therapy, modalities of administration by NGT in epileptic comatose patients should be enhanced.

Therapeutic monitoring of antiepileptic drugs in comatose patients.

OBJECTIVE: In this study, we aimed to analyze the trough plasmatic levels (C0) of the antiepileptic drugs (AED) administered by nasogastric tubes (NGT) in comatose patients and to draw up recommendations for therapeutic drug monitoring (TDM) and for the modalities of AED administration by NGT. METHODS: We conducted a retrospective study on comatose patients addressed over six years and 10 months in Clinical Pharmacology for C0 measurement of AED administered by NGT. RESULTS: In this study, the sex-ratio was 2.38 (44 patients). The patients' median age was 24 years. There was 14.5% of children (≤16 years). Among the 103 samples, C0 measurement concerned valproic acid in 57%, phenobarbital in 28 % and carbamazepine in 15%. Two AED or more were associated in 42% of patients. AED were associated to other drugs in 85% of cases. The AED C0 were subtherapeutic in 71% of cases. C0/Dp lower than recommanded in 65 %. In these samples, 55% presented at least one drug association with the concerned AED. In 45% of the cases, there was no drug association but a non-respect of modalities of AED administration by NGT in patients. CONCLUSION:   The drug monitoring is a useful tool to assess drug-drug interactions and to control modalities of AED administration in comatose patients.

Fatal Kounis syndrome with stent thrombosis secondary to amoxicillin/clavulanic acid use: A case report and literature review.

Anaphylactic reactions are often induced by drugs, and the most frequent ones are penicillin derivates. The concurrence of acute coronary syndrome with hypersensitivity and anaphylactic or anaphylactoid reactions constitutes the Kounis syndrome. We report a case of a coronary stent thrombosis with a fatal outcome complicating an anaphylactic shock induced by amoxicillin-clavulanic acid association. A 58-year-old woman with a history of triple coronary stenting was treated by amoxicillin/clavulanic acid association for pharyngitis. One hour after the first drug intake, she developed an anaphylactic shock with acute constricting chest pain. She received intravenous hydrocortisone and was transferred to emergency department. The patient received epinephrine intravenously with fluid perfusion and oxygen. Electrocardiogram showed Pardee waves in the anterior precordial leads. Cardiac enzyme levels (troponin I) were disturbed. The patient was transferred to the coronary care unit with a diagnosis of acute myocardial infarction. The coronary angiography revealed anterior interventricular stent thrombosis. The patient experienced a cardiogenic shock with an important hemodynamic repercussion, and she died few hours later despite emergency care. The responsibility of amoxicillin-clavulanic acid association was retained in the genesis of this anaphylactic shock in front of a suggestive delay, a compatible evolution and a high semiotic score. Amoxicillin/clavulanic acid use may cause Kounis syndrome. The use of epinephrine is a challenging decision. We suggest that Kounis syndrome should be considered in the differential diagnosis of acute coronary syndrome.

Protective effect of Ulva lactuca extract during hepatic cold preservation in rats.

Introduction In recent years, many marine resources have drew attention in the research for bio-active compounds to develop new drugs and health foods. (1) Marine algae are now considered as a rich source of antioxidants (2). It is known that seaweeds contain numerous bioactive substances that have the ability to lower cholesterol, reduce blood pressure, promote healthy digestion; and antioxidant activity (3). Natural antioxidants are interesting compounds due to their properties which help prevent oxidative stress (4), among other potentially beneficial actions. For instance, several biological effects have been attributed to flavonoids, such as anti-tumoral, anti-inflammatory, anti-ischemic and anti-aggregate plaquetary activities. These activities are believed to be in part related to the antioxidant properties of the compounds, namely in scavenging radical oxygen species (ROS). (5, 6) The cold ischemia constitute a situation of oxidative stress in touch with liberation of oxygenated radicals, these situations incited the researchers to find means for the improvement of the conservation of organs allowing to prolong the durations of the cold ischemia of certain organs (in particular the liver) with conservation of the maximum functional value. However, the constant efforts led by the teams of transplantation to develop transplants, the conservation of organs remains a problem to be resolved. (7) Conservation solution of organ appears as being a stemming to remedy the fatal effects of the ischemia-reperfusion. For our part, we think that seaweeds have not delivered their secrets and yet especially that the marine environment of the Tunisian coast still remains little exploited in spite of the big variety of the fauna and the flora of the coast. We envisage in this work, to study a sort of seaweed collected on the Tunisian quotation in the region of "Chott Meriem" (North West of Tunisia). The purpose of our work is to estimate the capacity of extracts stemming from the green seaweed Ulva lactuca to improve the conservation solution of organs against the hepatic effects of ischemia.

Animal model of liver ischemia reperfusion: biochemical and histological evaluation.

INTRODUCTION: During last years, significant progress was made in the comprehension of the hepatic lesions after Ischemia-Reperfusion episode in order to improve the Results in practice clinical. AIM: To avoid or reduce the damage induced by Ischemia-Reperfusion, we developed a model of hepatic Ischemia-Reperfusion with variable periods of reperfusion from 0 to 24 hours.  METHODS: Our study related to rats Wistar males.  Six various groups were studied: the first reference group (without neither ischemia and reperfusion), the second group with ischemia of 90 min and without reperfusion and the 3end , 4end, 5end and 6end groups in addition to ischemia, underwent a reperfusion of 30 min, 2h, 6h and 24h respectively.  The damage of hepatic Ischemia-Reperfusion was evaluated by a biochemical test based on the proportioning of transaminases and an anatomopathologic study by optical microscopy for the determination of the degree of hepatic attack.  RESULTS: The RESULTS obtained seem to show an aggravation of the liver lesions and an increase in the plasmatic rates of AST and ALT in relation with the duration of the reperfusion.  Indeed, the maximum of damage was observed after 2 hours of reperfusion. We observed a reduction in the lesions after 6h and 24h of reperfusion.  CONCLUSION: Our work enabled us to describe a simple model of hepatic Ischemia-Reperfusion with functional, biochemical and anatomopathologic tests.

CORM-3, a water soluble CO-releasing molecule, uncouples mitochondrial respiration via interaction with the phosphate carrier.

Carbon monoxide is continuously produced in small quantities in tissues and is an important signaling mediator in mammalian cells. We previously demonstrated that CO delivered to isolated rat heart mitochondria using a water-soluble CO-releasing molecule (CORM-3) is able to uncouple mitochondrial respiration. The aim of this study was to explore more in depth the mechanism(s) of this uncoupling effect. We found that acceleration of mitochondrial O2 consumption and decrease in membrane potential induced by CORM-3 were associated with an increase in mitochondrial swelling. This effect was independent of the opening of the mitochondrial transition pore as cyclosporine A was unable to prevent it. Interestingly, removal of phosphate from the incubation medium suppressed the effects mediated by CORM-3. Blockade of the dicarboxylate carrier, which exchanges dicarboxylate for phosphate, decreased the effects induced by CORM-3 while direct inhibition of the phosphate carrier with N-ethylmaleimide completely abolished the effects of CORM-3. In addition, CORM-3 was able to enhance the transport of phosphate into mitochondria as evidenced by changes in mitochondrial phosphate concentration and mitochondrial swelling that evaluates the activity of the phosphate carrier in de-energized conditions. These results indicate that CORM-3 activates the phosphate carrier leading to an increase in phosphate and proton transport inside mitochondria, both of which could contribute to the non-classical uncoupling effect mediated by CORM-3. The dicarboxylate carrier amplifies this effect by increasing intra-mitochondrial phosphate concentration.

[Therapeutic Drug Monitoring of Valproic Acid in Children: A Prospective Study of The Effect of The Compliance and The Economic Level on the Trough Plasmatic Concentrations and Epileptic Seizures]. / Suivi thérapeutique de l'acide valproïque chez l'enfant : étude prospective de l'effet de l'observance et du niveau économique sur les concentrations plasmatiques résiduelles et les crises épileptiques.

INTRODUCTION: Valproic acid (VA) is a widely used antiepileptic drug. Because of its pharmacokinetic variability and the influence of intrinsic and extrinsic factors such as the treatment compliance, VA therapeutic drug monitoring (TDM) is recommended in children. The aim of this study is to evaluate the effect of treatment compliance and the economic level on VA tough plasmatic concentration (TPC) and epileptic rhythm in children. MATERIAL AND METHODS: A one-year prospective study (August 2008-August 2009) concerning children (age≤5 years) regularly treated by VA who had a VA TDM. So, 276 plasmatic samples from 238 children were collected. The children were divided in two groups as following: the group 1 (G1) presenting a good compliance and a reliable questioning and the group 2 (G2) presenting a bad compliance and a non reliable questioning. We evaluated the interindividual variability by correlating the TPC to the dose. Then, we divided the hole group in function of their economic levels (low-medium-high). RESULTS: Sex ratio male/female was 1.3. Median age was 5 years+/-3,9. The mean TPC was 62 µg/mL [0.12-131 µg/mL]. VA TPC were in the therapeutic range (TR) in 62%. Adverse drug reactions were noted in 4.2% of the children. G1 represented 70% of the children and G2, 30%. The TPC were in the TR in 67% of G1 and 51% of G2 (p=0.02). There was a significant difference between the TPC in G1 and G2 (p=0.02).There was no significative difference in the TPC in function of the economic levels. There was no correlation between TPC and the administered doses. The epileptic seizures were more spaced in children with therapeutic TPC than those with TPC in the TR (p=0.002) and in G1 than in G2 (p=0.03). CONCLUSIONS: Compliance should be appropriate in order to optimize the TDM rule. A good compliance and a therapeutic TPC allow a better control of epileptic seizures.

Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report.

Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer.

Pharmacokinetik population of methotrexate in tunisian population with acute lymphoblastic leukemia.

BACKGROUND: The use of high dose of MTX in the treatment of the leukemia is actually better controlled by renal preparation, control of plasma concentrations and administration of folinic acid. However, High dose MTX has been proven to cause substantial toxicity and have high intra-and inter-patient variability. Population pharmacokinetic analysis is a useful tool for identification of sources of pharmacokinetic variability during anticancer drug development and can aid the design of alternative dosing regimens to enhance their efficacy and safety. AIM: The aim of our study is to developed and validate a population pharmacokinetics model of our population. We hereby describe the clinical covariates (age, sex and clearance of the creatinine) that influence MTX pharmacokinetic for predicting optimal dose to reduce MTX toxicity. METHOD: It is a prospective study achieved between January 2005 to January 2012 in the Service of Clinical Pharmacology. Including 273 patients treated for acute lymphocytic leukaemia 2582 plasma concentration was achieved. The data have been analyzed with Nonmem© software (non linear regression to mixed effect). RESULTS: The age of our patients varied from 2 to 23 years with an average of 13 years. The patients received high dose MTX therapy (1 to 8 g/m2) in 24 hours infusion every 15 days. Three compartiment models describe the pharmacokinetic of MTX. The most important covariables affecting the model were clearance of the creatinine, age and weight. We obtained a good correlation between the predicted and the observed concentrations. CONCLUSION: The development of population pharmacokinetics model of MTX allows us to propose a therapeutic diagram adapted to every patient according to its morphological and pharmacological features while taking in consideration the therapeutic objective.

[Development and validation of a new HPLC method for determination of Lamotrigine and clinical application]. / Mise au point validation d'une method de dosage de la lamotrigine par chromatographie liquid à haute performance et application clinique.

BACKGROUND: Lamotrigine is an effective anticonvulsant drug used in the treatment of epilepsy. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and some concentration-dependent side effects. AIM: The aim of this study was to develop and validate a new method for lamotrigine quantitation in plasma using HPLC with UV/visible detection. METHODS: A rapid HPLC-UV method was developed for the determination of lamotrigine in plasma. All solvents used were HPLC grade. RESULTS: After liquid-liquid extraction, chromatographic separation was achieved using an RP 18 (250 mm) column. The mobile phase was composed of acetonitrile and 0.1 M potassium dihyrogenophosphate (25/75) (v/v). Barbital sodium was used as internal standard. This technique was linear over the 2 µg/mL to 50 µg/mL range (r= 0.99). Detection and quantification limits were 0.07 µg/mL and 0.21 µg/mL, respectively. Within-day coefficient of variation (13.37 to 16 %) and day-to-day coefficients of variation (15.68 to 16.63 %) at three different concentrations. Under these conditions, each analysis required no longer than 10 min. We finally evaluated the plasma concentrations of lamotrigine in Tunisian patients treated with this drug. CONCLUSION: The results found are similar to those previously described and the developed method is repeatable and reproducible. It can be used for clinical applications.

Vancomycin therapeutic drug monitoring in cerebrospinal fluid.

Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF.

Appraisal of ChatGPT's Aptitude for Medical Education: Comparative Analysis With Third-Year Medical Students in a Pulmonology Examination.

BACKGROUND: The rapid evolution of ChatGPT has generated substantial interest and led to extensive discussions in both public and academic domains, particularly in the context of medical education. OBJECTIVE: This study aimed to evaluate ChatGPT's performance in a pulmonology examination through a comparative analysis with that of third-year medical students. METHODS: In this cross-sectional study, we conducted a comparative analysis with 2 distinct groups. The first group comprised 244 third-year medical students who had previously taken our institution's 2020 pulmonology examination, which was conducted in French. The second group involved ChatGPT-3.5 in 2 separate sets of conversations: without contextualization (V1) and with contextualization (V2). In both V1 and V2, ChatGPT received the same set of questions administered to the students. RESULTS: V1 demonstrated exceptional proficiency in radiology, microbiology, and thoracic surgery, surpassing the majority of medical students in these domains. However, it faced challenges in pathology, pharmacology, and clinical pneumology. In contrast, V2 consistently delivered more accurate responses across various question categories, regardless of the specialization. ChatGPT exhibited suboptimal performance in multiple choice questions compared to medical students. V2 excelled in responding to structured open-ended questions. Both ChatGPT conversations, particularly V2, outperformed students in addressing questions of low and intermediate difficulty. Interestingly, students showcased enhanced proficiency when confronted with highly challenging questions. V1 fell short of passing the examination. Conversely, V2 successfully achieved examination success, outperforming 139 (62.1%) medical students. CONCLUSIONS: While ChatGPT has access to a comprehensive web-based data set, its performance closely mirrors that of an average medical student. Outcomes are influenced by question format, item complexity, and contextual nuances. The model faces challenges in medical contexts requiring information synthesis, advanced analytical aptitude, and clinical judgment, as well as in non-English language assessments and when confronted with data outside mainstream internet sources.

Population pharmacokinetics and Bayesian estimation of cyclosporine in a Tunisian population of hematopoietic stem cell transplant recipient.

PURPOSE: Therapeutic drug monitoring of cyclosporine minimizes the risk of toxicity and acute rejection after transplantation. Areas under the curve (AUCs) rather than trough concentration-based monitoring are recommended. Population pharmacokinetics (PopPK) modeling and Bayesian estimation seem to be the best way to predict cyclosporine disposition and dose requirements to achieve the therapeutic target in an individual patient because of the possibility of predicting cyclosporine AUC using only a few blood samples. Our objectives were to build a PopPk model for cyclosporine in a Tunisian population of HSCT patients and to develop a Bayesian method for the estimation of individual cyclosporine AUC. PATIENTS AND METHODS: The PopPk of cyclosporine was studied using nonlinear mixed effects modeling (NONMEM) in 30 patients (index group) receiving cyclosporine on a twice-daily basis. Ten blood samples were collected after steady-state morning cyclosporine dose. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements in an independent group of 30 patients (test group). RESULTS: A two-compartment model with first-order absorption and a lag time provided the best fitting. The population mean estimate and interindividual variability from the final model for CL, Ka, Tlag, V1, V2, and Q were 25.4 L/h (CV = 38.72 %), 0.214 h(-1)(CV = 28.5 %), 0.382 h, 10.9 L (85.73 %), 496 L, and 5 L/h, respectively. Covariates had no discernible effects on cyclosporine pharmacokinetics in our population. Bayesian estimation provided an accurate estimation of AUC, although a bias was observed leading to slight underprediction of AUC (bias -1.03 %). A very satisfactory precision was observed (RMSE 12.07 %). CONCLUSION: We report a PopPK model for cyclosporine in Tunisian HSCT patients. Bayesian estimation using only three concentrations provides good prediction of cyclosporine exposure. These tools allow us to routinely estimate cyclosporine AUC in a clinical setting.

[Munchhausen syndrome by proxy revealed by falsely toxic methotrexate levels]. / Syndrome de Münchausen par procuration révélé par des méthotrexatémies toxiques artificielles.

Methotrexate is an antifolate drug used intravenously at high-dose in acute lymphocytic leukemia (ALL). Therapeutic drug monitoring is required to identify patients at risk of developing toxicity and to control folinic acid rescue. We report a case of Münchausen syndrome by proxy revealed by high and persistent falsely toxic methotrexate plasmatic levels. A 12 year-old child was treated with chemotherapy including methotrexate every 70 days for an ALL. The last methotrexate plasmatic level was 0.15 µmol/L at the 72th hour of the infusion. Then, he was treated by oral rout low-dose methotrexate. Ten days after methotrexate infusion, the patient consulted for asthenia, vomiting and presented a mucositis. Methotrexate plasmatic level was 2323 µmol/L. Renal function was normal. All drugs' intake was stopped. Folinic acid rescue was instituted. Even though there was no clinical sign of toxicity, therapeutic drug monitoring showed persistent high methotrexate plasmatic levels. Investigations eliminated measurement errors and pharmacokinetic problems. A deliberate methotrexate addition in each child blood sample brought by the mother was highly suspected. We confirmed this hypothesis by measuring methotrexate plasmatic levels in three samples: one brought by the mother, the second brought by the child's doctor and the last collected in our laboratory. Methotrexate plasmatic levels were respectively over 10,000 µmol/L (first sample) and lower than 0.02 µmol/L (the two others). The diagnosis of Munchausen's syndrome by proxy revealed by falsely toxic methotrexate plasmatic levels was made and the mother was addressed to the psychiatric department.

Comparing real-life carbamazepine exposure between innovator and generic formulation.

BACKGROUND: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE). METHODS: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C0) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®). RESULTS: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C0/dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C0/dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16). CONCLUSION: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same.

Is there a ceiling lamotrigine serum level in epileptic children in remission?

INTRODUCTION: Seizure control, in patients with epilepsy, is proportionally associated with health-related quality of life. Antiepileptic therapy leads to seizure remission in most cases. However, some patients are resistant to treatment despite achieving high doses which can be explained by interindividual variability of antiepileptic drugs' metabolism. A ceiling exposure, in epilepsy, helps to adapt the therapeutic strategy in a faster way and to prevent unnecessary exposure to adverse drug reactions. Due to the increasing use of new generations of antiepileptic drugs, we aimed to explore the distribution of lamotrigine (LMT) trough serum levels in epileptic children, stratified between remission and ongoing seizures, in order to determine whether there is a ceiling effect associated with remission. METHODS: We conducted a retrospective study (2012-2021) including children, with generalized epilepsy (2-18 years), addressed for a therapeutic drug monitoring of LMT trough serum levels. Patients in remission, should have as lasting three times the longest pre-treatment seizure-free interval and more than one year. RESULTS: The population of 114 children with generalized epilepsy was divided in to groups: epileptic children in remission (36) and epileptic children with ongoing seizures (78). There was no significant difference in age and sex in the two groups. Median LMT daily dose and trough serum levels were significantly higher in group 2. The highest LMT serum trough level was 11µg/mL in group 1 and 23.1µg/mL in group 2. Valproate was associated in 29%. There was no significant difference of the distribution of valproate in the two groups (P=0.08). CONCLUSIONS: Children in remission had a LMT trough serum levels under 11µg/mL and a daily dose of 3.36mg/kg/day or less. These results suggest that this LMT serum level and daily dose might be associated with a ceiling effect in epileptic children.