|Year : 2020 | Volume
| Issue : 1 | Page : 36-43
Efficacy of steroids in childhood drug-resistant epilepsy
Dina S.A Elmagid
Department of Pediatrics, Mansoura University Children Hospital, Mansoura, Egypt
|Date of Submission||09-Feb-2020|
|Date of Decision||09-Feb-2020|
|Date of Acceptance||26-Feb-2020|
|Date of Web Publication||26-Jun-2020|
PhD Dina S.A Elmagid
Lecturer of Pediatrics, Mansoura University Children Hospital, Mansoura, 050
Source of Support: None, Conflict of Interest: None
Background Epilepsy is considered the most frequent chronic neurologic condition in childhood. In childhood epilepsy, the incidence rates range from 0.5 to 8 per 1000 children per year. Drug-resistant epilepsy (DRE) is defined according to the International League against Epilepsy as a failure of adequate trials of greater than or equal to 2 appropriately used, tolerated, and appropriately chosen regimens of antiepileptic drugs to achieve seizure freedom. It has been described that steroids and adrenocorticotropic hormone are effective treatment modalities in DRE children. They may have anticonvulsive properties through their endocrine criteria and their effect on neuronal excitability and stabilization of membrane. They are believed to induce changes in the transmission of neurochemicals due to changes in gamma-aminobutyric acid uptake or serotonin turnover mediated through the mineralocorticoid and glucocorticoid receptors.
Objectives The aim of this study was to evaluate the efficacy of oral prednisolone regimen and hybrid corticosteroid regimens in the treatment of DRE and to assess the possible side effects of both regimens.
Patients and methods This study was a prospective randomized clinical trial which was conducted at the neurology outpatient clinic and department of the Mansoura University Children Hospital. It included 49 pediatric patients diagnosed as DRE according to the International League against Epilepsy 2010 definition as failure of adequate trials of two or more drugs to achieve freedom from seizures. They were divided into two groups, the first group (25 patients) received oral prednisolone and the second (24 patients) received intravenous methylprednisolone followed by oral prednisolone. Both regimens were applied in addition to conventional antiepileptic drugs. The response to the treatment is graded as: ‘free from seizures,’ ‘response is good’ (reduction of seizures more than 50% including seizure free), or ‘response is poor’ (<50% reduction, considered as therapy failure).
Results Our study showed that of the 25 patients enrolled in group 1 and received high-dose oral prednisolone (14/25) 56% showed good response (decrease in seizure frequency by >50%), of whom seven (28%) became seizure free, while (11/25) 44% showed poor response (decrease of seizure frequency by <50%) and of the 24 patients enrolled in group 2 and received hybrid regimen consists of methylprednisolone and low-dose prednisolone (13/24) 54% showed good response, six (25%) of them became free from seizures, while (11/24) 46% showed poor response. And there is no significant difference as regards the efficacy of the steroid regimens used in the two groups (P=0.97) but the regimen used in group 2 showed lesser adverse effects.
Conclusion The use of hybrid corticosteroid regimen composed of initial pulses of methylprednisolone followed by low-dose oral prednisolone in the treatment of DRE is as effective as the use of high-dose oral prednisolone from the start but with less adverse-effect profile.
Keywords: antiepileptic drugs, corticosteroids, drug-resistant epilepsy
|How to cite this article:|
Elmagid DS. Efficacy of steroids in childhood drug-resistant epilepsy. Alex J Pediatr 2020;33:36-43
| Introduction|| |
Epilepsy is practically defined by the International League against Epilepsy (ILAE) as two unprovoked (or reflex) seizure that occurs within greater than 24 h apart or one unprovoked (or reflex) seizure and probability of further seizures similar to general recurrence risk (≥60%) after two unprovoked seizures, occurring over the next 10 years or diagnosis of an epilepsy syndrome .
Childhood epilepsy is considered the most frequent chronic childhood neurologic condition and affects about 0.5–1% of them . Its incidence rates range from half to eight per 1000 children per year ,,.
The principal risk factors for childhood seizures are: premature birth , high temperature , mental disability , delayed discharge from neonatal ICU or positive family history ; mother’s smoking and alcohol abuse during pregnancy double the risk incidence of seizures .
ILAE has recently developed a global consensus definition of drug-resistant epilepsy (DRE) as a failure of adequate trials of greater than or equal to 2 appropriately used, tolerated, and appropriately chosen regimens of antiepileptic drugs (AEDs), in combination or monotherapies, to achieve seizure freedom . Medically resistant childhood epilepsy cases are estimated in proportion that varies from 20 to 40% ,,,,.
It is consistently noted that there are poor health outcomes in children with DRE and it is suggested by preliminary evidence that comorbid conditions such as migraine and depression affect negatively the quality of life and seizure outcome ,. There is also a cognitive deficit in those children due to a combination of repeated episodes of status epilepticus, prolonged attacks of seizures, and high frequency of seizures . Children with DRE have an increased mortality rate, estimated at 1.37/100 children per year ,,.
The pathogenesis of DRE may be due to multiple and variable factors with both environmental and genetic factors implicated with several theories of how DRE develops ,.
Treatment with AEDs is the standard treatment strategy for DRE 5% of DRE children per year will show remission of seizures as a result of changes of medications . Other therapeutic options that include steroids, epilepsy surgery, neurostimulation therapy, immunoglobulin therapies, and diet therapy are used to help the resumption of development of those patients with DRE and also to control seizures .
It has been described that steroids and adrenocorticotropic hormone (ACTH) are effective treatment modalities in DRE children ,,.
The mechanism of antiepileptic effects of corticosteroids is unknown. ACTH and other corticosteroids have endocrine effects and also affect neuronal excitability and membrane stabilization, and through these effects they may have anticonvulsive properties. It is suggested that corticosteroids may induce neurochemical transmission changes due to changes in γ-aminobutyric acid uptake or serotonin turnover mediated through the mineralocorticoid and glucocorticoid receptors . It is thought by others that interaction of glucocorticoids with the central nervous system may be mediated by affection of voltage-dependent calcium channels and transcription regulators ,. The expression of corticotropin-releasing hormone and its downregulation may be important . Furthermore, it is suggested that immunomodulation may be the mechanism of action in Landau–Kleffner syndrome and continuous slow waves during sleep syndrome ,.
| Objective|| |
Based on the hypothesis that corticosteroids have a role in the treatment of DRE children, the present study was carried out to evaluate the efficacy of oral prednisolone regimen and hybrid corticosteroid regimens in the treatment of DRE and to assess the possible side effects of both regimens.
| Patients and methods|| |
A total of 49 children with epilepsy treated with AEDs were included in this study. The patients were diagnosed as DRE according to The ILAE 2010 definition as adequate trials of two drugs (or more) with failure to achieve freedom from seizures with these criteria (appropriately used, tolerated, appropriately chosen regimens of AEDs), in combination or as monotherapies. The study was a prospective randomized clinical trial and the cases were taken as a consecutive sample from the children attending the neurology outpatient clinic in Mansoura University Children Hospital.
Exclusion criteria consisted of presence of infantile spasms, Landau–Kleffner syndrome, or epilepsy with continuous spike waves during slow-wave sleep, or patients previously received any steroid therapy with AEDs, patients with progressive degenerative or metabolic disorders, or presence of comorbidity of different disorders.
The protocol of our study was approved by the Ethics Committee of Mansoura Faculty of Medicine.
All studied patients were subjected to full history and examination, and they were divided into two groups: the first group composed of 25 patients who received AEDs that are previously prescribed in combination with 2 mg per kg per day oral prednisolone for 6 weeks, then it has decreased gradually during a further 2 weeks , and the second group composed of 24 patients and received 3 days intravenous methylprednisolone (20 mg/kg/day) followed by 8 weeks of oral steroid (0.5 mg/kg every other day) including a taper phase .
Both regimens were applied in addition to conventional AEDs. Response to treatment and common side effects were evaluated clinically by history, examination, measuring weight, blood pressure, and measuring blood sugar in regular outpatient visits every 1 month for 6 months. The response to the treatment is graded as: ‘free from seizures,’ ‘response is good’ (reduction of seizures >50% including seizure free), or ‘poor response’ (reduction <50%, considered therapy failure). After steroid treatment cessation, electroencephalogram (EEG) was repeated for all patients to compare it with the one done before steroid treatment.
Data were analyzed using the Statistical Package of Social Science (SPSS) program for Windows (Standard version 21). The normality of data was tested first with Shapiro test. Qualitative data were described using percentage and number. Categorical variables association was tested using the χ2 test while Fischer’s exact test and Monte Carlo test were used when the expected cell count is less than 5. Continuous variables were presented as median (minimum–maximum) for nonparametric data. The two groups were compared with Mann–Whitney test. The significance threshold (P value) is fixed at 5% level.
The results were considered significant when the probability of error is less than 5% (P≤0.05), and nonsignificant when the probability of error is greater than 5% (P>0.05).
| Results|| |
Basic demographic characteristics of our patients are presented [Table 1]. The groups were not significantly different with respect to the age and sex (all values of P>0.05) ([Figure 1] and [Figure 2]).
The study showed that there were no significant differences among the two groups as regards the type of epilepsy and cause of epilepsy ([Table 2]).
Following steroid treatment in group 1 56% (14/25) of the children showed greater than 50% decrease in frequency of seizures, of them 28% (7/25) became seizure free. Following steroid treatment in group 2 54.2% (13/24) of the patients showed a reduction in seizure frequency of greater than 50%, of them 25% (6/24) became seizure free. Treatment failure ‘decrease in frequency of seizures less than 50%’ occurred in 44% (11/25) of patients in group 1 and 45.8% (11/24) in group 2. And the study showed that there were no significant differences as regards the efficacy of steroids therapy regimens between the two groups ([Table 3],[Table 4],[Table 5], [Figure 3]).
|Figure 3 Electroencephalogram of male patients aged 6 years in group 2 who became seizure free after treatment showing generalized activity (sharp slow wave and spike waves) before treatment (a) and normal electroencephalogram after treatment (b).|
Click here to view
This table showed that there is a statistically significant difference in side effects between both groups; 72% (18/25) of patients in group 1 have at least one side effect vs 16.7% (4/24) of patients having side effects in group 2. And the most common side effect was appearance of cushingoid features in both groups.
| Discussion|| |
The proportion of childhood medically resistant epilepsy cases varies from 20 to 40% ,,,. It is considered that standard of care for children with DRE is treatment with AEDs, but successful outcomes are usually small with this protocol of therapy alone . It has been described that ACTH and corticosteroids are effective treatment in children with DRE ,,.
So in the present study, we evaluate the efficacy of two different regimens of corticosteroids in the treatment of childhood DRE and also we assess the possible side effects of both regimens.
Our results showed that there is no significant difference as regards the efficacy of the steroid regimens used in the two groups (P=0.97).
A comparison with a 8-week course of oral prednisolone given at a dose of 2 mg/kg/d for 6 weeks and decreased gradually for further 2 weeks in the study of You et al.  is similar to what was done in group 1 in our work which showed a good response in (30/41)73% of patients, of whom 24 (59%) became seizure free and (11/41) 27% showed poor response. Our results compared unfavorably with these results. This may be due to the selection of cryptogenic epilepsy cases only with normal neuroimaging who did not have specific epileptic etiologies in the study of You et al.  Also, similar results were obtained by Sinclair in his study that was conducted in Canada. Sinclair found that 46% of 28 children with intractable epilepsy became seizure free, 36% showed significant reduction greater than 50% in seizure frequency, and only 18 % had no significant change in frequency of seizures when oral steroid was given at 1 mg/kg/day for 12 weeks (including daily therapy for 6 weeks followed by 6 weeks of gradual reduction of therapy) . The study of Verhelst and colleagues  including 36 children with drug-resistant epilepsies of different causes who received different steroid protocols showed less favorable results. Twenty-five percent of them became seizure free and 11% showed a decrease in seizure frequency of more than 50%. The author concluded that corticosteroids had effects as adjunctive treatments in DRE.
Another comparison with a 12-week hybrid regimen composed of 3 days (20 mg/kg/day) intravenous methylprednisolone, followed by alternate days of (0.5 mg/kg) oral steroids  which is similar to what was done in group 2 in our work and showed a good response in (9/21) 43% of patients, of whom six (29%) became seizure free and (12/21) 57% showed poor response. Our results match with these results.
The first reported use of oral steroids in combination with pulses of intravenous methylprednisolone was by Kramer and his colleagues with 30% of children in the study showing good response, but they concluded that the use of initial pulses of intravenous methylprednisolone in combination with prednisone did not increase efficacy. Also, they concluded that ACTH was found to be significantly more effective than oral steroids in reduction of seizure frequency with better response in, respectively, 92 and 35% of patients .
Bast et al.  recently reported in his study a good response in about 1/3 of children with DRE treated with intravenous steroids given every week on 3 consecutive days (≥4 pulses).
In the study of Sevilla-Castillo et al. , which was done on 14 patients, methylprednisolone pulse therapy was given as three pulses of 3 days every month with a good response initially in 83% of children and after discontinuation of methylprednisolone only one (7%) patient remained seizure free, 50% of patients showed a reduction of seizures by greater than 50 and 43% of patients showed poor response .
In our work, as regards the EEG after steroid treatment, of those who showed good response clinically about 57% in group 1 and 61.5% in group 2 showed improvement in EEG recording either in background activity or epileptiform discharges with no significant difference between the two groups (P=0.816), while in those who showed poor response clinically only one patient in group 1 and two patients in group 2 showed improvement in EEG recording with no significant difference between the two groups (P=0.534). We can conclude also that EEG recording results after steroid treatment correlated with the seizure outcome.
There is an agreement with what reported by You et al.  who documented that 60% showed improvement in their EEG backgrounds and 73% showed diminutions of generalized epileptiform discharges of those who showed good response clinically (>50% reduction of seizure frequency) and also there is an agreement as regards the finding of the good correlation between the EEG findings and the seizure outcomes.
In the study of Verhelst et al. , which was done on 32 patients, EEG changes (improvement of background activity, normalization, decrease in epileptiform activity) were recorded in 15 of the 36 different regimens of treatment and in all of the 13 responders. EEG improvement was observed only in two patients of 19 children without seizure frequency reduction. Our results are very similar to these results.
In our study, 22 (45%) patients suffered from at least one adverse effect. The majority of the adverse effects occurred in group 1. Eighteen patients suffered from adverse effects in group 1 vs four patients only in group 2. So, there is a statistically significant difference between both groups as regards the adverse effects (P<0.001).
It is important to mention that three patients stopped steroid therapy due to adverse effects, and were thus excluded from the statistical analysis. One patient was in group 1 and stopped treatment because the patient developed status epilepticus and was admitted to the intensive care unit. Two patients were in group 2 and stopped treatment due to the development of hyperglycemia during methylprednisolone pulses.
We found that 72% of patients in group 1 had adverse effects vs 17% of patients in group 2. In group 1 14 patients had cushingoid features, five patients had gastritis, two patients had hyperglycemia, one patient had hypertension, and one patient had irritability and behavioral disturbances, while in group 2 two patients had cushingoid features, one patient had gastritis, and one patient had irritability and behavioral disturbances.
All these adverse effects were tolerable and reversible during withdrawal and after stoppage of steroid therapy and there were no need to stop treatment regimens in both groups due to intolerability.
In comparison to another study, only 15% of patients were complaining of adverse effects in the form of weight gain, seeing flashes, and infection that need hospital admission. There is an agreement between our result in group 1 and these results .
Another comparison to the study of You et al. , which showed that all the patients were complaining of cushingoid features and one case each of sepsis, gastrointestinal bleeding, and hypertension. The treatment was stopped in two children with sepsis and gastrointestinal bleeding. There is an agreement between our result in group (2) and these results.
In the study of Bast et al. , the patients received methylprednisolone 3 consecutive days weekly for at least 4 weeks. Bast et al.  reported that 50% of patients developed adverse effects after 4 weeks that increased to 70% at the end of therapy. The adverse effects were infections, irritability, weight gain, hyperglycemia, and nephrocalcinosis. The high percentage of patients with adverse effects may be due to the long duration of corticosteroid treatment.
In the study of Sevilla-Castillo et al. , the patients received methylprednisolone pulses for 3 months, 5 days each month. Sevilla-Castillo et al.  reported that only two (14%) patients had adverse effects. One child showed mild hypertension, but it was not important to give any antihypertensive drugs or stop medication because blood pressure was controlled spontaneously. Another child had cramps in the muscles of lower limbs during methylprednisolone treatment, but treatment was not necessary to be stopped because it spontaneously resolved .
| Conclusion|| |
In conclusion, the use of hybrid corticosteroid regimen composed of initial pulses of methylprednisolone, followed by low-dose oral prednisolone in treatment of DRE is as effective as the use of high-dose oral of prednisolone from the start but with a less adverse-effect profile. The limitation of the current study is the small sample size, so further clinical trials should be done on a larger population with longer follow-up periods.
The research was supported by Mansoura Faculty of Medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]