|Year : 2006 | Volume
| Issue : 4 | Page : 199-206
Steroids in childhood epilepsy
Division of Paediatric Neurology, McMaster Children’s Hospital, McMaster University, 1200 Main St W, Hamilton, Ontario, Canada L8N 3Z5
Division of Pediatric Neurology, Michael G. DeGroote School of Medicine, McMaster University, McMaster Children’s Hospital, HSC 3N 11, 1200 Main St W, Hamilton, Ontario, Canada L8N 3Z5
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Treatment of epileptic encephalopathies can be very challenging as most anticonvulsant drugs fail to achieve good seizure control. Steroids are disease modifying as well as anticonvulsant in these conditions. Though steroids are accepted as the first-line treatment for infantile spasms, there are many unanswered questions with regard to the preparation, dose and duration of treatment. In this review a re-exploration of the literature is attempted. Putative mechanism of action of steroids in infantile spasms is also discussed. As steroids are being increasingly used in other epileptic encephalopathies and Rasmussen's encephalitis, a brief discussion on the role of steroids in these conditions is attempted. The review ends with the discussion on newer neuroactive steroids in the management of epilepsy.
Keywords: ACTH, childhood epilepsy, epileptic encephalopathy, infantile spasms, neurosteroids, steroids
|How to cite this article:|
Ramachandrannair R. Steroids in childhood epilepsy. Ann Indian Acad Neurol 2006;9:199-206
| Introduction|| |
The epilepsy syndromes that respond uniquely to ACTH and steroid therapy have an age-related onset during a critical period of brain development, as well as a characteristic regression or plateau of acquired milestones at seizure onset and long-term cognitive impairment. Epileptic encephalopathies (EE) are a group of conditions in which cognitive, sensorial and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures and/or major interictal paroxysmal activity. The clinical condition produced by EEs depends on the age of onset and may change over time, according to the successive age ranges. Steroids therapy is an accepted mode of pharmacological intervention in infantile spasms (IS). Sorel and Dusaucy-Bauloye, in 1958 reported that ACTH was effective in children with IS. Since then steroids have been used in other conditions like Lennox-Gastaut syndrome (LGS), Ohtahara syndrome and, Landau-Kleffner syndrome (LKS).
This review aims to discuss the evidence for the use of steroids in IS, putative mechanisms of action and some practical issues with regard to the clinical use of steroids in IS. Discussion on the role of steroids in other epileptic conditions and, neuroactive steroids follows at the end.
| I. Steroids in Infantile Spasms|| |
Infantile spasm is a catastrophic form of epileptic encephalopathy in childhood., There are numerous studies in the literature reporting the effectiveness of ACTH and oral corticosteroids in the treatment of IS. It is challenging to draw uniform conclusions from these studies as the methodology, inclusion criteria, dose and preparation of steroids, duration of therapy and outcome measures varied significantly across most studies. This is further compounded by the fact that most studies have been uncontrolled, un-blinded and retrospective, complicating the establishment of research-based recommendations for optimal treatment., In the following few paragraphs the author tries to answer some questions that might arise in the mind of a pediatric neurologist to decide on the optimal steroid treatment for a child with IS
What is the evidence to support the use of ACTH in IS?
Several studies reported the effectiveness of ACTH in IS. ,,,,,,,,,,,,, In these studies, age at onset of spasms ranged from one week to twenty four months and age at entry into the study ranged from one to thirty four months. All trials used video-electroencephalography (EEG) monitoring to document a treatment response. Two studies used synthetic ACTH, and one used, ACTH fragments. ACTH dosage varied from 0.2 IU/kg/day up to 150 IU/m 2sub /day and duration of treatment at the highest dose ranged from one to six weeks, with the total treatment time varying from four to twelveweeks. Forty-two to eighty seven per cent of the patients across studies had cessation of spasms. Time from initiation of treatment to cessation of spasms as stated in three studies was 8-12 days. Hrachovy et al and Yanagaki et al found no dose-related difference in the response rate of IS to ACTH therapy., In the randomized controlled trail by Baram et al of the 15 infants randomized to ACTH, 13 responded (86.6%). In a double blind, placebo-controlled, crossover study to compare the therapeutic effectiveness of ACTH (20 to 30 units/day), the response rate to ACTH was 42%. In 1980 Hrachovy et al reported that all the five children responded to low-dose ACTH, whereas Snead et al reported a 93% response rate in 15 children treated with high-dose therapy. Relapse rates were 20 and 36% respectively. Lombroso et al reported that in the 69 symptomatic patients treated with ACTH, 39% had cessation of spasms and EEG normalized in 32%. Response rates for cessation of spasms in these studies ranged from 59 to 100% and resolution of hypsarrhythmia from 57 to 97%, but relapse rates ranged from 9 to 62%. It is clear from these studies that ACTH is effective in controlling spasms in IS.
| Are oral steroids effective in IS?|| |
This question is very important, as treatment with oral steroid is non-invasive and less expensive. Two randomized controlled trials, used 2 mg/kg of prednisone for four to seven weeks and the response rate was 29 to 33%. In an open prospective study, 39 symptomatic and 38 cryptogenic patients, who were treated with prednisone 2 mg/kg, had cessation of spasms in 36 and 39% of cases, respectively. The EEG normalized in 28% of symptomatic patients and 42% of cryptogenic patients. In these three studies, the response rate using oral prednisone was not different from that which might be expected with no treatment based on limited natural history data and in none of the studies were the effects of oral steroids compared with those of a placebo group. Another study reported cessation of spasms and resolution of hypsarrhythmia in 59% of children treated with 3 mg/kg/day of prednisone. None of the controlled trials compared differing doses of oral corticosteroids. Though there is evidence to support the efficacy of oral steroid in IS, the response rates were not impressive.
Is ACTH superior to oral steroids in the treatment of IS?
In a prospective, randomized, single-blinded study; of 15 infants randomized to ACTH, 13 responded by EEG and clinical criteria (86.6%); seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure). Four of the 14 patients given prednisone responded (28.6%, with complete clinical-EEG correlation), significantly less than with ACTH. Twenty four patients with infantile spasms were entered in a double blind, placebo-controlled, crossover study to compare the therapeutic effectiveness of ACTH (20 to 30 units/day) with that of prednisone (2 mg/kg/day). A major difference between the effectiveness of ACTH and that of prednisone in stopping the spasms and improving the EEG pattern was not demonstrated. Nine patients responded to ACTH (five initial drug, four crossover) and seven patients responded to prednisone (four initial drug, three crossover). Snead et al demonstrated that high-dose ACTH therapy was superior to prednisone, with cessation of spasms in 100% of patients treated with ACTH vs 59% resolution of spasms in the prednisone group. The EEG normalized in 97% of ACTH-treated patients vs 50% in the prednisone group. Two of the three studies demonstrated the superior efficacy of ACTH compared to oral steroid. However, the double-blind study failed to show any difference. Hence it is difficult to draw any concrete conclusion regarding the relative efficacy of ACTH and oral steroid.
A few studies looked into the efficacy of other steroid preparations in the treatment of infantile spasms. Yamamoto et al reported the effect of dexamethasone palmitate in a group of five symptomatic patients with West syndrome, aged 4-11 months. A single intravenous injection of liposteroid (0.25 mg/kg) was administered seven times in three months (total dosage = 1.75 mg/kg). Another five patients with symptomatic West syndrome, aged 6-10 months received ACTH (0.025 mg/kg/day) intramuscularly for six weeks (total dosage = 0.625 mg/kg). Spasms and hypsarrhythmia disappeared in all patients in the liposteroid therapy group within four doses; however, partial seizures and focal spikes on EEG reappeared in three patients two months after the end of liposteroid therapy. In the ACTH therapy group, spasms and hypsarrhythmia similarly disappeared during treatment in all patients, but spasms reappeared two months after therapy in two patients and partial seizures reappeared in one patient three months after therapy. Authors concluded that glucocorticoid incorporated in a lipid emulsion is useful for the treatment of West syndrome. In a study, which compared vigabatrin and oral hydrocortisone in children with infantile spasm secondary to tuberous sclerosis, only five patients had complete control of spasm with hydrocortisone (total=11).
Are steroids better than Vigabatrin in the treatment of IS?
The United Kingdom Infantile Spasms Study (UKISS) compared the effects of vigabatrin (VGB) with those of prednisolone and tetracosactide in the treatment of infantile spasms in a multi center, randomized controlled trial. The primary outcome was cessation of spasms on days 13 and 14. Minimum doses were VGB 100 mg/kg per day, oral prednisolone 40 mg per day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days. 107 children were randomly assigned to VGB (n=52) or hormonal treatments (prednisolone n=30, tetracosactide n=25). Proportions with no spasms on days 13 and 14 were: 40 (73%) of 55 infants assigned hormonal treatments (prednisolone 21/30 [70%], tetracosactide 19/25 [76%]) and 28 (54%) of 52 infants assigned VGB (difference 19%, P =0·043). Two other studies compared VGB with steroids in the treatment of infantile spasms., Forty-two infants (22 males, 20 females) aged between two to nine months with newly diagnosed infantile spasms, were included in the trial by Vigevano et al . Cessation of spasms was observed in 11 (48%) of the patients randomized to VGB and in 14 (74%) of those randomized to ACTH. VGB was more effective than ACTH as treatment for cerebral malformations or tuberous sclerosis, whereas ACTH proved more effective in perinatal hypoxic/ischemic injury. The efficacy of the two drugs was similar in cryptogenic cases. In the retrospective study by Cossette et al , the drugs were of similar efficacy, but the outcome measure was 12 months spasm-free. In both studies, the rate of EEG improvement was superior for ACTH as compared with vigabatrin, but the relapse rate was higher for ACTH-treated children. Side effects were more common in patients treated with corticosteroids (27 to 37%) compared with 6 to 13% of patients treated with VGB. However, the potential retinal toxicity of VGB remains is major concern in infants in whom, monitoring the visual function can be challenging.
Does steroid treatment influence the long-term cognitive outcome?
Some information about the long-term outcome in IS are available through the following studies. One prospective study reported long-term follow-up (mean duration, 50 months) in 64 patients treated with low-dose ACTH (20 IU) or 2 mg/kg of prednisone. There was a 5% mortality rate in symptomatic patients. Cryptogenic patients had a better outcome. There was no significant difference in outcome for ACTH treatment compared with prednisone. Delay in initiation of treatment of >5 weeks from onset of the spasms had no influence on long-term cognitive outcome or on the development of epilepsy. In the second prospective study, follow-up beyond six years was reported in 102 children (cryptogenic cases). Fifty percent of ACTH-treated patients were developmentally normal, 62% were seizure-free and 39% had a normal EEG. When ACTH was compared with other therapies such as oral steroids, benzodiazepines or conventional anticonvulsants, there was a significant difference in favour of ACTH for psychometric development and achieving a seizure-free state ( P < 0.05). An improved neurodevelopmental outcome also was associated with early commencement of therapy of < 1 month. Infants enrolled in UKISS were followed up until clinical assessment at 12-14 months of age. Neurodevelopment was assessed with the Vineland Adaptive Behavior Scales (VABS) at 14 months of age. Absence of spasms at final clinical assessment (hormone 75% vs VGB 76%) was similar in each treatment group. Mean VABS score did not differ significantly. In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated to hormone treatment than in those to allocated VGB (88.2 vs 78.9]. This study reported that better initial control of spasms by hormone treatment in those with no identified underlying aetiology might lead to improved developmental outcome. Kivity et al assessed the long-term cognitive and seizure outcomes of 37 patients with cryptogenic infantile spasms receiving standardized treatment regimen of high-dose tetracosactide depot followed by oral prednisone. Cognitive outcomes were determined after 6 to 21 years and analyzed in relation to treatment lag and pre-treatment regression. Normal cognitive outcome was found in all 22 (100%) patients of the early-treatment group (within one month). This study indicated that early treatment of cryptogenic infantile spasms with a high-dose ACTH protocol was associated with favorable long-term cognitive outcomes. Once major developmental regression lasted for a month or more, the prognosis for normal cognitive outcome was poor.
Are steroids effective in children without hypsarrythmia?
A recent study from Japan analyzed the short- and long-term effects of ACTH therapy in 30 patients with epileptic spasms (ESs) who did not meet the criteria of West syndrome (WS). The age at onset of ESs and at ACTH therapy ranged from 2 to 82 months and from 11 to 86 months, respectively. Excellent responses were obtained in 19 (63%), as a short-term effect. Authors concluded that ACTH therapy was worth trying for patients with resistant ESs, even without features of WS. However, the long-term effect was uncertain because recurrences of various types of seizures, including focal, were frequently observed.
Practical steroid therapy
It is evident that though the literature is replete with numerous studies, there is no consensus regarding the duration of steroid treatment. On the other hand, some clues exist to suggest superior efficacy of ACTH over oral steroids and, high dose ACTH over low-dose. The author favors the following regimen., The initial dose of ACTH is 150 IU/m 2/day intramuscularly in two divided doses for one week. In the second week, 75 IU/m 2 per day is given, followed by 75 IU/m 2 every other day in the third week. Over the next six weeks, the dose is gradually tapered. If relapse occurs, the dose may be increased to the previously effective dose for two weeks and another tapering begun. If seizures continue, the dose may be increased to 150 IU/m 2 per day and the regimen restarted. Absence of response at the highest dose warrants treatment with VGB. Many pediatric neurologists begin a therapeutic trial with oral B6 as soon as the diagnosis of IS was made. The author is unaware of any contraindication to the simultaneous use of B6 and steroids, though this makes it challenging to differentiate the therapeutic efficacy of either drug.
ACTH is not given if abnormal baseline results are obtained in the following: haemogram, urinalysis, electrolyte panel, renal function and serum calcium, phosphorus and glucose levels. Baseline blood pressure and electrocardiogram are also recorded. Parents should be advised regarding the signs of infection and accurate seizure diary. Control of hypertension is attempted with salt restriction and calcium channel inhibitor therapy. EEG is recorded one, two and four weeks after the start of ACTH to assess treatment response. A response is best defined as cessation of spasms as reported by the parents and absence of hypsarrythmia pattern in awake and sleep EEG.
| Adverse Effects of Steroids|| |
ACTH and steroids can produce many side effects. Cushingoid features and extreme irritability are seen frequently. Hypertension is less common. Other side effects include sepsis, hyperglycemia, metabolic abnormalities involving the electrolytes, calcium and phosphorus,,, and heart failure., The cause of the apparent cerebral atrophy following steroid therapy is obscure.,
Mechanisms of action in infantile spasms
The effects of ACTH are mediated via stimulation of the G-coupled cell surface ACTH receptor, alternatively known as the melanocortin-2 (MC-2) receptor. ACTH additionally has the capacity to cross-react with other melanocortin receptors. Absence of an animal model of IS impairs our ability to understand the mechanism of action of ACTH and steroids. Infantile spasms occur within a narrow range of age of onset and various abnormalities are causally linked. However IS may also occur without apparent cause. The effect of ACTH and corticosteroids in IS spasms is frequently 'all or none'. These observations support the theory that due to various aetiologies, a significant stress response is experienced by the developing brain; resulting in this age-dependent epileptic encephalopathy. Within this very narrow developmental window, ACTH and steroids may be able to reset the deranged homeostatic mechanisms of the brain, thereby reducing the convulsive tendency and improving the developmental trajectory. There is evidence to suggest that ACTH effects in IS may be independent of steroidogenesis. Efficacy studies have demonstrated superiority of ACTH to corticosteroids in treating IS and also its efficacy in adrenal-suppressed patients. ACTH has direct effects on brain function: increasing dendrite outsprouting in immature animals; stimulating myelination; regulating the synthesis, release, uptake and metabolism of dopamine, norepinephrine, acetylcholine, serotonin and GABA; regulating the binding at glutamatergic, serotoninergic, muscarinic type 1, opiate and dopaminergic receptors; and altering neuronal membrane lipid fluidity, permeability and signal transduction.,,,, A possible "common excitatory pathway," which was consistent with the many aetiologies of IS and, explained the confinement of this disorder to infancy, was proposed by Brunson et al . This notion was based on the fact that all of the entities provoking IS activated the native "stress system" of the brain. This involved increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH caused severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decreased the production and release of CRH in certain brain regions. The hypothesis, that ACTH directly influenced limbic neurons via the melanocortin receptors, focused on the effects of ACTH on the expression of CRH. Experimental data showed that ACTH potently reduced CRH expression in amygdala neurons. This down-regulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust, established clinical effects of ACTH in the therapy of IS.,,,,,,
Other agents in infantile spasms
Other agents and approaches studied in small, uncontrolled trials include valproate, nitrazepam, pyridoxine, IVIG, topiramate, zonisamide and the ketogenic diet.,,,,, However there is insufficient evidence of efficacy and safety to recommend any of these therapies at this time.
| II. Other Seizure Disorders|| |
Few studies are available on treatment of other intractable epileptic disorders with steroids. Response to anticonvulsant drug therapy is poor in these disorders, but is sometimes improved by the antiepileptic drugs used in infantile spasms. Steroids have been found useful in patients with LGS. Snead et al treated 64 children who had myoclonic seizures without EEG evidence of hypsarrythmia or other intractable seizures. Seventy three percent of the 40 children treated with ACTH had seizure control, but none of the 30 prednisone-treated children. Ten children with LGS and intractable seizures were treated with prednisolone at a dose of 1 mg/kg/day for six weeks followed by withdrawal over the next six weeks and achieved seizure freedom in seven and seizure reduction in the rest. Long-term prognosis is usually unchanged in Ohtahara syndrome after treatment with ACTH, VGB or zonisamide. Uncontrolled trials of steroids or ACTH have been reported to reduce seizure frequency in severe myoclonic epilepsy of childhood. Oguni et al retrospectively analyzed 81 patients with myoclonic-astatic epilepsy of early childhood to investigate the most effective treatment. The most effective treatment was ketogenic diet, followed by ACTH and ethosuximide.
Following the initial report by McKinney and McGreal on the beneficial effect of ACTH in LKS, many reported improvements in seizure control and language in children with LKS treated steroids., Marescaux et al treated five children with Landau-Kleffner with antiepileptic drugs, sleep-modifying drugs and corticosteroids. Phenobarbital, carbamazepine and phenytoin were ineffective or worsened the EEG and neuropsychological symptoms, whereas valproate, ethosuximide and benzodiazepines were partially or transiently efficacious. Corticosteroid treatment resulted in improved speech, suppression of seizures and normalization of the EEG in three children. Sinclair and Snyder treated 10 children with LKS and two children with Continuous Spike and Waves during slow wave Sleep (CSWS) using corticosteroids. All but one patient manifested significant improvement in language, cognition and behavior, which continued after the corticosteroid trial. Some authors used initial short course of intravenous methylprednisolone followed by oral prednisolone. A combination of valproate and a benzodiazepine ameliorated epileptic seizures and electroencephalographic spikes and waves in two children with LKS, but speech disturbances persisted. Both patients were treated with an intravenous infusion of high-dose methylprednisolone sodium succinate (20 mg/kg daily) for three consecutive days. This infusion was repeated three times with a four-day interval between treatments, which resulted in a rapid improvement in speech ability. After intravenous therapy, prednisolone was given orally (2 mg/kg daily for one month, then gradually withdrawn), which maintained the clinical improvement in speech. Corticosteroids should be given in high doses as soon as the diagnosis is firmly established. Early diagnosis, before mutism or global deterioration develops, appears to be essential for effective therapy with minimal neuropsychological sequelae.
Treatments advocated in Rasmussen's encephalitis (RE) include: anticonvulsants, high dose steroids, ACTH, IV IgG, plasmapheresis, antiviral agents or hemispherectomy. Dulac reported the effect of steroids in patients with epilepsia partialis continua. Six of the seven patients treated with IV high dose methylprednisolone (400 mg/m 2), followed by oral prednisone, showed an improvement in seizure control, which was variably sustained over a two-year follow-up period. In another study, ten of 17 patients showed 25-75% reduction in seizure frequency. Granata et al reported immunomodulatory treatments in 15 patients with RE (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, plasmapheresis and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere was the only treatment that halted disease progression, authors concluded that immunomodulation could be considered when early surgery was not feasible, in late-onset patients with slower disease progression and in the few cases of bilateral disease.
| III. Neurosteroids|| |
Neuroactive steroids refer to steroids that are active on neural tissue; they may therefore be synthesized endogenously in the brain or may be synthesized by classic endocrine tissue but act on neural tissues. Dysfunction of GABAA receptor-mediated inhibition is implicated in a number of neurological and psychiatric conditions including epilepsy and affective disorders. Some of these conditions have been associated with abnormal levels of certain endogenously occurring neurosteroids, which potently and selectively enhance the function of the brain's major inhibitory receptor, the GABAA receptor. Consistent with their ability to enhance neuronal inhibition, such steroids exhibit in animals and humans anxiolytic, anticonvulsant and anesthetic actions. Neurosteroids, exemplified by the potent progesterone metabolite, 5 alpha-pregnan-3 alpha-ol-20-one can be synthesized de novo in the CNS both in neurones and glia, in levels sufficient to modulate GABAA receptor function. Neurosteroid levels are not static, but are subject to dynamic fluctuations, for example during stress or the later stages of pregnancy. These observations suggest that these endogenous modulators may refine the function of the brain's major inhibitory receptor and thus, play an important physiological and pathophysiological role. Ganaxolone (GNX) is a member of a novel class of neuroactive steroids, which modulates the GABAA receptor complex via a unique recognition site, distinct from those of benzodiazepines and barbiturates. Preclinical data from an array of chemically- and electrically-induced seizure models demonstrate that GNX possesses broad-spectrum anticonvulsant activity with potential clinical utility in both generalized and partial seizures, as well as cocaine-induced seizures. In a multi center, open-label, add-on trial, investigating the safety and efficacy of GNX in a population of children with refractory infantile spasms or with continuing seizures after a prior history of infantile spasms a total of 20 children aged between seven months to seven years were enrolled. Concomitant anticonvulsant drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of four weeks and maintained for eight weeks before tapering and discontinuation. Spasm frequency was reduced by at least 50 in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated and adverse events attributed to GNX were generally mild. However further investigation with randomized, controlled study design is warranted before this agent can be recommended for clinical use.
| Conclusions|| |
Steroids are the first line of treatment in non-tuberous sclerosis IS. Though the optimal duration of treatment is yet to be defined, most centers use two to four weeks of intense steroid therapy. ACTH may have a better therapeutic efficacy over oral steroids. High dose ACTH produces better spasm control, but the side effects can be more. Effect of steroids is via direct as well as CRH mechanisms. Further studies are waited for the clinical use of new neuroactive steroids. Steroids are being increasingly used in the treatment of LKS. Effect of steroids in other EE has not been very exciting. Immunomodulation with steroids can provide short-term improvement in RE.
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