Dexamathasone Pulse Therapy in Refractory Childhood Seizure Disorders

Corticosteroids, either as adrenocortciotrophic hormone (ACTH) or synthetic preparations of steroids have been used widely for the treatment of intractable epileptic disorders of childhood since long time. Livingston and Sorel reported the benefits of ACTH in West syndrome, an infantile form of epileptic encephalopathy [1,2]. Since then, numerous studies have been done regarding wide usage of corticosteroid in different preparations in therapy-resistant epilepsies of childhood although there is no consensus opinion regarding their efficacy [3,4]. Moreover, there is no regional or national strategy recommendations of uniformity in dosing, duration and choice of steroids [5]. There were few reports of pulsatile corticosteroid, as an alternative to ACTH in such intractable seizure disorders in ch8ildren and its efficacy as well safety [6,7]. We report here a retrospective study of efficacy and adverse side effects of pulsatile dexamethasone in the treatment of childhood intractable epileptic disorders.

15 patients were enrolled on a retrospective basis and charts were analyzed between 2012 and 2015; all these patients had intractable epilepsies and on several medications. The patients included in this study had the diagnosis, as classified according to International criteria of diagnosis of epilepsies as follows: West syndrome, Lannox-Gestot syndrome, Dravet syndrome, severe myoclonic epilepsy of infancy and electric status epilepticus of slow wave sleep. Informal written consent was obtained from parents prior to treatment regarding mode of administration of steroids, possible side effects and they were advised to report, if any. Baseline electroencephalogram were done prior to starting treatment and at the end of the study period of seven months. All of them were admitted to the ward and base line investigations to rule out acute or chronic infections were done. Patients received 20mg/m2 of intravenous dexamethasone daily early morning for 3 days and subsequently on monthly basis for at least seven cycles. 12 patients adhered to the strict regime of 7 cycles of treatment and the rest could not complete. The defaulters were mostly non-responders to initial treatment. Routine biochemical investigations namely electrolytes and random blood sugar were done and no antibiotic prophylaxis was given. Blood pressure was monitored during the admissions and steroid administration was withheld, if high. No oral steroids were prescribed to the patients at time of discharge. Clinical response in the form of seizure frequency, response were graded into complete seizure freedom (100%) partial response (more than 50% but less than 100%) and poor response with no change in seizure frequency (0-50%). Similarly, EEG response was also graded as good (100%) moderate (50%) and poor (0%).

Treatment response was assessed as per the classification and noted that no patient had total response to treatment (100%) but moderate response was noted in 8 out of 15 patients (50%) and poor response in the rest of 7 (0%). The non responders were 4 patients of Dravert syndrome, 2 with Lannox-Gestaut and one with infantile spasm (West syndrome). All other patients, (3) with electrical status epilepticus in slow wave sleep and severe myoclonic epilepsy of infancy (2) showed moderate response (50% reduction in seizure frequency) and 2 patients of West syndrome and I with LGS showed similar response as above (50%). The time of onset of response was noted in one patient with West syndrome soon after the first pulse therapy period with 50% reduction in seizure frequency by the time of discharge but the rest showed the response in varying periods within the completion of the study period. EEG response was concurrent to that of clinical response in terms of sharp wave paroxysmal frequency and evidence was much appreciated in patients with West syndrome and electrical status epilepticus of slow wave sleep. The commonest adverse event noted was hypertension in 6 patients low potassium in 3 and I patient had high blood sugar. All these side effects were transient and did not persist after the completion of cycles of treatment. 12 patients were compliant to this pulse therapy treatment schedule with proven efficacy and parents of seven patients insisted to continue the treatment for long duration.

Intractable childhood epileptic syndrome forms a spectrum of therapy resistant epilepsies where conventional and new antepileptic medications do not prove much benefit. Corticosteroids used in various forms appear to influence the seizure outcome in a few patients to a greater extent in various studies but the exact mechanism of their influence is still unknown [8]. Dysfunction of brain adrenal axis is said to play an important role in seizures evolution and propagation [9]. Increase in serum levels of cortisols and suppression of corticotrophin releasing hormone levels by the steroids could be the one of the possible effect of its benefit [10]. Reduction in cerebral blood circulation, reduced cerebral oedema, increased enzymatic activity if brain, increase in cerebral glucose levels were other probable mechanisms of alleviation of seizure activity [11] Although complete response (100%) to steroid therapy were not achievable in our group of patients, a 50% reduction in seizure frequency in 8 patients (53%) is well appreciated by the parents and the parents of six patents sought advice from us to restart or continue the therapy. Pulsatile steroids either in the form of adrenocorticotrophic hormone (ACTH) or steroids were found to be beneficial in West syndrome as first line therapy and the responder within the first pulse therapy of such patient was an expected outcome. Our study proved that pulsatile steroid therapy was beneficial and probably a treatment option in patients with West syndrome, Lannox Gestaut syndrome, severe myoclonic epilepsy of infancy and electric status epilepticus of slow wave sleep. Adverse events namely hypertension, electrolyte disturbances, hyperglycemia as described above were transient and did not require any long term followup. Complete response (100%) to treatment, not achievable in any of our patients could not be explained; possibly the comorbidity of developmental delay, starting pulsatile steroid therapy late after significant delay with trial of combination of other antiepileptic medications and their possible interaction could be the reason. Thus, it is postulated by us that earlier administration of pulsatile therapy of steroids in the above epileptic encephalopathy of childhood, once the diagnosis is made, could avoid the unnecessary, inadvertent usage of many anticonvulsant medications as well better treatment response.

Pulsatile steroid therapy in the form of dexamethasone injections is an effective therapeutic option in patients with childhood onset epileptic encephalopathy. Earlier administration of this mode of treatment could not only alleviate the problem of seizure severity and frequency but also the usage of multiple antiepileptic medications and their side effects. Its well known that the major drawbacks of steroid use being seizure recurrence after discontinuation and significant side effects from long-term use Dravert syndrome, a form of severe myoclonic epilepsy of infancy may not respond to this treatment.

1. Klein R, Livingston S (1950) The effect of adrenocorticotrophic hormone in epilepsy. J Pediatr 35: 733-742.
2. Sorel L, Dusaucy- Bauloye A (1958) A propos de 21 cas d’hypsarrhythmia de Gibbs Gibbs. Son traitment spectaculaire par L’ACTH. Acta Neurol Psychiatr Berg 58: 130-141.
3. Jayakar PB, Seshia SS (1991) Electrical status epilepticus during slow wave sleep: a review. J Clin Neurophysiology 8(3): 299-311.
4. Snead OC, 3rd, Benton JW, Myers GJ (1983) ACTH and prednisone in childhood seizure disorders. Neurology 33: 966-970.
5. Bobele GB, Bodensteiner JB (1994) The treatment of infantile spasms by child neurologists. J Child Neurol 9(4): 432-435.
6. Karenfurt M, Wilken B, Hanefed F (2002) Pulsatile dexamethasone pulse therapy in symptomatic infantile spasms (Abstract) Neuropediatrics 6: A52.
7. Haberlandt E, Weger C, Sigl SB, Rauchenzauner M, Scholl-Bürgi S, et al. (2010) Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes. Pediatr Neurol 42(1): 21-2
8. Sinclair DB (2003) Prednisone therapy in pediatric epilepsy. Pediatr Neurol 28(3): 194-198.
9. Liu JL, He B, Fang F, Tang CY, Zou LP (2007) Analysis of single nucleotide polymorphisms in the melanocortin-4 receptor promoter in infantile spasms. Neuropediatrics 38(6): 304-309.
10. Baram TZ (1993) Pathophysiology of massive infantils spasms: Perspective on the putative role of the brain adrenal axis. Ann Neurol 33: 231-236.
11. Riikonen R (1983) Infantile spasms: some new theoretical aspects. Epilepsia 24: 159-168.