Efficacy of Pyridoxine in Early-Onset Idiopathic Intractable Seizures in Children

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1 Indian J Pediatr (2010) 77: DOI /s y ORIGINAL ARTICLE Efficacy of Pyridoxine in Early-Onset Idiopathic Intractable Seizures in Children Devendra Mishra & Veena Kalra & Rachna Seth & Sheffali Gulati & Narayan Saha Received: 9 April 2009 / Accepted: 18 August 2010 / Published online: 10 September 2010 # Dr. K C Chaudhuri Foundation 2010 Abstract Objective To identify pyridoxine responsive seizures among children with early onset intractable seizures, and to identify pyridoxine-dependency as a subset in this group. Methods Patients with neonatal onset idiopathic, intractable seizures were identified over a 6-month period and subjected to a pyridoxine trial, at the Pediatric Neurology Clinic of a tertiary-care teaching hospital in New Delhi, India. This consisted of an intravenous infusion of 100 mg of pyridoxine over 10-min with a simultaneous EEG monitoring. This procedure was carried out in the EEG laboratory with all appropriate precautions (including availability of resuscitation equipment and trained personnel). Continuous EEG monitoring was done throughout the infusion and till 20 min later, to look for correction of EEG abnormalities. All patients were then prescribed oral pyridoxine, mg/kg/day divided TDS for 6 weeks, in addition to their current anticonvulsant therapy. Patients were reviewed every 15 days regarding compliance and change in seizure frequency. A reduction in seizure frequency by 50% of the baseline was considered as response (significant change), meriting further continuation of pyridoxine therapy. In patients who remained seizure free on pyridoxine therapy, previous anti-epileptics were gradually tapered one by one. Devendra Mishra, Rachna Seth and Narayan Saha: Enrolled patients and carried out the therapy, under supervision of Sheffali Gulati and Veena Kalra. Veena Kalra: Conceptualized and planned the study. All the authors were involved in the decision to publish and approval of the final manuscript. DM did the literature search and manuscript preparation. Veena Kalra edited the manuscript for important intellectual content and would be the guarantor. D. Mishra (*) : V. Kalra : R. Seth : N. Saha Child Neurology Division, Department of Pediatrics, Ansari Nagar, New Delhi , India drdm@rediffmail.com D. Mishra Pediatric Neurology Division, Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, 2, BSZ Marg, New Delhi , India V. Kalra Pediatric Neurology, Indraprastha Apollo Hospitals, New Delhi, India R. Seth Department of Pediatrics, New Delhi, India S. Gulati Child Neurology Division, Department of Pediatrics, Ansari Nagar, New Delhi , India N. Saha Child Neurology Section, Dhaka Medical College, Dhaka, Bangladesh

2 Indian J Pediatr (2010) 77: Results 621 children with active epilepsy were seen at the PNC, of which 48 had early-onset, medical intractable epilepsy, and 21 children (13 males and 8 females), aged between 11 month and 38 month were enrolled. The median age at onset of seizure was 5.1 months. The major seizure type was focal in 3 and generalized in 18 (including infantile spasm in 11). No patient had normalization of EEG during the trial. Two patients (9.5%) had a response during the 2 weeks of oral treatment and oral therapy was continued. No toxicity or side-effects of pyridoxine were observed in these two patients over a follow-up of more than 18 months. Conclusions Pyridoxine responsive seizures contribute a significant proportion to early-onset idiopathic intractable epilepsy in childhood. Routine use of pyridoxine in the management of early onset resistant seizures would go a long way in identifying these patients early. Keywords Antiepileptic drugs. India. Infantile spasms. Pyridoxine. Resistant epilepsy Introduction Pyridoxine is used for management of seizure disorder in three settings viz., (i) seizures that respond to pyridoxine and require life-long supplementation with therapeutic doses of pyridoxine, pyridoxine dependent seizures (PDS, MIM ); (ii) early-onset seizures responsive to pyridoxine but not requiring life-long pyridoxine supplementation, pyridoxine-responsive seizures (PRS); and, (iii) high-dose pyridoxine for the treatment of major seizure disorders of young children e.g., West syndrome [1]. It has been suggested that pyridoxine dependency is often underdiagnosed, both because of occasional atypical presentation [2], and infrequent use of pyridoxine in intractable seizures of early onset in infants in India [3, 4]. Moreover, occasional reports of initial response to phenobarbitone followed by later intractability [5], suggest that pyridoxine responsive seizures may not be identified in infancy. As this would likely lead to resistant/intractable seizure with or without developmental delay [1], we conducted this study to identify pyridoxine responsiveness in children with early-onset, idiopathic, intractable seizures. Material and Methods This study was conducted over a 6 month period in a tertiary-care teaching hospital in New Delhi, India. Enrollment After informed, written consent of the parents/ caregivers, all children <5 yrs attending the Pediatric Neurology Clinic (PNC) with intractable seizures, who fulfilled the inclusion criteria were enrolled in the study. Inclusion criteria (i) Intractable seizures i.e., seizures had persisted for more than 6 months under regular administration of three or more appropriate antiepileptic drugs (AEDs), except pyridoxine; (ii) the seizure frequency was more than once per day; (iii) onset of epilepsy in the first 18 months of life. Exclusion criteria (i) Those with underlying structural (congenital malformations, tumors, chromosomal disorders, and dysmorphic syndromes), infectious (meningitis, encephalitis and neurocysticercosis), metabolic (inborn errors of metabolism, electrolyte and endocrine disorders) or posttraumatic etiologies; and, (ii) prior pyridoxine trial or use of vitamin B6 for management of seizures (use of multivitamin preparations containing pyridoxine was not an exclusion criteria). MRI of brain, EEG, serum electrolytes, blood lactate and ammonia, blood gases, and urine reducing substance are routinely done for all resistant epilepsy patients at our clinic, and the data was available for all patients. Urine organic acids and serum amino acid were available for those needing the same for management. Other treatment options for epilepsy, including other newer AEDs, ketogenic diet, and epilepsy surgery were available to those patients who were not enrolled or did not respond to the present treatment protocol. At enrollment, a structured proforma was filled with the caregiver, including the age at onset, seizure semiology and frequency, family history, birth and development history, development quotient (DQ) assessment, fundus evaluation, review of previous neuroimaging and EEG, treatment history, and a detailed CNS examination. All enrolled patients were asked to maintain a seizure diary, which was reviewed and the proforma updated at each follow-up visit. Intervention An EEG was recorded for all patients. Those with abnormal EEG were given a pyridoxine trial. This consisted of an intravenous infusion of 100 mg of pyridoxine (Vitneurin, Glaxo Pharma, Mumbai, India; containing (per ml): vitamin B6 25 mg; vitamin B1 50 mg; vitamin B mg; D-panthenol 25 mg), diluted in saline, over 10-min with a simultaneous EEG monitoring [3]. This procedure was carried out in the EEG laboratory with all appropriate precautions (including availability of resuscitation equipment and trained personnel). Continuous EEG monitoring was done throughout the infusion and till 20 min later, to look for correction of EEG abnormalities. All patients were then prescribed oral pyridoxine, mg/kg/day divided TID for 6 wks, in addition to their current anticonvulsant therapy. No changes were made in the anticonvulsants.

3 1254 Indian J Pediatr (2010) 77: Fig. 1 Flow chart of patients in the study 48 Patients with intractable epilepsy evaluated 27 Excluded 7 Post-meningitic 11 Neonatal hypoglycemia 5 Structural cortical lesion 3 Neurocutaneous syndromes 5 Refused consent 21 Given IV pyridoxine 21 No EEG Response 21 Oral pyridoxine for 6 weeks 2 50% seizure reduction 19 No change or <50% seizure reduction 1 Pyridoxine-dependent seizure 1 Pyridoxine-responsive seizures Follow-up Patients were reviewed every 15 days regarding compliance and change in seizure frequency. A reduction in seizure frequency by 50% of the baseline was considered as response (significant change), meriting further continuation of pyridoxine therapy. Those patients who remained seizure-free on pyridoxine therapy, previous AEDs were gradually tapered one by one over the next 3-months. infusion. Two patients (9.5%) had a response during the 2 wks of oral treatment with pyridoxine (and unchanged previous anticonvulsants), and oral therapy was continued. One 19-month old patient with global developmental delay, and generalized tonic-clonic seizures and myoclonic seizures since 6-1/2 months of age, who had previously received phenobarbitone and phenytoin, and was presently Results During the period of this study, 621 children with active epilepsy were seen at the PNC. After appropriate management, 48 had early-onset, medically intractable epilepsy, of which, 27 were excluded (Fig. 1). Twenty-one children (13 males and 8 females), aged between 11 month and 38 month, were defined as having idiopathic intractable epilepsy and were enrolled in the study. The median age at onset of seizure was 5.1 months. The major seizure types were focal in 3 and generalized in 18 (including infantile spasm in 11) (Table 1). No patient had normalization of EEG during the trial, nor was any EEG suppression noted during the pyridoxine Table 1 Characteristics of the study population (n=21) Characteristic Sex, male (%) 13 (61.9%) Type of seizure Focal 3 Generalized 18 (IS at onset) 7 Number of anticonvulsants 3(2 5) used, mode (range) Anticonvulsants used Sodium valproate, phenobarbitone, phenytoin, carbamazepine, clonazepam, clobazam, lamotrigine, topiramate EEG findings Generalized polyspike (7), multifocal (4), generalized spikes (7), focal (3)

4 Indian J Pediatr (2010) 77: receiving valproate, clobazam and lamotrigine, had complete cessation of seizures within 2 wks of pyridoxine. Following which all three anticonvulsants were gradually tapered without recurrence of seizures. Inadvertent discontinuation of pyridoxine by the patients led to breakthrough seizures, which again ceased within a week of restarting oral pyridoxine therapy. A diagnosis of PDS was thus confirmed. In another 3½-yr old patient with myoclonic seizures and developmental delay, seizure frequency decreased to 20% after pyridoxine therapy. A diagnosis of PRS was made. Pyridoxine was continued in addition to the previous anticonvulsants (phenobarbitone, valproate and clonazepam) and the long-term seizure control in the next 18 months was better than before pyridoxine (seizure frequency reduced to 20 30% of baseline). No toxicity or side effects of pyridoxine were observed in these two patients over a follow-up of more than 18 months. Discussion The role of pyridoxine in the treatment of epilepsy is wellrecognized [6] including use of vitamin B6 (both pyridoxine and pyridoxal phosphate) for intractable seizures [7, 8] and high-dose pyridoxine for the management of West syndrome [9]. Despite many reports of late presentation [10], and initial response to other AEDs [5], pyridoxine is still commonly considered only for the management of neonatal seizures by most physicians. Moreover, as previously reported, even that is quite uncommon in Indian patients [3, 4]. Although many authorities feel that trials of B6 for seizure are frequently unrewarding [6], we conducted this trial to determine the proportion of intractable epilepsy in children being contributed by pyridoxineresponsiveness, an eminently treatable condition, with usually a good prognosis. The demonstrated 9.5% prevalence of response to pyridoxine showed that many of these patients are being missed in early life and, thus contributing to the burden of active epilepsy and also, possibly, developmental delay/mental retardation. There exist many reports of vitamin B6 use as an adjuvant therapy for epilepsy. Jiao, et al. [7]. used intravenous pyridoxine for seizure control in Chinese children and found it to be effective and safe for treatment of recurrent seizures. More recently, Wang, et al. [8]. used pyridoxine and/or pyridoxal phosphate (PLP) to achieve good seizure control in 11 of 94 children (11.7%) with idiopathic intractable epilepsy. There were some patients who exclusively responded to pyridoxal phosphate in their study [8]. If a similar situation also exists in India, the proportion of children responding could have been higher, had we also used PLP in our study. We could not do so due to its non-availability. Both the patients responding to pyridoxine did not show any normalization of EEG during pyridoxine trial. This phenomenon has also been reported previously. Delayed clinical response [1] and delayed normalization of EEG [3] are some of the atypical features recognized amongst recent reports. Bass et al. reported a child in whom repeated pyridoxine trials were required to demonstrate pyridoxine dependency, as the initial two pyridoxine trials at 6 day and 3 months age did not result in seizure/eeg response [11]. There are other reports of abnormal EEG persisting up to several weeks after seizure cessation with pyridoxine trial [3, 12]. These cases probably either demonstrate subclinical electrical seizures that later subside with continued pyridoxine use, or the need for a higher initial pyridoxine dose for EEG response. In our study population (those receiving pyridoxine later in life, after uncontrolled epilepsy); this delayed response could also be because of EEG changes secondary to repeated seizures. EEG findings have also been reported to correlate with the long-term prognosis, with those with persistently abnormal EEG backgrounds despite pyridoxine therapy being moderately to severely retarded, and others with normal EEGs having normal/near normal development on long-term follow up [13]. Recently, elevated serum and CSF pipecolic acid levels, and elevated aminoadipic semialdehyde levels in various body fluids have been shown to be associated with PDS [14]. We could also have used elevated levels of these compounds to enable confirmation of the diagnosis without recourse to withdrawal test. However, as these facilities were not available to us, the final diagnosis of pyridoxine-dependent seizures was only possible in the traditional way, as has previously been suggested [15]. We used an injection which contains more vitamins than only pyridoxine. Although, this has been used previously; [3, 15, 16] the possibility of response to some compound other than pyridoxine, and risk of toxicity to other vitamins remain. The high proportion of pyridoxine-responsiveness in this pilot study underscores the need for larger, preferably blinded studies to validate the findings. Till then, the results justify a trial of B6 in all idiopathic, intractable epilepsy with onset in infancy. Acknowledgements DM and RS were working as Senior Research Associate with Human Resource Development Group, Council of Scientific and Industrial Research, Government of India, during the period of the present work. The organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Role of Funding Source Conflict of Interest None. None.

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