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Ineffectiveness of topiramate and levetiracetam in infantile
spasms non-responsive to steroids
Open labeled randomized prospective study Adel A. Mahmoud, MD, FRCP, Tamer M. Rizk, MD, FRCPCH, Ahmed A. Mansy, MD, Jaffar A. Ali, PHD,
Mohamad A. Al-Tannir, DMD, MPH.
respond to prednisone (2mg/kg/day in 2 divided doses) were recruited and randomized into 2 groups. ماتيسارتيفيلو تاماريبوت نيراقعلا ةيلاعف ينب ةنراقم :فادهلأا
They were randomly assigned to either topiramate (group 1; 1mg/kg/day for 3 days then increased by تانوزيتروكلا لشف دعب ةيلفطلا تاجنشتلا جلاعل يناث طخك 1mg/kg/day every third day up to 6mg/kg/day) or levetiracetam (group 2; 10mg/kg/day for 5 days and then increased by 10mg/kg/day every 5 days up to نمم ينماع نوضغ يف ًاعيضر 60mg/kg/day). The study was conducted in the 40 ىلع ةسارد تيرجأ :ةقيرطلا
Pediatric Neurology Department at the National يومفلا نوزيتروكلل ةبيجتسم ريغ ةيلفط تاجنشت نم نوناعي Neuroscience Institute of King Fahad Medical City, 1 ىلولأا ةعومجلما( تاماريبوت راقع ىلع امإ ًايئاوشع مهميسقتو Riyadh, Kingdom of Saudi Arabia between January /غلم 6 ىلإ لصتل ةعرلجا عفرت مث مايأ 3 ةدلم مويلا يف غلك/غلم /غلم 10 ةيناثلا ةعومجلما( ماتيسارتيفيل راقع وأ مويلا يف غلك Results: Of the 20 patients included in the final data
/غلم 60 ىلإ لصتل ةعرلجا عفرت مث مايأ 5 ةدلم مويلا يف غلك analysis, 11 (55%) were administered topiramate ،لافطلأا باصعأ مسق يف ةساردلا هذه تيرجأ .)مويلا يف غلك and 9 (45%) levetiracetam. Eighteen patients did ،ضايرلا ،ةيبطلا دهف كللما ةنيدم ،ةيبصعلا مولعلل ينطولا زكرلما not respond to the first drug, and subsequently to the other drug when crossed-over. Two patients with 2008 رياني نم ةرتفلا للاخ ةيدوعسلا ةيبرعلا ةكلملما infantile spasm responded to either one drug without crossover. Their EEGs improved with time. ليلحتل ةيئاهنلا ةلحرلما يف اوجردأ ضيرم 20 ينب نم :جئاتنلا
Conclusion: The present study demonstrated the
ineffectiveness of topiramate and levetiracetam 9و تاماريبوت راقعب مهجلاع تم ضيرم )55%( 11 تانايبلا suggesting current treatment modalities are grossly لك نم طقف ًادحاو نأ ظحول .ماتيسارتيفيل راقعب )45%( inadequate underscoring the urgent need for more ةعومجلما نم 10 بجتسي ملو جلاعلل ةباجتسا رهظأ ةعومجم research efforts to overcome current deficiencies. Two .ةيناثلا ةعومجلما نم 8و ىلولأا patients with cryptogenic infantile spasm responded to treatment suggesting the potential for treatment of such patients with these 2 drugs, and merits further تاماريبوت راقع نم لاك نأ ةيلالحا ةساردلا ترهظأ :ةتماخ
.ةيلفطلا تاجنشتلا جلاع يف ينيلاعف ريغ ماتيسارتيفيل راقعو Neurosciences 2013; Vol. 18 (2): 143-146
تاجنشتلل لاعف جلاع لجأ نم بوؤدلا ثحبلا نم ديزلما ةيلاعف حرتقي يذلا رملأا ؛جلاعلل طقف ناضيرم باجتسا ةيلفطلا From the Pediatric Neurology Department (Mahmoud, Mansy) National Neuroscience Institute, the Research & Scientific Publications .تارابتخلاا نم ديزلما ءارجإ قحتسيو نيراقعلا Center (Ali, Al-Tannir) King Fahad Medical City, and the Pediatric Neurology Department (Rizk), Al-Takhassusi Hospital, Riyadh, Objective: To compare the effectiveness of 2 novel
antiepileptic drugs, topiramate and levetiracetam, as Received 30th September 2012. Accepted 15th January 2013. a second line treatment for infantile spasm when oral Address correspondence and reprint request to: Dr. Adel A. Mahmoud, Pediatric Neurology Department, National Neuroscience Institute, Methods: Forty infants under 2 years with clinically-
King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. Tel. +966 (1) 2889999 Ext. 7288. Fax. +966 (1) 2889999 Ext. 1391. and EEG-proven infantile spasms that did not Neurosciences 2013; Vol. 18 (2) 143
Topiramate and levetiracetam in infantile spasms … Mahmoud et al Infantile spasm (IS) or West syndrome is a well clinically- and EEG-proven IS. The study recruited recognized age-related malady that begins between 40 patients that had failed to respond to treatment 4 and 6 months, with most cases occurring prior to with steroids (namely, prednisone). Prednisone was 12 months in over 90% of affected infants. This is used instead of ACTH due to non-availability. The important as cases with IS presenting late are usually inclusion criteria were infants less than 2 years of age, overlooked.The American Academy of Neurology and IS proven clinically and by EEG manifestations. and the Child Neurology Society established practice Children with epileptic syndromes other than IS guidelines for the treatment of IS in childrThe (for example, Ohtahara, early myoclonic epilepsy of practice guidelines suggest that steroids are “probably infancy or Lennox-Gastaut syndromes) were excluded. effective” while vigabatrin (VGB) is “possibly effective” Infants exhibiting adverse events were documented. in treating IS. Studies proved the superiority of For ethical considerations and in accordance with the VGB in cases of tuberous sclerosis. However, parents Helsinki Declaration and Belmont Report Ethical express reluctance to the administration of VGB codes, we stopped recruitment at 20 patients due to because it could predispose the patient to retinal the ineffectiveness of LEV and TPM. Thus, only 20 toxicity or demy especially when the child children were included in our final data analysis. The is free of either tuberous sclerosis or blindness. At the Institutional Review Board at King Fahad Medical City present moment, there is no consensus on the drug (KFMC), Riyadh, Kingdom of Saudi Arabia approved of choice if adrenocorticotropic hormone (ACTH) the study. The study was performed with parents’ failed to elicit the desired response, when VGB is not informed consent.
suitable or recommended. There is an obvious need Study design. The study was performed in an
to identify other efficacious treatment modalities for open labeled randomized prospective manner. The IS. Topiramate (TPM) is a monosaccharide derivative randomization sequence was generated by the STATA with sulfamate functionality. It was developed as an computer program version 10 (STATACorp LP, College antiepileptic as McN-4853 and showed potency equal Station, TX, USA). Infantile spasm patients non- to that of phenytoin. Topiramate has been utilized in responsive to prednisone (Austria GmbH, Linz, Austria) the United Kingdom since 1995 and was approved by for 2 weeks were recruited, and those that underwent the Federal Drug Administration (FDA) in 1997. Its the following investigations were eligible for inclusion exact pharmacology has not been established, but its in the study. During their initial visit, all patients in this various attributes may explain its role in the treatment trial underwent the following baseline investigations; of epilepsy. Its anhydrase-inhibiting effect may namely: complete blood count, electrolytes, liver contribute to its antiepileptic properLevetiracetam function test, EEG, MRI, CT of the brain, metabolic (LEV) is a pyrrolidone derivative unrelated to any of work up, and vital signs. Urine dipsticks were used the antiepileptic drugs currently in use. It was approved to measure sugar twice daily or whenever required. by the FDA, the European Union, and various other Electrolytes were measured whenever required. The countries. Its chemical name is (S)-alpha-ethyl-2-oxo- patients were carefully monitored for signs of infection. pyrrolidine acetamide. Its mechanism of action is not Vital signs were recorded thrice daily and whenever known. Its mode of action may explain its pharmacology. required.
In vivo studies show that inhibitory CNS effects of LEV Eligible patients were assigned to 2 groups for treatment with either TPM (group 1) or LEV (group In the present study, we investigated the effectiveness 2) in a randomized manner. For reasons of good of TPM and LEV in eligible IS patients in situations medical practice, a washout period for prednisone was not considered, as the infants needed medication to counter the seizures. At four weeks of therapy, patients Methods. We conducted this study in the Pediatric that did not respond to either drug were subsequently
Neurology Department, National Neuroscience crossed-over to the other drug without a washout Institute of King Fahad Medical City, Riyadh, Kingdom period. If the patients responded to the crossed-over of Saudi Arabia between January 2008 and December drug, the treatment was continued for 2 weeks more 2010. The patients were in their first 2 years of life with and examined during follow-up subsequently. At six weeks, treatment was continued for a further 2 weeks if either drug elicited a positive response. Patients that Disclosure. The authors declare no conflicting interests,
did not show a response to treatment were considered support or funding from any drug company.
as failed treatment. Successful treatment was defined as a decrease in clinical seizures by more than 50% as well Topiramate and levetiracetam in infantile spasms … Mahmoud et al as disappearance of abnormal EEG findings. Failure of cryptogenic type of the disease became seizure-free after treatment was defined as inability to achieve successful 10 days of treatment, one with TPM and the other with LEV without crossover indicated by return to normal The TPM was initially administered at a dosage of EEG patterns. It is of interest that 2 patients with 1mg/kg/day for 3 days then increased by 1mg/kg/day cryptogenic IS responded to treatment suggesting a every third day up to 6mg/kg/day. Patients achieving potential trend for treatment of such patients with these the primary end-point at any stage above the dosage 2 drugs; however, this requires a larger sample size and a of 5mg/kg/day would be maintained on that dose multicenter investigation to conclusively determine the until the end of the 4 weeks of therapy. After 4 weeks of therapy, the patient was evaluated for achievement effectiveness of TPM and LEV. of the primary end-point. If the primary end-point The use of TPM in IS has been reported by Glauser was not achieved LEV was administered and dosage et al, who noted that only 4 of 13 (30.8%) patients with symptomatic spasms responded when doses Likewise, LEV was administered at a dose of 10mg/ up to 25 mg/kg/day were used. The most frequently kg/day for 5 days and then increased by 10mg/kg/day reported adverse effects were: drowsiness, irritability, every 5 days up to 60mg/kg/day. Patients achieving the hyperthermia, and anorexia.In an earlier open label primary end-point at any stage above the dose of 40mg/ study on the long-term response to TPM in 8 children kg/day would be maintained on that dose until the end with IS, 7 (87.5%) patients experienced >50% spasms of the 4 weeks of therapy. After 4 weeks, the patient was evaluated for achievement of the primary end-point. If the primary end-point was not achieved TPM was Table 1 - Ineffectiveness of topiramate and levetiracetam in infantile
administered and dosage escalated as per protocol. The infants’ parents were informed regularly and when needed regarding their infants’ progress. The Symptomatic
or idiopathic
parents notified the team of any adverse events as well infantile spasm
as frequency and duration of seizures.
Descriptive statistics for the study was performed using the Statistical Package for Social Sciences (SPSS Results. Twenty patients received treatment. Seventy
percent of the infants were males. Of the 20 infants, 2 (10%) were diagnosed with cryptogenic infantile spasm. Eleven patients received TPM and the remaining 9 received LEV with a random allocation. However, 2 (10%) of the patients with the cryptogenic type of IS responded successfully to either one of the drugs Medication was crossed-over for 18 non-responsive patients. These 18 patients did not respond to either drug when administered individually with one drug and following crossover, with the other drug. Discussion. The present study intended to include
at least 40 patients with IS in the investigation, with 20 patients on each drug (TPM or LEV). However, it became clear to the investigators that both drugs failed to control the spasm or to normalize the EEGs in the first 18 of 20 patients. Consequently, the investigators were compelled to terminate the study prior to completion due to ethical considerations when the ineffectiveness of the drugs (TPM and LEV) became apparent during In the present study involving 20 children aged less than 2 years suffering from IS, only 2 patients with the m - months, D - days, TPM - topiramate, LEV - levetiracetam Neurosciences 2013; Vol. 18 (2) 145
Topiramate and levetiracetam in infantile spasms … Mahmoud et al reduction, and 4 of 8 (50%) became seizure-free on In conclusion, the present study has demonstrated a mean dose of 29mg/kg/dayIt is not possible to that both TPM and LEV are not effective in controlling generalize the findings of these studies due to the very seizures or in normalizing the EEG in symptomatic IS. Two patients with cryptogenic IS responded to Studies on TPM performed in recent years have treatment suggesting the potential for treatment of shown it to be nontoxic to, and well tolerated by such patients with these 2 drugs; however, this requires infants. In the present study, TPM and LEV appeared a larger sample size and a multicenter investigation to to be well tolerated in the study population, but a conclusively determine the effectiveness of TPM and previous study implicates TPM in development of LEV.
asymptomatic kidney In an open label study Acknowledgments. We acknowledge the effort of Samar A.
undertaken by Hosain et al on 10 newly diagnosed Mahmoud in reviewing and correcting the text of the manuscript. cases of IS, treatment with TPM with doses up to 20mg/kg/day revealed none had symptomatic acidosis. References
Of these 10 patients, one patient was seizure-free, 4 had a 50% reduction, and 3 had at least 25% r 1. Likewise, a number of other studies have shown the limited efficacy of more than 50% reduction in spasms 2. in a few patients following administration of TPM.
in seizure rate is not regarded as a reliable end-point in West syndrome. The normalization of EEG is thought 3. A multicenter, retrospective, and uncontrolled 4. study to evaluate the effectiveness and safety of LEV in 81 children younger than 4 years with refractory epilepsy observed that LEV maintained its effectiveness 5. in patients with focal epilepsy and West syndrome. The study noted LEV was well tolerated. The study recorded adverse events in 18 (34%) patients of which 6. Rosenfeld WE, Berkovic S, Knowlton R on behalf of Lev N01057 the main side effects were drowsiness and nervousness. PGTC Study Group. Efficacy and Safety of Levetiracetam 3000 These adverse events were either within tolerable mg/day (Pediatric Dose 60 mg/kg/day) as Adjunctive Therapy limits or were resolved in time with dosage reduction in Adult and Pediatric Idiopathic Generalized Epilepsy Patients Experiencing Primary Generalized Tonic-Clonic Seizures or discontinuation of the drug. Lawlor and D (Poster Presentation). Proceedings of the 1st North American reported a case of successful cessation of seizures and Regional Epilepsy Congress; 2006 Dec 1-5; San Diego (CA). resolution of seizure activity as demonstrated by 7. normalized EEG following treatment with LEV in an 11-month-old infant with a 5-months history of seizures and a 3-months history of IS resistant to treatment with 8. The most crucial outcome of the present study is the 9. demonstration of the ineffectiveness of both TPM and LEV in ameliorating IS. This finding was ascertained by demonstration of abnormal EEG in the treated patients. 10. It is cautioned that a decrease in symptoms alone is insufficient evidence for effectiveness of treatment. The most accurate means of determining effectiveness of the treatment is attainment of normal EEG. The literature does not offer other efficacious treatment modalities for 12. IS, and the present study has clearly demonstrated the ineffectiveness of TPM and LEV in alleviating IS. This situation underscores the urgent need for more research 13. efforts to overcome current deficiencies pertaining to


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