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Topiramate for the treatment of infants
with early myoclonic encephalopathy
Mohammed M. Jan, MBChB, FRCP(C), Saleh S. Baeesa, MBChB, FRCS(C), Zaitoon M. Shivji, RET, REMGT.
Early myoclonic encephalopathy (EME) is a were included. In addition to daily seizures, they all had rare epileptic syndrome characterized by neonatal onset of global hypotonia, developmental delay, and progressive severe recurrent seizures of multiple types often resistant to microcephaly. The syndrome was cryptogenic in 3, and one antiepileptic drugs (AEDs). Topiramate (TPM) is a new AED, which has a wide spectrum of antiepileptic activities electroencephalograms showed generalized epileptic burst suggesting a potentially valuable therapeutic profile. There is suppression pattern. Infants were tried on multiple AEDs (6- limited clinical data available on TPM use in infants and our 11, mean 7.5) with no success. Topiramate was added at age aim is to report our experience with TPM for the treatment of 5-12 months (mean 9) reaching a maximum dose of 5.5-10 infants with intractable seizures secondary to EME.
mg/kg/day (mean 7.6). The infants were then followed for upto 19 months (mean 13.5). After introducing TPM, one infant Methods:
Prospective, open label, add on trial of TPM in became completely seizure free and 3 had significant (>50%) treating a series of infants with EME at King Faisal Specialist seizure reduction. Electroencephalograms in 3 infants showed Hospital and Research Centre and King Abdul-Aziz marked improvement. One infant had weight loss that University Hospital, Jeddah, Kingdom of Saudi Arabia resulted in discontinuing the drug after 6 months. Follow-up between June 1999 and March 2002. Topiramate was started renal ultrasound findings were normal in all infants.
at 12.5 mg/day and was increased by doubling the dose everyweek until the minimum effective dose was reached (seizure Conclusions:
Topiramate is effective and safe in treating free outcome) or up to a maximum of 10 mg/kg/day. infants with intractable epilepsy secondary to EME. Results:
Four consecutive infants (2 males and 2 females) Neurosciences 2003; Vol. 8 (2): 110-112
arly myoclonic encephalopathy (EME) is a rare multiple types (myoclonic, clonic, and tonic). The epileptic syndrome that consists of 2 clinically seizures are frequently resistant to antiepileptic drugs similar syndromes closely related to infantile spasms.1 (AED). The electroencephalogram (EEG) shows These include early infantile epileptic encephalopathy striking epileptic burst suppression pattern that may described by Ohtahara et al in 1987,2 and neonatal later evolve to atypical or modified hypsarrhythmia.
myoclonic encephalopathy described by Aicardi in Early myoclonic encephalopathy can be lesional (central 1990.3 Some authors suggested that the separation nervous system (CNS) malformations, migration between these syndromes might be artificial.4 In this disorders), metabolic (mitochondrial, amino acid, and paper, we will use the term early myoclonic encephalopathy to be inclusive of both clinical entities.5 hyperglycinemia), or cryptogenic. Regardless of the Early myoclonic encephalopathy is characterized by etiology, infants with EME carry poor prognosis for neonatal presentation of severe recurrent seizures of complete seizure control and neuro-developmental From the Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia.
Received 8th July 2002. Accepted for publication in final form 2nd October 2002.
Address correspondence and reprint request to: Dr. Mohammed M. S. Jan, Department of Neurosciences, King Faisal Specialist Hospital and Research Centre,MBC J-76, PO Box 40047, Jeddah 21499, Kingdom of Saudi Arabia. Tel. +966 (2) 6677777 Ext. 5819. Fax. +966 (2) 6677777 Ext. 5813. TPM for early myoclonic encephalopathy . Jan et al outcome.1-3,5 Topiramate (TPM) is a new AED, whichappears to have multiple modes of action includingsodium channel blockade, gamma-aminobutyric acidenhancement, glutamate antagonism, and weak carbonicanhydrase inhibition.6-8 This wide spectrum ofantiepileptic actions suggests a valuable and broadtherapeutic profile. There is limited clinical dataavailable on TPM use in infants and young children.9-17However, the current clinical experience is encouraging.
Clinical trials have shown that TPM is effective whenused adjunctively in children with refractory partial andsecondary generalized seizures.12 It was also found to beuseful as adjunctive therapy in the management ofLennox-Gastaut syndrome, severe myoclonic epilepsy ofinfancy, and West syndrome.12-14 In this paper, we reportour experience with TPM for the treatment of infants Figure 1 - Electroencephalogram (coronal montage) of a 7-month-old infant diagnosed with early myoclonic encephalopathy before with intractable seizures secondary to EME.
introducing topiramate. The features are consistent withgeneralized epileptic burst suppression pattern.
Methods. A series of consecutive infants diagnosedwith EME was identified prospectively. Patients were explain their state. In addition these infants had global identified through referrals and consultations to the hypotonia, developmental delay, and progressive pediatric neurology service at King Faisal Specialist microcephaly. Brain computed tomography (CT) and Hospital and Research Centre (KFSH&RC) and King magnetic resonance imaging (MRI) were performed in Abdul-Aziz University Hospital, both in Jeddah, all cases and revealed mild nonspecific atrophy in 2. No Kingdom of Saudi Arabia, between June 1999 and March malformations or developmental abnormalities were 2002. King Abdul-Aziz University Hospital is the main detected. Detailed metabolic workup was unrevealing teaching center of the western region in collaboration except in one girl who had nonketotic hyperglycinemia.
with KFSH&RC. Both are multispecialty adult and The syndrome was therefore cryptogenic in the other 3 pediatric hospitals providing tertiary medical care for infants. Initial EEGs showed generalized epileptic burst most of the regional population of western KSA. Patient suppression pattern (Figure 1). The infants were tried on
and disease related data was collected during the initial multiple AEDs (6-11, mean 7.5) with no success, visit. The diagnosis of EME was based on the clinical including the newer AEDs, B6, steroids, and intravenous features and EEG findings. The seizures were of immunoglobulins. Before introducing TPM, the infants neonatal onset, mixed, and intractable (defined as were receiving 2-3 AEDs. Topiramate was added to the recurrent seizures that failed to respond to at least 3 other AEDs at age 5-12 months (mean 9). The final antiepileptic medication trials singly or in combination Topiramate dose ranged between 50-100 mg/day (mean despite using maximum doses or doses resulting in 65) divided twice per day, corresponding to 5.5-10 mg/ therapeutic drug levels). After consenting to drug use, kg/day (mean 7.6). The infants were then followed for infants were started on TPM in an open label, add on up to 19 months (mean 13.5). After the introduction of trial. Topiramate was added to the other antiepileptic TPM, one infant became completely seizure free and 3 drug therapy at a starting dose of 12.5 mg/day and was had significant (>50%) seizure reduction. All infants gradually increased by doubling the dose every week continued to receive other AEDs (1-2 in addition to until the minimum effective dose was reached (achieving TPM). The EEGs in 3 infants revealed marked a seizure free outcome) or up to a maximum dose of 10 improvement in terms of epileptiform discharges, but mg/kg/day. Follow-up by one pediatric neurologist was continued to show background abnormalities. The EEG performed to document therapeutic response and features evolved to that of Lennox-Gastaut syndrome in occurrence of side effects. Therapeutic response was one boy who was followed to the age of 27 months. No recorded as complete (no seizures), good (>50% seizure side effects or drug interactions were noted in 3 infants.
reduction), fair (<50% seizure reduction), or none (no One infant had initial weight loss and subsequent poor weight gain that resulted in discontinuing the drug after6 months. Follow-up renal ultrasound was normal in all Results. Four consecutive infants (2 males and 2 females) were included. All infants had many dailyseizures that started early in the neonatal period (mean Discussion. The study results suggest that TPM is age of 3 days). The seizures were of multiple types an effective and well-tolerated AED when used in (myoclonic, clonic, and tonic), however, myoclonic infants with EME. Three of our infants had significant seizures were the most common. There were no seizure reduction and one became completely seizure prenatal, natal, or postnatal complications that would free. This is very impressive, as all of them had very Neurosciences 2003; Vol. 8 (2) 111
TPM for early myoclonic encephalopathy . Jan et al difficult seizures, which were resistant to multiple AEDs. Most EEGs also showed marked improvement interms of epileptiform discharges. Other investigators 1. Aicardi J. Epilepsy and other seizure disorders. In: Diseases of have successfully used TPM in infants primarily with the nervous system in childhood. 2nd ed. London (UK): Mac myoclonic epilepsy;13,14,16 however, there are no reports of using it in EME. Our maximum dose did not exceed 2. Ohtahara S, Ohtsuka Y, Yamatogi Y, Oka E. The early infantile epileptic encephalopathy with suppression bursts: developmental 10 mg/kg/day which was based on other reported aspects. Brain Dev 1987; 9: 371-376.
experience and the drug company’s recommendations.
3. Aicardi J. Neonatal myoclonic encephalopathy and early Preliminary data on the pharmacokinetics of TPM in infantile epileptic encephalopathy. In: Neonatal seizures. New infants appears to be linear with higher plasma clearance York (NY): Raven Press; 1990. p. 41-49.
than that reported for older children, and therefore 4. Lombroso CT. Early myoclonic encephalopathy, early infantile substantially higher than that reported for adults.15 This epileptic encephalopathy and benign and severe infantile means that infants may require significantly larger doses contributions. J Clin Neurophysiol 1990; 7: 380-408.
per kilogram than older children and adults. These 5. Volpe JJ. Neonatal seizures. In: Neurology of the newborn. 4th authors recommended titration to effect and not absolute ed. Philadelphia (PA): WB Saunders Company; 2001. p.
TPM dose should guide therapy in this age group.15 It is possible that higher doses (>10 mg/kg/day) may prove to 6. White HS, Brown D, Skeen GA, Woodbury DM. The anticonvulsant topiramate displays a unique ability to potentiate We did not encounter any significant side effects in 3 GABA evoked chloride currents. Epilepsia 1995; 36: S39.
infants, however, TPM had to be discontinued in one 7. White HS, Brown D, Skeen GA, Hamsworth WL, Sofia RD. The investigational anticonvulsant topiramate potentiates GABA infant because of weight loss. In one long term response evoked currents in mouse cortical neurons. Epilepsia 1995; 36:
trial of TPM in infants with West syndrome, the drug was well tolerated in that no patients discontinued 8. Severt L, Coulter DA, Sombati D, DeLoprenzo RJ. Topiramate because of adverse events.14 This is also the experience selectively blocks kainate currents in cultured hippocampal of other investigators who used TPM in young infants.16 neurons. Epilepsia 1995; 36: S38.
Mild to moderate behavioral and cognitive side effects 9. Glauser TA. Preliminary observations on topiramate in pediatric may be difficult to recognize in our young epilepsies. Epilepsia 1997; 38: S37-S41.
10. Glauser TA. Topiramate use in pediatric patients. Can J Neurol
developmentally delayed patients. We used a slow rate Sci 1998; 25: S8-S12.
of drug introduction and tended to use the minimum 11. Dooley JM, Camfield PR, Smith E, Lagevin P, Ronen G.
effective dose. Rapid dose titration has been implicated Topiramate in intractable childhood onset epilepsy - a cautionary in these side effects.13 Recently, Takeoka et al17 reported note. Can J Neurol Sci 1999; 26: 271-273.
mild metabolic acidosis (decreased serum bicarbonate) 12. Ormrod D, McClellan K. Topiramate: a review of its use in in children treated with TPM, presumably related to childhood epilepsy. Paediatric Drugs 2001; 3: 293-319.
13. Nieto-Barrera M, Candau R, Nieto-Jimenez M, Correa A, del carbonic anhydrase inhibition. We did not routinely Portal LR. Topiramate in the treatment of severe myoclonic screen for this abnormality in our patients. Caution is epilepsy in infancy. Seizure 2000; 9: 590-594.
needed when TPM is used in infants with conditions that 14. Glauser TA, Clark PO, McGee K. Long term response to may predispose to acidosis or poor weight gain. topiramate in patients with west syndrome. Epilepsia 2000; 41:
Although long term safety and possible adverse effects have not been fully established in infants, TPM 15. Glauser TA, Miles MV, Tang P, Clark P, McGee K, Doose DR.
may represent an option for infants with high seizure Topiramate pharmacokinetics in infants. Epilepsia 1999; 40:
frequency unresponsive to standard AED. We found it 16. Kugler SL, Sachdeo RC. Topiramate efficacy in infancy.
effective and safe in treating infants with intractable Pediatr Neurol 1998; 19: 320-322.
epilepsy secondary to early myoclonic encephalopathy.
17. Takeoka M, Holmes GL, Thiele E, Bourgeois BF, Helmers SL, Careful monitoring of the body weight is needed in these Duffy FH, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001; 42: 387-392.

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