Age and antiepileptic drugs influence topiramate plasma levels in children

The influence of age and comedication on the dose-to-level ratio of topiramate was examined in 91 children with epilepsy treated with topiramate. The topiramate dosing and plasma concentrations, as well as those of their concomitant antiepileptic drugs were examined retrospectively. The dose-to-level ratio was used as a measure of clearance and was calculated as the weight-normalized topiramate dose (mg/kg/day) divided by the steady-state trough plasma drug level in the child. The children were classified in age groups and treatment groups; topiramate was administered with an enzyme inducer (n = 32), with a nonenzyme inducer (n = 49), or as monotherapy (n = 10). The topiramate clearance in children aged 0-8 years compared with those aged 9-17 years was more than twofold higher if treated with an enzyme-inducing antiepileptic drug and 1.5-fold higher if treated with a nonenzyme inducer. Children receiving enzyme inducers had a more than twofold higher clearance compared with those who did not. Within all age groups, significant differences in topiramate clearance were observed between those receiving enzyme inducers and those receiving nonenzyme inducers or monotherapy. Thus younger age and concomitant enzyme inducers, both acting independently, significantly increased the clearance of topiramate in children. This effect has to be considered to optimize treatment in the individual patient.     

Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years

PURPOSE: To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs). METHODS: Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method. RESULTS: TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs. CONCLUSIONS: Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.     

A study of topiramate pharmacokinetics and tolerability in children with epilepsy

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CL/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher (P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 mL/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.     

Efficacy and tolerability of topiramate in children younger than 2 years old

To evaluate the efficacy and tolerability of topiramate in children with epilepsy younger than 2 years of age, we retrospectively reviewed the records of patients treated at our institution between 2001 and 2003. Thirteen children ages 5 to 23 months, five boys and eight girls, were identified. Seizure types were partial (five), generalized tonic-clonic (three), myoclonic (one), and infantile spasms (four). The mean age at seizure onset was 9.7 months. Topiramate was started at a mean age of 11.4 months (4-23 months). The number of antiepileptic drugs prior to topiramate therapy ranged from zero to four. One patient had been on the ketogenic diet. Topiramate was used as monotherapy in seven children and as polytherapy in six children. Mean follow-up was 14 months. The mean dose of topiramate was 8.8 mg/kg/day (2.5-18 mg/kg/day). The degree of seizure reduction was as follows: > 75% in five (38.5%) children, 50% to 75% in three (23%) children, and 0 to 25% in five (38.5%) children. Three of four (75%) patients with infantile spasms had a > 75% reduction in seizures. Adverse effects occurred in two children, including lethargy, hyperthermia, and anorexia. In children younger than 2 years of age, for whom the antiepileptic drug armamentarium is limited, topiramate appears to be an efficacious and safe therapeutic alternative for a variety of seizure types.     

Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy

BACKGROUND: In the face of availability of newer antiepileptic drugs (AEDs) such as lamotrigine and topiramate, there is need to reassess the role of older AEDs in the treatment of juvenile myoclonic epilepsy (JME). OBJECTIVES: To explore whether lamotrigine and topiramate monotherapy or polytherapy can be effective options in the treatment of JME, and to determine whether older AEDs, such as phenytoin and carbamazepine, have a role in the treatment of JME. DESIGN: A retrospective cohort study. SETTING: A large academic teaching hospital. PATIENTS: Seventy-two consecutive JME patients treated with valproic acid, lamotrigine, topiramate, phenytoin, or carbamazepine between April 1, 1991, and March 31, 2001. METHODS: We compared the efficacy of valproic acid, lamotrigine, and topiramate monotherapy or polytherapy in the control of different seizure types of JME, and compared their efficacy and tolerability with the efficacy and tolerability of phenytoin and carbamazepine. RESULTS: Seizure outcome did not differ when patients receiving valproic acid monotherapy (n = 36) were compared with those receiving lamotrigine monotherapy (n = 14), and when patients receiving valproic acid polytherapy (n = 22) were compared with those receiving lamotrigine polytherapy (n = 21) or topiramate polytherapy (n = 15) (P>.05 for all). The combined data of myoclonic seizure control by all 3 AEDs were poorer when compared with the combined data of generalized tonic-clonic seizure control by all 3 AEDs (P =.03), but not when compared with the combined data of absence seizure control by all 3 AEDs (P =.43). Valproic acid, lamotrigine, and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures (P<.01 for all), but not of generalized tonic-clonic seizures (P>.11 for all). CONCLUSIONS: Lamotrigine and topiramate are effective alternative options to valproic acid in the treatment of JME. Lamotrigine is an effective option as monotherapy and polytherapy. Topiramate is an effective option as polytherapy, but more data are needed to determine if it is an effective option as monotherapy. More effective therapy is needed to improve myoclonic seizure control. Older AEDs, such as phenytoin and carbamazepine, may not be indicated in JME patients.     

Topiramate monotherapy as broad-spectrum antiepileptic drug in a naturalistic clinical setting.

Topiramate was assessed in an open-label trial as broad-spectrum antiepileptic monotherapy, independently from the epilepsy type or syndrome. Adults and children aged 2 years and older, who were diagnosed with epilepsy within the last 5 years, treatment-naive or failing prior treatment with one antiepileptic drug (AED), received individually adjusted doses of topiramate, after escalation to 100mg/day over 4 weeks (maximum 400mg/day) or 3mg/kg/day over 6 weeks (maximum 9 mg/kg/day), respectively. Patients were followed for >or=7 months and optionally up to a maximum of 13 months. Data were analysed for all patients (n=692), as well as for focal (n=421) and generalized epilepsies (n=148). The median topiramate dose used was 125 mg/day in adults and 3.3mg/kg/day in children (or=50% reduction in mean monthly seizure frequency. Patients with focal and generalized epilepsies alike responded to treatment (73.9 and 83.8% with at least 50% seizure reduction): 39.4% of patients with focal epilepsy and 61.5% of those with generalized epilepsy were seizure-free. The mean monthly seizure frequency was significantly reduced versus baseline at all visits (p<0.001). Similar response rates were obtained from the 237 patients completing the 1-year observation period. During the mandatory 7-month period of study, 8.8% of patients reported insufficient tolerability as a reason for dropout. The most frequent adverse event was paraesthesia. Our results support findings that emerge from controlled studies that topiramate is effective and well tolerated when used as initial or second monotherapy. They also suggest that in a naturalistic setting, overall good retention on treatment and seizure freedom are observed at low doses in a broad spectrum of epilepsies.     

Topiramate Pharmacokinetics in Infants

PURPOSE: This study's goal was to provide preliminary data on the pharmacokinetics of topiramate (TPM) in a cohort of infants (younger than 4 years) participating in an open-label trial of TPM in refractory infantile spasms. METHODS: The pharmacokinetics of TPM were assessed in infants receiving a stable TPM dose for >7 days during the extension phase of this trial. Blood samples were drawn just before and 0.5. 1, 1.5, 2, 4, 6, 8, and 12 h after the morning TPM dose. TPM plasma concentrations were determined by fluorescence polarization immunoassay. The noncompartmental analysis module of WinNonlin was used to calculate individual patient pharmacokinetics profiles. RESULTS: Five infants (ages, 23.5-29.5 months) formed the study cohort. These infants had been given TPM for a median of 9 months (range, 6-11 months) and were currently receiving between 11 and 38.5 mg/kg/day TPM. One was receiving TPM monotherapy, whereas four were taking concomitant antiepileptic medications (AEDs; n = 2, enzyme-inducing agents; n = 2, non-enzyme-inducing drugs). TPM pharmacokinetics in infants appears to be linear. In this cohort, mean TPM plasma clearance (CL/F, 66.6+/-27.4 ml/h/kg) was slightly higher than that reported for children and adolescents and therefore substantially higher than that reported for adults. TPM CL/F was higher and the calculated half-life shorter in the infants receiving concomitant enzyme-inducing AEDs. CONCLUSIONS: Based on this small cohort of patients, it appears that infants may require significantly larger TPM doses, based on weight, than children, adolescents, or adults. Titration to effect and not absolute TPM dose should guide therapy in this age group.     

Prospective study of first-choice topiramate therapy in newly diagnosed infantile spasms

OBJECTIVE: This was a prospective open study to establish the efficacy, tolerability, and problems associated with the use of topiramate as first-choice drug in children with infantile spasms. METHODS: Open-label follow-up study, ranging from 24 to 36 months, of the cases of 54 patients with infantile spasms treated initially with topiramate as first-choice drug. RESULTS: Thirty-one patients (57.4%) were seizure free for more than 24 months; 9 patients were treated with topiramate alone and 22 patients with topiramate plus nitrazepam and/or valproate. In 44 cases (81.4%), the reduction of seizure frequency from baseline was greater than 30%, whereas in 10 cases (18.6%), there was poor or no response. The average dosage applied was 5.2 mg/kg per day (maximum dosage, 26 mg/kg per day; minimum dosage, 1.56 mg/kg per day). Adverse events occurred in 14 patients (26%). They included poor appetite leading to anorexia, absence of sweating, and sleeplessness. CONCLUSIONS: Topiramate proves to be an effective and safe first-choice drug not only as adjunctive but also as monotherapy of infantile spasms in children younger than 2 years.     

Problems of Combination Drug Therapy in Children

Summary: Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy: toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.     

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age

Purpose: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic–pharmacodynamic (PK–PD) modeling and simulation bridging. Methods: Several models were developed in pediatric and adult populations to relate steady‐state trough plasma concentrations (C_min ) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. Key Findings: A two‐compartmental population PK model with first‐order absorption described the time course of topiramate C_min as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK–PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C_min and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK–PD modeling data, the dosing regimen expected to achieve a 65–75% seizure freedom rate after 1 year for pediatric patients age 2–10 years is approximately 6–9 mg/kg per day. Significance: This analysis indicated no difference in PK–PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2–10 years of age.     

Effect of topiramate on intractable seizures in Taiwanese children

We performed a prospective study to evaluate the effect of topiramate as an adjunctive therapy in Taiwanese children with intractable partial epilepsy and generalized epilepsy. Thirty children aged from 2 to 16 years (8.5 +/- 3.8 years) were enrolled in this study. Eighteen children (60.0%) had partial epilepsy, and 12 children (40.0%) had generalized epilepsy. These children were experiencing more than one seizure per month even under a stable antiepileptic regimen treatment. Topiramate was begun at 1 mg/kg x day, and the dosage was raised by 1 mg/kg x day each week. Titration continued for 4 weeks or more. The maximal dosage was 10 mg/kg x day. In children with partial epilepsy, six children (33.3%) achieved > or = 50% frequency reduction, while eight children (44.4%) achieved a seizure-free state. In children with generalized epilepsy, including infantile spasms, four children (33.3%) achieved > or = 50% frequency reduction, while five children (41.7%) achieved a seizure-free state. The most common adverse effect was poor appetite (10.0%). No idiosyncratic reactions to topiramate were found. Only one patient discontinued topiramate because of central hyperventilation. Topiramate can be used as an adjunctive antiepileptic drug for intractable epileptic children in Taiwan.     

Vigabatrin, lamotrigine, topiramate and serum carnitine levels

Clinical studies indicate a decrease in free and total carnitine in children treated with old-generation antiepileptic drugs (especially valproate). Here, we studied the effect of new-generation antiepileptic drugs on serum carnitine levels. Serum carnitine levels were measured in 91 children: 24 treated with vigabatrin, 28 treated with lamotrigine, and 21 treated with topiramate. These drugs were given as monotherapy (54 children) or polytherapy (19 children). Eighteen additional children treated with valproate served as control subjects. Reduced mean serum carnitine level was evident only in children treated with valproate, with mean free and total carnitine level of 26.9 +/- 8.6 micromol/L and 29.1 +/- 10.4 micromol/L, respectively. In contrast, the mean serum carnitine levels of children treated with vigabatrin, lamotrigine, or topiramate were similar and normal. In these children, the free carnitine levels were 38.5 +/- 7.8 micromol/L, 37.2 +/- 7.7 microg/mL, and 40.4 +/- 8.7 micromol/L, respectively, and total carnitine levels were 43.5 +/- 8.8 micromol/L, 44.4 +/- 9.2 micromol/L, and 45.5 +/- 9.8 micromol/L (+/-S.D.), respectively. Only 4 children (treated with valproate) exhibited considerably lower serum carnitine levels. None of these children had significant clinical adverse effects attributable to carnitine deficiency. In conclusion, these new-generation antiepileptic drugs probably do not cause carnitine deficiency. In contrast, valproate may induce carnitine deficiency, but most cases are asymptomatic.     

Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet

This study was performed to evaluate carnitine deficiency in a large series of epilepsy children and adolescents treated with old and new antiepileptic drugs with or without ketogenic diet. Plasma free carnitine was determined in 164 epilepsy patients aged between 7 months and 30 years (mean 10.8 years) treated for a mean period of 7.5 years (range 1 month-26 years) with old and new antiepileptic drugs as mono or add-on therapy. In 16 patients on topiramate or lamotrigine and in 11 on ketogenic diet, plasma free carnitine was prospectively evaluated before starting treatment and after 3 and 12 months, respectively. Overall, low plasma levels of free carnitine were found in 41 patients (25%); by single subgroups, 32 out of 84 patients (38%) taking valproic acid and 13 of 54 (24%) on carbamazepine, both as monotherapy or in combination, showed low free carnitine levels. A higher though not statistically significant risk of hypocarnitinemia resulted to be linked to polytherapy (31.5%) versus monotherapy (17.3%) (P=.0573). Female sex, psychomotor or mental retardation and abnormal neurological examination appeared to be significantly related with hypocarnitinemia, as well. As to monotherapy, valproic acid was associated with a higher risk of hypocarnitinemia (27.3%) compared with carbamazepine group (14.3%). Neither one of the patients on topiramate (10), lamotrigine (5) or ketogenic diet (11) developed hypocarnitinemia during the first 12 months of treatment. Carnitine deficiency is not uncommon among epilepsy children and adolescents and is mainly linked to valproate therapy; further studies are needed to better understand the clinical significance of serum carnitine decline.     

The role of event related potentials in evaluation of subclinical cognitive dysfunction in epileptic patients

BACKGROUND/AIM: Cognitive dysfunction in epileptic patients may develop due to the neurophysiological changes related to seizures or antiepileptic drugs. The aim of this study was to evaluate the cognitive dysfunction in epileptic patients under antiepileptic drug therapy by the aid of event related potentials. METHOD: P300 latencies were obtained from Fz, Cz and Pz electrod positions from both epileptic patients (n=40) and age and sex matched control group (n=40). Epileptic patients were classified either idiopathic primary generalized (IPGE) (n=9) or secondary generalized epilepsy (SGE) (n=31) based on the ILAE classification. The effect of epilepsy type, treatment types (monotherapy/polytherapy), daily dosages and serum levels of antiepileptic drugs, age at onset and EEG abnormalities on P300 latencies were studied. RESULTS: P300 latencies were longer in the epileptics when compared to controls (P < 0.05). Besides, our results pointed out that P300 latencies were longer in IPGE when compared to SGE (P < 0.05). No statistically significant difference was determined between ERP parameters neither in monotherapy nor in polytherapy groups (p > 0.05). Antiepileptic drug subgroups revealed variable effects on ERP latencies. CONCLUSION: We believe P300 latencies may have an important role in the evaluation of subclinical cognitive dysfunction in epileptic patients treated with antiepileptic drugs.     

托吡酯单药治疗各型癫癎的临床研究

目的观察托吡酯单药治疗成人和儿童各型癫癎的临床效果与安全性.方法用开放性试验的方法对34例癫癎患者进行了添加转单药以及首诊单药的托吡酯治疗;以加用托吡酯前3个月的月均发作频率为基准,与单用或转换单用托吡酯进入稳定期后3个月的月均发作频率进行比较,按常规计算发作减少百分比的中位值和有效率百分比.结果托吡酯无论在添加转单药还是单药的治疗上均有明显疗效,且抗谱广,可用于单纯部分性发作有或全面性发作、复杂部分性发作有或全面性发作、婴儿痉挛症,无耐药现象.14岁以上者托吡酯单药治疗的剂量明显低于添加治疗组.托吡酯的副反应以中枢神经系统最常见,但导致治疗中断的副反应尚未见到.结论托吡酯是一个广谱抗癫癎药,疗效肯定,无耐药性,无严重副反应,可用于单药治疗.     

Oxcarbazepine in infants and young children with partial seizures

In this open-label study, the safety, tolerability, and pharmacokinetics of oxcarbazepine as monotherapy or adjunctive therapy were studied in infants and young children with partial seizures. In a 30-day treatment phase, oxcarbazepine was titrated from 10 mg/kg/day to 60 mg/kg/day. Blood samples for analysis of the oxcarbazepine metabolite, the 10-monohydroxy derivative (MHD), were obtained at regular intervals. Patients completing the treatment phase entered a 6-month extension phase. Safety and tolerability were assessed throughout the study. Twenty-four patients (mean [range] age, 20.4 [2-45] months) were enrolled. Nineteen (79%) patients completed the treatment phase and, together with one patient who discontinued prematurely during the treatment phase, entered the extension phase. Thirteen of 20 (65%) patients completed the extension phase. The most common adverse events were pyrexia, ear infection, and irritability. Whether patients (n = 23) received enzyme-inducing antiepileptic drugs or not, MHD concentrations were consistent with those predicted from a linear, one-compartment, population-pharmacokinetic model based on a model previously fitted for 3- to 17-year-old children. Oxcarbazepine was safe and well tolerated in infants and young children. The pharmacokinetic profile of MHD was predicted by extension of a model based on older children.     

The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy

Purpose: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. Methods: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16–36 years; n = 247) and oldest (55–92 years; n = 155) tertiles. We analyzed one‐year retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6‐month seizure freedom. Key Findings: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One‐year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6‐month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 μg/ml). Significance: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one‐year retention is comparable. Some patients may benefit from high serum levels of LTG.     

Topiramate in children with west syndrome: a retrospective multicenter evaluation of 100 patients

The aim of this study is to investigate the efficacy and tolerability of topiramate in a large number of children with West syndrome. The authors performed a retrospective, questionnaire-based data collection in specialized epilepsy units in Germany. Patients with West syndrome and hypsarrhythmia could be included if topiramate treatment had started at an age of < or =3 years. Data of 100 patients were evaluated. Nearly all patients were severely affected and had been treated with multiple antiepileptic drugs with insufficient effect. Topiramate was introduced at a median age of 11.9 months. The median starting dosage was 1.6 mg/kg body weight per day, increased to a median maximum dosage of 12.0 mg/kg. Sixty-one patients received between 1 and 3 antiepileptic drugs in addition to topiramate. The median daily dose considered by the attending physicians to be most effective regarding seizure reduction was 10 mg/kg. A significant reduction in the number of seizures per week was achieved. A total of 17.5% of patients became free of seizures, and in 47%, the seizure frequency decreased by at least 50%. Hypsarrhythmia or status-like electroencephalography patterns remitted in 18 of 83 cases. Side effects were reported in 25% of children and included mostly sedation, loss of appetite, weight loss, and metabolic acidosis. These side effects were statistically related to the number of additional antiepileptic drugs but not to the topiramate dosage. In 17% of patients, topiramate treatment was discontinued because of side effects and in a further 4% because of worsening of seizures. In 44% of patients, treatment was continued for more than 3 months. In conclusion, the data suggest that topiramate is a useful drug in treating West syndrome. However, because of the inherent limitations of the retrospective study design, future prospective controlled studies should be performed.     

The potential for QT prolongation by antiepileptic drugs in children

Cardiac arrhythmia may be one of the major causes of sudden unexpected death in children with epilepsy. We assessed drug-induced QT prolongation to establish whether the use of antiepileptic drugs contributes to sudden unexpected death. A total of 178 children with epilepsy (93 males and 85 females, with ages ranging from 1 month to 18.9 years; mean age 7.0 +/- 4.1 years) were involved in the study. The QT intervals were manually measured and corrected using Fridericia's formula (QTFc = QT/RR(1/3)). The mean corrected QT interval (QTc) of 152 children on antiepileptic drugs during the study period was 0.40 +/- 0.03 s, and for 26 age-matched, antiepileptic drug-free control patients it was 0.40 +/- 0.03 s. The mean QTc of the children with monotherapy was 0.40 +/- 0.03 s for the valproate group (n = 42), 0.39 +/- 0.02 s for the carbamazepine/oxcarbazepine group (n = 34), and 0.40 +/- 0.02 s for the topiramate group (n = 26), respectively. There was no statistically significant difference among the groups as assessed by analysis of variance. In addition, there was no significant difference between the monotherapy group (n = 109; 0.40 +/- 0.02 s) and the polytherapy group (n = 43; 0.39 +/- 0.03 s). Major antiepileptic drugs may not precipitate prolongation of the QT interval into sudden unexpected death in children with epilepsy, however further studies are required.     

Concentration-Effect and Concentration-Toxicity Relations with Lamotrigine: A Prospective Study

Summary: This prospective study was designed to ascertain whether measurement of lamotrigine (LTG) concentrations in the epilepsy clinic could be used to predict the onset of complete seizure control or the emergence of adverse effects. LTG was initiated in doses of 25 or 50 mg daily in 69 patients with newly diagnosed or poorly controlled epilepsy and was increased monthly in 50–mg increments until the patient became seizure-free for at least 6 months or developed adverse effects that abated after a reduction in dosage. LTG and other antiepileptic drug (AED) concentrations were measured at each clinic visit but were not supplied to the investigator examining the patients. Overall, 19 patients either withdrew due to lack of efficacy or defaulted from the clinic. Of the remaining 50 patients, 32 (19 monotherapy, 13 polytherapy) became seizure-free at widely varying daily LTG doses (median 200 mg, range 25–850 mg) and concentrations (median 3.8 mg/L, range 1.4–18.7 mg/L). Likewise, the 18 patients (5 monotherapy, 13 polytherapy) who experienced intolerable side effects showed substantial variations in daily LTG doses (median 300 mg, range 100–900 mg) and concentrations (median 4.0 mg/L, range 0.4–18.5 mg/L). No useful concentration-effect or concentration-toxicity relation with LTG could be demonstrated in this study; therefore, we believe that routine therapeutic drug monitoring with this new AED is not currently indicated.