Hypohidrosis Related to the Administration of Topiramate to Children

PURPOSE: Topiramate (TPM) is an antiepileptic agent, first licensed in the United Kingdom in 1994, that is used in the treatment of patients with refractory seizure disorders. TPM is a monosaccharide d-fructose derivate, with sulfamate function, and so far, few adverse side effects have been reported. METHODS: We describe three patients with epilepsy who were treated with TPM and developed hypohidrosis, heat and exercise intolerance, as well as fever. The sudomotor function was assessed after peripheral stimulation with pilocarpine iontophoresis. RESULTS: Sweat response was reduced in all three patients. Signs and symptoms ceased after drug suppression. CONCLUSIONS: This side effect associated with TPM, which has not been described previously, can be clinically significant during heat stress and exercise challenge.     

丙戊酸和托吡酯对癫(癎)患儿游离肉毒碱的影响

目的探讨丙戊酸(VPA)和托吡酯(TPM)对癫癎患儿游离肉毒碱的影响。方法35例癫癎患儿,年龄6～8岁,男20例,女15例,其中12例予VPA单药治疗,11例予TPM单药治疗,12例予VPA及TPM联合治疗6～8个月。15例健康儿童作为正常对照组。测定血浆游离肉毒碱的浓度。结果VPA组血浆游离肉毒碱的浓度明显低于对照组及TPM组,VPA-plus- TPM组与VPA组比较差异无显著性,TPM组与对照组比较差异无显著性。结论VPA可降低癫癎患儿血浆游离肉毒碱水平,而TPM对血浆游离肉毒碱无明显影响。     

Topiramate enhances the risk of valproate-associated side effects in three children

PURPOSE: We present three children with severe therapy-refractory epilepsy who tolerated valproate (VPA) well in various combinations with other antiepileptic drugs (AEDs) but developed typical VPA side effects in combination with topiramate (TPM). METHODS: The clinical symptoms began with apathy in all three children; two of them also had hypothermia. Furthermore all children had elevated blood ammonia levels, one child in combination with increased liver transaminases and one with thrombocytopenia. RESULTS: All children recovered completely after discontinuation of VPA or TPM. CONCLUSIONS: TPM seems likely to enhance the risk of side effects usually attributed to VPA and not described in TPM monotherapy. Our case reports suggest that possible adverse effects of VPA should be given particular attention when VPA is combined with TPM.     

Comparison of the Steady-State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions. Methods: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy. Results: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for 2 weeks without VPA. TPM plasma peak concentration (C_max) and area under the concentration-versus-time curve during a 12–h dosing interval (AUC_0–12) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 ± 4.6 and 11.6 ± 3.2 ml/min during TPM monotherapy and were 29.8 ± 4.2 and 12.4 ± 2.7 ml/min during VPA concomitant therapy. VPA AUC_(0–12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 ± 4.1 ml/min during monotherapy and was 13.8 ± 4.0,14.1 ± 3.9, and 14.5 ± 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued. Conclusions: Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.     

Fanconi syndrome caused by antiepileptic therapy with valproic Acid

PURPOSE: Valproic acid (VPA) is commonly used as an antiepileptic drug (AED). Regular screening for renal side effects is uncommon. Fanconi syndrome, a generalized dysfunction of renal proximal tubular cells, occurs with some inborn errors of metabolism. In addition, it can be acquired by exposure to several toxic substances. We report a case of Fanconi syndrome after long-term therapy with VPA. METHODS: An 8-year-old severely disabled and developmentally retarded boy with epilepsy was treated with VPA over a period of 7 years. He was hospitalized after a status epilepticus with laboratory findings suggesting a Fanconi syndrome. A PubMed-based worldwide review of the literature revealed that Fanconi syndrome is a rare side effect in children during long-term VPA treatment. We analyzed all 10 previously published cases by comparing age, underlying diseases, medication, and outcome. RESULTS: Examination revealed metabolic acidosis suggestive of renal tubular malfunction. Based on typical clinical and laboratory findings, an acquired Fanconi syndrome was diagnosed. This was treated with large doses of sodium bicarbonate. After discontinuation of VPA, renal function completely normalized within 2 months. CONCLUSIONS: Fanconi syndrome appears to be a rare but severe consequence of long-term VPA therapy. Therefore patients treated with VPA should be checked regularly for the possible development of VPA-induced Fanconi syndrome.     

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.
Method: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.
Results: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.
Conclusion: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.     

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.     

Oral rapid loading of valproic acid—An alternative to the usual saturation scheme?

Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies. Due to its broad field of application and its good compatibility, VPA is one of the most frequently prescribed antiepileptic drugs (AED) worldwide. Previous studies have examined the safety and tolerability of rapid intravenous-loaded VPA in the treatment of epilepsy and status epilepticus, but rapid oral loading has not been evaluated in paediatrics systematically in the past. The standard titration scheme takes 10-14 days, some physicians prefer a slower titration of up to 4 weeks. At many institutes, especially children are treated as inpatients until the desired dosage is reached. This causes high costs to the health system and is very inconvenient for the families affected. We have developed a new loading scheme to achieve a therapeutic serum level on the third day of treatment, in order to minimize the time between the beginning of the therapy and reaching the therapeutic serum level. This is the first attempt at doing this with VPA for children with epilepsy.     

Transient hypohidrosis induced by topiramate

PURPOSE: Hypohidrosis during topiramate (TPM) treatment was recently reported in children. We describe an adult epilepsy patient who developed inability to sweat as well as heat intolerance while undergoing treatment with TPM. METHODS: To detect the site of the sweat block, patient underwent examination of sweat gland function, cardiovascular autonomic test, and body temperature rhythm determination. RESULTS: During TPM treatment, cardiovascular autonomic function and circadian rhythm of body core temperature were normal, whereas thermoregulatory sweat test (TST) showed anhydrosis. This adverse drug effect was quickly resolved after drug discontinuation. CONCLUSIONS: Because of normal cardiovascular autonomic function and central and peripheral thermoregulatory mechanisms, we hypothesize that hypohidrosis during TPM treatment could be due to a carbonic anhydrases (CA) block at the level of sweat gland.     

丙戊酸诱导胶质瘤细胞自噬及其机制研究

目的对丙戊酸诱导胶质瘤细胞发生自噬性死亡的过程进行观察,并初步探讨其可能的机制。方法丙戊酸处理人脑胶质瘤细胞系U87、T98G和SF295,台盼蓝染色检测细胞活性并计算细胞存活率;流式细胞仪测定细胞周期,透射电子显微镜和荧光测定仪观察细胞超微结构及自噬水平,West-ern blotting检测经丙戊酸处理后细胞内LC3-Ⅱ、Beclin-1、p-Akt和p-p70S6K等蛋白质的表达水平。结果经不同浓度丙戊酸处理后,人脑胶质瘤细胞系U87、T98G和SF295细胞活性明显受到抑制,其胶质瘤细胞半数抑制浓度分别为(2.45±0.32)、(4.78±0.62)和(6.62±0.95)mmol/L,其中丙戊酸对人脑胶质瘤细胞系U87具有较明显的杀伤作用(P<0.05)。透射电子显微镜观察可见人脑胶质瘤细胞系U87细胞胞质内有大量自噬体和自噬溶酶体,其自噬水平随丙戊酸浓度的升高而逐渐增强。经丙戊酸处理后,人脑胶质瘤细胞系U87细胞自噬相关蛋白LC3-Ⅱ和Beclin-1表达水平明显升高,而p-Akt和p-p70S6K表达水平明显降低。结论丙戊酸可诱导胶质瘤细胞发生自噬,其诱导胶质瘤细胞发生自噬的机制可能与阻断Akt信号转导通路有关。     

A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.     

Drug Interaction Profile of Topiramate

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy-tochrome P450 isoforms show an effect of TPM only on the CYP2C_meph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.     

Lamotrigine–valproic acid combination therapy for medically refractory epilepsy

Purpose:   A retrospective study of lamotrigine (LTG)–valproic acid (VPA) combination therapy in medically refractory epilepsy.
Methods:   Patients were identified with an adult epilepsy clinic database and were included if they had been on LTG–VPA combination therapy for at least 6 months. Patient demographics and information about epilepsy type, severity, and degree of medical intractability were obtained by retrospective chart review. The primary outcome measure was change in baseline seizure frequency, and patients were stratified into three groups: (i) seizure-free, (ii) improved (at least 50% reduction in baseline seizure frequency), and (iii) not improved.
Results:   Thirty-five patients met all inclusion–exclusion criteria. Epilepsy type was generalized in 25 patients (71%) and partial in 10 patients (29%). Before LTG–VPA treatment, 27 of 35 (77%) experienced disabling seizures on a monthly basis, and 17 of 35 (49%) of patients had at least one disabling seizure per week. Patients had previously failed treatment with a median of five antiepileptic drugs (AEDs), alone or in combination. With LTG–VPA therapy, 18 (51.4%) remained completely seizure-free, four (11.4%) were improved, and 13 (37.1%) were unimproved. Median follow-up was 42 months. Of the 22 patients who improved, 11 had previously failed LTG and VPA monotherapy. There was no significant difference between improved and unimproved patients with respect to demographics, epilepsy type or severity, or number of previously failed AEDs.
Discussion:   The combination of LTG and VPA should be considered in patients with medically refractory epilepsy. The effectiveness of this combination appears to be independent of epilepsy type or patient demographics.     

Safety of Topiramate: Adverse Events and Relationships to Dosing

Summary: To date, 1,809 individuals have been exposed to topiramate (TPM), primarily adults with partial-onset seizures. Of this total, 665 patients have been treated for more than 1 year, 177 for more than 3 years, and 67 for more than 5 years. The profile of treatment-emergent adverse reactions (TEAEs) observed with TPM at various dosages is based primarily on data from five double-blind, placebo-controlled trials in which 360 patients received TPM at target doses of 200–1,000 mg/day. Long-term safety is assessed on the basis of 1,001 patients treated with TPM in controlled and open trials for up to 5.3 years. Most of the commonly reported TEAEs were related to the central nervous system and were observed with greater frequency at dosages above the 200–600-mg/day range found to be optimal in dose ranging trials. Nephro-lithiasis not requiring surgery was seen in 1.5% of patients, and mild, dose-related weight loss was associated with TPM therapy. No clinically significant treatment-related abnormalities were observed in clinical laboratory parameters or in neurologic, electrocardiographic, oph-thalmologic, or audiologic tests.     

Valproate-induced hyperammonaemia in two epileptic identical twins

Summary The cases of two epileptic identical twins are described, one of whom had presented an episode of valproate (VPA)-induced stupor associated with very high blood ammonia (NH₃) concentrations. Both twins showed a similar marked increase of venous NH₃ concentrations after the administration of a single loading dose of VPA (800 mg).     

A study of the action of valproic acid on the kindling effect.

The effect of an antiepileptic drug, valproic acid (VPA), on an experimental form of epilepsy, the kindling phenomenon, is described. In cat, 50 mg/kg i.p. per day is sufficient to block the progressive establishment of generalized seizures produced normally by repetitive electrical stimulation of the amygdala. However, a focal afterdischarge persists during the entire treatment. Higher doses (75-150 mg/kg) are necessary to protect the animal against the generalized tonic-clonic seizure when the kindling phenomenon is established. These effects and the action of barbiturates, which was also tested, seem to attribute to VPA a complex role in the mechanism of this action.     

Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

Effects of valproic acid on sleep in children with epilepsy

Purpose:   Parents frequently report increased sleep duration in their children during treatment with valproic acid (VPA). We assessed sleep duration and sleep behavior before and after tapering VPA in children treated for more than 6 months.
Methods:   Sleep variables were assessed by questionnaire, diary, and actigraphy (for 7 consecutive days and nights) before and 8–12 weeks after termination of VPA.
Results:   Forty-six children (age range 1.7–17.4 years) completed the study. The questionnaire data showed no significant difference in bed and wake time, duration of sleep, and time to fall asleep before and after ending VPA treatment, although some qualitative measures on daytime sleepiness improved after tapering VPA. The actigraphy data revealed that the average sleep amount without VPA was reduced in 33 children (9 of them >30 min) and longer in 13 children (1 of them >30 min). The mean Assumed Sleep Time per Day decreased by 15.2 min or 9.5 min when the physiologic decrease of sleep duration within 0.3 years was considered. Also mean Actual Sleep Time per Day was significantly reduced after VPA termination (−15.2min; after correction −10.7 min). The reduction was only significant in children older than age 6 years.
Discussion:   Termination of VPA after long-term treatment leads to a significant reduction of sleep duration in children older than 6 years of age. The change was small in the majority, but considerable in a subgroup of children.     

Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.