Long-term Anticonvulsant Therapy Research Articles

Serum calcium deficiency and bone mineral density in patients on long-term anti-epileptic therapy

Introduction: Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AEDs). AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment and the pathogenesis of AED-associated fractures. The fracture rate in patients with epilepsy is 2–6 times higher than the rate observed in the general population. Only a few studies in India have studied the prevalence of osteopenia in patients on long-term AEDs. Purpose of Study: The purpose of this study is to find out the prevalence of osteoporosis and osteopenia and to correlate serum calcium levels with bone mineral density (BMD) by bone densitometer in patients with epilepsy on long-term AED therapy. Materials and Methods: The study was carried out at Government Medical College and Hospital where 50 cases having epilepsy of more than or equal to 2 years duration and 50 age- and sex-matched healthy controls were taken by comparing BMD and associated parameters. Results: Mean BMD value was low in cases as compared to controls in all age groups with a significant decrease in young age group and as the duration of AED therapy increased the mean BMD decreased.

Effect of Long-term Carbamazepine Therapy on Bone Health.

Introduction:Recent research reported that prolonged use of AET is associated with changes in bone metabolism, with consequent reduction in bone mineral density (BMD) and increased risk of fractures.Objectives:Therefore, the aim of our study was to investigate the effects of carbamazepine on serum levels of 25 -hydroxyvitamin D and on biomarker of bone formation and resorption (serum levels of osteocalcin).Material and methods:We measured serum levels of 25-OHD and osteocalcin (OCLN) in normal controls (n=30) and in epilepsy patients taking carbamazepine (CBZ) (n=50) in monotherapy for a period of at least twelve months. For each participant, mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry method.Results:The average value of vitamin D in serum was significantly lower in CBZ group than in control group (Vit D 17.03+12.86 vs. 32.03+6.99, p=0.0001). The average value of osteocalcin in serum was significantly higher in CBZ group than in control group (26.06+10.78 vs. 19.64+6, 54, p=0.004).BMD value in CBZ group was significantly lower than in control group (T. score CBZ: 0.08+1.38 vs. T. score control: 0.73+ 1.13, p=0.031; Z score CBZ:-0.05+1.17 vs. Z. score control: 0.55+0.79, p=0.015).Conclusion:AEDs are associated with bone disease, as evidenced by biochemical abnormalities and decreased BMD. Patients on long-term antiepileptic therapy, especially with enzyme-inducing agents, could benefit of routine measurement of biochemical markers of bone turnover, and BMD measurement as part of osteoporosis investigation.

Effect of antiepileptic drug (valproic acid) on children growth

BackgroundEpilepsy often requires long-term antiepileptic drug therapy. Antiepileptic drugs are potentially an effective treatment for patients with epilepsy. Poor adherence is, however, very common in patients experiencing side-effects due to AEDs. The aim of this studyThe aim of this study was to evaluate the effects of AED monotherapy by VPA on alterations in serum calcium levels and statural growth and body mass index in pediatric patients newly diagnosed with epilepsy. Patients and methodsThe present study included 25 children, newly diagnosed with epilepsy and maintained on VPA monotherapy for at least one year. The serum levels of patients taking VPA were routinely monitored. Another 25 children with a history of simple febrile convulsions were included as a control group. All patients and controls were selected from Al-Azhar University hospital (new Damietta) during the period from June 2011 to June 2012. The main screening assessments included seizure frequency, vital signs, physical and neurologic examinations, medical history, and standard clinical laboratory tests (e.g., CBC, BUN, SGPT, SGOT); all these parameters were estimated at the start of the study, at 6 and 12months. Weight and height measurements were recorded at the start of the study and at 6 and 12months of continuous treatment of valproic acid. In addition serum calcium and glucose levels were obtained at the same time. ResultsThere was no significant difference between study and control groups at basal time regarding height, weight or BMI. On the other hand, there was a significant increase of weight and BMI and a decrease of height centiles at 6months and 1year; and as regards serum glucose, there was no significant difference between study and control group at basal time, while there was a significant increase in the study group in the control group at 6months and 1year. On the other hand, there was no significant difference between cases and controls as regards serum calcium at any time. ConclusionChildhood and adolescence are crucial periods in which to attain peak bone mass, and it is a crucial period for growth in general; and most patients with epilepsy are diagnosed and treated in this period, therefore, AEDs, and especially VPA, should be used with caution in pediatric patients with epilepsy.

Proximal tubular renal dysfunction on treatment with valproic acid

A 10-year-old severely disabled Italian boy on long-term treatment with valproic acid presented with tubular proteinuria, generalized aminoaciduria, normoglycemic glucosuria, and phosphate wasting. Since no other explanation for these renal tubular abnormalities was found, the treatment with valproic acid was discontinued. The abnormalities resolved within 5 months after discontinuing this anticonvulsant. We recommend screening patients on long-term anticonvulsant therapy with valproate periodically for renal tubular dysfunction, either via urinalysis or via measurement of urinary lactate/creatinine ratio, if clinical suspicion is high.

The Kleine-Levin syndrome

Why write an editorial on a rare and enigmatic disorder, which is difficult to diagnose, lacks a definite laboratory test and is hardly mentioned in the classical text books i.e., 18 sentences in Bradley’s Neurology in Clinical Practice [1], and 15 words including the two stating the name of the syndrome in Menkes Textbook of Child Neurology [2]. The average practicing pediatric neurologist is entitled to meet at least once, an adolescent with a history of episodic hypersomnia. He will most probably consider a number of possibilities in the differential diagnosis which are nicely outlined in the review on The KleineLevin syndrome (KLS) in this issue [3], and might also raise the possibility of KLS. However, when such a youngster presents for the first time, the diagnostic dilemma is much more difficult. In the majority of cases studies such as lumbar puncture, electroencephalography, brain imaging and urinary toxicology screen will be performed, a psychiatry consult will be obtained and the boy or girl will be admitted to the hospital. In many, a provisional diagnosis of “flu” or “encephalitis” will be reached and in some with non-specific electroencephalographic changes the diagnosis of epilepsy will be offered followed by recommendation for long-term anticonvulsant therapy, especially on a repeated event. We have been encountered with patients in whom drug abuse was suspected with consequent legal implications. Rarely the hypersexual behavior may be inter-

Vitamin D levels in epileptic children on long-term anticonvulsant therapy

Background Long-term anticonvulsant therapy, especially with enzyme inducers, has been associated with low 25-hydroxyvitamin D [25(OH)D] levels and high prevalence of vitamin D deficiency. However, there have been inconsistent results in studies on the effect of long-term, non-enzyme inducer anticonvulsant use on vitamin D levels.Objective To compare 25(OH)D levels in epileptic children on long-term anticonvulsant therapy and non-epileptic children. We also assessed for factors potentially associated with vitamin D deficiency/insufficiency in epileptic children.Methods This cross-sectional study was conducted at two pediatric neurology outpatient clinics in Jakarta, from March to June 2013. Subjects in the case group were epileptic children, aged 6-11 years who had used valproic acid, carbamazepine, phenobarbital, phenytoin, or oxcarbazepine, as a single or combination therapy, for at least 1 year. Control subjects were non-epileptic, had not consumed anticonvulsants, and were matched for age and gender to the case group. All subjects’ 25(OH)D levels were measured by enzyme immunoassay.Results There were 31 epileptic children and 31 non-epileptic control children. Their mean age was 9.1 (SD 1.8) years. Most subjects in the case group were treated with valproic acid (25/31), administered as a monotherapy (21/31). The mean duration of anticonvulsant consumption was 41.9 (SD 20) months. The mean 25(OH)D level of the epileptic group was 41.1 (SD 16) ng/mL, lower than the control group with a mean difference of 9.7 (95%CI 1.6 to 17.9) ng/mL. No vitamin D deficiency was found in this study. The prevalence of vitamin D insufficiency in the epileptic group was higher than in the control group (12/31 vs. 4/31; P=0.020). No identified risk factors were associated with low 25(OH)D levels in epileptic children.Conclusion Vitamin D levels in epileptic children with long-term anticonvulsant therapy are lower than that of non-epileptic children, but none had vitamin D deficiency.

Vitamin D levels in epileptic children on long-term anticonvulsant therapy

Background Long-term anticonvulsant therapy, especially with enzyme inducers, has been associated with low 25-hydroxyvitamin D [25(OH)D] levels and high prevalence of vitamin D deficiency. However, there have been inconsistent results in studies on the effect of long-term, non-enzyme inducer anticonvulsant use on vitamin D levels.Objective To compare 25(OH)D levels in epileptic children on long-term anticonvulsant therapy and non-epileptic children. We also assessed for factors potentially associated with vitamin D deficiency/insufficiency in epileptic children.Methods This cross-sectional study was conducted at two pediatric neurology outpatient clinics in Jakarta, from March to June 2013. Subjects in the case group were epileptic children, aged 6-11 years who had used valproic acid, carbamazepine, phenobarbital, phenytoin, or oxcarbazepine, as a single or combination therapy, for at least 1 year. Control subjects were non-epileptic, had not consumed anticonvulsants, and were matched for age and gender to the case group. All subjects’ 25(OH)D levels were measured by enzyme immunoassay.Results There were 31 epileptic children and 31 non-epileptic control children. Their mean age was 9.1 (SD 1.8) years. Most subjects in the case group were treated with valproic acid (25/31), administered as a monotherapy (21/31). The mean duration of anticonvulsant consumption was 41.9 (SD 20) months. The mean 25(OH)D level of the epileptic group was 41.1 (SD 16) ng/mL, lower than the control group with a mean difference of 9.7 (95%CI 1.6 to 17.9) ng/mL. No vitamin D deficiency was found in this study. The prevalence of vitamin D insufficiency in the epileptic group was higher than in the control group (12/31 vs. 4/31; P=0.020). No identified risk factors were associated with low 25(OH)D levels in epileptic children.Conclusion Vitamin D levels in epileptic children with long-term anticonvulsant therapy are lower than that of non-epileptic children, but none had vitamin D deficiency.

Levetiracetam – epilepsy treatment, pharmacokinetics, mechanism of action, interaction and toxicity

Kozlowski Piotr, Czepinska-Cwik Wioleta, Kozlowska Magdalena, Kozlowska Karolina. Levetiracetam – epilepsy treatment, pharmacokinetics, mechanism of action, interaction and toxicity. Journal of Education, Health and Sport. 2015;5(4):143-150. ISSN 2391-8306. DOI: 10.5281/zenodo.16694 http://ojs.ukw.edu.pl/index.php/johs/article/view/2015%3B5%284%29%3A143-150 https://pbn.nauka.gov.pl/works/553762 http://dx.doi.org/10.5281/zenodo.16694 Formerly Journal of Health Sciences. ISSN 1429-9623 / 2300-665X. Archives 2011 – 2014 http://journal.rsw.edu.pl/index.php/JHS/issue/archive Deklaracja. Specyfika i zawartośc merytoryczna czasopisma nie ulega zmianie. Zgodnie z informacją MNiSW z dnia 2 czerwca 2014 r., ze w roku 2014 nie bedzie przeprowadzana ocena czasopism naukowych; czasopismo o zmienionym tytule otrzymuje tyle samo punktow co na wykazie czasopism naukowych z dnia 31 grudnia 2014 r. The journal has had 5 points in Ministry of Science and Higher Education of Poland parametric evaluation. Part B item 1089. (31.12.2014). © The Author (s) 2015; This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland and Radom University in Radom, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 20.01.2015. Revised 27.03.2015. Accepted: 27.03.2015. LEVETIRACETAM – EPILEPSY TREATMENT, PHARMACOKINETICS, MECHANISM OF ACTION, INTERACTION AND TOXICITY Piotr Kozlowski 1 , Wioleta Czepinska-Cwik 2 , Magdalena Kozlowska 3 , Karolina Kozlowska 4 1 Katedra i Zaklad Anatomii Prawidlowej Czlowieka, UM w Lublinie 2 Klinika Chorob Wewnetrznych, 1 Wojskowy Szpital Kliniczny z Polikliniką w Lublinie 3 Katedra i Zaklad Farmakologii doświadczalnej i Klinicznej, UM w Lublinie 4 Instytut Filologii Angielskiej, KUL Uniwersytet Medyczny w Lublinie ul. W. Chodźki 1, 20-093 Lublin e-mail: piotr7176@gmail.com Abstract Epilepsy is a common chronic neurological disorder that requires a long-term antiepileptic drug therapy. Epilepsy affects approximately 1% of the world’s population, so about 50 million people worldwide have epilepsy. It more likely occurs among children and people over the age of 65. This chronic condition is characterized by recurrent, unprovoked epileptic seizures. Although there are many innovative methods of seizure control, such as neurosurgery, vagal nerve stimulations (VNS) and ketogenic diet, pharmacology is most forceful method of epilepsy treatment. Unfortunately, anticonvulsant drugs are not always effective; the number of non-responding patients is higher than 30% [2,25,29,31]. Levetiracetam (LEV) is one of the newest AEDs, marketed worldwide only since 2000 [29]. This novel antiepileptic drug has a unique and non-standard mechanism of action. The structure of LEV is similar to the prototypical nootropic drug piracetam. Its novel mechanism of action is connected with the synaptic vesicle protein SV2A in the brain. The elimination plasma half-live of LEV is approximately from 6 to 8 hours among adults. About 66% of the drug is excreted unchanged and 27% as inactive hydrolysis product [12]. LEV is mainly removed by the kidneys so that elimination parallels kidney function (renal clearance: 0,6 ml/min/kg) [3,12,32]. LEV was found to be well tolerated and effective in all types of seizures in adults and children [18]. It can be also used in combinations with other AEDs. The drug may also be useful in treatment of Lennox-Gastaut syndrome [9]. This article reviews available published data on LEV in the treatment of adults and children, including information about LEV`s pharmacokinetics, chemistry, mechanism of action, interactions and toxicity. Key words: levetiracetam, antiepileptic drugs, seizures, epilepsy.

Acute symptomatic epileptic seizures and status epilepticus

Acute symptomatic seizures (ASS) are the seizures of different etiology that occur in close temporary relationship to acute damage of the central nervous system arising simultaneously due to metabolic, toxic, infectious and inflammatory factors and structural brain damage. At the time of its origin, ASS is often not distinguished from epileptic seizures in the clinical and electrophysiological parameters, although represent a fundamentally different state from the point of view of pathogenesis, therapy and prognosis. Tactics in the ASS and symptomatic epileptic status of any nature provides for the immediate carrying out differential diagnosis and differential treatment. Treatment of ASS includes two aspects: reduction in ictal activity (seizures) and prevention of future development of seizures through the elimination or correction of physiological trigger of the attacks and the decision to conduct a long-term antiepileptic drug therapy if the risk of seizures is saved.

Epilepsy and outcome in FOXG1-related disorders.

FOXG1-related disorders are associated with severe intellectual disability, absent speech with autistic features, and epilepsy. Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements. Duplications of 14q12 often present with infantile spasms, and have subsequent intellectual disability with autistic features. Long-term epilepsy outcome and response to treatment have not been studied systematically in a well-described cohort of subjects with FOXG1-related disorders. We report on the epilepsy features and developmental outcome of 23 new subjects with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications. Subjects had either chromosomal microarray or FOXG1 gene sequencing performed as part of routine clinical care. Development and epilepsy follow-up data were collected from medical records from treating neurologists and through telephone parental interviews using standardized questionnaires. Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic mutations (p = 0.0002). All of the duplication FOXG1 children with infantile spasms responded to hormonal therapy, and only one required long-term antiepileptic therapy. In contrast, more children with deletions/intragenic mutations required antiepileptic drugs on follow-up (p < 0.0005). All subjects with FOXG1-related disorders had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. All had impaired verbal language and social contact, and three duplication subjects were formally diagnosed with autism. Subjects with deletion/intragenic mutations, however, had significantly worse ambulation (p = 0.04) and functional hand use (p < 0.0005). Epilepsy and developmental outcome characteristics allow clinicians to distinguish among the FOXG1-related disorders. Further genotype-phenotype studies of FOXG1 may help to elucidate why children develop different forms of developmental epilepsy.

Probable drug-induced liver injury associated with aliskiren: Case report and review of adverse event reports from pharmacovigilance databases

A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported. A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis 1 month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient's AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILI-specific causality assessment instrument, it was determined that aliskiren use was the probable cause of the patient's liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected aliskiren hepatotoxicity, including 6 reports of liver failure and 12 reports of deaths. Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Improvement in AST and ALT concentrations was observed shortly after the drug was discontinued.

Derangements in bone mineral parameters and bone mineral density in south Indian subjects on antiepileptic medications.

Background:Although there are reports describing the association of alternations of bone and mineral metabolism in epileptic patients with long-term anticonvulsant therapy, there are only limited Indian studies which have looked at this aspect.Objectives:This study was done to compare the prevalence of changes in bone mineral parameters and bone mineral density (BMD) in ambulant individuals on long-term anticonvulsant therapy with age- and body mass index (BMI)-matched healthy controls.Materials and Methods:There were 55 men (on medications for more than 6 months) and age- and BMI-matched 53 controls. Drug history, dietary calcium intake (DCI), and duration of sunlight exposure were recorded. Bone mineral parameters and BMD were measured.Results:The control group had a significantly higher daily DCI with mean ± SD of 396 ± 91 mg versus 326 ± 101 mg (P = 0.007) and more sunlight exposure of 234 ± 81 vs 167 ± 69 min (P = 0.05). BMD at the femoral neck was significantly lower in cases (0.783 ± 0.105 g/cm2) when compared to controls (0.819 ± 0.114 g/cm2). Majority of the patients (61%) had low femoral neck BMD (P = 0.04). There was no significant difference in the proportion of subjects with vitamin D deficiency (<20 ng/mL) between cases (n = 32) and controls (n = 37) (P = 0.234).Conclusions:Vitamin D deficiency was seen in both the groups in equal proportions, highlighting the existence of a high prevalence of this problem in India. Low femoral neck BMD found in cases may stress the need for supplementing calcium and treating vitamin D deficiency in this specific group. However, the benefit of such intervention has to be studied in a larger proportion of epileptic patients.

Unusual presentation of pseudoaneurysm with trochanteric fracture femur with associated long-term antiepileptic therapy.

Arterial injury following impalement due to a trochanteric hip fracture-fragment per se has been documented rarely. We report a case of pseudoaneurysm of profunda femoris artery at the first perforator branch in a 48-year-old male, with trochanteric hip fracture following a fall during an epileptic episode. Persistent recalcitrant pain, globular swelling in the groin, unexplained drop in the haemoglobin level, and color doppler ultrasonography findings were salient features to the diagnosis. Additionally, we collected all reported cases of pseudoaneurysm associated with hip fractures. We reviewed the literature regarding the incidence, treatment, and prognosis for the same. Acute vascular injury was probably caused by the spikes of fractured lesser trochanter which was found to be displaced superomedially. All trochanteric fractures especially those with displaced lesser trochanter fragment should be closely watched for the possibility of vascular injury. Early diagnosis and treatment in a staged manner can prevent the catastrophic vascular event and hence the limb.

Pediatric Seizures

On the basis of strong evidence, treatment is highly dependent on the seizure semiology results, electroencephalography (EEG) findings, and origin. • On the basis of moderate evidence and consensus, vigorous use of video EEG recordings and home video cameras should be used to delineate the epileptic syndromes. • On the basis of strong evidence, pediatric epilepsy syndromes have common comorbidities. As a consensus, some pediatric epilepsy centers consider referral to a neuropsychologist to be first-line care in these patients. • On the basis of strong evidence and consensus, antiepileptic drug therapy has its own complications and should be discontinued after an appropriate treatment course. • On the basis of moderate evidence and consensus, uncontrolled seizures put patients at risk for significant morbidity and mortality.

Long-term anti-epileptic drug therapy and metabolic bone disase in children

Epilepsy is a common chronic brain dysfunction in children. Studies have showed that antiepi- leptic drugs （AED） affect the hydroxylation of vitamin D in liver and kidney and inhibit the calcification of bone, mainly by up-regulating cytochrome oxidase P450 and promoting the resolution of vitamin D, and then increasing serum parathyroid hormone compensatory. Long-term use can cause children metabolic bone disease occurrence, clinical manifestations include bone pain, short stature, rickets, teeth agenesis, fracture, etc. AED firstly affect the hormones related to bone metabolism in vivo,so that the present researches focus on biochemical tests and meas- urement of sclerotin and bone density. In the children＇s long-term use of antiepileptic drug treatment at the same time,the application of Vitamin D,calcium and exercise can prevent the occurrence of metabolic bone disease. Key words: Antiepileptic drug; Metabolic bone disease in children

Bone mineral density in children with long-term antiepileptic therapy

Vitamin D active metabolites deficit that is al: tered by negative calcium and phosphorus balance is a potential complication during long-term antiepileptic drug therapy. The aim of this study was to examine lumbar bone mineral density (BMD) in epileptic children receiving antiepileptic drug therapy longer than one year. The examined sample consisted of 34 epileptic children, 18 male and 16 female, aged 6-12 (9.77+/-2.01) years, treated with carbamazepine, valproate, phenobarbital, lamotrigine or their combination without vitamin D supplementation. The lumbar spine BMD (L1-L4) was estimated by a Lunar densitometer and obtained results were compared with results of 35 matched population of healthy children from the control group. Lumbar BMD Z-score was significantly lower in female patients treated with antiepileptic therapy compared with those in the control group (-1.048+/-1.35 vs. -0.399+/-0.518; p=0.03). Bone mineral density Z-score decrease of both gender groups receiving antiepileptic polytherapy was significantly lower compared to the control group (-1.153+/-0.938 vs. -0.043+/-0.815; p=0.007). Therapy duration had no influence on the lumbar BMD level decrease either in boys (rxy=0.33; p=0.174) or in girls (rxy=0.02; p=0.935) treated with antlepileptic therapy. Our results have indicated that antiepileptic drug therapy usage longer than one year can have adverse affects on the lumbar spine BMD (L1-L4) in epileptic children, and that prophylactic vitamin D supplementation is also necessary in these patients.

Predisposing Factors of Posterior Reversible Encephalopathy Syndrome in Acute Childhood Leukemia

A retrospective chart review was performed on 19 patients aged <18 years who developed posterior reversible encephalopathy syndrome as a complication during treatment of acute childhood leukemia. Posterior reversible encephalopathy syndrome was most often observed during acute lymphoblastic leukemia induction chemotherapy (n = 9, 47.4%) and after hematopoietic stem cell transplantation (n = 8, 42.1%). Among eight patients with the complication of posterior reversible encephalopathy syndrome after hematopoietic stem cell transplantation, five (62.5%) had a history of hypertension. In contrast, among 11 patients with the complication of posterior reversible encephalopathy syndrome without hematopoietic stem cell transplantation, only one (9.1%) had a history of hypertension. Moreover, unlike other leukemia induction chemotherapy, posterior reversible encephalopathy syndrome developed only in patients who received acute lymphoblastic leukemia induction chemotherapy. Posterior reversible encephalopathy syndrome patients required long-term anticonvulsant therapy (n = 9, 50.0%) and manifested intractable seizures (n = 3, 16.7%). Sequelae were evident in long-term follow-up magnetic resonance images (n = 5, 26.3%). Acute lymphoblastic leukemia chemotherapy regimens apparently comprised the main predisposing factors for posterior reversible encephalopathy syndrome complicated during induction chemotherapy, compared with hypertension and immunosuppressive agents after hematopoietic stem cell transplantation.

Long-term anticonvulsant therapy leads to low bone mineral density--evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells.

Anticonvulsant therapy causes changes in calcium and bone metabolism and may lead to decreased bone mass with the risk of osteoporotic fractures. The two widely used antiepileptic drugs phenytoin and carbamazepine are recognized to have direct effects on bone cells. The aim of our study was to measure the influence of long-term treatment with antiepileptic drugs on bone mineral density (BMD) and to look on direct effects of carbamazepine and phenytoin on human osteoblast-like cells. BMD was measured by dual-energy X-ray absorptiometry. Markers of bone formation and bone resorption were determined in serum and urine. Data of 59 patients were compared to 55 age and sex matched controls. Direct effects of phenytoin and carbamazepine on human osteoblast-like cells were investigated in experimental studies. BMD in the lumbar spine region (L2 through L4) was significantly lower in the patient group as compared to controls (p < 0.0004). At femoral sites BMD was lower in patients, but this difference did not reach statistical significance. The decrease in BMD at both sites was dependent on the duration of therapy. Excretion of pyridinoline crosslinks was markedly increased in the patients. 25-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 were significantly decreased in patients. Proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Both, phenytoin and carbamazepine inhibited cell growth at concentrations equivalent to therapeutic doses for the treatment of epileptic diseases. Our clinical and experimental data indicate that long-term treatment with anticonvulsant drugs leads to a lower BMD. The experimentally observed decrease in bone cell proliferation might be clinically associated with impaired new bone formation. Beside alterations in calcium and vitamin D homeostasis leading to osteomalazia, direct effects of anticonvulsant drugs on bone cells may contribute to the damaging effects on the skeletal system.

Serum Thyroid Hormone Levels in Epileptic Children Receiving Anticonvulsive Drugs

How to Cite this Article: Mahyar A, Ayazi P, Dalirani R, Hosseini SM, Daneshi Kohan MM. Serum Thyroid Hormone Levels in Epileptic Children Receiving AnticonvulsiveDrugs. Iranian Journal of Child Neurology 2011;5(4):21-24.ObjectiveThe aim of this study was to investigate serum thyroid hormone levels in epileptic children receiving anticonvulsive drugs.Materials & MethodsIn this case- control study, 30 epileptic children who were receiving anticonvulsive drugs (case group) were compared with 30 healthy children (control group). This study was carried out in the Qazvin Children's Hospital (Qazvin, Iran) from October to December 2007. Both groups were matched for age and sex. Thyroid hormone levels were measured using a radioimmunoassay and immunoradiometric assay. Data were analyzed using Chi-square and Student's t-tests.ResultsThe mean serum T3 and T4 levels in the case group were 2.36 ± 0.73 nmol/L and 95.96 ± 27.01 nmol/L, respectively, and the corresponding values in the control group were 1.88 ± 0.93 nmol/L and 147.46 ± 35.77 nmol/L, respectively. The mean serum thyroid-stimulating hormone (TSH) levels in the case and control groups were 2.73±0.73 mIU/mL and 2.49 ± 2.17mIU/mL, respectively.ConclusionThis study revealed that long-term consumption of anticonvulsive drugs resulted in a decline in serum T4 levels and an increase in serum T3 levels, but had no effect on TSH levels. 1. Johnston M. Neurodegenerative disorders of childhood;Spingolipidoses. Nelson textbook of pediatrics, 17th edPhiladelphia: Saunders; 2004.P.2031-2.2. Sankar R, Koh S, Wu J, Menkes J. Paroxysmal disorders.In(eds): Menkes JH, Sarnat HB, Maria BL. ChildNeurology; 2006.P.7:877.3. Shiva S, Ashrafi M, Mostafavi F, Abasi F, RahbariA, Shabanian R. Effects of anticonvulsant drugs onthyroid function tests. Iranian Journal of pediatrics2003;13(02):101.4. Kimura M, Yoshino K, Suzuki N, Maeoka Y. Effect ofantiepileptic drugs on thyroid function. Psychiatry andclinical neurosciences. 1995;49(4):227-9.5. Eris Pural J, Delrio-Garma M, Delrio - Castro – GagoM. Long Term treatment of children with epilepsy withvalprovats or carbamazepin, may cause subclinicalhypothyroidism. Epilepsia 1999;40(12):1961.6. Isojarvi JIT, Turkka J, Pakarinen AJ, Kotila M,Rattya J, Myllyla VV. Thyroid function in men takingcarbamazepine, oxcarbazepine, or valproate for epilepsy.Epilepsia 2001;42(7):930-4.7. Vainionpaa LK, Mikkonen K, Rattya J, Knip M,Pakarinen AJ, Myllyla VV, et al. Thyroid function ingirls with epilepsy with carbamazepine, oxcarbazepine,or valproate monotherapy and after withdrawal ofmedication. Epilepsia 2004;45(3):197-203.8. Verrotti A, Basciani F, Morresi S, Morgese G, ChiarelliF. Thyroid hormones in epileptic children receivingcarbamazepine and valproic acid. Pediatric neurology2001;25(1):43-6.9. Kantrowitz L, Peterson M, Trepanier L, Melian C,Nichols R. Serum total thyroxine, total triiodothyronine,free thyroxine, and thyrotropin concentrations in epilepticdogs treated with anticonvulsants. Journal of the AmericanVeterinary Medical Association 1999;214(12):1804.10. Schroder-van der Elst J, Van der Heide D, Van der BentC, Kaptein E, Visser T, DiStefano J. Effects of 5, 5 -diphenylhydantoin on the thyroid status in rats. Europeanjournal of endocrinology 1996;134(2):221.11. Schonberger W, Grimm W, Schonberger G, SinterhaufK, Scheidt E, Ziegler R. [The influence of primidone onthyroid function (author’s transl)]. Dtsch Med Wochenschr1979;104(25):915-7.12. Tiihonen M, Liewendahl K, Waltimo O, Ojala M,Valimaki M. Thyroid status of patients receiving longtermanticonvulsant therapy assessed by peripheralparameters: a placebo-controlled thyroxine therapy trial.Epilepsia 1995;36(11):1118-25.13. Benedetti MS, Whomsley R, Baltes E, Tonner F. Alterationof thyroid hormone homeostasis by antiepileptic drugsin humans: involvement of glucuronosyltransferaseinduction. Eur J Clin Pharmacol 2005;61(12):863-72.

Effects of long‐term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Long-term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long-term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme-inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme-inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C-reactive protein (hs-CRP), or thiobarbituric acid reactive substances (TBARS). Long-term monotherapy with older-generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme-inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs-CRP. On the other hand, patients on enzyme-inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long-term LTG monotherapy. Patients with epilepsy who were receiving long-term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long-term AED therapy, particularly in aged and high-risk individuals.