Chronic Anticonvulsant Therapy Research Articles

Calcium Homeostasis Abnormalities in Patients Taking Chronic Anticonvulsants Therapy – A Cross-sectional Study

Introduction: Epilepsy is a well-known disease entity that is responsible for a significant amount of morbidity. The purpose of this research is to determine the frequency of calcium homeostasis abnormalities in patients who are taking chronic anticonvulsant medication and to analyze the levels of Vitamin D in the serum of patients who are taking chronic anticonvulsant medication. Materials and Methods: The SVRRGGH general medicine department in Tirupati conducted this cross-sectional single-centered prevalence study. The study included outpatients, inpatients, and acute medical care (AMC) patients. After applying the inclusion and exclusion criteria, the study randomly selected 100 seizure disorder patients from the SVRRGH in Tirupati. Epilepsy patients who participated in the study were asked about medication, compliance, and seizure control. Anticonvulsant usage and duration were recorded. Serum calcium, Vitamin D, alkaline phosphatase (ALP), and parathormone were measured. Hypoalbuminemia caused calcium adjustments. Liver and renal function tests ruled out other major causes of hypovitaminosis D. Results: In this study, 36% were hypocalcemic and 64% were normocalcemic. There was a significant association between a number of drugs, duration of up to 12 months, normal Vitamin D levels, and good seizure levels with hypocalcemia ( P < 0.001). Around 25% had high ALP levels and 75% had normal ALP levels. High ALP levels were significantly associated with hypocalcemia ( P < 0.001). Conclusion: Chronic anticonvulsant therapy is associated with significant hypocalcemia and hypovitaminemia D, and our findings suggest that calcium and Vitamin D supplementation might be beneficial for patients experiencing these conditions.

Abstract 76: Alteration in bone metabolism and bone mineral density with chronic anti-epileptic drug therapy in North Indian population

Objective: Anti-epileptic drugs are the mainstay of treatment of epilepsy. Prolong use of anti-epileptic medicines can lead to reduction in bone mineral density (BMD), resulting in 2-6-fold increase in fracture risk. This study was carried out to assess the impact of AEDs on the markers of bone turnover and BMD in North Indian patients.Methods: In this hospital based observational study sixty adult patients with epilepsy, on antiepileptic drugs were included. Serum calcium, phosphorus, alkaline phosphatase (ALP), albumin, 25 (OH) vitamin D and intact Parathyroid hormone (iPTH) and BMD (at lumbar spine with DEXA) were measured in all study subjects.Results: The serum level of calcium, phosphorus and 25(OH) Vitamin D was significantly decreased and iPTH and ALP levels were increased in patients taking anti-epileptic drugs for > 5 years. There was a significant negative correlation between serum calcium, phosphorus and vitamin D levels and significant positive correlation with ALP and iPTH levels with duration anti-epileptic therapy. There was negative correlation between the T-score and anti-duration of anti-epileptic therapy.Conclusions: Use of anti-epileptic (both old and new) medication in adults is associated with decline in BMD, calcium, vitamin D and phosphorus levels and elevation in iPTH and ALP levels.

Alteration in bone metabolism and bone mineral density with chronic antiepileptic drug therapy

Alteration in bone metabolism and bone mineral density with chronic antiepileptic drug therapy

Farmaci antiepilettici, vitamina D e mineralizzazione ossea: le evidenze e le azioni

The possible negative effects of antiepileptic drugs on bone metabolism with the consequent possible risks have been discussed in the literature for more than 30 years. Two reviews of the literature attempted to answer the following clinical questions: “Should vitamin D supplementation be used in children receiving antiepileptic drugs?”, “Do children on chronic antiepileptic drug therapy have to perform bone densitometry (DEXA) to assess the state of bone mineralization”? The evidence suggests to prescribe a prophylaxis with vitamin D at 400 IU/day to children on antiepileptic therapy and without other risk factors and provide them with indications regarding correct eating, motor and sun exposure lifestyles. Higher doses will be evaluated in case of coexistence of risk factors. DEXA screening may be useful in children on antiepileptic therapy and with a history of fractures (particularly multiple or low impact fractures) or in children on prolonged antiepileptic therapy and in the presence of additional risk factors (e.g. infantile cerebral palsy).

Awareness of vitamin B7: A growing problem in clinical practice

Biotin (vitamin B7, hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid) is not synthesized by mammals: dietary sources include plant based foods, yeast, liver, kidneys, heart, pancreas, egg yolk, poultry, and cow’s milk. Synthesis via the gut bacteria may also play a role. Recommended daily allowances are based on normal intake; EU RDA is 50 μg/day, the US adequate intake (AI) for adults is 30 μg/day.Biotin is required for the function of four carboxylases: pyruvate carboxylase, propionyl CoA carboxylase, multiple CoA carboxylase, and acetylCoA carboxylase I and II. Holocarboxylase synthase is required to attach biotin to their active sites. Biotin also modulates the expression of up to 2000 genes, and has effects on immune function, largely through biotinylation of histones and other proteins.Biotinidase, the enzyme which splits biotin from biotinyl lysine (biocytin), and from peptides containing biocytin, recycles biotin from endogenous turnover and facilitates absorption from exogenous sources, together with the sodium-dependent multivitamin transporter.Nutritional deficiency of biotin is rare and most cases relate to inborn errors of biotin metabolism and transport, long-term use of parenteral nutrition, chronic anticonvulsant therapy, or avidin binding of dietary biotin due to excessive ingestion of egg whites.Excessive ingestion of biotin from supplements is increasingly common. Biotin has no direct toxicity, but high circulating levels can interfere with many commercially available immunoassays which use the interaction between biotin and streptavidin. This can result in a spurious but plausible biochemical picture of disease supported by two or more independent immunoassay based tests.The laboratory detection of functional biotin deficiency relies upon detection of multiple carboxylase deficiency, identified and followed by measurement of urinary 3-hydroxyisovaleric acid (3HIVA, ideally using isotope dilution GC-MS, or isotope dilution-LC-MSMS (ID-LC-MSMS)) or plasma 3-hydroxyisovaleryl carnitine (3HIVc, measured using ID-LC-MSMS). These methods are reviewed, together with methods for assessing biotinidase activity.This chapter also describes methods for the direct measurement of biotin in foods, blood, serum/plasma, and urine. These relied for many years on microbiological assays. These were followed by binding assays using avidin with radioactive biotin or enzyme linked biotin as tracers, with or without chromatographic separation to distinguish between biotin, metabolites of biotin, and biotinylated peptides. Latterly, the introduction of specific assays using ID-LC-MSMS should allow traceable and harmonized assay of plasma/serum biotin. These could be particularly helpful to detect excessive ingestion of biotin supplements.We conclude that there is a need for laboratory methods with adequate sensitivity and specificity to reliably diagnose biotin deficiency and monitor biotin levels in patients receiving supplements. There are a limited number of reliable markers of biotin status and no single marker can reliably distinguish moderately deficient biotin from sufficient and supplemented. Measurement of 3HIVA and 3HIVc, the functional markers of biotin status, is currently the recommended approach.

Drug-Drug Interactions Among Hospitalized Children Receiving Chronic Antiepileptic Drug Therapy.

Children treated with chronic medications are at risk of drug-drug interactions (DDIs) when hospitalized with an acute illness and prescribed new medications. We aimed to measure the prevalence of potential DDIs (pDDIs) among hospitalized children treated with antiepileptic drugs (AEDs) and to evaluate the impact of computerized physician order entry (CPOE) on pDDIs. We analyzed a national sample of pediatric hospitalizations from 2005 to 2012 associated with administration of an AED and identified those prescribed a second medication with risk of a DDI. The prevalence of hospitalizations associated with a pDDI was calculated for each AED. We identified the drugs most commonly implicated in pDDIs and factors associated with pDDIs. Rates of pDDIs were measured in pre- and post-CPOE implementation periods. A pDDI was identified in 181 380 (41.7%) hospitalizations associated with the use of an AED, with 117 880 (27.1%) classified as severe pDDIs. AEDs most often implicated with a pDDI were phenobarbital, valproic acid, and phenytoin. Hospitalizations with pDDIs were associated with increased length of stay and a greater number of medications, ICU admissions, and operating room procedures. The implementation of CPOE did not result in a change in the rate of pDDIs (42.7% before versus 40.8% after; P = .48). Children treated with AEDs are at risk of pDDIs while hospitalized. The use of CPOE has not been associated with a significant decrease in the rate of pDDIs. Additional investigation to better define the impact of pDDIs and to advance development of clinical decision support within CPOE systems is warranted.

Greater Calcium Intake is Associated with Better Bone Health Measured by Quantitative Ultrasound of the Phalanges in Pediatric Patients Treated with Anticonvulsant Drugs.

We aimed to investigate and compare the effects of chronic antiepileptic therapy on bone health in pediatric patients using quantitative ultrasound of the phalanges (QUS) and controlling for potential confounding factors, particularly nutrient intake. The amplitude-dependent speed of sound (Ad-SoS) was measured in 33 epileptic children and 32 healthy children aged 6.5 ± 3.1 and 6.3 ± 1.1 (mean ± SD) years, respectively. There were no significant differences in the demographics such as age, weight and height between epileptic children and the control group children. None of the children in the epileptic or the treatment group were found to have a vitamin D deficiency. There were no significant differences in laboratory tests between groups. Lower QUS figures were found in the epileptic children (p = 0.001). After further adjustment for potential confounders such age, height, weight, calcium intake, vitamin D intake, physical activity and sex, the differences remained significant (p < 0.001). After further classification of the participants based on the tertile of calcium intake, no significant differences were found between patients and healthy controls in the greatest tertile of calcium intake (p = 0.217). We conclude that anticonvulsant therapy using valproate may lead to low bone mass in children and that an adequate intake of calcium might counteract such deleterious effects.

Changes in balance function with chronic antiepileptic drug therapy: A twin and sibling study.

To investigate cross-sectional and longitudinal differences in static and dynamic standing balance measures and lower limb muscle strength in patients who are treated chronically with antiepileptic drugs (AEDs). Twenty-six AED exposure-discordant same-gender twin and sibling pairs were studied. Clinical and laboratory balance examinations were conducted twice, separated by at least 1 year. The mean within-pair differences in balance measures were calculated cross-sectionally at baseline and follow-up, and longitudinally. No significant mean within-pair difference was found at baseline in age (44 years), weight, and height (p > 0.05). Between study assessments, the median (interquartile range [IQR]) interval was 3.0 (2.1-4.3) years in users and 2.9 (2.0-4.4) years in nonusers. The median duration of AED therapy was 19 (11-21) years. At baseline and follow-up, cross-sectional sway measures from posturography (Chattecx Balance System) and clinical static balance tests showed poorer performance in users compared to nonusers on several test conditions (p = 0.002-0.032). At follow-up, the users took longer than nonusers to complete the Four-Square-Step Test (p = 0.005) and Five-Times-Sit-to-Stand Test (p = 0.018). A greater annual rate of deterioration in sway was found in users compared to nonusers using posturography on the anteroposterior tilting platform task with distraction (p = 0.032). In both groups, higher baseline sway predicted greater annual deterioration in sway in all platform conditions (β = 0.3-0.5, p < 0.001-0.013). The annual change in measures did not differ between groups in the clinical balance and lower limb strength assessments. In this longitudinal twin and sibling study, chronic AED users had poorer standing balance compared to nonusers. Users showed greater deterioration in postural sway with one dynamic platform condition. AEDs may progressively impair balance mechanisms, although this requires further investigations. Repeated dynamic posturography could provide a basis for preventive trials for maintaining or improving balance.

Long-term follow-up in children with benign convulsions associated with gastroenteritis

BackgroundThe outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations. AimTo assess the long-term neurological outcome of a large sample of children presenting with CwG. MethodsWe reviewed clinical features of 81 subjects presenting with CwG (1994–2010) from three different Italian centers with a follow-up period of at least 3 years. ResultsFollow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7%). Fourteen children (17.3%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7%), and a transient photosensitivity in one (1.2%). No recurrence of CwG was observed. Three patients (3.7%) presented with a febrile seizure and two (2.5%) with an unprovoked seizure, but none developed epilepsy. ConclusionsThe long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy.

Etiology, characteristics and outcome of seizures after pediatric hematopoietic stem cell transplantation

PurposeEpileptic seizures are frequent manifestations after hematopoietic stem cell transplantation (HSCT). In this retrospective single-center study we evaluated electroclinical features and analyzed etiologies and outcome of seizures after pediatric HSCT. MethodsOf 261 children transplanted between 2000 and 2010, we identified and analyzed data of 28 patients with seizures within a year from HSCT. ResultsMost frequent etiologies were posterior reversible encephalopathy syndrome (PRES, 14 patients) and central nervous system (CNS) infections (4 patients). Seizures were the presentation of the underlying complications in 22 patients. Sixteen episodes of status epilepticus were identified. Seizures secondary to PRES were usually longer and associated with non-convulsive signs. Early neuroimaging and EEG monitoring proved to be crucial to diagnose and treat seizures and their causes. No patients developed epilepsy suggesting that chronic antiepileptic therapy is not necessary in these patients. Overall survival was 32.3% over 5 years in patients with seizures and 45.8% in patients without seizures (p<0.05). Multivariate statistical analysis identified as independent risk factors for seizures a diagnosis of non-oncological disease and cord blood stem cell transplantation. ConclusionsSeizures in transplanted children are a severe event and are associated with high morbidity and poor outcome. In particular, patients with non-oncological diseases and cord blood stem cell transplantation have to be considered at high risk of seizures. Moreover, this study underlines the importance of early recognition of non-convulsive clinical signs and of EEG monitoring for a prompt diagnosis and an appropriate management of seizures and their causes.

Role of piracetam on cognitive function in epilepsy and with antiepileptics in rats

Background: To study extent of cognitive impairment by epilepsy & antiepileptic treatment and evaluate the role of piracetam on it. Methods: 48 animals were divided into 6 groups: I-Control, II- Topiramate, III-Topiramate+Piracetam, IV-Valproate, V-Valproate+Piracetam, VI-Piracetam. Baseline cognitive functions were measured using Cook’s pole climbing apparatus (CPCA) and Elevated plus maze (EPM). In CPCA, on completion of training, number of avoidances (NOA) out of 10 trials were noted while in EPM, transfer latency (TL) was measured. Kindling was induced by 30mg/kg Pentylenetetrazol (PTZ), i.p. to all groups (except Group I) on alternate days till seizures developed. Groups were treated with respective drugs orally for 21 days and cognitive functions measured again. Results: Significant decrease in NOA & increase in TL was observed after PTZ kindling. Topiramate further significantly impaired NOA and TL whereas Valproate significantly reduced NOA in CPCA but increase in TL was not significant. Treatment with Piracetam significantly increased Topiramate, Valproate and PTZ kindling induced decrease in NOA as also significantly reduced Topiramate and PTZ kindling induced increase in TL. Conclusion: Seizures are associated with cognitive impairment. Cognitive impairment caused by Sodium valproate differs from Topiramate. Piracetam, a known nootropic can be used in alleviating cognitive impairment associated with epilepsy & chronic antiepileptic therapy.

Topiramate and visual loss in a patient carrying a Leber hereditary optic neuropathy mutation

We describe a 43-year-old patient who experienced visual loss 4 years after beginning antiepileptic therapy with topiramate. Ophthalmological and neurological examinations led to a preliminary diagnosis of bilateral toxic optic neuritis. Mitochondrial genome sequence analysis detected a Leber hereditary optic neuropathy 11778G>A mutation. The possibility that topiramate might favor a conversion disease, alerts physicians to seek a history of blindness in patients undergoing chronic antiepileptic therapy.

Rotavirus Gastroenteritis and Seizures in Young Children

In this retrospective cohort study, a clinical and administrative database of children hospitalized at Primary Children's Medical Center, Salt Lake City, Utah, between January 1, 2002, and December 31, 2006, was used to identify those with laboratory-confirmed rotavirus infections and at least one seizure. In all, 59 children were identified, 34 of whom (58%) had no other potential medical explanation for their seizures. Of these 34 children, 23 (68%) were afebrile at seizure onset and 11 were febrile. Electroencephalography was performed for 21 of the 34 children (62%); all findings were normal, except for a child with slowing related to cerebral edema. Twenty-six of the 34 children (76%) had neuroimaging studies; all findings were normal, except for the child with cerebral edema and a child with an incidental arachnoid cyst. Twenty of the 34 children (59%) had a lumbar puncture; again, all findings were normal. All 34 children recovered uneventfully, including the 6 children who spent at least 1 day in an intensive care unit. Follow-up data on 27 of these children identified 2 children (7%) who required chronic anticonvulsant therapy. The results indicate that seizures associated with rotavirus infection are a relatively benign neurologic condition in young children. With few exceptions, neurodiagnostic studies do not influence management or outcome.

Insights into liaison between antiepileptic drugs and bone

The adverse effect on bone caused by chronic anticonvulsant therapy causes multiple abnormalities in calcium and bone metabolism, varying from bone turnover, without significant loss of cortical or trabecular bone, to osteopenia/osteoporosis and to osteomalacic disorder. The studies conducted to date have documented anticonvulsant bone disease as a state of increased bone remodeling. With the newer antiepileptic drugs (AEDs) gaining importance and starting to replace conventional medicines, it may be appropriate to compare them with the conventional AEDs and to examine their impact on multiple aspects of bone health. This review focuses on the status of the bony effects of AEDs.

Adiponectin and visfatin concentrations in children treated with valproic acid

Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy.

Body composition, insulin resistance, leptin, vitamin D and novel markers of bone metabolism in children on chronic antiepileptic therapy

Body composition, insulin resistance, leptin, vitamin D and novel markers of bone metabolism in children on chronic antiepileptic therapy

Bone density and bone turnover markers in patients with epilepsy on chronic antiepileptic drug therapy

In this comparative, cross-sectional study, we evaluated 55 patients with epilepsy on chronic use of antiepileptic drugs (AED); [(38 females and 17 males, 35 +/- 6 years (25 to 47)] and compared to 24 healthy subjects (17 females/7 males). Laboratorial evaluation of bone and mineral metabolism including measurements of bone specific alkaline phosphatase (BALP) and carboxyterminal telopeptide of type I collagen (CTX-I) were performed. Bone mineral density (BMD) was measured by DXA. BALP and CTX-I levels did not differ significantly between the groups. CTX-I levels were significantly higher in patients who were exposed to phenobarbital (P< 0.01) than those who were not. Patients presented BMD of both sites significantly lower than the controls (0.975 +/- 0.13 vs. 1.058 +/- 0.1 g/cm(2); p= 0.03; 0.930 +/- 0.1 vs. 0.988 +/- 0.12 g/cm(2); p= 0.02, respectively). Total hip BMD (0.890 +/- 0.10 vs. 0.970 +/- 0.08 g/cm(2); p< 0.003) and femoral neck (0.830 +/- 0.09 vs. 0.890 +/- 0.09 g/cm(2); p< 0.03) were significantly lower in patients who had been exposed to phenobarbital, in comparison to the non-phenobarbital users. In conclusion, patients on AED demonstrate reduced BMD. Among the AED, phenobarbital seems to be the main mediator of low BMD and increases in CTX-I.

Surgical Treatment for Acute Symptomatic Refractory Status Epilepticus: A Case Report

A previously healthy 10-year-old boy developed generalized convulsive status epilepticus following a mild febrile illness. Prolonged video-electroencephalographic monitoring revealed frequent right hemispheric electrographic seizures that were refractory to high-dose suppressive therapy. Ictal and interictal magnetoencephalography demonstrated dipole sources projecting from the right mesial temporal region. Diffusion-weighted imaging showed restricted diffusion involving the right hippocampus. Right anterior temporal lobectomy resulted in cessation of status epilepticus. At 1-year follow-up, he attends regular school and has infrequent nocturnal seizures on chronic antiepileptic drug therapy. Surgical treatment should be considered to stop status epilepticus in selected cases of acute symptomatic refractory status epilepticus with no preexisting epilepsy or magnetic resonance imaging abnormalities and may avoid the complications associated with prolonged high-dose suppressive therapy.

Bone Mineral Status in Pediatric Outpatients on Antiepileptic Drug Monotherapy

Drug-induced osteopenia has been reported in institutionalized children on chronic antiepileptic drug therapy. The aim of this study was to assess longitudinally bone mineral status in pediatric outpatients on antiepileptic drug monotherapy. The study group consisted of 30 ambulatory children on a normal diet: 15 on valproic acid, 11 on carbamazepine, and 4 on phenobarbital monotherapy. Bone mineral density, serum active vitamin D (1,25-dihydroxyvitamin D), and certain biochemical markers of bone formation (calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, osteocalcin, calcitonin, and urinary calcium to serum creatinine and urinary phosphorus to serum creatinine ratios) were studied at the beginning of antiepileptic drug monotherapy and at the end of 2 years of treatment. Age- and sex-specific Z-scores of bone mineral density were measured at anterior-posterior L2-L4 by dual-energy x-ray absorptiometry. Drug-induced osteopenia was defined in only two patients (one on carbamazepine and the other on phenobarbital monotherapy), with Z-scores of bone mineral density less than -1.5. Serum levels of active vitamin D and biochemical markers were not significantly correlated with the Z-scores of bone mineral density. We detected a frequency of antiepileptic drug-induced osteopenia of 6.7% in pediatric outpatients after 2 years of monotherapy. However, osteopenia was not attributed to a defect in serum active vitamin D production owing to hyperparathyroidism in children on antiepileptic drug monotherapy.

Posterior reversible encephalopathy syndrome in children with cancer

To identify predisposing factors, radiologic features, and clinical outcome of posterior reversible leucoencephalopathy (PRES) in children receiving cancer treatment. We identified 11 patients (7 female) who had radiological and clinical features consistent with PRES and were treated for cancer at St. Jude Children's Research Hospital between January 1995 and January 2005. Clinical and radiographic data were abstracted from their records. The average age at the time of PRES onset was 10.4 years. Primary diagnoses were acute leukemia (n = 8), non-Hodgkin lymphoma (n = 2), and Ewing sarcoma (n = 1). PRES occurred in 8 patients during the induction phase of treatment, and all 11 patients had hypertension (5 chronically). Seizure activity was proximate to cytarabine and tacrolimus administration in three patients and further seizures occurred with re-administration of these medications in two patients. Coagulation and chemistry studies were normal. Concurrent brain magnetic resonance imaging (MRI) demonstrated T2 signal abnormalities in all 11 patients, restricted diffusion in 4, and hemorrhage in 3. Follow-up MRI showed chronic changes consistent with a previous hemorrhage in three and evidence of prior parenchymal ischemia in one. Three patients developed epilepsy and remain on chronic anticonvulsant therapy. PRES is an increasingly recognized complication of pediatric cancer treatment. Risk factors for PRES in pediatric cancer patients include hypertension (not necessarily acute), remission induction chemotherapy, and administration of tacrolimus. MR images often show atypical findings, some of which are irreversible. A significant number of patients develop epilepsy despite clinical and radiographic evidence of recovery.