Peter Borusiak

Valproic Acid–induced Hepatopathy: Nine New Fatalities in Germany from 1994 to 2003

Summary:  Purpose: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. We provide an update on hepatotoxic side effects in Germany between 1994 and 2003.

Prevalence of epileptiform discharges in healthy children—New data from a prospective study using digital EEG

Purpose:  Data on epileptiform electroencephalography (EEG) discharges in healthy children are limited, with published studies dating back more than 20 years. Moreover, analyses have been performed exclusively using paper‐recorded EEG, and reported prevalences differ significantly. With recent reports using these data as reference suggesting an increased prevalence of epileptiform EEG discharges in children with behavioral disturbances, acquisition of exact prevalence data has become even more critical. The aim of our study was to analyze the frequency of epileptiform EEG discharges in healthy children using digitally recorded EEG (DEEG) and to compare these data to those of previously published studies.

Facial palsy: Etiology, outcome and management in children

BACKGROUND Currently there is much controversy whether to treat idiopathic facial palsy with corticosteroids with sparse data on the natural course of the disease in children. METHODS We performed a prospective study on all children <15 years of age who were admitted to our unit for facial palsy between 1st July 1998 to 30th June 2008. All patients received a standardized work-up and follow-up. Therapy consisted of symptomatic treatment either with (in case of neuroborreliosis) or without a 14 day course of intravenous antibiotics. FINDINGS 106 patients were included in our study. The calculated incidence for facial palsy was 21.1/100000/year for children <15 years. The incidence for neuroborreliosis (NB) in this age group was calculated to be 4.9/100000/year. The overall rate of complete recovery was 97.6% with significantly faster recovery in younger children and in patients with NB as compared to idiopathic facial palsy. Both patients with incomplete recovery were at least 14 years old and presented late in the course of the disease. CONCLUSION Based on the rate of 97.6% spontaneous complete recovery we believe that the routine use of corticosteroids in children with facial palsy is not justified, unless there is new data from controlled trials in children.

Antiepileptic Drugs and Bone Metabolism in Children: Data from 128 Patients

There are conflicting results concerning bone metabolism in children receiving antiepileptic medication, with data concentrating on neurologically impaired patients. We performed a multicenter cross-sectional study in otherwise healthy children who received monotherapy with valproic acid, oxcarbazepine, lamotrigine, sulthiame, levetiracetam, or topiramate for at least 6 months. Data on calcium, phosphorus, alkaline phosphatase, 25-OH vitamin D, and parathormone were collected. Among 128 patients, 24.4% had hypocalcemia, 25.4% hypophosphatemia, and 13.3% (n = 17) 25-OH vitamin D levels <10 ng/mL. All patients were clinically asymptomatic. Mean calcium concentrations were found to be significantly lower among the study population (2.41 mmol/L) compared with healthy controls (2.53 mmol/L). Lowest mean concentration was observed in patients treated with sulthiame followed by oxcarbazepine and valproic acid. No influence of calcium intake or therapy on bone metabolism was noted. Effects on bone metabolism of anticonvulsive monotherapy are not restricted to neurologically impaired children but also affect otherwise healthy children.

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations

PURPOSE PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. METHODS We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years). RESULTS The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. SIGNIFICANCE The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.

Late-onset cardiac arrhythmia associated with vagus nerve stimulation

We report on a 13-year-old boy who first presented at the age of 5 years with refractory complex partial seizures (CPS) with and without secondary generalization. Despite a thorough workup no cause could be identified. After unsuccessful medical treatment attempts with 13 different antiepileptic drugs (AED) finally a vagus nerve stimulator (VNS; vagus nerve stimulation) was implanted in 2002 (NCP Type 101; Cyberonics, Houston, TX, USA). The intraoperative findings revealed no anatomic abnormalities and the lead test passed uneventfully. Eighteen months prior to the reported incident, seizure frequency was stable with three to five CPS per month under medication with phenobarbital (PB), felbamate (FBM), and zonisamide (ZNS). Due to former probably drug-related rickets the patient received also calcium and vitamin D supplementation with parameters of calcium metabolism stable within normal limits. VNS stimulation parameters were unchanged for the last years prior to the reported adverse effect (30 s on, 5 min off, 2.25 mA, frequency 20 Hz, pulse width 250 ms). Six and a half years after implantation a significant increase of seizure frequency was observed without apparent cause. Interventions with lorazepam, chloralhydrate, clobazam, and acetazolamide and a change of basic medication (i.e., stopping FBM) were unsuccessful. Suddenly an intermittent and self-terminating complete heart block with bradycardia occurring every 15–25 min lasting for 20–40 s over a time span of 2 h was recorded (Fig. 1). Several minutes later an asystole for 6 s was witnessed on the electrocardiogram (ECG) monitor. Assuming an influence of the VNS device, the stimulator was turned off and the bradyarrhythmia dissolved. Breakage of leads or abnormal placement of electrodes was ruled out by X-ray. A cardiological examination as well as laboratory workup did not reveal any abnormalities. Seizures were finally terminated with thiopental. Outpatient followup including close ECG monitoring did not show any further episodes of cardiac arrhythmias. More than 50,000 VNS implantations have been performed worldwide. Large studies have reported both effectiveness and safety of the device. Despite the close proximity of VNS and centers controlling cardiovascular function initial studies in both animals and humans failed to demonstrate a relevant effect on cardiac function. Recent studies produced inconsistent results [7, 8, 11, 13, 15], mostly focusing on severe incidents associated with the intraoperative lead test during VNS implantation [1, 3, 5, 6, 14]. All patients made an uneventful recovery (Table 1). Only recently were the first two patients with late onset of cardiac arrhythmia, years after implantation, reported [2, 9]. In our patient an influence of the VNS is the most likely explanation, as cardiac arrhythmias subsided immediately following inactivation of VNS. However, since the incident took place during a phase of increased seizure frequency, and seizures (in particular status epilepticus) are well known to affect cardiac rhythm, it might be possible that these circumstances as well as changes in medication predisposed our patient to bradyarrhythmia. Most data for people with VNS compared with those with severe complex partial-onset epilepsy without the device failed to demonstrate an increased mortality rate, albeit encompassing less than 5 years after VNS implantation [4]. Considering the long time interval between the VNS implantation and the adverse event in our patient it might P. Borusiak (&) M. Zilbauer S. Cagnoli M. Heldmann A. Jenke Zentrum fur Kinderund Jugendmedizin, HELIOS Klinikum Wuppertal, Heusnerstr. 40, 42283 Wuppertal, Germany e-mail: peter.borusiak@helios-kliniken.de

Magnetic Resonance Imaging of the Brain in Children With Headache The Clinical Relevance With Modern Acquisition Techniques

The aim of this study was to evaluate the frequency of abnormal findings in magnetic resonance imaging (MRI) in children with headache, the clinical relevance of these findings, and whether more sophisticated technologies also result in more relevant abnormal findings. The MRIs of 1004 children with age ranging from 1 to 17 years were retrospectively analyzed. Children who were investigated with established sequences (n = 419) were compared with those examined with state-of-the-art MRI acquisition technology (n = 585). In 216/1004 investigations, MRI was performed because of headache (74/216 with established sequences, 142/216 with state-of-the-art acquisition technology). In 114/216 (52.8%) patients with headache, the MRI was abnormal with relevant findings in 23/114 patients and findings without clinical relevance in 91/114 children. A higher incidence of abnormal findings than in previous reports was found but there was only limited clinical gain of information using modern sequences in children with headache.

Serum neuron-specific enolase in children with febrile seizures: time profile and prognostic implications

Compared to publications of elevated levels of neuron-specific enolase (NSE) in adult patients with single seizures or epilepsy, data in children are rare. We studied serial NSE serum concentrations in children after febrile convulsions (FC). In addition, the predictive value of NSE levels in serum for recurrence of FC or further development of epilepsy was determined. Serum NSE levels were determined at (1) 0-2 h, (2) 6-8 h and (3) 20-24 h after a first or second FC in children aged 4 months to 6 years. Eighty-two patients (35 female, 47 male) aged four months to 5.7 years were included. Seventy-one children had generalized, and seven focal FC. The seizures in the remaining four patients could not be properly classified. During the follow-up of 14-28 months 13 patients had at least one more FC and in five epilepsy due to recurrent afebrile seizures was diagnosed. There was no statistically significant elevation of NSE concentration in the group of children with FC or the group with recurrent FC or epilepsy. The comparison of the NSE values at different times after FC did not show any significant differences either. It seems from our results that NSE activity cannot be used as a predictor for possible brain damage caused by FC and that it is not of predictive value considering further FC or development of epilepsy. We cannot confirm the published results of the elevation of NSE serum levels in adults with single seizures or status epilepticus.

Soluble telencephalin in the serum of children after febrile seizures

Sirs: Febrile seizures (FS) affect 3–5 % of all children. Although FS are generally considered as benign, there is an ongoing debate whether they are a risk factor for later development of temporal lobe epilepsy (TLE) [2]. Telencephalin (TLN) – intercellular adhesion molecule-5 (ICAM-5) – is a neuronal glycoprotein. It is unique among the family of five identified ICAMs because only TLN is expressed on somatodendritic membranes of neo-cortical neurons in the most rostral segment of the mammalian brain [6]. Increased concentration of soluble TLN (sTLN) in serum and cerebral spinal fluid has been reported in adults with temporal lobe epilepsy [5] and acute encephalitis [4, 5]. No significant elevations of TLN were found in other neurological diseases such as generalized epilepsy, Alzheimer’s disease or multiple sclerosis [5]. In order to obtain further information about the potential role of sTLN as a neuronal marker, we investigated postictal serum levels of TLN in 48 children (21 female, 27 male) aged five to 63 months (mean 28.3 ± 14.9) with a first or second FS. The study was approved by the ethics committee of the University of Munster. All patients were followed for at least 36 months up to 42 months. The control group consisted of 43 age and sex matched children with fever but without FS. Samples were collected within 24 hours following the seizure. Soluble TLN was measured with a sensitive sandwich immunoassay with two mouse monoclonal antibodies to the extracellular domains of human telencephalin. We compared serum concentrations with a standard curve generated from recombinant telencephalin. As in previous publications we considered sTLN levels under 8 ng/ml as normal values [4], between 8 and 30 ng/ml as modest elevation and above 30 ng/ml as significantly increased. The mean and standard deviations were calculated for continuous variables. Increased values of sTLN were detected in nine children with FS and in nine of the control group without any significant differences between the two groups (Fig. 1). No significant correlation between the sTLN values and the following variables was demonstrated: age at onset of the FS, family history considering FS or epilepsy, seizure duration, seizure classification (generalized vs. focal), temperature at admission, simple FS vs. complex FS. During the follow-up five children had at least one more febrile seizure and in four patients diagnosis of epilepsy was established because of recurrent afebrile seizures. In all those children as well as in the group with recurrent FS no association with sTLN levels could be established. Published data on TLN suggest that this protein may be an indicator for neocortical neuron damage. The fact that TLN serum values were significantly increased in patients with temporal lobe epilepsy but not in adults with generalized epilepsies suggests ongoing pathophysiological events mainly in the mesiotemLETTER TO THE EDITORS

Prevalence of Epileptiform Discharges in Healthy Infants.

Most studies on epileptiform discharges in young children were performed using analog electroencephalographic (EEG) recording systems and a limited numbers of electrodes that might have a lower detection rate for epileptiform discharges than modern digital recording systems. Knowing the prevalence of epileptiform discharges in healthy children is critical for a valid interpretation of findings in patients with a suspected epileptic disorder. We reviewed EEG recordings of 393 otherwise healthy children aged 12 to 60 months using digital EEG recording with respect to epileptiform discharges. We found epileptiform discharges in 3 children aged 12, 34 and 55 months resulting in a prevalence of epileptiform discharges in our cohort of 0.76% (95% confidence interval 0.0% to 1.62%). The prevalence of epileptiform discharges in children younger than 5 years is by far lower than in older children, and the digital findings are in accordance with previous data of conventional EEG.