Dieter Wenzel

Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus.

Since its first clinical use in France in 1963, valproic acid (VPA) has rapidly established itself worldwide as one of the major antiepileptic drugs, with a broad efficacy for treatment of both generalized and partial seizures in children and adults.1 In October 1996, an IV VPA formulation was approved in Germany for the short-term supplementation of an established oral VPA treatment in patients with epilepsy, when oral-to-parenteral substitution becomes necessary.2 However, IV VPA also offers the opportunity to treat epileptic emergency situations such as prolonged or serial seizures, or even patients with status epilepticus (SE). We report on 41 children with therapy-resistant SE treated with IV VPA. The clinical details of our patients are listed in the table. All children had SE that was refractory to commonly recommended IV antiepileptic drugs (i.e., benzodiazepine compounds, phenytoin, and barbiturates). Whereas 22 of these children received antiepileptic long-term therapy that started before this SE event, SE was the initial presentation of an …

Radiation therapy of optico–hypothalamic gliomas (OHG) – radiographic response, vision and late toxicity

BACKGROUND Management strategies for optic pathway gliomas include observation, surgery, irradiation, chemotherapy and a combination of these modalities. It has been the policy of our University Hospital to consider radiation as the standard treatment for progressive optic pathway gliomas. This report describes the clinical presentation, treatment patterns and outcome with special emphasis on the long term functional status of patients with optico-hypothalamic gliomas (OHG). PATIENTS AND METHODS Between 1975 and 1997, 25 patients with OHG were treated by radiation therapy (RT) following surgery or biopsy. All patients received a local RT with a 0.5-1 cm margin around the lesions as depicted on CT or MRI scans. Age adjusted radiation doses ranged from 45 to 60 Gy with a single fraction size of 1.6-2 Gy. Endpoints of the study were: radiographic response, survival, progression-free survival and time to endocrinologic toxicity as well as the visual function during follow-up. The median follow-up time was 9 years (range, 1.5-23 years). RESULTS A partial response was noted in six (24%) of the patients, 13 (52%) patients had a stable tumour throughout the observation period and six (24%) patients had a tumour progression. Overall survival and progression-free survival rates were 94 and 69% at 10 years, respectively. A significant influence on progression-free survival was noted for age at diagnosis (P=0.04) and total dose (P=0.05). Nine out of 13 (69%) patients aged below 10 years compared with 3/12 (25%) patients aged above 10 years experienced hypothalamic-pituitary deficiency (P=0.008) during follow-up. As for visual acuity, nine patients had an improvement, another 13 patients a stable situation and three patients a measurable deterioration. Visual field deficits improved in three, remained unchanged in 16 patients and worsened in only one patient. CONCLUSION Postoperative RT with a total dose above 45 Gy should be considered as standard treatment in OHG with documented progression. Close radiographic monitoring and lifelong yearly evaluation for the need of possible hormone replacement are strongly recommended.

The Endocrine Spectrum of Arachnoid Cysts in Childhood

Background: On clinical grounds, arachnoid cysts are usually associated with neurological dysfunction. There is little information concerning their involvement in endocrinological disorders. Patients: The experience in 6 children (birth to 12 years) with hypothalamic-pituitary disturbances secondary to the presence of intracranial arachnoid cysts is reported and the literature is reviewed. Results: Three of our children were diagnosed with isolated hormone abnormalities (2 children with precocious puberty and 1 child with growth hormone, GH deficiency). One child presented the unusual combination of GH deficiency and precocious puberty. The remaining 2 children developed panhypopituitarism associated with diabetes insipidus. Conclusion: Arachnoid cysts may cause a wide spectrum of endocrinological disorders. Periodical and complete follow-up of every patient is recommended.

HIF-1-regulated vasoactive systems are differentially involved in acute hypoxic stress responses of the developing brain of newborn mice and are not affected by levetiracetam.

Hypoxia-inducible transcription factor-1 (HIF-1) is critically involved in adaptive endogenous mechanisms to hypoxic brain injury by transcriptional activation of specific target genes that restore oxygen supply. Exogenously, neuroprotective properties of levetiracetam (LEV) have been suggested in experimental cerebral ischemia and epilepsy. We aimed to elucidate 1) effects of acute hypoxic distress on HIF-1 and vasoactive target genes, and 2) effects of LEV on HIF-1-regulated mechanisms in the brain at early developmental stages. To this end, we studied the impact of hypoxia in the presence or absence of LEV on the O2-dependent HIF-1alpha subunit as well as on VEGF and iNOS in the developing brain of normoxic and hypoxic mice. C57BL/6 mice (P0, P7) were treated with saline or LEV (i.p.; 50 mg/kg) 1 h before exposure to either normoxia (21% O2; N) or hypoxia (8% O2 of 6 h; H) without reoxygenation. HIF-1alpha was analyzed by Western blot and immunohistochemistry and mRNA levels were quantified by TaqMan RT-PCR. Hypoxia led to prominent accumulation of cerebral HIF-1alpha protein in cortical neurons and glial cells and significant up-regulation of VEGF mRNA at P0 (N, 0.018+/-0.002, vs. H, 0.031+/-0.003, n=6; p<0.05) and P7 (N, 0.096+/-0.032, vs. H, 0.873+/-0.069, n=7; p<0.001). Interestingly, we detected a significant decrease of iNOS mRNA levels in hypoxic brains. LEV treatment did not alter HIF-1alpha accumulation either in normoxic or hypoxic brains (P0, P7). Moreover, significant changes of VEGF and NOS mRNA levels did not occur with the exception that hypoxia-induced decreased iNOS levels were not observed in P0 brains. We conclude that acute systemic hypoxia differentially affects expression of HIF-1-regulated vasoactive factors in the newborn mouse brain. Of clinical importance, LEV treatment did not alter crucial HIF-1-regulated neuroprotective mechanisms.

CNS late effects after ALL therapy in childhood. Part II: Conventional EEG recordings in asymptomatic long-term survivors of childhood ALL- An evaluation of the interferences between neurophysiology, neurology, psychology, and CNS morphology

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electro-encephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n = 45, 95.8%), followed by hypersynchrone activities (n = 1.0, 21.3%) and interhemispheric differences/focal slowing (n = 6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group.

Effectiveness of lamotrigine in children with paroxysmal kinesigenic choreoathetosis.

Paroxysmal kinesigenic choreoathetosis (PKC) is a rare movement disorder, characterized by recurrent, brief involuntary dystonic attacks that are provoked by sudden movements. Pathophysiology is uncertain, but a channelopathy is discussed. Treatment recommendations favour antiepileptic drugs (AEDs) acting on voltage‐gated neuronal ion channels. This report summarizes the history of three children (6, 8, and 10 years of age) with idiopathic PKC successfully treated with low doses of lamotrigine, an AED acting primarily via neuronal voltage‐sensitive sodium channels.

Neonatal Somatosensory Evoked Potentials: Maturational Aspects and Prognostic Value

The aim of this prospective study was to evaluate the diagnostic role of somatosensory evoked potentials (SEP) during the neonatal period with regard to maturational changes and prognostic value in perinatal hypoxic-ischemic encephalopathy. Median nerve SEP analysis was performed in 31 healthy infants (group A1, 33-35 weeks, n = 10; group A2, 36-37 weeks, n = 11; group A3, 38-41 weeks, n = 10) and in 10 term infants with hypoxic-ischemic encephalopathy (group B). Cortical latency N1 and central conduction time values were analyzed for group A in relation to postconceptional age and postnatal age and for group B in relation to degree of hypoxic-ischemic encephalopathy and neurodevelopmental outcome (at the mean age of 6.6 + or - 1.6 years). Central latencies were correlated with postconceptional age but not postnatal age. Mean N1 latency and central conduction time values did not differ significantly between groups A1 and A2; the most pronounced decrease was between groups A2 and A3 (postconceptional ages 36-37 vs 38-41 weeks). In group B, central latencies were prolonged, compared with controls (P < 0.001), but were not significantly correlated with long-term outcome in patients with moderate hypoxic-ischemic encephalopathy (n = 6). Neonatal SEP analysis thus is an objective and noninvasive method for assessing functional integrity of the somatosensory pathway. In term infants, SEPs are a valuable additional tool for early diagnosis of hypoxic-ischemic encephalopathy, but are not prognostic of neurodevelopmental long-term outcome in moderate hypoxic-ischemic encephalopathy.

Quantitative EEG in long-term survivors of acute lymphoblastic leukemia

Conventional and quantitative aspects of electroencephalographic recordings obtained during a follow-up surveillance study in long-term survivors of acute lymphoblastic leukemia in childhood were investigated with respect to differences in central nervous system prophylaxis given during antileukemic therapy and compared with data derived from healthy controls. Central nervous system prophylaxis consisted either of cranial irradiation (18 Gray, group A, n = 8) or intermediate high-dose methotrexate (2000 mg/m2; group B, n = 5), each combined with intrathecal methotrexate. Conventional electroencephalographic analysis revealed comparable results in all three study groups. However, quantitative electroencephalography showed significantly increased absolute power scores for all frequency bands in both long-term survivor groups. Relative power estimates revealed a significant increase in delta/tau activities in both prophylaxis groups compared to healthy controls, which were countered by decreased percentage power scores in the alpha-range. Quantitative electroencephalographic comparisons between both central nervous system prophylaxis groups revealed only small differences in quantity, not quality, of the observed power disturbances with slightly higher deviations in irradiated long-term survivors than in nonirradiated ones. Topographical distributions of spectral band power were comparable between all three study groups without evidence for therapy-related topographical differences.

A Cross-Sectional Study of Dehydroepiandrosterone Sulfate in Prepubertal Children with Myelomeningocele

Objective: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. Patients and Methods: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6–10.1 years, mean 8.1 ± 0.4) with isolated pubarche (Tanner stage PH 2–4, B1 or testes volume ≤3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0–11.9 years; mean 6.8 ± 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. Results(mean ± SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2–4, r = 0.49, p < 0.01). 10/11 patients aged 2–4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 ± 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 ± 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. Conclusion: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.

Diagnosesicherung des Morbus Alexander in vivo durch Mutationsanalyse des GFAP-Gens

ZusammenfassungFallbericht. Anhand eines Fallberichts werden der typische Verlauf eines Morbus Alexander vom infantilen Typ und die Möglichkeit der nichtinvasiven, molekulargenetischen Diagnosesicherung in vivo dargestellt. Aus den klinischen Befunden mit progressiver Makrozephalie, zerebralen Anfällen und Entwicklungsstillstand ergab sich zusammen mit dem neuroradiologischen Bild einer frontotemporal betonten Leukodystrophie die Verdachtsdiagnose eines Morbus Alexander.Der Nachweis einer heterozygoten De-novo-Mutation im GFAP-Gen (GFAP: glial fibrillary acidic protein) (R239H) des Patienten ermöglichte die Diagnosesicherung. Schlussfolgerung. Durch den Mutationsnachweis im GFAP-Gen sind die frühe Diagnosesicherung eines Morbus Alexander sowie ggf. eine Pränataldiagnostik möglich.AbstractCase report. We report an infant diagnosed as having infantile Alexander disease because of the clinical presentation with macrocephaly, seizures and developmental delay and the typical MRI findings of frontotemporal white matter lesions. In accordance to the recently described association between mutations in the GFAP (glial fibrillary acidic protein) gene and Alexander disease, GFAP was sequenced.A heterozygous de novo mutation of the GFAP gene (R239H) was found in our patient. Conclusion. Molecular genetic analysis enabled an early and non-invasive diagnosis in vivo.