Gabriele Wohlrab

Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency

Aim  We report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine‐dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO).

Neonatal seizures with tonic clonic sequences and poor developmental outcome

Seizures consisting of a tonic followed by a clonic phase have rarely been described in neonates and are not included in the current classifications of neonatal seizures. Our video archive of 105 neonates with seizures or suspected seizures revealed six neonates with such tonic clonic or tonic myoclonic sequences. Two of those neonates had pyridoxine dependent seizures. The other four neonates had drug refractory seizures and demonstrated similarities in electro-clinical pattern, clinical course and outcome. Their seizures started with tonic posturing and after 10-20s tonic posturing was superimposed by focal or multifocal cloni or myocloni. Ictal EEG started with voltage attenuation followed by bilateral or alternating focal epileptic discharges. The interictal EEG was abnormal. One child died, while the other three children became seizure free but had severe motor delay and mental retardation. In one of those three children, a de novo missense mutation was detected in the voltage gated potassium channel gene KCNQ2, indicating a genetic relationship between drug refractory neonatal seizures of unknown etiology with tonic clonic or myoclonic sequences and the well-known syndrome of benign familial neonatal convulsions (BFNC).

Adverse Effects of Vigabatrin in Angelman Syndrome

Summary: New antiepileptic drugs designed for enhancing GABAergic inhibition, such as vigabatrin (VGB) may be effective in Angelman syndrome (AS), because associated convulsions could be related to a reduced GABA‐receptor density or receptor abnormality. From our preliminary experiences in four children with AS treated with VGB, we conclude that it may induce and increase seizures in patients with AS.

Proven Startle-provoked Epileptic Seizures in Childhood: Semiologic and Electrophysiologic Variability

Summary:  Purpose: To delineate further the clinical and electrophysiologic features of proven startle‐provoked epileptic seizures (SPESs) in children.

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy.

Electroencephalographic evolution of hypsarrhythmia: Toward an early treatment option

Purpose:  A retrospective study for a classification of prehypsarrhythmic elecroencephalographies (EEGs) was carried out to enable an early treatment option for West syndrome.

Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation

Boys with unexplained West syndrome should be examined for a mutation in the Aristaless related homeobox gene, especially, when the family history is positive for mental retardation and epilepsy. X-linked West syndrome is very rare. We report on two brothers with West syndrome and dystonia with polyalanine expansion of the Aristaless related homeobox gene (ARX). The index patient (Fig. 1a; III-2) was the second child of non-consanguineous parents, born in 2001 at term, after an uneventful pregnancy and delivery (birth weight 3659 g, 75th percentile; length 51 cm, 75th percentile; head circumference 35 cm, 50th percentile). At the age of 3 months he developed infantile spasms and a hypsarrhythmic EEG pattern. He promptly responded to vigabatrin therapy. At 5 months a generalised dystonia, i.e. increased muscle tone with dystonic posturing of limbs, was evident. At the age of 3 years, he is able to walk a few steps with help and grasping objects is very difficult. He has no expressive speech. The elder brother of the index patient (Fig. 1a; III-1) was born in 1996 by caesarean section because of neonatal macrosomia (birth weight 4200 g, 90th percentile; length 53 cm, 90th percentile; head circumference 38 cm, >90th percentile). At the age of 3 months he showed dystonic movements and marked truncal hypotonia. One month later he developed infantile spasms and a hypsarrhythmic EEG pattern. He did not respond to vigabatrin, but to ACTH. At the age of 8 years he is wheel-chair bound, not talking, grasping objects is not possible. In both children metabolic tests and neuroimaging (MRI) were normal. Actually, both brothers suffer from a severe dystonia, mental impairment and rare generalised tonic-clonic seizures (the older brother), treated with valproic acid. The family history was remarkable. In the maternal uncle (Fig. 1a; II-3, now 37 years old), spastic tetraplegia, mental retardation and epilepsy have been present since early infancy. In retrospect, the epilepsy syndrome could not be classified. MRI was not performed in this uncle, the mother or the grandmother. From the pedigree and the clinical findings we suspected a mutation in the ARX gene. Following informed consent, a sequence analysis of the coding region and flanking intronic sequences of the ARX gene was performed. The male proband (index patient; Fig. 1a; III-2) as well as his brother and uncle were found to be hemizygous for a 21 bp GCG repeat expansion in exon 2 of the ARX gene c.333_334ins(GCG)7, which expands the first of four alanine tracts from normally 16 to 23 alanine residues (Fig. 1b,c). Both the mother (Fig. 11; II-2) and the maternal grandmother (Fig. 1a; I-2) were identified as heterozygous mutation carriers using an optimised fluorescence-based PCR assay. Mutations in the ARX gene have been found in a broad spectrum of disorders including X-linked infantile spasms (ISSX)/West syndrome, mental retardation [2], ataxia and dystonia (Partington syndrome), syndromic and non-syndromic forms of mental retardation, myoclonic epilepsy and X-linked lissencephaly with abnormal genitalia (XLAG) [5, 6,8]. The mutation found in our Swiss family, which is not related to previously reported families, has been described before in boys with infantile spasms and normal MRI, severe mental and motor retardation [7]. In addition to Partington syndrome, dystonia was described in a few unpublished Australian and Norwegian cases [6], but G. Wohlrab (&) AE B. Schmitt AE E. Boltshauser Department of Neuropaediatrics and Neurophysiology, University Children’s Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland E-mail: gabriele.wohlrab@kispi.unizh.ch Tel.: +41-1-2667701 Fax: +41-1-2667165

Vigabatrin therapy in infantile spasms: Solving one problem and inducing another?

That is, most of the children with infantile spasms have symptomatic etiology and later mental deficiency, but all of the mentally retarded patients were excluded in the studies of Gaily et al. (2009) and Vanhatalo et al. (2002). 4. The same investigators that were involved in the Gaily et al. (2009) study have also reported VAVFL of older children in only 4 of 53 patients (8%) at the University Hospital of Helsinki (Rintahaka et al., 2000). It is not clear to me why the patients in this population have a much smaller risk of VAVFL compared to patients in other reports, where the prevalence in children appears to be similar to that seen in adults (Spencer & Harding, 2003). The prevalence of VAVFL in six series of children was 35% (63 of 186 children); in 15 published series of adults, the prevalence was 39% (354 of 896 adults) (Sorri, 2001). Is there a genetic difference between the populations of children in these latter studies and the population examined by Gaily et al. (2009)? Or was the kinetic perimetry test not used appropriately in the studies of Rintahaka et al. (2000) and Gaily et al. (2009)? The reliability of the kinetic perimetry has been criticized on the grounds that the operator might (consciously or subconsciously) attempt to obtain a ‘‘correct’’ field, which in turn could cause a bias in the results. The reliability of the kinetic perimetry depends on the examiner’s skills. 5. The long-term use of VGB treatment by Gaily et al. (2009) of up to 29.8 months in children with idiopathic spasms, is surprising given that half of these patients stopped having spasms within a few days of the start of VGB therapy. 6. Even just one child with mild VAVFL is too many. He or she will never receive a driver’s license. Moreover, reports from animal experiments have been alarming. Drugs that increase brain c-aminobutyric acid (GABA) levels, such as the GABA transaminase inhibitor VGB, can cause apoptotic degeneration during the brain growth-spurt period (Bittigau et al., 2003). 7. The earliest sustained onset of the VGB-induced retinal defect in infants is 3.1 months (Ovation Pharmaceuticals Inc., 2007), and retinal defects ranged from 15– 31% (University of Toronto, 2007). The lowest total dose of VGB (914 g) was associated with VAVFL in one study (Vanhatalo et al., 2002), and detected at the time of the first visual field defect (VFD) test. It is possible that VFDs develop even earlier. Although it has been recommended that ‘‘infants should be tested at baseline and at 3-month intervals for the first 18 months of treatment, and then every 6 months thereafter with electroretinography (ERG)’’ (Ovation Pharmaceuticals Inc., 2007; Willmore et al., 2009), such procedures would be impractical because ERG requires sedation. In conclusion, available data suggest that VFDs after VGB therapy in children might be as frequent as in adults, and no safety period can yet be given. To address this issue, it remains important that infants treated with VGB for infantile spasms be studied in larger numbers when they are old enough to cooperate.

Does amplitude-integrated electroencephalogram background pattern correlate with cerebral injury in neonates with hypoxic-ischaemic encephalopathy?

To determine the correlation between amplitude‐integrated electroencephalogram (aEEG) background pattern and cerebral magnetic resonance imaging (MRI) in infants with hypoxic‐ischaemic encephalopathy (HIE) and to examine whether the correlation changes with therapeutic hypothermia.

Benign Focal Epileptiform Discharges in Children After Severe Head Trauma: Prognostic Value and Clinical Course

Summary: Purpose: To assess the occurrence and prognosis of benign focal epileptiform discharges (BFED) in EEG after severe head trauma (SHT) in children.