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Contains fulltext : 293517.pdf (Publisher’s version ) (Open Access) BACKGROUND: Guillain-Barré syndrome (GBS) has a highly variable clinical course and outcome as indicated by the risk of developing respiratory failure and residual inability to walk. Prognostic models as Erasmus GBS Respiratory Insufficiency Score (EGRIS) developed in adult patients are inaccurate in children. Our aim was to determine the prognostic factors of respiratory failure and inability to walk in children with GBS and to develop a new clinical prognostic model for individual patients (EGRIS-Kids). METHODS: A multicenter retrospective cohort study was performed using the data of children (younger than 18 years) fulfilling the diagnostic criteria for GBS from the NINDS. This study was performed in two independent cohorts from centers in Germany, Switzerland, Austria (N = 265, collected 1989-2002) and The Netherlands (N = 156, collected 1987-2016). The predicted main outcomes were occurrence of respiratory failure during the disease course and inability to walk independent at one year after diagnosis. RESULTS: In the combined cohort of 421 children, 79 (19%) required mechanical ventilation and one patient died. The EGRIS-kids was developed including: age, cranial nerve involvement and GBS disability score at admission, resulting in a 9 point score predicting risks of respiratory failure ranging from 4 to 50% (AUC = 0.71). A lower GBS disability score at nadir was the strongest predictor of recovery to independent walking (at one month: OR 0.43 95%CI 0.25-0.74). CONCLUSIONS: EGRIS-Kids and GBS disability score at admission accurately predict the risk of respiratory failure and inability to walk respectively in children with GBS, as tools to personalize the monitoring and treatment.

Several controlled studies have shown that in children with cerebral palsy, botulinum toxin A (BTX/A) can decrease muscular hyperactivity associated with spasticity and improve function. Studies have hitherto focused on the dimensions of impairment and functional limitations. In this pilot study with BTX/A in children with cerebral palsy, we used the Pediatric Evaluation of Disability Inventory (PEDI) to evaluate the effect of treatment. PEDI is a reliable and valid instrument that focuses on assessing disability in daily life. Patients with cerebral palsy (n = 17, median age 5.5 years, age range 2.5 to 16.5 years) were treated with BTX/A for pes equinus (n = 8) or adductor spasm (n = 9). PEDI assessment was carried out before and 1 month after the first treatment with BTX/A. Scaled scores were calculated according to the user’s manual for the Mobility domain with scores near „0” reflecting low capability and scores near „100” reflecting high capability. We found a significant improvement in the mobility domain-caregiver dimension from 52.3% ± 26.6% to 56.6% ± 26.7% (mean, standard deviation P < 0.05), as well as in the self care domain-functional skills from 63.6% ± 18.7% to 65.2% ± 19.6% (mean, standard deviation P < 0.05). Our data indicate that in young patients with cerebral palsy, BTX/ A therapy of the lower extremity can reduce the disability. For these patients PEDI is a valuable assessment instrument that reflects the effect of treatment with BTX/A on the disability. (J Pediatr Neurol 2003; 1(1): 29-34).

Neurochirurgisch zu behandelnde Fehlbildungen und Erkrankungen beruhen sehr haufig auf Anlagestorungen, bei deren Zustandekommen genetische und exogene Faktoren mit sehr wechselndem Gewicht zusammenwirken. Einzelne Erkrankungen sind unmittelbar mit bekannten pathogenen Mutationen assoziiert, wahrend fur andere die Bedeutung der Genetik lediglich epidemiologisch beispielsweise aus Zwillingsstudien zu schliesen ist. Bekannte toxische Einflusse (z. B. Valproat-Embryopathie) manifestieren sich nie bei allen exponierten Kindern, sodass auch hier begunstigende genetische Faktoren postuliert werden mussen. In diesem Kapitel kann aus einer Flut von genetischen Informationen nur ein kleiner Teil dargestellt werden, dessen Kenntnis dem Kinderneurochirurgen hilft, genetische, fur den Patienten und dessen Familie wichtige Implikationen zu erkennen. Das genetische Wissen erweitert sich kontinuierlich, sodass auch aktuelle Lehrbucher meist schon uberholt sind. Systematische und aktuelle Informationen konnen auch im Internet aufgefunden werden. Im Zweifel wird sicher meist die Beiziehung eines Fachgenetikers erforderlich sein.

EEG-fMRI has been used in epilepsy as a tool to indentify epileptic networks involved in the generation of spikes and seizures. The method is based on the measure of blood flow changes and allows the high temporal resolution of EEG to be combined with the high spatial resolution of MRI to evaluate brain networks involved in generating intrinsic brain signals. The main focus of research in generalized epilepsies is the understanding of underlying mechanisms, while EEG-fMRI in focal epilepsies has also been evaluated as a method for focus localization in presurgical epilepsy. Despite its extensive use over recent years, EEG-fMRI in epilepsy is still not established as a routine clinical tool, as it faces many methodological challenges which complicate its interpretation. In some patients the sensitivity of the method is low due to a lack of sufficient number of interictal spikes; the correct manner for statistical analysis as well as thresholding are still being debated. The present review gives a short overview of clinical applications of EEG-fMRI in epilepsy and discusses in detail new developments in the field which may allow methodological challenges to be overcome in the future.

Introduction Benign epilepsy with centrotemporal spikes (BECTS) is a common epilepsy syndrome in childhood. Besides the occurrence of seizures, mild cognitive impairments and behavioral problems affecting language skills, spatial perception, memory, executive function, and academic achievement might be present. There is no international consensus about the decision whether or not to treat affected children. The influence of treatment on cognitive functions is debated. Methods Patients diagnosed with BECTS were assessed in short term auditory memory, long-term verbal memory, intelligence and behavior using the “number recall” test from the Kaufman assessment battery for children, the “verbal learning memory test”, the “culture free intelligence test” and the “child behavior checklist” prior to a randomized controlled antiepileptic therapy and after a treatment period of 6 months with either sulthiame or levetiracetam. Results 43 of 44 randomized patients were analyzed. One patient had to be excluded due to protocol violation. Patients who completed the study showed a non-significant improvement in parent-reported behavioral problems under therapy. Cognitive skills were not affected. Conclusion The present data suggest that antiepileptic drug treatment of children with BECTS with either sulthiame or levetiracetam does not affect cognitive performance. Behavior improved in a subset of patients though not reaching statistical significance.

Metachromatic leukodystrophy (MLD) is a progressive white matter disease caused by arylsulfatase A deficiency. Demyelination in the nervous system is detected by cerebral magnetic resonance imaging (MRI) and neurophysiological studies. We present three children with infantile MLD, who had difficulties in standing and walking with absent reflexes. Protein levels in cerebral spinal fluid (CSF) were elevated and nerve conduction studies revealed slowing down of motor nerve conduction velocity. Initial cerebral MRIs showed no white matter changes. Consecutively, all three children developed clinical symptoms of neurodegenerative disease. Follow-up MRI and arylsulfatase A testing led to diagnosis of MLD. We conclude, that in young children who present with an acute/subacute demyelinating polyneuropathy, MLD is a differential diagnosis.

Das Aicardi-Goutieres-Syndrom (AGS) ist eine seltene, schwere, progrediente Enzephalopathie, die meist im fruhen Sauglingsalter beginnt. Sie ist gekennzeichnet durch intrazerebrale Verkalkungen, Leukodystrophie, chronische Liquorlymphozytose und Interferon-α-Erhohung im Liquor. Die Befunde lassen an eine intrauterine Infektion denken. Es handelt sich jedoch um eine genetisch und phanotypisch heterogene, uberwiegend autosomal-rezessiv vererbte Erkrankung mit entsprechendem Wiederholungsrisiko. Klinik und Laborbefunde zeigen Parallelen zum infantilen systemischen Lupus erythematodes. Bislang wurden 4 unterschiedliche Gene identifiziert, weitere werden vermutet. Sie kodieren fur Nukleasen, die am Abbau zelleigener DNA-RNA-Reste beteiligt sind. Die bekannten Mutationen fuhren zu einem Aktivitatsverlust und chronischer Uberstimulation des angeborenen Immunsystems. Uber intrazellulare Signalkaskaden kommt es, vergleichbar wie bei Virusinfektionen, zu einer vermehrten Bildung von Interferon-α. Bei bekannter Mutation ist eine pranatale Diagnose moglich.

Zusammenfassung80 bis 90% aller spinalen Muskelatrophien (SMA) entfallen auf den autosomal-rezessiven Typ des Kindes- und Jugendalters, dessen Gen (SMN-Gen) auf Chromosom 5 identifiziert werden konnte. Auf Grund einer Duplikation dieses Chromosomenabschnittes liegt das Gen in zwei Kopien vor (SMN1 und SMN2), die sich lediglich in fünf Nukleotiden unterscheiden. Diese Unterschiede führen jedoch zu unterschiedlichem mRNA-Spleißen, indem nur das SMN1-Gen zu einem stabilen Genprodukt führt (SMN-Protein), während das Genprodukt von SMN2 instabil ist. Heterozygotes Fehlen von SMN1 führt zur SMA, während die Zahl der dennoch vorhandenen SMN2-Kopien den Schweregrad der Erkrankung bestimmt (SMA TypI bis III). Das SMN-Protein ist in allen Zellen an der Regulation der mRNA Synthese beteiligt. In den Motoneuronen scheint es zusätzlich eine besondere Rolle bei Wachstum und Differenzierung der Axone zu haben. Aktuelle experimentelle Therapieansätze zielen darauf ab, das Spleißverhalten des SMN2-Gens zu verbessern, sodass eine erhöhte Konzentration von funktionellem SMN-Protein resultiert. Erste klinische Studien sind in Vorbereitung.

We assessed the cardiac findings in Duchenne muscular dystrophy (DMD) and Becker-Kiener muscular dystrophy (BMD) patients in the large outpatient group of our single-center institution. The analysis included the revision of patient records (retrospectively) and current echocardiography, electrocardiogram (ECG), and Holter ECG data (prospectively). Reduced left ventricular fraction shortening (FS)25% was found in 24% of all patients (50 DMD, 12.1 +/- 4.7 years: 20 BMD, 17.1 +/- 8.5 years). Median age of onset of FS25% was 16.8 +/- 1.0 in DMD and 30.4 +/- 3.4 in BMD; (p0.05). Holter ECG in DMD demonstrated sinus tachycardia in 26% deprivation of circadian rhythm in 31%, and reduced heart rate variability in 51%. For these reasons, we recommend carrying out echocardiography annually in DMD and BMD10 years. Because the rate of disturbances in the cardiac autonomic nervous system is high in DMD, we also recommend Holter ECG annually. Further investigation should be conducted to determine if treatment with ss-blockers and ACE inhibitors in combination reduces cardiac autonomic nervous imbalance, thus improving patient outcome in DMD.

1987 berichtete Watanabe erstmals uber eine in 50% der Falle familiar auftretende gutartige Epilepsie mit komplexen Partialanfallen bei Sauglingen und Kleinkindern (BPEI). Die spater von Vigevano beschriebenen Familien wiesen alle von Watanabe definierten Kriterien auf, zeigten jedoch einen strikt autosomal-dominanten Erbgang und eine Kopplung auf Chromosom 19q. In ihrem neuesten Vorschlag fur ein Diagnoseschema akzeptiert die ILAE die beiden Syndrome als "benign-non familial/autosomal dominant-infantile seizures". Mit Hilfe einer multizentrischen Datenbank wurden 24 Patienten mit BPEI identifiziert. In 2 grosen betroffenen Familien wurde die genetische Kopplung auf Chromosom 19q analysiert. Alle Patienten erfullten die von Watanabe aufgestellten klinischen Kriterien, das interiktale EEG bot jedoch eine hohere Rate an Auffalligkeiten als bisher beschrieben. 14 der 24 Patienten hatten eine positive Familienanamnese fur benigne Epilepsien, in 2 Familien uber 3 Generationen. Die benignen NF/AD infantile seizures sind 2 hochstwahrscheinlich genetisch distinkte, klinisch aber sehr nah verwandte Epilepsiesyndrome mit gutartigem Verlauf. Das Spektrum der Watanabe-Epilepsie ist weiter als initial definiert; ein interiktal pathologisches EEG schliest die Diagnose dieses gutartigen Epilepsiesyndroms nicht aus.

Danon disease (DD) is a rare lysosomal glycogen storage disease with normal acid maltase activity, which is characterised clinically by cardiomyopathy and myopathy, and a variable degree of mental retardation. The causative gene, LAMP2, has been mapped to chromosome Xq24-q25. LAMP2 encodes a lysosome-associated membrane glycoprotein. We identified a novel LAMP2 mutation of the exon 8 splice acceptor site (IVS7-1G --> A) in an affected male and female, which predicts abnormal splicing. Both affected individuals presented solely with hypertrophic cardiomyopathy. Muscle weakness and mental impairment were absent. Diagnosis of Danon disease was established by muscle biopsy, when the male index patient developed transient severe muscle weakness following heart transplantation. Typical biopsy findings were also found in a heart muscle specimen. Demonstration of the LAMP2 mutation in affected male and female siblings is compatible with X-linked dominant inheritance. Danon disease should be actively looked for in cardiomyopathy patients.

A newborn male child was admitted with hypoxemia, high output failure, hypertrophic right lower limb with a segmental pink naevus flammeus, lymphatic edema, subcutaneous varices and multiple arteriovenous fistulae (AVF) spinal and pelvine; findings of the Klippel-Trenaunay- / Parkes-Weber-Overlap Syndrom (KTW). Because of a threatening right heart insufficiency caused by the shuntvolume, the child was embolized as early as 5 months of age. In the course of 5 years, a total of 17 spinal and pelvic feeding arteries were occluded in 6 sessions using Histoacryl, Platincoils or Ethibloc. The low weight of the child's body (4.3 kg) and cardiac insufficiency (CI) limited the amount of contrast agent and fluid. To reduce the amount of contrast agent used for diagnostic purposes we analyzed the pathological hemodynamics by magnetic resonance angiography (MRA). Within 5 years normal bodily development took place with no sings of exponential growth of the affected leg. We understand the “newly formed” fistulae in the current angiography as a local hemodynamic activation of persistent primitive arteriovenous communication caused by mesodermal disturbances, the degree of which correlate with the prognosis.

Background Isolated optic neuritis (ON) in childhood may remain a single episode or mark the clinical beginning of multiple sclerosis (MS). Higher age and pathological cranial MRI (cMRI) at presentation were previously demonstrated as independent risk factors of conversion to MS. Objective To further evaluate potential MS risk factors, including cerebrospinal fluid findings (CSF), in children with ON as a first demyelinating event. Methods Children with isolated uni- or bilateral ON as a first demyelinating event below age 18 were included in this retrospective multicenter cohort study. The minimal follow-up (FU) for those not converting to MS according to McDonald 2010 was 2 years. Age, sex, laterality of ON, cMRI (no vs ≥1 MS-compatible lesion outside the optic nerves) and intrathecal oligoclonal IgG bands (OCB) were assessed as risk factors using simple and multiple Cox proportional-hazards regressions. Results Of 357 included children 284 had uni- and 73 bilateral isolated ON. Median FU of patients not developing MS was 4.2 years (range 2.0–22.0). Univariate analyses revealed age (HR 1.15, 95% CI 1.10–1.22, p Conclusion Cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON as a first demyelinating event.

Intracerebral aneurysms are rare. However they are potentially life-threatening. Today by means of ultrasound investigations these malformations can occasionally be identified prenatally. In these cases questions of intrauterine therapy, mode and time of delivery and postnatal treatment have to be discussed with the parents. We describe two cases with prenatal diagnosis of intracerebral arteriovenous malformations, diagnostic workup, therapeutic options and fetal outcome.

Epidemiologie. Krankheiten der peripheren Nerven konnen bei Kindern wie bei Erwachsenen sehr verschiedene Ursachen haben. Akute para-sowie postinfektiose Neuropathien und hereditare Polyneuropathien machen jeweils etwa 1/3 der Gesamtzahl der Falle aus. Von den chronisch verlaufenden Krankheiten sind im Kindesalter mehr als 3/4 hereditar bedingt.

Das zum Medikament gewordene Toxin etablierte sich spater als Therapie der Wahl in der Erwachsenenneurologie fur den Torticollis spasmodicus, den Blepharospasmus und den Hemispasmus facialis. Die intramuskulare Injektion von Botulinum-Toxin A gilt hier als effektives, sicheres und nebenwirkungsarmes Therapieverfahren. Seit Beginn der 90er Jahre liegen Erfahrungen bei der Anwendung von Botulinum-Toxin A bei spastischen Bewegungsstorungen im Kindesalter vor. Chancen und Grenzen dieser therapeutischen Moglichkeit sollen – gemeinsam mit den korrespondierenden Erfahrungen aus der Neurologie – dargestellt werden.

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 electroencephalographic (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=10, 21.3%) and interhemispheric differences/focal slowings (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. Med. Pediatr. Oncol. 29:121–131, 1997. © 1997 Wiley-Liss, Inc.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disease involving the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA). The main symptoms include retardation of psychomotor and language development, muscle hypotonia and non-progressive ataxia. Therapy consisting of approximately 75 mg/kg per day of vigabatrin, an irreversible inhibitor of GABA-transaminase, is reported to lead to some improvement of the clinical condition in affected patients. We report on a 12-year-old boy with SSADH deficiency who, when treated with 75 mg/kg per day of vigabatrin, showed marked amelioration of symptoms but also EEG changes and two generalized seizures. On discontinuing vigabatrin therapy, the seizures resolved and the EEG improved, but the patient's clinical condition deteriorated to its pre-treatment state. A stable EEG without the recurrence of seizures as well as renewed improvement of cognitive and behavioural functions was achieved with a reduced vigabatrin dose of 25 mg/kg per day. We conclude that vigabatrin in SSADH deficiency should be administered in a gradually increasing dosage combined with frequent evaluation of the clinical condition and the EEG.

Summary: Since our last report on valproate (VPA)-related hepatotoxicity in 1988, 8 other children have died of VPA-associated liver failure in Germany and Switzerland. We compared the clinical course of these children with that of 6 children with a reversible outcome of severe hepatotoxicity related to VPA. Thirty-five percent of patients with fatal liver failure were normally developed, 23.5% were receiving VPA monotherapy, and 35·3% were aged s2 years. The initial clinical symptoms of VPA-related hepatotoxicity were nausea, vomiting, apathy or coma, and increasing seizures in more than 50% of patients, in combination with febrile infections at onset of symptoms. As compared with the series of German patients reported in 1988, one third of the fatalities occurred after the first 6 months of therapy as compared with 6% in the 1988 series. Clinical symptoms and laboratory findings were the same in patients with reversible and with fatal outcome. Early or immediate withdrawal of VPA after the first signs of VPA-associated hepatotoxicity may be responsible for the increased number of children who recovered after VPA-related severe liver failure. The pathogenesis of liver failure during VPA treatment remains unknown; metabolic defects and cofactors such as polypharmacy or infections have become increasingly likely to contribute by depleting intracellular CoA. Worldwide, 132 patients have died of VPA-associated liver failure and/or pancreatitis. Because a group at risk for fatalities with VPA cannot be defined precisely, patients treated with VPA and their families must be made well aware of the clinical symptoms of hepatotoxicity such as apathy, vomiting, or increased seizure frequency, especially in the presence of febrile infections. Laboratory tests and clinical controls during the first 6 months of therapy should not be neglected. ReSUMe On presente le cas de 8 enfants morts pendant le traitement a l'acide valproique (VPA) en Allemagne et en Suisse depuis 1988. Chez 2 enfants, le developpement psychomoteur a ete normal. Deux enfants etaient sous monotraitement au VPA, 2 enfants etaient âges de moins de trois ans. Deux enfants montraient les premiers symptomes apres les 6 premier mois du traitement, ce qui a ete le cas seulement chez 6% des patients presentes en 1988 (Scheffner et al., 1988). Les premiers symptdmes de l'hepatotoxicite menancante etaient nausee, vomissement et apathie, frequemment en combinaison avec une infection febrile, chez les 8 enfants morts comme chez 6 enfants dont l'hepatotoxicite etait reversible, qui sont egalement presentes en detail dans cette communication. Les paramteres de laboratoire correspondaient a la defaillance hepatique chez tous les enfants. L'interval entre les premiers symptomes jusqu'a la discontinuation du VPA s'est raccourci a quelques jours depuis 1988, ce qui pourrait expliquer l'augmentation relative des cas reversibles. Le metabolite anorma1 4-ene-VPA ne joue aucun role ni pour la detection ni pour le traitement de la defaillance hepatique. Les mecanismes pathogeniques decesifs restent obscurs, une depletion intracellulaire du CoA soit en combinaison avec des maladies metaboliques ou soit avec une polytherapie ou une infection febrile paraissent au centre du pathomechanism. Au total, 132 cas d'hepatotoxicite fatale en relation avec le traitement au VPA ont ete decrits dans le monde entier. Comme il est impossible de delimiter avec precision un groupe au risque majeur pendant le traitement au VPA, les symptomes cliniques de l'hepatotoxicite menancante doivent etre bien connus B chaque patient traite au VPA et a sa famille. Des controles cliniques et des examens de laboratoire au moins une fois par mois pendant le six premiers mois du traitement ne doivent pas etre negliges. L'augmentation du pourcentage de l'hepatotoxicite reversible indique la possibilite de diminuer les complications fatals en se toujours rendant compte du probleme de l'hepatotoxicite pendant le traitement au VPA. RESUMEN Se presenta 8 pacientes fallecidos durante el tratamiento con acido valproico (VPA) en Alemania y en Suiza desde 1988. En 2 de los ninos el desarollo psicomotor era normal, 2 estaban bajo monoterapia, 2 eran menores de 3 anos. Dos de los ninos mostraban sus primeros sintomas de la hepatotoxicidad amenazadora despues de los 6 primeros meses del tratamiento, un porcentaje mucho mas elevado que los 6% encontrados en 1988 (Scheffner et al., 1988). Los primeros sintomas eran nausea, vomito, y apatia, frequentemente juntos con una infecion febril, sin diferencia entre los ninos fallecidos y 6 otros pacientes con una hepatotoxicidad reversible, tambien descritos en esta communicacion. Los parametros de laboratorio patologicos correspondian a la insuficiencia del higado. El intervalo entre los primeros sintomas de la hepatotoxicidad y la dicontinuacion del VPA era solo algunos dias desde 1988, lo que podria explicar el aumento relativo de los casos reversibles. El metabolito anomal 4-en-VPA no tiene ningun valor ni por la diagnosis ni por el tratamiento de la hepatotoxicidad asociada con el VPA. Los mecanismos patogenicos no estan claros, la reduccion del CoA a1 nivel intracelular sea por causa de una politerapia o de una infecion febril o sea en el contexto con un defecto metabolico parece en el centro del patomechanismo. En total, estan descritos en la literatura 132 pacientes fallecidos por hepatotoxicidad durante el tratamiento con VPA. Como no se ha logrado definir con precision el grupo con riesgo mayor durante el tratamiento con VPA, los sintomas de la hepatotoxicidad amenazadora tienen que ser bien conecidos por los pacientes bajo terapia con el VPA y tambien por sus familias. Controles clinicos y de laboratorio al menos uns vez por mes durante los 6 primeros meses del tratamiento parecen perentorios. El aumento relativo de los casos reversibles indica la possibilidad de reducir los fallecimentos relacionados al VPA si la vigilancia por este problema quede constante. ZUSAMMENFASSUNG Die klinischen Verlaufe von 8 Kindern, die seit 1988 in Deutschland und der Schweiz an einem Valproat (VPA)-assoziiertem Leberversagen verstorben sind, werden 6 Patienten mit einem reversiblen Verlauf gegenubergestellt. Zwei der 8 verstorbenen Kinder waren normal entwickelt, 2 erhielten eine VPA-Monotherapie, und ebenfalls 2 waren unter 3 Jahre alt: Die ersten Zeichen eines drohenden Leberversagens waren Ubelkeit, Erbrechen, Apathie und Koma, oder eine Zunahme der Anfalls-frequenz, bei mehr als der Halfte der Patienten bei einem gleichzeitig bestehenden fieberhaften Infekt. Vergleicht man die seit 1988 aufgetretenen Todesfalle unter VPA mit den zuvor berichteten (Scheffner et al., 1988), fallt eine Zunahme der Komplikationen jenseits des 6.Behandlungsmonats auf (ein Drittel der neuen Patienten im Vergleich zu 6% der fruheren Serie). Im Hinblick auf die klinischen Symptome und die Laborveranderungen unterschieden sich die irreversiblen nicht von den reversiblen Krankheitsverlaufen. Ein sofortiges Absetzen des VPA bei Auftreten von verdachtigen Symptomen kannte seit 1988 zu einem hoheren Anteil von reversiblem Leberversagen gefuhrt haben. Der abnormale VPA-Metabolit 4-en-VPA erwies sich als nicht spezifisch fur die VPA-assozierte Hepatotoxizitat, die Bestimmung der VPA-Metabolite hat sich weder fur die Diagnostik noch fur das Verstandnis des Leberversagens unter VPA fur nutzlich erwiesen. Der Pathomechanismus der VPA-assozierten Hepatotoxozitat bleibt unklar, ein Absinken des intrazellularen CoAs entweder durch Co-Faktoren wie Polytherapie oder fieberhafte Infekte oder durch metabolische Defekte scheint jedoch eine zentrale Rolle zu spielen. Weltweit sind bisher insgesamt 132 Patienten an einem Leberversagen unter einer VPATherapie verstorben. Da eine Risikogruppe fur diese Komplikation nicht scharf abgegrenzt werden kann, mussen alle Patienten und deren Familien die klinischen Symptome der VPA-assozierten Hepatotoxizitat kennen, um so ein rasches Absetzen des VPA bei Auftreten solcher Symptome zu ermoglichen. Klinische Kontrollen sowie Laborkontrollen bleiben wahrend der ersten 6 Behandlungsmonate mindestens einmal monatlich erforderlich. Eine unverandert hohe Aufmerksamkeit fur das Problem der VPA-assozierten Leberkomplikationen kann moglichweise dazu beitragen, die Anzahl der Todesfalle in Verbindung mit einer VPA-Therapie zu vermindern.

Quality of life (QOL) is important for the survivors of malignancies. We investigated health-related QOL in 51 patients treated with iodine-125 (¹²⁵I) brachytherapy for childhood low-grade gliomas. Instruments included a questionnaire on life situation, German versions of PEDQOL (8-18 years), EORTC QLQ-30 and head and neck module HN-35 (18 years), strength and difficulties questionnaire, "Fertigkeitsskala Münster Heidelberg", and an adapted Rankin score. The time lapsed since ¹²⁵I-brachytherapy was 134 months (median, range: 29-293 months). 57% of the patients were over 18 years of age, 34% were 11-17 years old and 8% were younger. 14 had undergone other treatments after ¹²⁵I brachytherapy. Over half of the18 year olds reported residual problems; 68% were disabled, 38% to a severe degree. Many of the young adults still lived with their parents and 17% were jobless. 43% of the children/adolescents needed rehabilitative treatment, 20% visited special schools and 71% were disabled, 33% severely. The patients and their caregivers rated their QOL as not different from that of the normal population. However, many QOL dimensions correlated to the severity of disability. Comparison of QOL outcomes between different treatment measures would require a prospective study controlling for the most important factors of influence.

Mobius syndrome is classically characterized by bilateral facial and abducens nerve paralysis in combination with limb defects. However, more cranial nerves may be involved in this syndrome and certainly merit special attention when formulating a treatment plan. Although well described, knowledge of surgical treatment options is surprisingly rudimentary outside the plastic surgical literature. Affected children are often subjected to years of unsuccessful „conservative“ treatment, mainly consisting of physiotherapy, thus, ignoring the pathology of this syndrome. In addition to physical symptoms significant psychological disabilities are almost uniformly encountered in affected patients. Traditionally, local muscle transpositions were performed with reasonable success in order to address the lack of facial animation, lack of lower lip support as well as speech difficulties. Modern reconstruction, however, consists of microsurgical free functional muscle transfers. A case of a 14 year old patient with Mobius syndrome is presented who was treated conservatively for >8 years without visible success regarding facial animation. A free functional gracilis muscle transfer was performed using the temporal vessels for revascularization and the motor nerve to the masseter for reinnervation. Ten weeks postoperatively the patient was able to voluntarily activate the muscle. A marked improvement of self-esteem has also been noted postoperatively. Close cooperation between pediatricians and plastic surgeons need to be reinforced to allow comprehensive treatment of facial palsy. Ultimately, this will allow us to provide affected children with the best treatment modality possible.

In 79 children treated for acute lymphoblastic leukaemia according to protocol ALL-BFM 81, serial EEG examinations were performed before, during and after therapy. Diffuse changes of the background activity were observed in 64% of the children at the time of diagnosis. During induction and reinduction treatment with vincristine andl-asparaginase, and with some delay after CNS irradiation, a marked slowing developed in up to 65% of patients. Children who had not been irradiated showed transient disturbances during treatment with medium-dose-methotrexate. Reinduction induced more abnormal EEGs in the children who had been irradiated. At the end of maintenance therapy, only slight EEG changes were found. No differences between the irradiated and non-irradiated group were then seen. Children with CNS leukaemia or seizures differed from those with an uncomplicated treatment in that they more often showed focal and persistent disturbances. In 39 patients who stayed in first remission for at least 18 months after the termination of treatment, a follow up investigation was performed. From the EEG examination, including power spectral analysis, no differences were found between irradiated and non-irradiated patients. Slowing of the dominant frequency was seen in the patients with more severe leukaemia and in those whose EEG had been markedly abnormal at diagnosis. The visually evoked potentials were normal in all groups of patients. In the brainstem auditory evoked potential, a prolongation of the latency of wave I and a decrease of the I–V interval was found in irradiated patients. We conclude that the diffuse EEG changes frequently emerging during treatment are reversible. Persistent or lateralized changes can indicate a neurological complication. Neurophysiological abnormalities found at long-term follow up, for the most part cannot be attributed to side-effects of the treatment but rather to disease related factors.

A major activator of antigen presenting cells (APC) is gamma interferon a product of activated T-lymphocytes. CNS is not well studied and represents a unique system with respect to the immune reactions. Neopterin is an indirect marker of gamma interferon deliberation and may give some new information on the role of APC in CNS. Neopterin in serum and cerebrospinal fluid (CSF) was determined by specific RIA in children who were lumbar punctured to exclude meningitis. Neopterin was found in various concentrations in serum and CSF of all patients (n = 47). Bacterial meningitis (group 3) was diagnosed in 12 and aseptic meningitis in 18 children (group 2). CSF was drawn in 17 children with febrile convulsions (group 1). Elevated serum neopterin in childhood was only reported in children with an atypical PKU, while data on CSF neopterin were published only in a few cases of adults with CNS involvement. The results show that the APC is stimulated rapidly in childhood similar as in adults following severe viral or bacterial infections. Furthermore neopterin in CSF is not only explained by alteration of the blood-brain barrier but also it may reflect local intrathecal response with activation of accessory cells (APC) in the CNS itself. Between the stimulation of the cellular immune system indicated by increased levels of neopterin and the severity of the disease seems to be a positive correlation.

Zerebrale Anfalle gehoren zu den haufigsten Symptomen einer Erkrankung des Gehirns im Kindesalter. Treten sie akut im Rahmen einer vorubergehenden Funktionsstorung auf, so spricht man von Gelegenheitsanfallen (⊡ Ubersicht). Rezidivierende, nicht durch ausere Ereignisse provozierte Anfalle fuhren zur Diagnose einer Epilepsie. Die Pravalenz der Gelegenheitsanfalle wird im Kindesalter mit mindestens 5% angegeben, die der Epilepsien mit 0,5%.

Die infantile neuroaxonale Dystrophie (INAD) wurde erstmals 1952 von Seitelberger beschrieben. Cowen und Olmstead pragten 1963 den Namen, und Ramaekers et al. gaben 1987 einen aktuellen Uberblick. Es handelt sich um ein seltenes, autosomal-rezessiv erbliches Leiden, dessen biochemischer und molekulargenetischer Hintergrund bislang ungeklart ist. Pathologisch-anatomisch finden sich in der grauen Substanz, vor allem in den Hinterhornern und Clarkeschen Saulen des Ruckenmarks, in den Hirnstammkernen und in der Substantia nigra grose eosinophile Spheroide, die axonalen Anschwellungen entsprechen. Kleinere eosinophile Korperchen finden sich im Ruckenmarksvorderhorn, im Kortex und in den Stammganglien. Sie stellen vergroserte prasynaptische Endigungen dar. Elektronenmikroskopisch bestehen die Spheroide und eosinophilen Korperchen aus Aggregaten von glatten Membranen und tubularen Strukturen. Pathophysiologisch wird unter anderem eine Storung des retrograden axonalen Transports diskutiert.

Differenzialdiagnose der cerebellaren Funktionsstorungen. Das Kleinhirn ist das Koordinationszentrum fur Gleichgewicht, Muskeltonus und zielgerichtete muskulare Aktivitat. Seine Funktionsstorungen werden durch Ausfalle dieser Funktionen erkennbar. Bei Erkrankungen des Urkleinhirns (Lobus flocculonodularis) resultiert eine schwere Gleichgewichtsstorung. Storungen des Altkleinhirns (Wurm) fallen durch Rumpf- und Gangataxie auf. Lasionen des Neocerebellum (Hemispharen) fuhren zu ipsilateraler Extremitatenataxie, Dysmetrie, Dysdiadochokinese und Intentionstremor. Unter den Kleinhirnerkrankungen sind akute, meist erworbene Ataxien von chronischen, meist hereditaren Ataxiesyndromen zu unterscheiden.