Background: Craniopharyngiomas are tumorous embryogenic malformations. As the survival rate after craniopharyngioma is high (92 %), prognosis and quality of life (QoL) in survivors mainly depend on adverse late effects such as obesity. Patients and methods: We analyzed 214 children and adolescents with craniopharyngioma. The records of 185 patients (86 %) were available for retrospective analysis of weight profiles and risk factors for obesity. Quality of life (QoL) was measured in 145 patients by the Fertigkeitenskala Münster/Heidelberg score (FMH) and in 77 patients by PEDQOL questionnaire. Results: Eighty-two of 185 patients (44 %) developed severe obesity (body mass index [BMI] > 3 SD). Obese patients were compared with 79 patients (43 %) who kept normal weight (BMI < 2 SD). No differences between obese and normal weight patients were found in terms of gender distribution, age at diagnosis and follow-up period. However, the BMI SDS at the time of diagnosis was higher (p < 0.0001) in patients who developed obesity than in those who did not. Furthermore, obese patients presented with bigger tumors (p < 0.05) and a higher rate of a hydrocephalus requiring a shunt (p < 0.05) and hypothalamic involvement (p < 0.05). The mothers of patients who developed severe obesity had a higher BMI (p < 0.001) at the time of diagnosis. Obese patients had a higher height-SDS at diagnosis (p < 0.05) and at the time of last follow-up (p < 0.05) when compared with normal weight patients. A prediction model for severe obesity after craniopharyngioma was calculated by logistic regression based on the risk factors: patient's BMI > 2 SD at diagnosis (p < 0.05; odds ratio: 16.4), hypothalamic involvement (p < 0.05; odds ratio: 3.4) and maternal BMI > 25 kg/m² (p < 0.05; odds ratio: 4.6). Significant increases in BMI (p < 0.001) occurred during the early post-operative period especially during the first three years after diagnosis. FMH percentiles correlated negatively with BMI SDS (Spearman r: - 0.37; p < 0.001). Children with craniopharyngioma rated their QoL more negative (p < 0.05) in regard to physical abilities, cognitive functioning and social functioning when compared with healthy children of the same age group. Severely obese patients with craniopharyngioma estimated their QoL lower (p < 0.05) for all domains except for autonomy, cognition and familial integration in comparison with non-obese patients. Conclusion: Hypothalamic tumor involvement and familial disposition for obesity are risk factors for the development of severe obesity in patients with craniopharyngioma. As weight gain starts early after diagnosis and severe obesity causes a reduction in QoL, early therapeutic efforts should be considered in patients at risk. To confirm our results the prospective multicenter study Kraniopharyngeom 2000 on children and adolescents with craniopharyngioma was initiated (www.kraniopharyngeom.com). Hintergrund: Kraniopharyngeome sind tumoröse Fehlbildungen embryonalen Ursprungs. Die Überlebensrate der Patienten ist hoch (92 %), so dass Prognose und Lebensqualität der Patienten von Spätfolgen abhängig sind. Kraniopharyngeome mit suprasellärer Ausbreitung führen häufig zu hypothalamischen Essstörungen und ausgeprägter Adipositas der Patienten. Patienten und Methoden: Im Rahmen einer multizentrischen Querschnittuntersuchung wurden 214 Kinder und Jugendliche mit Kraniopharyngeom nachuntersucht. Die Krankenunterlagen von 185 Patienten (86 %) wurden ausgewertet hinsichtlich des Gewichtsverlaufs und der Risikofaktoren für eine Adipositas. Die Lebensqualität wurde mittels Fertigkeitenskala Münster/Heidelberg (FMH) (n=145) und PEDQOL-Fragebogen (n=77) gemessen. Ergebnisse: 82 von 185 Patienten (44 %) entwickelten eine schwere Adipositas (Körpermassen-Index [BMI] > 3 SD). Die Gruppe der adipösen Patienten wurde verglichen mit 79 Patienten (43 %), die im Verlauf normalgewichtig (BMI < 2 SD) blieben. Zwischen beiden Gruppen bestanden keine Unterschiede hinsichtlich der Geschlechtsverteilung, des Lebensalters bei Diagnose und der Nachbeobachtungszeit. Patienten, die eine schwere Adipositas entwickelten, boten bereits zum Zeitpunkt der Kraniopharyngeom-Diagnose und im weiteren Verlauf einen höheren BMI-SDS (p < 0,001) und Körperhöhen-SDS (p < 0,05) als Patienten, die normalgewichtig blieben. Darüber hinaus waren die Kraniopharyngeome der adipösen Patienten größer (p < 0,05), zeigten häufiger eine Hypothalamusbeteiligung (p < 0,05) und machten häufiger (p < 0,05) einer Liquorableitung notwendig. Mütter adipöser Patienten hatten einen höheren BMI zum Zeitpunkt der Tumordiagnose als Mütter von Patienten, die normalgewichtig blieben. Mittels logistischer Regressionsanalyse wurde ein Vorhersagemodell für das Auftreten einer schweren Adipositas (BMI-SDS > 3 SD) bei Kraniopharyngeom anhand folgender Faktoren entwickelt: BMI des Patienten > 2 SD bei Diagnose (p < 0,05; Odds Ratio: 16,4), Hypothalamusbeteiligung (p < 0,05; Odds Ratio: 3,4) und mütterlicher BMI > 25 kg/m² (p < 0,05; Odds Ratio: 4,6). Der mittels FMH-Skala ermittelte Perzentilenwert für die Lebensqualität zeigte eine negative Korrelation (Spearman r: - 0,37; p < 0,001) mit dem BMI-SDS. Kraniopharyngeompatienten schätzten ihre Lebensqualität hinsichtlich physischer, kognitiver und sozialer Funktionen negativer (p < 0,05) ein als gesunde Gleichaltrige. Adipöse Patienten hatten im Vergleich zu normalgewichtigen Patienten eine niedrigere (p < 0,05) Selbsteinschätzung ihrer Lebensqualität in allen PEDQOL-Domänen außer für Autonomie, kognitive Fähigkeiten und familiäre Integration. Schlussfolgerung: Eine Hypothalamusbeteiligung des Kraniopharyngeoms sowie eine familiäre Disposition für Übergewicht sind wichtige Risikofaktoren für die Entstehung einer ausgeprägten Adipositas von Kranio-pharyngeompatienten. Da die Adipositasentwicklung bereits präoperativ beginnt und bei postoperativer Progredienz zu gravierender Beeinträchtigung der Lebensqualität führt, sind frühzeitige Interventionen zur Gewichtsregulation von Risikopatienten empfehlenswert. Die multizentrische prospektive Beobachtungsstudie Kraniopharyngeom 2000 wurde initiiert zur Bestätigung unserer retrospektiv gewonnenen Ergebnisse. (www.kraniopharyngeom.com)

Focal cortical dysplasias (FCDs) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. However, little is known about the clinical characteristics of epilepsy in these patients. In order to elucidate the clinical characteristics of their epilepsy, 120 pharmacoresistant patients including children and adults with histologically proven FCD were studied retrospectively. Age at seizure onset was analysed in the total group and compared between subgroups with different localization and different histological subtypes of FCD. The role of febrile seizures with respect to dual pathology was investigated. Seizure semiology was analysed focusing on initial seizure type and change of seizure semiology during the course of disease. Finally, transient responsiveness to antiepileptic drug therapy was studied. In the majority of patients, epilepsy began in the first 5 years of life. However, onset of epilepsy could also occur in the second or third decade until the age of 60. Age at epilepsy onset was not significantly different between temporal, extratemporal and multilobar localization of FCD. Patients without cytoarchitectural abnormalities (mild malformations of cortical development, FCD 1a according to Palmini) had significantly later epilepsy onset (P= 0.001) compared with patients with cytoarchitectural abnormalities (FCD 1b, 2a and 2b according to Palmini). In patients with additional hippocampal sclerosis (dual pathology) febrile seizures were significantly more frequently reported (P = 0.02) than in patients without dual pathology. Moreover, patients with dual pathology and febrile seizures significantly more frequently presented with severe hippocampal sclerosis (Wyler Grade 3–4) as compared with patients with dual pathology in the absence of febrile seizures (P = 0.03). First observed seizures were mainly tonic or generalized tonic–clonic. A change of seizure semiology seemed to be age-dependent and occurred between the age of >1 and 14 years. About 15.8% of the patients presented with status epilepticus during the course of disease. About 17% of the patients showed transient responsiveness (≥1 year seizure freedom) to antiepileptic drug therapy either after initial therapy (50%) or later in the course of epilepsy (50%). Patients with FCD represent a heterogeneous group. Different age at epilepsy onset and transient responsiveness to antiepileptic drugs in ∼17% of patients may reflect different dynamics in epileptogenicity of the underlying FCD. Dual pathology may be associated with different pathomechanisms in patients with and without febrile seizures.

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

The purpose of this study was to assess whether the histological subtype of focal cortical dysplasia and dual pathology affect surgical outcome in patients with medically intractable epilepsy due to focal cortical dysplasia (FCD). We retrospectively analysed the outcome of 67 patients from 2 to 66 years of age at follow-up periods of 6 to 48 months after epilepsy surgery. Histological subtypes were classified according to Palmini and included a few cases with mild histological abnormalities corresponding to the definition of mild malformations of cortical development. The seizure outcome was classified according to Engel and evaluated at the last follow-up visit as well as at follow-up periods of 12 and 24 months after surgery. The outcome in patients with FCD and additional hippocampal pathology (dual pathology) was analysed separately. Distribution of histological subtypes differed in temporal and extratemporal localization, with a significantly higher extratemporal prevalence of FCD type 2. There was a tendency towards better postsurgical outcome related to the last follow-up visit in patients with more subtle abnormalities classified as mild malformations of cortical development (mMCD) (63% Engel Ia), FCD type 1a (67% Engel Ia) and FCD type 1b (55% Engel Ia) compared with patients with FCD type 2a (43% Engel Ia) and FCD type 2b (Taylor type) (50% Engel Ia). Considering the outcome at follow-up periods over 12 and 24 months, complete seizure-freedom was achieved significantly more often in patients with FCD type 1 and mMCD than with FCD type 2, and seizure reduction by less than 75% (Engel IV) occurred in more patients with FCD type 2a compared with the other subgroups. This tendency was seen in the whole patient group and in the extratemporal subgroup. Patients with dual pathology almost always had temporal lobe epilepsy; the outcome in this patient group was generally favourable (66% complete seizure-freedom at the last follow-up visit). The outcome remained almost constant with longer periods of follow-up. We conclude that patients with FCD type 1 and mMCD had a better outcome compared with those with more severe forms of cortical dysplasia. A higher incidence of FCD type 1 in temporal localization did not allow the effects of histological subtype and localization to be separated. A subanalysis of extratemporal FCDs, however, revealed a similar tendency for a better outcome with FCD type 1, suggesting that the histological subtype itself seems to be at least a relevant cofactor influencing postsurgical outcome.