Kognitive Fähigkeiten und funktionelle Magnetresonanztomographie von Kindern mit unilateralen perinatalen Infarkten

Hintergrund Bisherige Forschungsergebnisse zum Risiko kognitiver Beeinträchtigungen nach perinatalen Infarkten sind uneinheitlich. Die nonverbale Intelligenz scheint besonders vulnerabel zu sein, da nach linksseitigen Infarkten Sprach-funktionen in die rechte Hemisphäre lateralisiert werden können. Dies kann nach bisherigen Forschungsergebnissen zu einer Reduktion der Kapazität für ursprüngliche rechtshemisphärische Funktionen führen. Eine pharmako-refraktäre Epilepsie, eine häufige Komplikation nach perinata-len Infarkten, kann zu einer dramatischen Beeinträchtigung der kognitiven Entwicklung führen. Weniger gut verstanden ist jedoch die Rolle von gut ein-gestellten Epilepsien. Wir untersuchten, ob eine gut eingestellte Epilepsie, sowie andere in der Literatur beschriebene Risikofaktoren wie eine motori-sche Beeinträchtigung, die Läsionsgröße, die Läsionsseite und die Sprachla-teralisation einen Einfluss auf die nonverbalen und verbalen Fähigkeiten von Kindern mit unilateralen perinatalen Infarkten haben. Außerdem prüften wir, ob verbale und nonverbale Fähigkeiten die gleichen Risikofaktoren für eine eingeschränkte kognitive Entwicklung teilen, oder ob sich die beiden Domä-nen unterschiedlich entwickeln. Methodik Wir rekrutierten 23 Patient:innen mit unilateralen perinatalen Infarkten (16 linksseitig), davon 8 Patient:innen mit gut eingestellter Epilepsie (9-26 Jahre), 15 Patient:innen ohne Epilepsie (8–23 Jahre), und 23 gesunde Kontrollen (8–27 Jahre). Wir erfassten die nonverbalen Fähigkeiten mit dem Test of Nonverbal Intelli-gence (TONI-4), einem Motorik-unabhängigen Testverfahren, das Ergebnis-verzerrungen durch handmotorische Einschränkungen verhindert. Die verbalen Fähigkeiten wurden durch den Potsdam Illinois Test für Psycho-linguistische Fähigkeiten (P-IPTA) untersucht, einem Sprachentwicklungstest. Die Sprachlateralisation wurde durch funktionelles MRT, die Läsionsgröße MR-volumetrisch erfasst. Die Handfunktion wurde durch den Jebson Taylor Handfunktionstest analysiert. Ergebnisse Patient:innen mit Epilepsie zeigten signifikant niedrigere nonverbale und ver-bale Fähigkeiten als Kontrollen. Patient:innen ohne Epilepsie schnitten ver-gleichbar mit typisch entwickelten Gleichaltrigen ab. Die Entwicklung einer Epilepsie korrelierte demnach in beiden Domänen mit einem schlechteren kognitiven Abschneiden. Multiple Regressionsanalysen ergaben Epilepsie als einzigen signifikanten Risikofaktor für beeinträchtigte nonverbale und verbale Fähigkeiten. Wir fanden zudem keinen systematischen Unterschied zwischen verbalen und nonverbalen Fähigkeiten. Dementsprechend zeigten die verbalen und non-verbalen Fähigkeiten eine starke Korrelation. Schlussfolgerung In unserer Kohorte von Kindern mit perinatalen Infarkten ohne Epilepsie reicht offenbar das neuroplastische Potential der intakten Hemisphäre für eine wei-testgehend normale Entwicklung nonverbaler und verbaler kognitiver Fähig-keiten, unabhängig von Läsionsgröße, Läsionsseite oder Sprachlateralisation. Epilepsien scheinen das neuroplastische Potential der intakten Hemisphäre zu reduzieren, sogar wenn sie gut eingestellt sind. Wir fanden keine Evidenz für eine unterschiedliche Entwicklung verbaler und nonverbaler Funktionen nach perinatalen Infarkten. Im Speziellen wurden die sprachlichen Fähigkeiten nicht vorzugsweise geschont im Verhältnis zu den nonverbalen Fähigkeiten

Atypical language organization following perinatal infarctions of the left hemisphere is associated with structural changes in right-hemispheric grey matter.

AIM To assess how atypical language organization after early left-hemispheric brain lesions affects grey matter in the contralesional hemisphere. METHOD This was a cross-sectional study with between-group comparisons of 14 patients (six female, 8-26 years) with perinatal left-hemispheric brain lesions (two arterial ischemic strokes, 11 periventricular haemorrhagic infarctions, one without classification) and 14 typically developing age-matched controls (TDC) with functional magnetic resonance imaging (fMRI) documented left-hemispheric language organization (six female, 8-28 years). MRI data were analysed with SPM12, CAT12, and custom scripts. Language lateralization indices were determined by fMRI within a prefrontal mask and right-hemispheric grey matter group differences by voxel-based morphometry (VBM). RESULTS FMRI revealed left-dominance in seven patients with typical language organization (TYP) and right-dominance in seven patients with atypical language organization (ATYP) of 14 patients. VBM analysis of all patients versus controls showed grey matter reductions in the middle temporal gyrus of patients. A comparison between the two patient subgroups revealed an increase of grey matter in the middle frontal gyrus in the ATYP group. Voxel-based regression analysis confirmed that grey matter increases in the middle frontal gyrus were correlated with atypical language organization. INTERPRETATION Compatible with a non-specific lesion effect, we found areas of grey matter reduction in patients as compared to TDC. The grey matter increase in the middle frontal gyrus seems to reflect a specific compensatory effect in patients with atypical language organization

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80–0.94) ormissed the criterion onlymarginally (90% confidence interval of c(max) 0.75–0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules

The long-term negative impact of childhood stroke on language.

OBJECTIVES This study aims to investigate the long-term language outcome in children with unilateral childhood stroke in comparison to those with perinatal strokes and typically developing individuals and to explore the impact of lesion-specific modifiers. METHODS We examined nine patients with childhood stroke, acquired between 0;2 and 16;1 years (CHILD; 3 female, median = 13.5 years, 6 left-sided), 23 patients with perinatal strokes (PERI; 11 female, median = 12.5 years, 16 left-sided), and 33 age-matched typically developing individuals (CONTROL; 15 female, median = 12.33 years). The language outcome was assessed using age-appropriate tasks of the Potsdam Illinois Test of Psycholinguistic Abilities (P-ITPA) or the Peabody Picture Vocabulary Test (PPVT). For group comparisons, study-specific language z-scores were calculated. Non-verbal intelligence was assessed using the Test of Non-verbal Intelligence (TONI-4), language lateralization with functional MRI, and lesion size with MRI-based volumetry. RESULTS All four patients with childhood stroke who initially presented with aphasic symptoms recovered from aphasia. Patients with childhood stroke showed significantly lower language scores than those in the control group, but their scores were similar to those of the patients with perinatal stroke, after adjusting for general intelligence (ANCOVA, language z-score CHILD = -0.30, PERI = -0.38, CONTROL = 0.42). Among the patients with childhood stroke, none of the possible modifying factors, including lesion side, correlated significantly with the language outcome. CONCLUSION Childhood stroke, regardless of the affected hemisphere, can lead to chronic language deficits, even though affected children show a "full recovery." The rehabilitation of children and adolescents with childhood stroke should address language abilities, even after the usually quick resolution of clear aphasic symptoms

Non-verbal Intelligence in Unilateral Perinatal Stroke Patients With and Without Epilepsies

Background: The risk factors for impaired cognitive development after unilateral perinatal stroke are poorly understood. Non-verbal intelligence seems to be at particular risk, since language can shift to the right hemisphere and may thereby reduce the capacity of the right hemisphere for its originary functions. Pharmaco-refractory epilepsies, a frequent complication of perinatal strokes, often lead to impaired intelligence. Yet, the role of well-controlled epilepsies is less well-understood. Here, we investigated whether well-controlled epilepsies, motor impairment, lesion size, lesion side, and lateralization of language functions influence non-verbal functions. Methods: We recruited 8 patients with well-controlled epilepsies (9–26 years), 15 patients without epilepsies (8–23 years), and 23 healthy controls (8–27 years). All underwent the Test of Non-verbal Intelligence, a motor-independent test, which excludes biased results due to motor impairment. Language lateralization was determined with functional MRI, lesion size with MRI-based volumetry, and hand motor impairment with the Jebson-Taylor Hand Function-Test. Results: Patients with epilepsies showed significantly impaired non-verbal intelligence [Md = 89.5, interquartile range (IQR) = 13.5] compared with controls (Md = 103, IQR = 17). In contrast, patients without epilepsies (Md = 97, IQR = 15.0) performed within the range of typically developing children. A multiple regression analysis revealed only epilepsy as a significant risk factor for impaired non-verbal functions. Conclusion: In patients with unilateral perinatal strokes without epilepsies, the neuroplastic potential of one healthy hemisphere is able to support the development of normal non-verbal cognitive abilities, regardless of lesion size, lesion side, or language lateralization. In contrast, epilepsy substantially reduces this neuroplastic potential; even seizure-free patients exhibit below-average non-verbal cognitive functions

Comparative bioavailability of the microemulsion formulation of cyclosporine (Neoral) with a generic dispersion formulation (Cicloral) in young healthy male volunteers

The aim of this study was to compare the bioavailability of cyclosporine (CyA) from the generic dispersion formulation Cicloral (CIC) with the microemulsion formulation Neoral (NEO) and the original Sandimmune (SIM) capsules after single doses of 100, 300, or 600 mg of drug, respectively. The study was performed according to an open 3-period cross-over design with 12 young healthy male volunteers for each dosage. The concentrations of CyA and its main metabolites were determined by high performance liquid chromatography in whole blood and urine up to 48 hours postdosing. Peak concentrations and area under the time-concentration curve were greater for the NEO and CIC formulations compared with SIM, and the mean bioavailability of CIC was significantly (P<0.05) lower compared with NEO. The bioavailability of SIM compared with NEO was 54% to 71%, in agreement with previous results. Bioequivalence was not demonstrated between CIC (test) and NEO (reference) as the 90% confidence intervals were outside the 80% to 125% guidelines based on log-transformed AUCs, and were 75.2% to 87.7% at 100 mg, 79.2% to 91.8% at 300 mg, and 76.6% to 94.5% at 600 mg doses. The respective values for Cmax were 78.9% to 94.6%, 80.7% to 95.0%, and 71.4% to 84.1%. A good correlation was demonstrated between the urinary recovery of CyA and the AUC4. Therefore, the urinary recovery of CyA may be helpful as a surrogate parameter for the systemic exposure of patients to CyA. Whereas the relative amount of hydroxylated metabolites (AM1, AM9, AM1c) was similar for all formulations and doses, the urinary recovery of the N-demethylated metabolite AM4N decreased with increasing dose indicating saturable metabolism. No relationship could be demonstrated between CYP3A activity using dextromethorphan as a probe for the metabolic clearance of CyA