Annette Hackenberg

Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

Factors affecting cognitive outcome in early pediatric stroke

Objective: We examined cognitive performance in children after stroke to study the influence of age at stroke, seizures, lesion characteristics, neurologic impairment (NI), and functional outcome on cognitive outcome. Methods: This was a prospectively designed study conducted in 99 children who sustained an arterial ischemic stroke (AIS) between the age of 1 month and 16 years. All children underwent cognitive and neurologic follow-up examination sessions 2 years after the insult. Cognitive development was assessed with age-appropriate instruments. Results: Although mean cognitive performance was in the lower normative range, we found poorer results in subtests measuring visuoconstructive skills, short-term memory, and processing speed. Risk factors for negative cognitive outcome were young age at stroke, seizures, combined lesion location (cortical and subcortical), as well as marked NI. Conclusions: We recommend that all children with a history of AIS undergo regularly scheduled neuropsychological assessment to ensure implementation of appropriate interventions and environmental adjustments as early as possible.

Long-term outcome after arterial ischemic stroke in children and young adults

Objective: To compare long-term outcome of children and young adults with arterial ischemic stroke (AIS) from 2 large registries. Methods: Prospective cohort study comparing functional and psychosocial long-term outcome (≥2 years after AIS) in patients who had AIS during childhood (1 month–16 years) or young adulthood (16.1–45 years) between January 2000 and December 2008, who consented to follow-up. Data of children were collected prospectively in the Swiss Neuropediatric Stroke Registry, young adults in the Bernese stroke database. Results: Follow-up information was available in 95/116 children and 154/187 young adults. Median follow-up of survivors was 6.9 years (interquartile range 4.7–9.4) and did not differ between the groups (p = 0.122). Long-term functional outcome was similar (p = 0.896): 53 (56%) children and 84 (55%) young adults had a favorable outcome (modified Rankin Scale 0–1). Mortality in children was 14% (13/95) and in young adults 7% (11/154) (p = 0.121) and recurrence rate did not differ (p = 0.759). Overall psychosocial impairment and quality of life did not differ, except for more behavioral problems among children (13% vs 5%, p = 0.040) and more frequent reports of an impact of AIS on everyday life among adults (27% vs 64%, p < 0.001). In a multivariate regression analysis, low Pediatric NIH Stroke Scale/NIH Stroke Scale score was the most important predictor of favorable outcome (p < 0.001). Conclusion: There were no major differences in long-term outcome after AIS in children and young adults for mortality, disability, quality of life, psychological, or social variables.

Infantile epileptic encephalopathy, transient choreoathetotic movements, and hypersomnia due to a De Novo missense mutation in the SCN2A gene

Mutations of the SCN2A gene have originally been described in association with benign familial neonatal-infantile seizures (BFNIS). Recently, single patients with more severe phenotypes and persisting epileptic encephalopathies have been recognized. We report the case of a girl with severe infantile onset epileptic encephalopathy and a de novo missense mutation in the SCN2A gene (c.4025T > C/ = ; p.L1342P/ = ), who presented with a transient choreatic movement disorder, hypersomnia, and progressive brain atrophy. Whole exome sequencing did not reveal any other disease causing mutation. Our patient contributes to the expanding phenotypic spectrum of SCN2A-related disorders and underlines the importance of genetic workup in epileptic encephalopathies.

Mycoplasma pneumoniae intrathecal antibody responses in Bickerstaff brain stem encephalitis.

The pathogenesis of Mycoplasma pneumoniae encephalitis is not established. We report, for the first time, the case of a patient with severe Bickerstaff brain stem encephalitis in whom we detected intrathecal production of M. pneumoniae-specific antibodies, contrasting the findings in another patient with less severe encephalitis in whom we detected intrathecal M. pneumoniae DNA but no specific antibodies. Our observations suggest that intrathecal M. pneumoniae-specific antibody responses may contribute to a more severe course of M. pneumoniae encephalitis.

Severe childhood Guillain‐Barré syndrome associated with Mycoplasma pneumoniae infection: a case series

We report seven children with recent Mycoplasma pneumoniae infection and severe Guillain‐Barré syndrome (GBS) that presented to two European medical centres from 1992 to 2012. Severe GBS was defined as the occurrence of respiratory failure, central nervous system (CNS) involvement, or death. Five children had GBS, one Bickerstaff brain stem encephalitis (BBE), and one acute‐onset chronic inflammatory demyelinating polyneuropathy (A‐CIDP). The five patients with severe GBS were derived from an original cohort of 66 children with GBS. In this cohort, 17 children (26%) had a severe form of GBS and 47% of patients with M. pneumoniae infection presented with severe GBS. Of the seven patients in this case series, five were mechanically ventilated and four had CNS involvement (two were comatose). Most patients presented with non‐specific clinical symptoms (nuchal rigidity and ataxia) and showed a rapidly progressive disease course (71%). Antibodies against M. pneumoniae were detected in all patients and were found to be intrathecally synthesised in two cases (GBS and BBE), which proves intrathecal infection. One patient died and only two patients recovered completely. These cases illustrate that M. pneumoniae infection in children can be followed by severe and complicated forms of GBS. Non‐specific clinical features of GBS in such patients may predispose a potentially life‐threatening delay in diagnosis.

Fatal outcome of rhino-orbital-cerebral mucormycosis due to bilateral internal carotid occlusion in a child after hematopoietic stem cell transplantation.

Rhino-orbito-cerebral mucormycosis is a rare fulminant opportunistic fungal infection that particularly occurs in immunocompromised patients. We present a case of fatal invasive rhino-orbito-cerebral mucormycosis complicated by bilateral thrombotic occlusion of the internal carotid artery with consequent cerebral infarction in a 5-year-old boy after hematopoietic stem cell transplantation for acute pre-B-cell lymphoblastic leukemia.

Feasibility, Safety and Outcome of Recanalisation Treatment in Childhood Stroke.

Intravenous thrombolysis and endovascular therapy (IVT/EVT) are evidence‐based treatments for adults with arterial ischemic stroke (AIS). However, randomized controlled trials in pediatric patients are lacking. This study aimed to describe feasibility, safety, and outcome of IVT/EVT in children with AIS.

Intrathecal Anti-GalC Antibodies in Bickerstaff Brain Stem Encephalitis.

1Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Erasmus MC–Sophia Children’s Hospital, University Medical Center, Rotterdam, The Netherlands 2Division of Infectious Diseases and Hospital Epidemiology, and Children’s Research Center (CRC), University Children’s Hospital of Zurich, Zurich, Switzerland 3Division of Neurology, and Children’s Research Center (CRC), University Children’s Hospital of Zurich, Zurich, Switzerland 4Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands 5Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Infantile Basal Ganglia Stroke after Mild Head Trauma Associated with Mineralizing Angiopathy of Lenticulostriate Arteries: An Under Recognized Entity

Basal ganglia infarction in young children, mostly after mild head trauma, has been repeatedly reported. The pathogenesis and the risk factors are not fully understood. Lenticulostriate vasculopathy, usually referred to as basal ganglia calcification, is discussed as one of them. We describe five young (7-13 months old on presentation) male children who suffered from hemiparesis due to ischemic stroke of the basal ganglia, four of them after minor head trauma. All of them had calcification in the basal ganglia visible on computed tomography or cranial ultrasound but not on magnetic resonance imaging. Follow-up care was remarkable for recurrent infarction in three patients. One patient had a second symptomatic stroke on the contralateral side, and two patients showed new asymptomatic infarctions in the contralateral basal ganglia on imaging. In view of the scant literature, this clinic-radiologic entity seems under recognized. We review the published cases and hypothesize that male sex and iron deficiency anemia are risk factors for basal ganglia stroke after minor trauma in the context of basal ganglia calcification in infants. We suggest to perform appropriate targeted neuroimaging in case of infantile basal ganglia stroke, and to consider prophylactic medical treatment, although its value in this context is not proven.