De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

Congruence and Discrepancy of Interictal and Ictal EEG With MRI Lesions in Pediatric Epilepsies.

Purpose. To evaluate the congruence or discrepancy of the localization of magnetic resonance imaging (MRI) lesions with interictal epileptiform discharges (IEDs) or epileptic seizure patterns (ESPs) in surface EEG in lesional pediatric epilepsy patients. Methods. We retrospectively analyzed presurgical MRI and video-EEG monitoring findings of patients up to age 18 years. Localization of MRI lesions were compared with ictal and interictal noninvasive EEG findings of patients with frontal, temporal, parietal, or occipital lesions. Results. A total of 71 patients were included. Localization of ESPs showed better congruence with MRI in patients with frontal lesions (n = 21, 77.5%) than in patients with temporal lesions (n = 24; 40.7%) (P = .009). No significant IED distribution differences between MRI localizations could be found. Conclusions. MRI lesions and EEG findings are rarely fully congruent. Congruence of MRI lesions and ESPs was highest in children with frontal lesions. This is in contrast to adults, in whom temporal lesions showed the highest congruency with the EEG localization of ESP. Lesional pediatric patients should be acknowledged as surgical candidates despite incongruent findings of interictal and ictal surface EEG.

Childhood haemorrhagic stroke: a 7-year single-centre experience.

BACKGROUND: In recent years, there has been increasing research interest in improving diagnostic and management protocols in childhood arterial ischaemic stroke (AIS). However, childhood stroke comprises, in approximately equal parts, both arterial ischaemic and haemorrhagic stroke (HS). OBJECTIVE: The aim of this study was to focus on the aetiology, clinical presentation, treatment and short-term outcome of children with spontaneous intracranial bleeding in a university hospital and elucidate differences to childhood AIS. DESIGN: We performed a retrospective analysis of electronic medical records of children (28 days-18 years) diagnosed with HS between 2010 and 2016. RESULTS: We included 25 children (male child, n=11) with a median age of 8 years 1 month. The most common clinical presentations were vomiting (48%), headache (40%) and altered level of consciousness (32%). In more than half of the patients, HS was caused by vascular malformations. Other risk factors were brain tumour, coagulopathy and miscellaneous severe underlying diseases. Aetiology remained unclear in one child. Therapy was neurosurgical in most children (68%). Two patients died, 5 patients needed further (rehabilitation) treatment and 18 children could be discharged home. CONCLUSIONS: HS differs from AIS in aetiology (vascular malformations as number one risk factor), number of risk factors ('mono-risk' disease), clinical presentation (vomiting, headache and altered level of consciousness) and (emergency) therapy.

Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug-resistant epilepsy.

Focal cortical dysplasia is a common cause of medically refractory epilepsy in infancy and childhood. We report a neonate with seizures occurring within the first day of life. Continuous video-EEG monitoring led to detection of left motor seizures and a right frontal EEG seizure pattern. Brain MRI revealed a lesion within the right frontal lobe without contrast enhancement. The patient was referred for epilepsy surgery due to drug resistance to vitamin B6 and four antiepileptic drugs. Lesionectomy was performed at the age of two and a half months, and histopathological evaluation confirmed the diagnosis of focal cortical dysplasia type IIb (FCD IIb). The patient is free of unprovoked seizures without medication (Engel Class I) and is normally developed at 36 months after surgery. The case study demonstrates that FCD IIb may cause seizures within the first day of life and that epilepsy surgery can be successfully performed in medically intractable patients with a clearly identifiable seizure onset zone within the first three months of life. Although radical surgery such as hemispherectomy and multi-lobar resections are over-represented in early infancy, this case also illustrates a favourable outcome with a more limited resection in this age group.

Mesial Temporal Sclerosis in SCN1A-Related Epilepsy: Two Long-Term EEG Case Studies.

Patients with temporal lobe epilepsy (TLE) due to mesial temporal sclerosis (MTS) are eligible candidates for resective epilepsy surgery. We report on 2 male patients aged 4 years with suspected TLE due to MTS who were referred for presurgical evaluation. Both patients came to medical attention within the first year of life suffering from febrile status epileptici and subsequent unprovoked seizures. The following years, moderate developmental delay was present. High-resolution magnetic resonance imaging confirmed hippocampal sclerosis. Continuous EEG video monitoring revealed seizure patterns contralateral to the MTS in both patients. Genetic analysis was performed as both the clinical presentation of the patients and EEG video monitoring findings were not consistent with the presence of the hippocampal sclerosis alone and revealed de novo mutations within exon of the SCN1A gene. Resective surgical strategies were omitted due to the genetic findings. In conclusion, both patients suffered from a dual pathology syndrome with ( a) TLE related to MTS resulting most likely from recurrent febrile status in early childhood and ( b) Dravet syndrome, which is most likely the cause of the febrile convulsions leading to the MTS in these 2 patients.

SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy.

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.

Childhood-Onset Epileptic Encephalopathy Associated With Isolated Focal Cortical Dysplasia and a Novel TSC1 Germline Mutation.

Tuberous sclerosis complex (TSC) is an autosomal-dominant inheritable neurocutaneous disease due to mutations within the TSC1 and TSC2 genes. Many patients present with West syndrome, a severe epilepsy syndrome characterized by the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia (continuous slow activity with an amplitude higher than 300 µV and multiregional spikes/polyspikes/sharp waves) and developmental regression. In this study, we report on a previously healthy patient with positive family history of epilepsy with new-onset epileptic encephalopathy at the age of 9 years. Clinical signs alone were not sufficient to establish the diagnosis of TSC but epilepsy panel screening revealed a novel frameshift mutation (c.90delA; p.Glu31Argfs*12) within the TSC1 gene. Segregation gene analysis detected the same mutation in the mother. Cranial magnetic resonance imaging (MRI) studies from the index patient and his mother revealed a similar pattern of isolated subcortical white matter lesions resembling most likely focal cortical dysplasia (FCD) type IIb. In summary, in these 2 related patients, a novel TSC1 frameshift mutation was associated with an isolated FCD type IIb in the absence of further CNS abnormalities usually encountered in patients with TSC, fostering our understanding of the broad mutation spectra in the TSC1 gene and the close relationship between cortical tubers and FCD type IIb.

Vertigo and dizziness in adolescents: Risk factors and their population attributable risk.

OBJECTIVES: To assess potential risk factors for vertigo and dizziness in adolescents and to evaluate their variability by different vertigo types. The role of possible risk factors for vertigo and dizziness in adolescents and their population relevance needs to be addressed in order to design preventive strategies. STUDY DESIGN: The study population consisted of 1482 school-children between the age of 12 and 19 years, who were instructed to fill out a questionnaire on different vertigo types and related potential risk factors. The questionnaire specifically asked for any vertigo, spinning vertigo, swaying vertigo, orthostatic dizziness, and unspecified dizziness. Further a wide range of potential risk factors were addressed including gender, stress, muscular pain in the neck and shoulder region, sleep duration, migraine, coffee and alcohol consumption, physical activity and smoking. RESULTS: Gender, stress, muscular pain in the neck and shoulder region, sleep duration and migraine were identified as independent risk factors following mutual adjustment: The relative risk was 1.17 [1.10-1.25] for female sex, 1.07 [1.02-1.13] for stress, 1.24 [1.17-1.32] for muscular pain, and 1.09 [1.03-1.14] for migraine. The population attributable risk explained by these risk factors was 26%, with muscular pain, stress, and migraine accounting for 11%, 4%, and 3% respectively. CONCLUSION: Several established risk factors in adults were also identified in adolescents. Risk factors amenable to prevention accounted for 17% of the total population risk. Therefore, interventions targeting these risk factors may be warranted.

Pediatric idiopathic intracranial hypertension - Is the fixed threshold value of elevated LP opening pressure set too high?

BACKGROUND: Idiopathic intracranial hypertension (IIH) in children is a rare condition of unknown etiology and various clinical presentations. The primary aim of this study was to evaluate if our pediatric IIH study group fulfilled the revised diagnostic criteria for IIH published in 2013, particularly with regard to clinical presentation and threshold value of an elevated lumbar puncture opening pressure. Additionally we investigated the potential utilization of MR-based and fundoscopic methods of estimating intracranial pressure for improved diagnosis. PATIENTS AND METHODS: Clinical data were collected retrospectively from twelve pediatric patients diagnosed with IIH between 2008 and 2012 and revised diagnostic criteria were applied. Comparison with non-invasive methods for measuring intracranial pressure, MRI-based measurement (MR-ICP) and venous ophthalmodynamometry was performed. RESULTS: Only four of the twelve children (33%) fulfilled the revised diagnostic criteria for a definite diagnosis of IIH. Regarding noninvasive methods, MR-ICP (n = 6) showed a significantly higher mean of intracranial pressure compared to a healthy age- and sex-matched control group (p = 0.0043). Venous ophthalmodynamometry (n = 4) showed comparable results to invasive lumbar puncture. CONCLUSION: The revised diagnostic criteria for IIH may be too strict especially in children without papilledema. MR-ICP and venous ophthalmodynamometry are promising complementary procedures for monitoring disease progression and response to treatment.

Epileptic Seizure, Postictal Hemiparesis, and Hyperleukocytosis.

Introduction: Acute ischemic stroke (AIS) is a rare event in infancy. Besides vasculopathy, thrombophilia, or cardiac disorders, cancer and chemotherapy are known predisposing factors for AIS. Leukemia can be associated with different abnormal coagulation parameters, but severe bleeding or thrombosis occurs rarely. Clinical Course: We report the case of a 2-year-old boy who was presented to our emergency ward after a prolonged seizure with right sided postictal hemiparesis. Cranial computed tomography scan revealed a large infarction and edema due to thrombosis of the left carotid artery, the middle cerebral artery, and the anterior cerebral artery. Laboratory workup showed 196 g/L leukocytes with 75% myeloid blast cells. Immediate exchange transfusion, hydration, and chemotherapy with cytarabine were started. During the hospital course intracranial pressure increased and the patient developed a unilateral dilated pupil unresponsive to light. Cranial computed tomography scan revealed a new infarction in the right middle cerebral artery territory. Refractory increased intracranial pressure and brain stem herniation developed, and the child died 3 days after admission to hospital. Conclusion: Seizures with postictal hemiparesis due to cerebral infarction can be a rare manifestation of acute myeloid leukemia. Leukocytosis and cancer-induced coagulopathy are main reasons for thrombosis and/or hemorrhage. High leukocyte counts need immediate interventions with hydration, careful chemotherapy, and perhaps exchange transfusion or leukapharesis. In the presence of thrombosis, anticoagulation must be discussed despite the risk of bleeding due to hyperfibrinolysis and low platelet counts. Mortality may be reduced by awareness of this rare presentation of leukemia and prompt institution of leucoreductive treatment.

Three-dimensional analysis of positional plagiocephaly before and after molding helmet therapy in comparison to normal head growth.

OBJECTIVE: Stereophotogrammetry enables a simple and radiation free longitudinal analysis of skull asymmetries: in a three-dimensional coordinate system various distances (length, breadth, cephalic index, oblique diameters, ear shift, head circumference) can be analyzed. We also defined separate volume sections in order to further quantify the degree of asymmetry in the posterior and anterior components of both sides of the head. PATIENTS AND METHODS: In 51 infants (mean age, 6 months; SD 0.97) with positional plagiocephaly, we determined these parameters at the beginning as well as at the end of molding helmet therapy (mean therapy time 4.9 months). Thirty-seven infants without positional deformity (mean age, 6.4 months; SD 0.3) served as control group and provided data about what appears to be normal and how these parameters change during growth over a comparable period of time. RESULTS: Compared with the control group, the plagiocephalic heads were more brachycephalic, but closely approximated the normal shape under molding therapy. The striking volume difference between the left and right posterior sections in the plagiocephalic children (the mean volume of the flattened side being 21% smaller than the one on the contralateral side) improved as well (to a residual difference of mean 8%) and ended up with a value close to the control group (mean 6%). CONCLUSION: There is a broad clinical application area for stereophotogrammetry analyzing skull morphology: In plagiocephalic infants we demonstrate impressive changes of head shape under molding therapy; in normal-looking infants we describe the extent of unperceived asymmetry.