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Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.

Objective Across stroke subtypes, carotid artery stroke carries the highest risk of recurrence. Despite initiation of best medical therapy (BMT), some patients suffer recurrent neurological events before undergoing carotid endarterectomy (CEA). The aim was to identify clinical predictors of early recurrent events in patients with symptomatic carotid stenosis (sCS) awaiting CEA on modern BMT. Methods The Helsinki Carotid Endarterectomy Study 2 (HeCES2) is a cross sectional, longitudinal, prospective, and consecutive cohort study, which enrolled 500 symptomatic or asymptomatic patients with carotid stenosis scheduled for CEA in a tertiary stroke centre. Symptomatic patients were included for this analysis (n = 324). Results Of all 324 patients with sCS, 39 (12%) had a recurrent cerebrovascular event at a median of six days after the index symptom: four had an ischaemic stroke (1.2%), 16 a hemispheric transient ischaemic attack (TIA; 4.9%), and 19 amaurosis fugax (AFX; 5.9%). The recurrence rate was 4.0 % (n = 13) within 48 h and 9.9% (n = 32) within two weeks. None of the patients (n = 108) presenting with ocular symptoms (AFX or retinal artery occlusion) suffered recurrent hemispheric TIA or stroke. In Cox regression analysis, comorbid hypertension (hazard ratio [HR] 6.58, 95% confidence interval [CI] 1.33–32.47), hemispheric TIA as the index symptom (HR 3.42, 95% CI 1.70–6.90), the number of prior attacks (HR 1.12, 95% CI 1.08–1.15), and high low density lipoprotein/high density lipoprotein ratio (HR 1.51, 95% CI 1.09–2.11) were independently associated with an increased risk of recurrent event, while a history of major cardiovascular event (HR 0.33, 95% CI 0.11–0.96) and high serum fibrinogen level (HR 0.59, 95% CI 0.41–0.86) were associated with a decreased risk. Conclusion More than every tenth patient with sCS experienced an early recurrent cerebrovascular event prior to scheduled CEA, despite optimal medication. However, stroke recurrence was lower than in earlier observational studies, which could be explained by improved care pathways, more aggressive medication, and expedited CEA. All recurrent strokes occurred in patients initially presenting with minor stroke.

Introduction: Every fifth ischemic stroke is caused by thromboembolism originating from an atherosclerotic carotid artery plaque. While prevention is the most cost-effective stroke therapy, antiplatelet and cholesterol-lowering drugs have a ceiling effect in their efficacy. Therefore, discovery of novel pathophysiologic targets are needed to improve the primary and secondary prevention of stroke. This article provides a detailed study design and protocol of HeCES2, an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis.Materials and Methods: Recruitment and carotid endarterectomies of the study patients with carotid atherosclerosis were performed from October 2012 to September 2015. After brain and carotid artery imaging, endarterectomised carotid plaques (CPs) and blood samples were collected from 500 patients for detailed biochemical and molecular analyses.Findings to date: We developed a morphological grading for macroscopic characteristics within CPs. The dominant macroscopic CP characteristics were: smoothness 62%, ulceration 61%, intraplaque hemorrhage 60%, atheromatous gruel 59%, luminal coral-type calcification 34%, abundant (44%) and moderate (39%) intramural calcification, and symptom-causing hot spot area 53%.Future plans: By combining clinically oriented and basic biomedical research, this large-scale study attempts to untangle the pathophysiological perplexities of human carotid atherosclerosis.Key MessagesThis article is a rationale and design of the HeCES2 study that is an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis.The HeCES2 study strives to develop diagnostic algorithms including radiologic imaging to identify carotid atherosclerosis patients who warrant surgical treatment.In addition, the study aims at finding out new tools for clinical risk stratification as well as novel molecular targets for drug development.

Background: Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.9) deficiency is a rare autosomal recessive disorder that is widely diagnosed by neonatal screening. Methods: We report long term follow up of a patient with MLYCD deficiency showing signs of neonatal hypoglycemia, mental retardation, developmental delay and rheumatoid arthritis. Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared. MLCYD gene sequence analysis was done to identify possible mutations. Expression analyses at mRNA and protein levels were also performed. Further, immunocytochemical studies were implemented to check for its subcellular localization. Results: MLYCD gene sequencing identified a novel compound heterozygous mutation (c.22 T>A, p.M1K, c.454 C>A; pH152N) in our patient and a heterozygous mutation in the healthy mother c.22 T>A; pM1K. Reduced expression of RNA and protein levels was observed. Immunocytochemical analysis showed diffused staining across the cytoplasm with apparent signs of intracellular mislocalization to the nucleus. Results also indicated subcellular colocalization of MLCYD with mitochondria was scant compared to control. Conclusion: Our patient was identified with a novel compound heterozygous MLYCD mutation at the N-terminal helical domain. This study indicates that protein mislocalization is a characteristic feature of MLYCD deficiency in our patient.

Objective: We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate. Methods: We performed whole-exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency. Results: Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS , encoding the O -phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain. Conclusions: These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation.

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations., Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.

Systematic computed tomography angiographic (CTA) studies investigating variation in internal carotid artery (ICA) luminal diameters (LDs) are scarce. Knowledge of the normal intra-individual LD variability would provide a cut-off value for detection of more subtle collapses. In addition, low intra-individual variability would allow using contralateral LD as a reference for estimation of stenosis degree in cases where ipsilateral measurement is hampered. Therefore, our aim was to investigate intra-individual LD variation of normal ICA. We retrospectively collected multidetector high-speed CTAs of 104 patients younger than 40 years who were considered not to have carotid pathology. We carried out independent measurements of the common carotid artery (CCA) and ICA LDs bilaterally from axial source images by two observers, analysing side-to-side LD differences from averaged double measurements with a paired t test. We discovered no significant side-to-side LD differences. In the female group, the mean differences (mm) with 95 % confidence intervals were 0.08 (0.00, 0.17) for CCA and 0.03 (−0.04, 0.11) for ICA, with ICA LD standard deviation of 0.4 mm. In the male group, these were: 0.06 (−0.04, 0.17), 0.02 (-0.07, 0.11) and 0.4 mm, respectively. We detected no ICA agenesis. The intrinsic intra-individual variation of the LD of normal ICA is minimal. This uniformity may serve as the basis for detection of subtle grades of side-to-side variation caused by pathology.

Cerebral palsy (CP) is characterized by difficulty in control of movement and posture due to brain damage during early development. In addition, tactile discrimination deficits are prevalent in CP. To study the function of somatosensory and motor systems in CP, we compared the reactivity of sensorimotor cortical oscillations to median nerve stimulation in 12 hemiplegic CP children vs. 12 typically developing children using magnetoencephalography. We also determined the primary cortical somatosensory and motor representation areas of the affected hand in the CP children using somatosensory‐evoked magnetic fields and navigated transcranial magnetic stimulation, respectively. We hypothesized that the reactivity of the sensorimotor oscillations in alpha (10 Hz) and beta (20 Hz) bands would be altered in CP and that the beta‐band reactivity would depend on the individual pattern of motor representation. Accordingly, in children with CP, suppression and rebound of both oscillations after stimulation of the contralateral hand were smaller in the lesioned than intact hemisphere. Furthermore, in two of the three children with CP having ipsilateral motor representation, the beta‐ but not alpha‐band modulations were absent in both hemispheres after affected hand stimulation suggesting abnormal sensorimotor network interactions in these individuals. The results are consistent with widespread alterations in information processing in the sensorimotor system and complement current understanding of sensorimotor network development after early brain insults. Precise knowledge of the functional sensorimotor network organization may be useful in tailoring individual rehabilitation for people with CP. Hum Brain Mapp 35:4105–4117, 2014. © 2014 Wiley Periodicals, Inc.

Summary Purpose Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. Methods We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video-EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. Key Findings SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation–negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation–positive patients. One showed evidence of a significant hypoxic–ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray–white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video-EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. Significance Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome.

Background Recently, navigated transcranial magnetic stimulation (nTMS) has been suggested to be useful in preoperative functional localization of motor cortex in patients having tumors close to the somatomotor cortex. Resection of tumors in anatomically predicted eloquent areas without adverse effects have emphasized functional plasticity elicited by intracranial pathology. Objective To describe functional plasticity of motor cortex indicated by nTMS in two patients with epilepsy. Methods nTMS, functional MRI (fMRI), diffusion-tensor (DT)-tractography and magnetoencephalography (MEG) were utilized to preoperatively localize motor cortical areas in the workup for epilepsy surgery. The localizations were compared with each other, with the cortical anatomical landmarks, and in one patient with invasive electrical cortical stimulation (ECS). Results In two out of 19 studied patients, nTMS identified motor cortical sites that differed from those indicated by anatomical landmarks. In one patient, nTMS activated preferentially premotor cortex rather than pathways originating from the precentral gyrus. MEG and fMRI localizations conformed with nTMS whereas ECS localized finger motor function into the precentral gyrus. Resection of the area producing motor responses in biphasic nTMS did not produce a motor deficit. In the other patient, nTMS indicated abnormal ipsilateral hand motor cortex localization and confirmed the functionality of aberrant motor cortical representations of the left foot also indicated by fMRI and DT-tractography. Conclusion nTMS may reveal the functional plasticity and shifts of motor cortical function. Epileptic foci may modify cortical inhibition and the nTMS results. Therefore, in some patients with epilepsy, the nTMS results need to be interpreted with caution with regard to surgical planning.

Background Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. Methods We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). Results H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. Conclusions Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.

Near-occlusion of the internal carotid artery (ICA) is a significant luminal diameter (LD) reduction beyond a tight atherosclerotic carotid stenosis (CS). Recognition of even subtle near-occlusions is essential to prevent underestimation of the stenosis degree. Our goal was to investigate the prevalence of near-occlusion among CS patients using a single standard criterion to facilitate its recognition, even when distal ICA LD reduction is not visually evident in computed tomography angiography (CTA). We analysed carotid artery CTAs of 467 patients with moderate-to-severe CS scheduled for endarterectomy. We performed measurements of the bilateral distal ICA LDs from thin axial source images and utilized a 1.0 mm intra-individual side-to-side distal ICA LD difference to distinguish near-occlusions, based on a previous study, aware of the vagaries of measurement. For analysis stratification, we excluded cases with significant carotid pathology affecting LD measurements. We discovered 126 near-occlusions fulfilling our criterion of ipsilateral near-occlusion: the mean LD side-to-side difference (mm) with 95% confidence interval being 1.8 (1.6, 1.9) and a standard deviation of 0.8 mm. Among the 233 cases not meeting our near-occlusion criterion, we found 140 moderate (50–69%) and 93 severe (70–99%) ipsilateral stenoses. The utilization of 1.0 mm cut-off value for the intra-individual distal ICA LD side-to-side difference to distinguish atherosclerotic ICA near-occlusion leads to a relatively high incidence of near-occlusion. In CTA, recently suggested to be used for near-occlusion diagnosis, a discriminatory 1.0 mm cut-off value could function as a pragmatic tool to enhance the detection of even subtle near-occlusions.

OBJECTIVE The middle interhemispheric variant of holoprosencephaly (MIHV) is a mild, rare variant of holoprosencephaly. Only a few cases of children with MIHV have been reported. Here we report in detail an adult case. METHOD The patient is a female in her 30s. The patient underwent an extensive neuropsychological examination, a neurological examination and a magnetic resonance imaging. RESULTS Neuroradiologically, the patient had a typical finding of MIHV, with the absence of the central corpus callosum and union of posterior frontal and anterior parietal gyri. In neuropsychological examination, the patient had average or above average performance in verbal comprehension, naming, reading and writing, and below average performance in perceptual reasoning, visuospatial abilities, processing speed and memory. Also difficulties in mathematical abilities, psychomotor skills, and executive functions were found. No gross neurological involvement was noted. She was diagnosed with atypical depression, post-traumatic stress disorder and a dissociative disorder in early adulthood. Despite cognitive deficits, she was able to achieve a tertiary level education. CONCLUSIONS This is the first adult case of MIHV described in detail. Our case emphasizes the possibility of a missed diagnosis of marked brain malformations in patients with craniofacial abnormalities. More cases and prospective follow-up studies are needed to understand the evolvement of both neuropsychological and psychiatric symptoms in these patients.

Importance Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. Objective To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). Design, Setting, and Participants A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. Interventions Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). Main Outcomes and Measures The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. Results Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). Conclusions and Relevance Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. Trial Registration clinicaltrials.gov Identifier:NCT00879892

Hypochondroplasia (HCH), an autosomal dominant skeletal dysplasia caused by mutations in the FGFR3 gene, has not been commonly associated with neurological problems. Temporal lobe dysgenesis associated with epilepsy was recently described in single patients. In this retrospective study, we assessed neurological and neuroimaging aspects of 13 FGFR3 (N540K) mutation verified HCH patients in Finland. Eight patients had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). Six of 13 patients had a history of seizures or epilepsy. Eight patients had undergone MRI. They all had structural abnormalities consistent with temporal lobe dysgenesis. Six patients had peritrigonal white matter reduction, and 4 had abnormally shaped lateral ventricles. We recommend a close follow-up of development in patients with HCH and a low threshold for neuroimaging.

Introduction The aim of this study was to evaluate prevalence of intracranial abnormalities in children with non-syndromic single suture craniosynostosis scheduled for cranial vault remodelling surgery using pre-operative magnetic resonance imaging. Patients and methods A retrospective analysis of brain magnetic resonance imaging studies of 129 non-syndromic single suture craniosynostosis children undergoing craniofacial surgery between January, 2004–October, 2010 was conducted. Statistical analysis was performed for child, maternal and sibling related predisposing factors for abnormal brain magnetic resonance imaging findings. The mean age of these 121 patients at the time of imaging was 21.6 months. The majority, 78% were males and 74% of the patients were scaphocephalic. Results In 18 (15%) patients abnormal brain findings were noted. The most common finding was Chiari 1 malformation in 11 (9%). Chiari 1 malformation comprised over half (61%) of the brain anomalies identified. None of these findings required any additional surgical procedures. None of the statistical analysis reached statistical significance. Conclusions Brain anomalies in connection with non-syndromic single suture craniosynostosis patients seem to be a coincidental event. We did not establish any specific craniosynostosis form to be regularly associated with abnormal brain magnetic resonance imaging findings. The routine use of pre-operative magnetic resonance imaging in non-syndromic single suture craniosynostosis patients seems to be of limited value in the search for associated intracranial malformations necessitating additional interventions.

Chiari type I malformation is a frequent incidental finding commonly associated with craniosynostosis. However, there seems to be a paucity of literature concerning the asymmetry of tonsillar herniation in patients with non-syndromic single-suture craniosynostosis. To study the asymmetry in this cohort, measurements of the right and left tonsils were made from sagittal images from both pre-operative and post-operative images from 11 patients with non-syndromic single-suture craniosynostosis. Pre-operatively, the mean difference between the caudal descent of all tonsils ranged from 0 to 7 mm, with a mean difference between sides of 2.45 mm. In three cases, cerebellar tonsils were symmetrically herniated. Post-operatively, the mean difference between caudal descent of all tonsils ranged from 0 to 4 mm, with a mean difference between sides of 1.45 mm. Four were symmetrically herniated. In patients with non-syndromic single-suture craniosynostosis, the tonsillar herniation is asymmetric in the majority of cases. Asymmetry of cerebellar tonsil herniation is a frequent finding in this cohort. The right tonsil is more inferiorly located in majority of cases, with predominance to the synostotic suture side in asymmetric craniosynostosis cases.

Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.

We sought to examine the pre- and postoperative changes of cerebellar tonsillar herniation by MR imaging in asymptomatic pediatric patients with nonsyndromic, single-suture craniosynostosis (N-SSSC), who underwent cranial vault remodeling surgery without suboccipital decompression. We required cerebellar tonsillar herniation through foramen magnum ≥3 mm for Chiari type I malformation (CMI). We hypothesized that the increase of intracranial volume by cranial vault remodeling would correct the asymptomatic CMI.We identified 9 patients among 121 N-SSSC children undergoing craniofacial surgery from January 2004 to October 2010 with CMI. However, two of them were excluded from the study due to missing postoperative MR images. In the final study population, six were males, five were scaphocephalic, while two were diagnosed with coronal synostosis.In four of the cases, the CMI was decreased in postoperative MR imaging varying from 6 to 12 mm. In three cases, the herniation remained stable. The median change of cerebellar tonsillar herniation was -6.5 mm.We conclude that asymptomatic patients with existing CMI may benefit from cranial vault remodeling surgery alone increasing the intracranial volume.

Few studies have focused on the neurodevelopment of infants on peritoneal dialysis (PD). Infants are the most demanding patient group on PD and thus are vulnerable to neurological sequelae. We studied 21 patients

Objective: Mitochondrial DNA polymerase γ (POLG1) mutations in children often manifest as Alpers syndrome, whereas in adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy. Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood. Methods: We investigated POLG1 in 136 children, all clinically suspected to have mitochondrial disease, with one or more of the following: ataxia, axonal neuropathy, severe epilepsy without known epilepsy syndrome, epileptic encephalopathy, encephalohepatopathy, or neuropathologically verified Alpers syndrome. Results: Seven patients had POLG1 mutations, and all of them had severe encephalopathy with intractable epilepsy. Four patients had died after exposure to sodium valproate. Brain MRI showed parieto-occipital or thalamic hyperintense lesions, white matter abnormality, and atrophy. Muscle histology and mitochondrial biochemistry results were normal in all. Conclusions: POLG1 analysis should belong to the first-line DNA diagnostic tests for children with an encephalitis-like presentation evolving into epileptic encephalopathy with liver involvement (Alpers syndrome), even if brain MRI and morphology, respiratory chain activities, and the amount of mitochondrial DNA in the skeletal muscle are normal. POLG1 analysis should precede valproate therapy in pediatric patients with a typical phenotype. However, POLG1 is not a common cause of isolated epilepsy or ataxia in childhood.

Hajdu–Cheney syndrome (HCS) is an autosomal dominant condition comprising osteolysis of the terminal phalanges, characteristic craniofacial abnormalities, dental anomalies, and proportionate short stature. The clinical and radiological findings develop and progress with age. Here, we report on a HCS patient with severe scoliosis and exceptionally massive dural ectasia. Congenital scoliosis and dural ectasia have not been reported previously in HCS. © 2011 Wiley-Liss, Inc.

The C10orf2 gene encodes the mitochondrial DNA helicase Twinkle, which is one of the proteins important for mitochondrial DNA maintenance. Dominant mutations cause multiple mitochondrial DNA deletions and progressive external ophthalmoplegia, but recent findings associate recessive mutations with mitochondrial DNA depletion and encephalopathy or hepatoencephalopathy. The latter clinical phenotypes resemble those associated with recessive POLG1 mutations. We have previously described patients with infantile onset spinocerebellar ataxia (MIM271245) caused either by homozygous (Y508C) or compound heterozygous (Y508C and A318T) Twinkle mutations. Our earlier reports focused on the spinocerebellar degeneration, but the 20-year follow-up of 23 patients has shown that refractory status epilepticus, migraine-like headaches and severe psychiatric symptoms are also pathognomonic for the disease. All adolescent patients have experienced phases of severe migraine, and seven patients had antipsychotic medication. Epilepsia partialis continua occurred in 15 patients leading to generalized epileptic statuses in 13 of them. Eight of these patients have died. Valproate treatment was initiated on two patients, but had to be discontinued because of a severe elevation of liver enzymes. The patients recovered, and we have not used valproate in infantile onset spinocerebellar ataxia since. The first status epilepticus manifested between 15 and 34 years of age in the homozygotes, and at 2 and 4 years in the compound heterozygotes. The epileptic statuses lasted from several days to weeks. Focal, stroke-like lesions were seen in magnetic resonance imaging, but in infantile onset spinocerebellar ataxia these lesions showed no predilection. They varied from resolving small cortical to large hemispheric oedematous lesions, which reached from cerebral cortex to basal ganglia and thalamus and caused permanent necrotic damage and brain atrophy. Brain atrophy with focal laminar cortical necrosis and hippocampal damage was confirmed on neuropathological examination. The objective of our study was to describe the development and progression of encephalopathy in infantile onset spinocerebellar ataxia syndrome, and compare the pathognomonic features with those in other mitochondrial encephalopathies.

BACKGROUND AND PURPOSE: Our aim was to evaluate whether increasing iodine concentration, at a constant total iodine dose, resulted in better brain tissue opacification in patients with acute stroke symptoms during their evaluation by first-pass CT perfusion (CTP). MATERIALS AND METHODS: One hundred two patients presenting to the emergency department within 3 hours of onset of acute stroke symptoms underwent CTP scanning. Three different concentrations of iodinated nonionic contrast material were used (300, 350, or 400 mg/mL). Total iodine dose (15 g) and injection rate (7 mL/s) were kept constant. There were 25, 53, and 19 patients in the different concentration groups, respectively; 5 patients were excluded due to uncorrectable motion artifacts. CTP scanning was performed at the level of the putamen, and data were analyzed by determining peak opacification for normal gray and white matter, arterial input, and venous output. Mean and SD values were calculated, and 3 concentration groups, stratified by region-of-interest location, were compared by using a single-tailed unpaired t test. RESULTS: Monotonic increasing peak opacification was observed in all region-of-interest locations. Statistically significant differences were observed between the 300 and 350 mg/mL, 300 and 400 mg/mL, as well as the 350 and 400 mg/mL groups (P < .01) in white matter, gray matter, and the arterial input. Statistical significance was seen in the venous output group between the 300 and 400 mg/mL (P < .005) and 350 and 400 mg/mL (P < .007) groups, but not between the 300 and 350 mg/mL (P = .2) groups. CONCLUSION: Increasing contrast concentration improves peak opacification of tissue, suggesting that CTP evaluation of patients with acute stroke is better performed with the highest available concentration contrast agent.

Objective Despite improved survival and neurodevelopmental outcome, children with hypoplastic left heart syndrome and other forms of univentricular heart remain at increased risk for cognitive, motor, and other neurologic deficits. Methods We examined 27 children with hypoplastic left heart syndrome or other forms of univentricular heart at a median age of 5.70 years (range 4.99–7.51 years) and performed brain computed tomography or magnetic resonance imaging on 20. Possible risk factors were correlated with outcome. Results Mean full-scale IQ among patients with hypoplastic left heart syndrome was 86.7; that among patients with other forms of univentricular heart was 89.1, with both differing significantly from the expected population mean ( P = .015 and P = .029, respectively). Cerebral palsy was diagnosed in 1 of 7 patients with hypoplastic left heart syndrome and 2 of 20 with other forms of univentricular heart. Brain computed tomography or magnetic resonance imaging revealed ischemic changes and infarcts or atrophy in 5 of 8 patients who had undergone the Norwood procedure and in 2 of 12 of those who had not ( P = .062). Abnormal computed tomographic findings correlated significantly with lower full-scale IQ ( P = .045) and verbal IQ ( P = .02). In the multiple linear regression model, diuresis the third day after the primary operation and cardiopulmonary bypass time in the bidirectional Glenn operation correlated significantly with the primary outcome of full-scale IQ. Conclusion In children with univentricular heart, intellectual and neurologic deficits are common. Perioperative and postoperative risk factors related to the primary phase and bidirectional Glenn operation contribute to these deficits.

Purpose: To evaluate the brains of newborns exposed to buprenorphine prenatally. Material and Methods: Seven neonates followed up antenatally in connection with their mothers' buprenorphine replacement therapy underwent 1.5T magnetic resonance imaging (MRI) of the brain before the age of 2 months. The infants were born to heavy drug abusers. Four mothers were hepatitis C positive, and all were HIV negative. All mothers smoked tobacco and used benzodiazepines. All pregnancies were full term, and no perinatal asphyxia occurred. All but one neonate had abstinence syndrome and needed morphine replacement therapy. Results: Neither structural abnormalities nor abnormalities in signal intensity were recorded. Conclusion: Buprenorphine replacement therapy does not seem to cause any major structural abnormalities of the brain, and it may prevent known hypoxic-ischemic brain changes resulting from uncontrolled drug abuse. Longitudinal studies are needed to assess possible abnormalities in the brain maturation process.

Injuries associated with child abuse involve typical imaging findings that should be recognized by every radiologist, because a radiologist may be the first person to raise doubts about abuse. Subdural and subarachnoid hemorrhages in the vicinity of the longitudinal cerebral fissure are characteristic of a brain injury resulting from shaking. Magnetic resonance imaging is the most recommendable method of imaging. At the acute stage, computed tomography is sufficient for the detection of conditions requiring immediate neurosurgical treatment, if magnetic resonance imaging is not possible. Ultrasonography is not sensitive enough for this purpose. Fractures in a child under the age of one year are always suspicious, especially rib fractures. Injuries of the liver, pancreas and intestine are often found in the abdominal region. Contrast-enhanced CT scan is the best investigation in injuries of the lungs and the abdominal region. If a suspicion of physical abuse is raised upon imaging studies, it is important to bring this to the notice of the attending physician and note the issue also in the report.

Objectives The purpose of the study was to evaluate the etiology and long-term outcomes of late-onset epileptic spasms (LOS). Methods This is a retrospective analysis of all consecutive patients seen at our center with onset of clusters of epileptic spasms between 1 and 3 years of age in 1995 through 2005. Results Overall, 17 children with LOS were identified. Overall, 14 children (82%) had structural etiology. Six patients received resective surgical treatment. Five had focal cortical dysplasia type 1 (FCD1) histology (29% of all the patients). Overall, 16 children were followed for 2 to 18 years. At the latest follow-up, seizure freedom was observed in 67% of the operated and in 50% of the nonoperated patients. Normal cognition or only mild mental deficiency was observed in nine patients (56%), of whom eight were seizure-free. All patients with intractable spasms had a severe mental deficiency. Conclusion The overall cognitive outcome of LOS was more favorable than in the previous reports and was associated with seizure freedom. FCD1 is a frequent etiology for LOS and the cognitive outcome of patients with FCD1 seemed to be favorable.

BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

Pitt-Hopkins syndrome is a rare dysmorphic mental retardation syndrome marked by daytime spells of overbreathing interrupted by apnoea. The dysmorphism consists of a large beaked nose, cup-shaped ears with broad helices, a wide mouth, Cupid's bow upper lip, wide and shallow palate and broad or clubbed fingertips. The four patients described so far have been sporadic and represented both sexes. In addition, a pair of sibs with atypical features has been reported as possible Pitt-Hopkins syndrome cases. We describe two unrelated Pitt-Hopkins syndrome patients in order to further define the phenotype. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp-wave discharges on electroencephalography. Magnetic resonance imaging in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Chromosomal analysis and subtelomere fluorescence in-situ hybridization studies were normal. No mutations were found in the MECP2 or ZFHX1B genes. Extensive metabolic and mitochondrial screens were normal. The electroencephalography and brain magnetic resonance imaging findings appear to be further diagnostic signs in Pitt-Hopkins syndrome, which is also one of the syndromes associated with Hirschsprung disease.

We studied 14 individuals with partial deletions of the long arm of chromosome 18, including terminal and interstitial de novo and inherited deletions. Study participants were examined clinically and by brain MRI. The size of the deletion was determined by segregation analysis using microsatellite markers. We observed that the phenotype was highly variable, even in two families with three 1st degree relatives. Among the 14 individuals, general intelligence varied from normal to severe mental retardation. The more common features of 18q-deletions (e.g., foot deformities, aural atresia, palatal abnormalities, dysmyelination, and nystagmus) were present in individuals lacking only the distal portion 18q22.3-qtel. Interstitial deletions exerted very heterogeneous effects on phenotype. In individuals with distal 18q22.3-q23 deletions, brain MRI was very distinctive with poor differentiation of gray and white matter on T2-weighted images.

Background: A new leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate was recently defined. The authors describe five new patients with this entity. Methods: Brain MRI was performed in all patients and spinal MRI and proton magnetic resonance spectroscopy ( 1 H-MRS) in four patients. Laboratory examinations ruled out classic leukodystrophies. Results: MRI showed signal abnormalities in the periventricular and deep white matter, in the pyramidal tracts, mesencephalic trigeminal tracts, in the cerebellar connections, and in dorsal columns of the spinal cord. MRS showed decreased N -acetylaspartate and increased lactate in the white matter of all patients. In one patient choline-containing compounds were elevated. A slowly progressive sensory ataxia and tremor manifested at the age of 3 to 16 years and distal spasticity in adolescence. One 13-year-old patient was asymptomatic. Conclusions: A slowly progressive sensory ataxia is a typical feature in this new leukodystrophy. MRS favors a primary axonal degeneration.

Background: Congenital bilateral perisylvian syndrome (CBPS) is characterised by bilateral perisylvian polymicrogyria and suprabulbar paresis. Mild tetraparesis, cognitive impairment, and epilepsy are frequently associated. Sensory deficits are surprisingly rare, even though polymicrogyria often extends to auditory and sensorimotor cortex. Objectives: To study the sensorimotor and auditory cortex function and location in CBPS patients. Methods: We mapped the sensory and motor cortex function onto brain magnetic resonance images in six CBPS patients and seven control subjects using sources of somatosensory and auditory evoked magnetic fields, and of rhythmic magnetoencephalographic (MEG) activity phase-locked to surface electromyogram (EMG) during voluntary hand muscle contraction. Results: MEG-EMG coherence in CBPS patients varied from normal (if normal central sulcus anatomy) to absent, and could occur at abnormally low frequency. Coherent MEG activity was generated at the central sulcus or in the polymicrogyric frontoparietal cortex. Somatosensory and auditory evoked responses were preserved and also originated within the polymicrogyric cortex, but the locations of some source components could be grossly shifted. Conclusion: Plastic changes of sensory and motor cortex location suggest disturbed cortex organisation in CBPS patients. Because the polymicrogyric cortex of CBPS patients may embed normal functions in unexpected locations, functional mapping should be considered before brain surgery.

To assess proton magnetic resonance (MR) spectroscopy in differentiating between low-grade gliomas and focal cortical developmental malformations (FCDMs).Eighteen patients with seizures and a cortical brain lesion on MR images were studied with proton MR spectroscopy. A metabolite ratio analysis was performed, and the metabolite signals in the lesion core were compared with those in the contralateral centrum semiovale and in the corresponding brain sites in 18 control subjects to separately obtain the changes in N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine-phosphocreatine (Cr). Ten patients had a low-grade glioma (three, oligodendrogliomas; three, oligoastrocytomas; three, astrocytomas; and one, pilocytic astrocytoma), and eight had FCDM (five, focal cortical dysplasias and three, dysembryoplastic neuroepithelial tumors). Linear discriminant analysis and Student t test were used for statistical comparisons.Loss of NAA and increase of Cho were more pronounced in low-grade gliomas than in FCDMs (NAA, -72% +/- 15 [+/- SD] vs -29% +/- 22, P.001; Cho, 117% +/- 56 vs 21% +/- 66, P.01). Changes in NAA and Cho helped differentiate low-grade gliomas from FCDMs, and changes in Cho and Cr helped differentiate astrocytomas from oligodendrogliomas and oligoastrocytomas. Metabolite NAA/Cho and NAA/Cr ratios helped differentiate low-grade gliomas from FCDMs but did not differentiate glioma subtypes.MR spectroscopy allows distinction between low-grade gliomas and FCDMs and between low-grade glioma subtypes. Metabolite changes are more informative than are metabolite ratios.

Kabuki syndrome is a rare dysmorphogenic disorder. The central nervous system is often involved, and epilepsy is a common symptom. The diagnosis is clinical, and no typical electroencephalographic findings have thus far been reported. We have documented temporo-occipital spikes in sleep electroencephalogram in all our three Kabuki patients. The location of the spikes was similar in all cases although their occurrence varied from continuous spiking to single spikes. We suggest that temporo-occipital spikes are typical in Kabuki syndrome and discuss the possible cause of this finding.

Purpose To study brain MRI findings in patients with 18q− syndrome and to correlate these findings with the results of the molecular breakpoint analysis. Materials and Methods Brain MR images of 17 patients with 18q− syndrome were evaluated. Segregation analysis was performed with 15 microsatellite markers to determine the deletion breakpoints and whether the deletion included the myelin basic protein (MBP) gene. Results One patient had an interstitial deletion of 18q which spared the MBP gene. He was the only one with normal brain MRI. All 16 patients with deletions including the MBP gene had abnormal white matter in MRI. The main finding was poor differentiation of gray and white matter on T2-weighted images due to increased white matter signal intensity. In addition, measured signal intensity of the white matter was significantly increased in patients compared with controls. Conclusions Poor differentiation of gray and white matter on T2-weighted images is the most typical MRI finding of the 18q− syndrome. These results support the postulation that abnormal myelination in 18q− syndrome is due to haploinsufficiency at or near the MBP locus. J. Magn. Reson. Imaging 2003;18:414–419. © 2003 Wiley-Liss, Inc.

Patient and graft survival rates of pediatric renal transplant recipients are currently excellent, but there are few reports regarding the long-term neurodevelopmental outcome after renal transplantation (Tx) in early childhood. Children with renal failure from infancy would be expected to have a less favorable developmental prognosis. We report the neurodevelopmental outcome in 33 school-age children transplanted between 1987 and 1995 when < 5 yr of age. We prospectively performed a neurological examination, magnetic resonance imaging (MRI) of the brain, electroencephalograms (EEGs), audiometry, and neuropsychological tests (NEPSY), and measured cognitive performance (WISC-R); we related these results to school performance and to retrospective risk factors prior to Tx. Twenty-six (79%) children attended normal school and 76% had normal motor performance. Six of the seven children attending a special school had brain infarcts on MRI. The EEG was abnormal in 11 (35%), and five (15%) received anti-convulsive treatment after Tx. Sensorineural hearing loss was documented in six patients. The mean intelligence quotient (IQ) was 87, and 6-24% showed impairment in neuropsychological tests. The children attending a special school had been more premature, but had not had a greater number of pre- or neonatal complications. They had experienced a greater number of hypertensive crises (p = 0.002) and seizures (p = 0.03), mainly during dialysis, but the number of septic infections and the mean serum aluminum levels were not significantly greater than in the children with normal school performance. In these previously lethal diseases, the overall neurodevelopmental outcome is reassuring. However, it is of crucial importance to further minimize the risk factors prior to Tx.

Aim Atypical sensory processing is common in children born extremely prematurely. We investigated sensory processing abilities in extremely low gestational age (ELGA) children and analysed associated neonatal risk factors, neuroanatomical findings and neurodevelopmental outcome. Methods We carried out a prospective study of 44 ELGA children, including 42 who had undergone brain magnetic resonance imaging (MRI) at term-equivalent age, when they were 2 years of corrected age. Their sensory processing abilities were assessed with the Infant/Toddler Sensory Profile questionnaire and their neurodevelopmental with a structured Hempel neurological examination, Griffiths Mental Developmental Scales and Bayley Scales of Infant and Toddler Development Third Edition. Results Sensory profiles were definitely or probably atypical (

Neurofibromatosis 1 is a hereditary symptom predisposing to cancer, affecting some 1,500 Finnish people. This systemic disease is most commonly detected through cutaneous findings. Although the cutaneous symptoms are harmless, they impair the patients' quality of life. The disease is, however, insidious, as the complications often become manifested from unexpected organ systems. For example cancers originally from nervous systems and severe bone lesions require rapid diagnosis and treatment. The healthcare personnel should thus be aware of the diagnosis of NF syndrome, and the patients should have sufficient knowledge of their disease.

Prior studies on extremely preterm infants have reported long-term prognostic value of absent secondary somatosensory cortex (SII) responses in magnetoencephalography (MEG) at term. The present work (i) further examines the potential added value of SII responses in neonatal neurological evaluation of preterm infants, and (ii) tests whether SII responses are detectable in routine neonatal electroencephalogram complemented with median nerve stimulation (EEG-SEP).Altogether 29 infants born28 gestational weeks underwent MEG, MRI, and neonatal neurological examination at term age, and Hempel neurological examination at 2-years corrected age. Term-age EEG-SEP was available for seven infants.While in neonatal neurological examination severely abnormal finding predicted unfavorable outcome in 2/2 infants, outcome was unfavorable also in 3/9 (33%) moderately abnormal and in 5/18 (28%) mildly abnormal/normal infants. Of these eight infants four had unilaterally absent SII responses in MEG, compared with only two of the 24 infants with favorable outcome. Furthermore, SII responses (when present in MEG) were also usually detectable in EEG-SEP.Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment.Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside.

Summary: Purpose: Proton magnetic resonance spectroscopic imaging (1H MRSI) can lateralize the epileptogenic frontal lobe by detecting metabolic ratio abnormalities in frontal lobe epilepsy (FLE). We used 1H MRS to lateralize and localize the epileptogenic focus, and we also sought to characterize further the metabolic abnormality in FLE. Methods: We measured signals from N-acetyl aspartate (NAA), choline-containing compounds (Cho), and creatine + phosphocreatine (Cr) in the supraventricular brain of 14 patients with frontal or frontoparietal epilepsy and their matched controls. The supratentorial brain also was segmented into gray matter, white matter, and cerebrospinal fluid classes. Regional metabolite alterations were compared with localizing and lateralizing results from other examination modalities and with histology from three patients. Results: Spectroscopy lateralized the epileptogenic focus in 10 patients in agreement with video-EEG and functional imaging. In four patients, spectroscopy showed bilateral, focal metabolic abnormality, whereas video-EEG suggested unilateral or midline abnormality. In the epileptogenic focus, Cho and Cr were increased by 23% and 14%, respectively, and NAA was decreased by 11%, suggesting metabolic disturbances both in the glial and in the neuronal cell pools. Two Taylor dysplasia lesions confirmed by histology and one with radiologic diagnosis showed high Cho and low or normal NAA, whereas two dysembryoplastic neurogenic tumors had normal Cho and low NAA. Contralateral hemisphere NAA/(Cho + Cr) was decreased in FLE, indicating diffusely altered brain metabolism. Segmentation of brain tissue did not reveal atrophic changes in FLE. Conclusions: Spectroscopy is useful in lateralizing frontoparietal epilepsy and shows promise as a “noninvasive biopsy” in epileptogenic lesions.

Item does not contain fulltext BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

The authors reorganized the emergency room (ER) by moving CT to the ER and streamlining triage by prenotification by emergency medical services (EMS), which reduced in-hospital delays and enhanced access to stroke thrombolysis. CT delay dropped from 1 hour 3 minutes +/- 14 minutes in 1999 to 7 +/- 2 minutes in 2004 (p0.0001). Door-to-needle time dropped from 1 hour 28 minutes +/- 7 minutes to 50 +/- 3 minutes (p0.001), while symptom-to-needle time dropped from 2 hours 44 minutes +/- 6 minutes to 2 hours 5 minutes +/- 4 minutes (p0.0001). From 23 patients in 1999, thrombolysis access was increased to 100 patients in 2004 and 183 patients in 2005.

We studied 88 patients with acute encephalitis using hexamethylpropyleneamine oxime and single photon emission computed tomography (SPECT). All patients had been initially treated with intravenous acyclovir. The etiology could be disclosed in 37 patients (42%), which included 15 patients with herpes simplex encephalitis, 7 with varicella-zoster encephalitis, and 29 with other encephalitides (Mycoplasma, adenovirus, influenza, rotavirus, rubella, Epstein-Barr, arbovirus, syphilis, and tuberculosis). Unilateral hyperperfusion in SPECT was an independent predictor of poor prognosis, whereas neither clinical outcome variables, such as seizures, state of consciousness, and focal neurologic findings, nor CSF or EEG findings were not. Focal unilateral hyperperfusion is an indicator of severe inflammation of the brain tissue and predicts a poor outcome as assessed in terms of activities of daily living after recovery.

Nine immunocompetent patients with acute herpes zoster encephalitis (HZE) were studied with the help of neurological, neuroradiological and neuropsychological investigations. All patients were treated with acyclovir. Neuropsychological performance was compared with that of a group of 16 healthy controls. Computed tomography of the head showed infarct-like hypodense lesions in two patients, involving the internal capsule in one case and the temporoparietal cortex and white matter in another. Hypoperfusion shown by single photon emission computed tomography, mostly involving the frontal areas bilaterally, was seen in six of the seven patients examined. Hyperperfusion as seen in herpes simplex encephalitis was not encountered. One patient remained mildly demented, but all the other patients recovered relatively well. Neuropsychological examination after acyclovir treatment showed a decline in memory and speed of cognitive processes, without circumscribed neuropsychological deficits. Six of the nine patients showed behavioural disinhibition, and mood changes were also observed. Memory impairment in HZE was not as global or as severe as is described after encephalitis due to herpes simplex virus. In HZE both the brain perfusion pattern and the neuropsychological test profile showed features compatible with subcortical dysfunction.

Long-chain 3-hydroxyacyl—coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in β-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis. J Pediatr 1997;130:67-76

Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective.Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls.For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4-60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor.The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future.

Tuberous sclerosis is a polymorphic, dominantly inherited syndrome caused by an inactivating mutation in a tumor suppressor gene. The disease involves benign tumors in several distinct organs such as the skin, kidneys, heart and central nervous system. The tumors interfere with organ function, but only some exhibit a significant tendency to grow. The clinical picture of tuberous sclerosis varies from nearly symptomless to a severe disease. Treatment of growing tumors associated with tuberous sclerosis is changing significantly, since their growth can be suppressed with rapamycin and its derivatives.