Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification.

Background: Long-term treatment with the vitamin K antagonist warfarin is widely used for the prevention of venous thrombosis and thromboembolism. However, vitamin K antagonists may promote arterial calcification, a phenomenon that has been previously studied in coronary and peripheral arteries, but not in extracranial carotid arteries. In this observational cohort study, we investigated whether warfarin treatment is associated with calcification of atherosclerotic carotid arteries. Methods: Overall, 500 consecutive patients underwent carotid endarterectomy, 82 of whom had received long-term warfarin therapy. The extent of calcification was assessed with preoperative computed tomography angiography, and both macroscopic morphological grading and microscopic histological examination of each excised carotid plaque were performed after carotid endarterectomy. Results: Compared with non-users, warfarin users had significantly more computed tomography angiography-detectable vascular calcification in the common carotid arteries (odds ratio 2.64, 95% confidence interval 1.51-4.63, P < 0.001) and even more calcification in the internal carotid arteries near the bifurcation (odds ratio 18.27, 95% confidence interval 2.53-2323, P < 0.001). Histological analysis revealed that the intramural calcified area in plaques from warfarin users was significantly larger than in plaques from non-users (95% confidence interval 3.36-13.56, P = 0.0018). Conclusions: Long-lasting warfarin anticoagulation associated with increased calcification of carotid atherosclerotic plaques, particularly in locations known to be the predilection sites of stroke-causing plaques. The clinical significance of this novel finding warrants further investigations.

Predictive Factors for Pre-operative Recurrence of Cerebrovascular Symptoms in Symptomatic Carotid Stenosis.

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.

A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome.

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.

Morphology and histology of silent and symptom-causing atherosclerotic carotid plaques - Rationale and design of the Helsinki Carotid Endarterectomy Study 2 (the HeCES2).

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 Messages This 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.

Molecular alterations in pediatric brainstem gliomas.

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.

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis.

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 ß-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.

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

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.

Recognizing subtle near-occlusion in carotid stenosis patients: a computed tomography angiographic study.

INTRODUCTION: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult with Middle Interhemispheric Variant of Holoprosencephaly: Neuropsychological, Clinical, and Radiological Findings.

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.

Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy.

OBJECTIVE: To identify the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy, intractable seizures, and intellectual disability. METHODS: We performed exome sequencing in the proband and whole-genome single nucleotide polymorphism genotyping (copy number variant analysis) in the proband-parent trio. We used heterologous expression systems to study the functional consequences of identified mutations. RESULTS: The search for potentially deleterious recessive or de novo variants yielded compound heterozygous missense (c.1202G>A, p.Cys401Tyr) and frameshift deletion (c.2396delG, p.Ser799IlefsTer96) mutations in ADAM22, which encodes a postsynaptic receptor for LGI1. The deleterious effect of the mutations was observed in cell surface binding and immunoprecipitation assays, which revealed that both mutant proteins failed to bind to LGI1. Furthermore, immunoprecipitation assays showed that the frameshift mutant ADAM22 also did not bind to the postsynaptic scaffolding protein PSD-95. CONCLUSIONS: The mutations identified abolish the LGI1-ADAM22 ligand-receptor complex and are thus a likely primary cause of the proband's epilepsy syndrome, which is characterized by unusually rapidly progressing cortical atrophy starting at 3-4 months of age. These findings are in line with the implicated role of the LGI1-ADAM22 complex as a key player in nervous system development, specifically in functional maturation of postnatal synapses. Because the frameshift mutation affects an alternatively spliced exon with highest expression in postnatal brain, the combined effect of the mutations is likely to be hypomorphic rather than complete loss of function. This is compatible with the longer survival of the patient compared to Lgi1 (-/-) and Adam22 (-/-) mice, which develop lethal seizures during the first postnatal weeks.

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

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.

[Radiological examinations in suspected physical abuse of a child]. / Radiologiset tutkimukset epäiltäessä lapsen fyysistä pahoinpitelyä.

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.

Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate.

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.

Etiology and Long-Term Outcomes of Late-Onset Infantile Spasms.

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.

Atypical sensory processing is common in extremely low gestational age children.

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 (<-1 SD) in half of the ELGA children, and the most common behavioural pattern was low registration (23%). Sensation seeking was associated with abnormalities in grey and/or white matter in the brain MRI (p < 0.01). Atypical oral sensory processing was associated with surgical closure of the patent ductus arteriosus (p = 0.02, adjusted p < 0.01). CONCLUSION: Atypical sensory processing in ELGA children was common, and children with neonatal neuroanatomical lesions tended to present specific behavioural responses to sensory stimuli. Surgical closure of the patent ductus arteriosus may predispose infants to feeding problems due to atypical oral sensory processing.

Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations.

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.

Evaluation of somatosensory cortical processing in extremely preterm infants at term with MEG and EEG.

OBJECTIVE: 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). METHODS: Altogether 29 infants born <28 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. RESULTS: 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. CONCLUSIONS: Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment. SIGNIFICANCE: Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside.

Safety in simultaneous EEG-fMRI at 3 T: temperature measurements.

BACKGROUND: In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), safety of the EEG equipment is ensured by the manufacturer only for localizers and fMRI sequences. To conduct a clinically feasible simultaneous EEG-fMRI study, other sequences, e.g. anatomical and B0-correction sequences, have to be acquired in the same imaging session. PURPOSE: To measure the temperature increase of the electrodes in different size EEG caps in a phantom and volunteers during magnetic resonance imaging (MRI) sequences typically used in clinical studies. MATERIAL AND METHODS: A phantom with EEG caps of size 52, 56, and 60 was imaged using several sequences in two 3 T MRI scanners to determine the maximum and average temperature increases in the electrodes. Additionally, three volunteer studies were performed for the EEG caps of sizes 56 and 60. The sequences were gradient echo based echo planar imaging sequence, T2-weighted turbo spin echo (T2-TSE), spin echo multiecho for B0-correction, diffusion tensor imaging and T1-weighted 3D sequences. RESULTS: In phantom studies the maximum temperature increase was 4.1℃ with a mean of 1.2 ± 1.1℃. In volunteer studies, the maximum temperature measured was 35.6℃ and the maximum temperature rise was 2.1℃ with a mean of 0.9 ± 0.7℃. Both were observed with a T2-TSE sequence. CONCLUSION: The temperature of the electrodes did not exceed the limits set by the IEC 60601-1 standard (43℃) or manufacturer (45℃), thus indicating a safe EEG-fMRI protocol in this respect.

The normal internal carotid artery: a computed tomography angiographic study.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.