Asymmetric laterality of Chiari type I malformation in patients with non-syndromic single-suture craniosynostosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic Overlap between Holoprosencephaly and Kallmann Syndrome.

Patients with Kallmann syndrome (KS; congenital hypogonadotropic hypogonadism and decreased/absent sense of smell), septo-optic dysplasia (SOD), or holoprosencephaly (HPE) reportedly have midline defects. In this study, we investigate a genetic overlap between KS, SOD, and HPE. Nineteen subjects (18 males, 1 female) with KS and without mutations in the known KS genes were screened for mutations in SOX2, SHH, SIX3,TGIF1,TDGF1,FOXH1,GLI2, and GLI3. One male carried 2 heterozygous missense changes, one in SIX3 (c.428G>A, p.G143D) and the other in GLI2 (c.2509G>A, p.E837K). Both of these genes have been implicated in the etiology of HPE and neither of these changes were present in 200 control subjects. Other variants found among the subjects were known polymorphisms. KS and HPE may display a genetic overlap. The involvement of genes implicated in the etiology of midline defects in patients with KS warrants further studies.

Morphometric comparison of foramen magnum in non-syndromic craniosynostosis patients with or without Chiari I malformation.

BACKGROUND: In order to compare the morphometry of foramen magnum (FM) in a matched-pair study, in children with non-syndromic craniosynostosis with and without Chiari I malformation (CMI), both brain magnetic resonance (MRI) and multidetector computed tomography (MDCT) images were utilized. METHODS: Brain MR images were retrieved from the Helsinki University Hospital Picture Archiving and Communications System to identify patients with CMI during 1.1.2004 to 31.3.2009. Age-, gender-, and craniosynostosis-matched controls were retrieved from the same cohort. Morphometric analysis of FM was carried out. RESULTS: Seven patients with non-syndromic craniosynostosis with CMI were recorded. In CMI patients, the absolute anteroposterior length was 33.4 mm as compared to 36.7 mm in controls (p = 0.023). The mean width was 28.1 and 29.9 mm (p = 0.29), and the cross-sectional area was 654.1 and 764.9 mm(2) (p = 0.11) in CMI and controls, respectively. In CMI patients, the relative anteroposterior length of the FM was, on average, 91 % of the control's measurements. On average, the width was 95 % and the cross-sectional area was 88 % of the control's results. CONCLUSIONS: In pediatric non-syndromic craniosynostosis patients, a statistically significant reduced anteroposterior diameter of the FM is found in patients with an adjacent CMI as compared to their age-, gender-, and type-matched controls of craniosynostosis.

The evolution of cerebellar tonsillar herniation after cranial vault remodeling surgery.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We conclude that asymptomatic patients with existing CMI may benefit from cranial vault remodeling surgery alone increasing the intracranial volume.

Brain anomalies in 121 children with non-syndromic single suture craniosynostosis by MR imaging.

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.

POLG1 manifestations in childhood.

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.

DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.

BACKGROUND: Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic magnetic resonance imaging and spectroscopic findings. The clinical features include childhood or juvenile onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2, encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leucoencephalopathy of young adults, multiple sclerosis (MS). OBJECTIVE: To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. METHODS: Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. RESULTS: All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134_K165del, and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. CONCLUSION: All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. The authors show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with MS.

Combined use of non-invasive techniques for improved functional localization for a selected group of epilepsy surgery candidates.

Invasive cortical mapping is conventionally required for preoperative identification of epileptogenic and eloquent cortical regions before epilepsy surgery. The decision on the extent and exact location of the resection is always demanding and multimodal approach is desired for added certainty. The present study describes two non-invasive preoperative protocols, used in addition to the normal preoperative work-up for localization of the epileptogenic and sensorimotor cortical regions, in two young patients with epilepsy. Magnetoencephalography (MEG) was used to determine the primary somatosensory cortex (S1) and the ictal onset zones. Navigated transcranial magnetic stimulation (nTMS) was used to determine the location and the extent of the primary motor representation areas. The localization results from these non-invasive methods were used for guiding the subdural grid deployment and later compared with the results from electrical cortical stimulation (ECS) via subdural grids, and validated by surgery outcome. The results from MEG and nTMS localizations were consistent with the ECS results and provided improved spatial precision. Consistent results of our study suggest that these non-invasive methods can be added to the standard preoperative work-up and may even hold a potential to replace the ECS in a subgroup of patients with epilepsy who have the suspected epileptogenic zone near the sensorimotor cortex and seizures frequent enough for ictal MEG.

CT perfusion identifies increased salvage of tissue in patients receiving intravenous recombinant tissue plasminogen activator within 3 hours of stroke onset.

BACKGROUND AND PURPOSE: In spite of the advent of thrombolytic therapy, CT-perfusion imaging is currently not fully used for clinical decision-making and not included in published clinical guidelines for management of ischemic stroke. We investigated whether lesion volumes on cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) maps predict final infarct volume and whether all these parameters are needed for triage to intravenous recombinant tissue plasminogen activator (rtPA). We also investigated the effect of intravenous rtPA on affected brain by measuring salvaged tissue volume in patients receiving intravenous rtPA and in controls. MATERIALS AND METHODS: Forty-four patients receiving intravenous rtPA and 19 controls underwent CT perfusion (CTP) studies in the emergency department within 3 hours of stroke onset. Lesion volumes were measured on MTT, CBV, and CBF maps by region-of-interest analysis and were compared with follow-up CT volumes by correlation and regression analysis. The volume of salvaged tissue was determined as the difference between the initial MTT and follow-up CT lesion volumes and was compared between intravenous rtPA-treated patients and controls. RESULTS: No significant difference between the groups was observed in lesion volume assessed from the CTP maps (P > .08). Coefficients of determination for MTT, CBF, and CBV versus follow-up CT lesion volumes were 0.3, 0.3, 0.47, with intravenous rtPA; and 0.53, 0.55, and 0.81 without intravenous rtPA. Regression of MTT on CBF lesion volumes showed codependence (R(2) = 0.98, P < .0001). Mean salvaged tissue volumes with intravenous rtPA were 21.8 +/- 17.1 and 13.2 +/- 13.5 mL in controls; these were significantly different by using nonparametric (P < .03) and Fisher exact tests (P < .04). CONCLUSIONS: Within 3 hours of stroke onset, CBV lesion volume does not necessarily represent dead tissue. MTT lesion volume alone can be used to identify the upper limit of the size of abnormally perfused brain. More brain is salvaged in patients with intravenous rtPA than in controls.

Increasing contrast agent concentration improves enhancement in first-pass CT perfusion.

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.

Brain magnetic resonance imaging of infants exposed prenatally to buprenorphine.

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 1.5 T 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.

CT angiographic analysis of carotid artery stenosis: comparison of manual assessment, semiautomatic vessel analysis, and digital subtraction angiography.

BACKGROUND AND PURPOSE: To compare multisection CT angiography (CTA) analyzed with source/maximum intensity projection (MIP) images as well as semiautomated vessel analysis software with intra-arterial digital subtraction angiography (DSA) in detection and grading of carotid artery bifurcation stenosis. METHODS: Consecutive patients with sonography evidence of a marked internal carotid artery stenosis underwent both carotid CTA and DSA (37 patients, 73 vessels). In CTA, the grade of stenosis was determined using axial source and MIP images as well as vessel analysis. The scans were blind-analyzed by 2 neuroradiologists using the NASCET criteria. RESULTS: Correlation of CTA source/MIP images versus DSA estimates of stenosis (R = 0.95) was higher than for the vessel analysis method versus DSA (R = 0.89). Compared with DSA, CTA source/MIP images underestimated high (78.2% versus 86.4%, P < .05) and moderate grades of stenosis (57.3% versus 63.1%, P < .05) to a lesser extent than the vessel analysis method (68.5% versus 83.5% and 51.8% versus 63.1%, P < .05). For a high-grade stenosis, sensitivity and specificity of source/MIP image CTA were 75% and 96%, respectively, whereas for the vessel analysis method, they were 47% and 96%, respectively. For moderate stenosis, the source/MIP image CTA sensitivity and specificity were 88% and 82%, respectively, and for vessel analysis method, 62% and 82%, respectively. CTA detected all 4 occlusions. CONCLUSION: In evaluation of carotid stenosis, CTA provides an adequate, less invasive alternative with a high correlation to conventional DSA, though it tends to underestimate clinically relevant grades of stenosis. Its accuracy is not improved by semiautomated analysis. The data support the use of CTA in confirming carotid occlusion.

Cerebroretinal microangiopathy with calcifications and cysts.

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.

Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment.

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 (p < 0.0001). Door-to-needle time dropped from 1 hour 28 minutes +/- 7 minutes to 50 +/- 3 minutes (p < 0.001), while symptom-to-needle time dropped from 2 hours 44 minutes +/- 6 minutes to 2 hours 5 minutes +/- 4 minutes (p < 0.0001). From 23 patients in 1999, thrombolysis access was increased to 100 patients in 2004 and 183 patients in 2005.

Value of imaging studies in vertiginous children.

OBJECTIVE: Imaging of the head is expensive and can be stressful for children, some of whom need anesthesia for the procedure. The aim of this study was to determine which vertiginous children benefit most from head imaging. METHODS: We conducted a retrospective chart review of all children aged under 18 years who were referred to the Helsinki University Children's Hospital Radiology Department (tertiary referral center) for head computerized tomography (CT) or magnetic resonance imaging (MRI) over a 1-year period. We analyzed and reviewed the medical records of 87 children who had undergone imaging of the head due to vertigo. RESULTS: Altogether 978 children underwent imaging of the head for various indications. Of these, 87 aged 0-16 years (mean age 8 years) were imaged because of vertigo. Abnormalities were seen in the images of 37 children; 23 were new findings and 14 showed no change in comparison to earlier deviant images. The most common abnormalities in head imaging were brain tumors, infections, multiple sclerosis lesions, and other lesions in T2-weighted images. Of the 23 vertiginous children with a new finding, 19 also had neurological deficits. While four children had no neurological symptoms, three had intense headaches. CONCLUSIONS: Head imaging is necessary for vertiginous children with neurological deficits or persistent headaches or who have sustained a head trauma. If vertigo is the only symptom without trauma, imaging studies will not aid diagnostic work-up.

De novo paracentric inversion 14q13q24.1 in a patient with severe involuntary movements, epilepsy, oligodontia and dysmorphic features.

We describe a 22-year-old woman with a de novo paracentric inversion of the long arm of chromosome 14 with breakpoints at q13 and q24 and associated with epilepsy, dysarthria and severe incapacitating involuntary movements present since birth. These movements were incessant when awake but absent when asleep. She had unusual facies with downward slant of palpebral fissures, epicanthi, broad philtral groove, flat malar region, large, cup shaped and low-set ears, and short neck. Her decidual and permanent dentition lacked all premolars and molars. Psychological assessment at ages 6 and 15 years showed mild mental retardation. In spite of the aggravation of the neurological symptoms no decline of mental capacity was observed. A brain MRI was normal at 19 years of age. Early on EEG showed changes compatible with partial epilepsy, and at later stages there was, contrary to expectation, only a mild background slowing. Urinary metabolic screening tests and a search for vacuolated lymphocytes were negative. Previously, four cases with a similar inversion have been described. Of these, three were familial with normal phenotype, and the fourth was de novo with severe mental retardation, microcephaly and involuntary movements. Our case is the second de novo inversion of the long arm of chromosome 14 with breakpoints at q13 and q24. The observations in the two patients suggest that this chromosomal rearrangement is associated with a congenital complex movement disorder.

Five new cases of a recently described leukoencephalopathy with high brain lactate.

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 (1H-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.

Electromagnetic function of polymicrogyric cortex in congenital bilateral perisylvian syndrome.

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.