Naci Kocer

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Behçet's disease : diagnostic and prognostic aspects of neurological involvement

Abstract This study was conducted to describe clinical and prognostic aspects of neurological involvement in Behçets disease (BD). Patients referred for neurological evaluation fulfilled the criteria of the International Study Group for Behçets Disease. We analyzed disability and survival by the Kaplan-Meier method, using Kurtzkes Extended Disability Status Scale (modified for BD) and the prognostic effect of demographic and clinical factors by Cox regression analysis. We studied 164 patients; of the 107 diagnostic neuroimaging studies: 72.1% showed parenchymal involvement, 11.7% venous sinus thrombosis (VST) and the others were normal. CSF studies were performed in 47 patients; all with inflammatory CSF findings (n=18) had parenchymal involvement. An isolated increase in pressure was compatible with either VST or normal imaging. The final diagnoses were VST (12.2%), neuro-Behçets syndrome (NBS) (75.6%), isolated optic neuritis (0.6%), psycho-Behçets syndrome (0.6%), and indefinite (11%). VST and NBS were never diagnosed together. Ten years from onset of BD 45.1% (all NBS) reached a disability level of EDSS 6 or higher, and 95.7±2.1% of the patients were still alive. Having accompanying cerebellar symptoms at onset or a progressive course is unfavorable. Onset with headache or a diagnosis of VST is favorable. Two major neurological diagnoses in BD are NBS and VST. These are distinct in clinical, radiological, and prognostic aspects, hence suggesting a difference in pathogenesis.

Traumatic Intracranial Carotid Tree Aneurysms

OBJECTIVE This study was designed to elucidate the requirements for angiographic evaluation in blunt head injuries, the timing of angiography, and the selection of appropriate therapeutic approaches. METHODS Twelve cases of traumatic aneurysms (TAs) in the intracranial carotid tree were analyzed in this study. Neurological examination results, computed tomographic scans, pre- and postembolization cerebral angiograms, and follow-up data were included. RESULTS In 11 of 12 cases, TAs were of cranial base origin; in 1 case, the aneurysm was located in the distal anterior cerebral artery. In seven of the cases with cranial base lesions, aneurysms were located in the intracavernous segment of the internal carotid artery; all of the computed tomographic scans for these cases demonstrated sphenoid sinus wall fractures and hematoma in the sphenoid sinus. In two cases, although the initial angiograms revealed no lesions, a second study performed 2 weeks later demonstrated the presence of aneurysms. Nine of the aneurysms were treated with endovascular techniques, two were managed conservatively, and the remaining one patient died with massive epistaxis while awaiting surgical treatment. No morbidity or additional permanent neurological deficits occurred in the endovascularly treated patient group. CONCLUSION Patients with head trauma who present with sphenoid sinus fractures and massive epistaxis should be evaluated for the development of TAs as soon as possible. If the patients exhibit fractures without epistaxis, angiography should be deferred for 2 to 3 weeks; if the first angiographic evaluation reveals normal findings, repeated epistaxis should prompt a second angiographic evaluation. Current treatment of TAs involves occlusion of the main artery through the use of endovascular techniques. Cases involving internal carotid artery TAs of cranial base origin and patients who do not tolerate test occlusion require extracranial-to-intracranial bypass surgery.

Gadolinium-Enhanced MR Cisternography to Evaluate Dural Leaks in Intracranial Hypotension Syndrome

Background and PURPOSE: We evaluated the use of MR cisternography after intrathecal administration of gadopentetate dimeglumine to detect the presence and localization of CSF leaks in 19 patients diagnosed with spontaneous intracranial hypotension syndrome according to the criteria of International Headache Society. MATERIALS AND METHODS: Lumbar puncture with an injection of 0.5 mL of gadopentetate dimeglumine into the subarachnoid space in the lumbar area was performed. MR images of the cervical, thoracic, and lumbar regions in axial, coronal, and sagittal planes with fat-saturated T1-weighted images were acquired. RESULTS: We observed objective CSF leakage in 17 (89%) of 19 patients. In 14 of these 17 patients, the site of dural tear was demonstrated accurately. In 3 of these 17 patients, the contrast leakage was diffuse, and site of the leak could not be located accurately. No leakage was observed in 2 patients. No complications were detected in any of the patients during the first 24 hours after the procedure or during the 6- to 12-month follow-up. CONCLUSION: The current results demonstrate the relative safety, accuracy, and feasibility of intrathecal gadolinium-enhanced MR cisternography to evaluate dural leaks.

Endovascular parent artery occlusion in large-giant or fusiform distal posterior cerebral artery aneurysms

Posterior cerebral artery aneurysms are amenable to deconstructive surgical treatment because of the rich collateral supply of the distal posterior cerebral artery. This report retrospectively analyses the outcome of endovascular parent artery occlusion for large or fusiform distal posterior cerebral artery aneurysms. Medical records and cerebral angiograms from two endovascular centres were analysed retrospectively. Eight patients with large or fusiform distal posterior cerebral artery (PCA) aneurysms were treated by endovascular occlusion of the segment of the PCA at the site of the aneurysm. Three of those were treated urgently after acute subarachnoid haemorrhage, the remainder had elective treatment. The clinical and angiographic outcomes in seven patients were assessed at 6 to 12 months. A single case of occipital infarction resulting in permanent homonymous hemianopia was the only permanent complication. Of the remaining patients, six made excellent recoveries and one was lost to follow-up. No recurrence or re-bleeding was noted. Endovascular parent artery occlusion may be an alternative to surgical parent artery occlusion in distal PCA aneurysms which are not convenient for selective endovascular treatment or surgical clipping.

Endovascular treatment of carotid cavernous sinus fistula: A systematic review

Carotid cavernous sinus fistulas are abnormal communications between the carotid system and the cavernous sinus. Several classification schemes have described carotid cavernous sinus fistulas according to etiology, hemodynamic features, or the angiographic arterial architecture. Increased pressure within the cavernous sinus appears to be the main factor in pathophysiology. The clinical features are related to size, exact location, and duration of the fistula, adequacy and route of venous drainage and the presence of arterial/venous collaterals. Noninvasive imaging (computed tomography, magnetic resonance, computed tomography angiography, magnetic resonance angiography, Doppler) is often used in the initial work-up of a possible carotid cavernous sinus fistulas. Cerebral angiography is the gold standard for the definitive diagnosis, classification, and planning of treatment for these lesions. The endovascular approach has evolved as the mainstay therapy for definitive treatment in situations including clinical emergencies. Conservative treatment, surgery and radiosurgery constitute other management options for these lesions.

Intrathecal Gadolinium-Enhanced MR Cisternography in the Evaluation of CSF Leakage

BACKROUND AND PURPOSE: Radiologic identification of the location of the CSF leakage is important for proper surgical planning and increases the chance of dural repair. This article describes our experience in analyzing clinically suspected cranial CSF fistulas by using MR imaging combined with the intrathecal administration of a gadolinium-based contrast agent. MATERIALS AND METHODS: A total of 85 consecutive patients with suspected CSF fistulas who presented with persistent or intermittent rhinorrhea or otorrhea lasting for more than 1 month between 2003 and 2007 were included in this study. RESULTS: We observed objective CSF leakage in 64 of 85 patients (75%). The CSF leak was located in the ethmoidal region in 37 patients (58%), in the superior wall of the sphenoid sinus in 8 patients (13%), in the posterior wall of the frontal sinus in 10 patients (15%), in the superior wall of the mastoid air cells in 6 patients (9%), and from the skull base into the infratemporal fossa in 1 patient (2%). Two patients (3%) showed leakage into >1 paranasal sinus. CONCLUSIONS: MR cisternography after the intrathecal administration of gadopentate dimeglumine represents an effective and minimally invasive method for evaluating suspected CSF fistulas along the skull base. It provides multiplanar capabilities without risk of radiation exposure and is an excellent approach to depict the anatomy of CSF spaces and CSF fistulas.

Endovascular treatment of ruptured intracranial aneurysms during pregnancy: report of three cases

Abstract. Subarachnoid hemorrhage from an intracranial aneurysm during pregnancy is a rare complication with high maternal and fetal morbidity-mortality. We report three cases of ruptured intracranial aneurysms during pregnancy, treated by the minimal invasive endovascular approach.

Endovascular treatment of Behçet's disease-associated intracranial aneurysms: report of two cases and review of the literature

Behçets disease (BD) is a well-known multisystem inflammatory disorder of unknown etiology. Aneurysms of the cerebral arteries are not commonly described in patients with BD. There are few cases of intracranial aneurysms with BD reported in the literature. In this study, we report endovascular treatment of BD-related ruptured intracranial aneurysms in two cases, and present a wide literature review of intracranial arterial aneurysms related to BD.

MRI and MRS in HMG-CoA lyase deficiency

3-Hydroxy-3-Methylglutaryl coenzyme A lyase (HMG-CoA) deficiency is a rare inborn error of leucine catabolism. The disease is characterized by recurrent episodes of metabolic acidosis, hyperammonemia without ketosis, hypoglycemia, lethargy, hepatomegaly, and seizures. This study has evaluated the magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings of three patients with HMG-CoA deficiency. The common findings on all of the MRI scans were multiple, coalescent, marked lesions in periventricular white matter and arcuate fibers, most prominently in frontal or periatrial regions that were superimposed on diffuse, slightly hyperintense subcortical white matter signal. Involvement of the caudate nucleus and the dentate nucleus were observed in the reported patients. MRS studies by both STEAM and PRESS spectra of all patients revealed a decrease in N-acetylaspartate and elevation in both myoinositol and choline. A pathologic peak at 1.33 ppm, which is compatible with lactate, and a particular peak at 2.42 ppm in all patients were also found. The combination of both MRI and MRS findings could be considered as being specific in patients with HMG-CoA lyase deficiency.