Askin Seker

The front door to meckel's cave: an anteromedial corridor via expanded endoscopic endonasal approach- technical considerations and clinical series.

OBJECTIVE Tumors within Meckels cave are challenging and often require complex approaches. In this report, an expanded endoscopic endonasal approach is reported as a substitute for or complement to other surgical options for the treatment of various tumors within this region. METHODS A database of more than 900 patients who underwent the expanded endoscopic endonasal approach at the University of Pittsburgh Medical Center from 1998 to March of 2008 were reviewed. From these, only patients who had an endoscopic endonasal approach to Meckels cave were considered. The technique uses the maxillary sinus and the pterygopalatine fossa as part of the working corridor. Infraorbital/V2 and the vidian neurovascular bundles are used as surgical landmarks. The quadrangular space is opened, which is bound by the internal carotid artery medially and inferiorly, V2 laterally, and the abducens nerve superiorly. This offers direct access to the anteroinferomedial segment of Meckels cave, which can be extended through the petrous bone to reach the cerebellopontine angle. RESULTS Forty patients underwent an endoscopic endonasal approach to Meckels cave. The most frequent abnormalities encountered were adenoid cystic carcinoma, meningioma, and schwannomas. Meckels cave and surrounding structures were accessed adequately in all patients. Five patients developed a new facial numbness in at least 1 segment of the trigeminal nerve, but the deficit was permanent in only 2. Two patients had a transient VIth cranial nerve palsy. Nine patients (30%) showed improvement of preoperative deficits on Cranial Nerves III to VI. CONCLUSION In selected patients, the expanded endoscopic endonasal approach to the quadrangular space provides adequate exposure of Meckels cave and its vicinity, with low morbidity.

Mapping a Mendelian Form of Intracranial Aneurysm to 1p34.3-p36.13

The identification of pathways that underlie common disease has been greatly impacted by the study of rare families that segregate single genes with large effect. Intracranial aneurysm is a common neurological problem; the rupture of these aneurysms constitutes a frequently catastrophic neurologic event. The pathogenesis of these aneurysms is largely unknown, although genetic and environmental factors are believed to play a role. Previous genomewide studies in affected relative pairs have suggested linkage to several loci, but underlying genes have not been identified. We have identified a large kindred that segregates nonsyndromic intracranial aneurysm as a dominant trait with high penetrance. Genomewide analysis of linkage was performed using a two-stage approach: an analysis of ~10,000 single-nucleotide polymorphisms in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals in all 23 kindred members. Analysis revealed significant linkage to a single locus, with a LOD score of 4.2 at 1p34.3-p36.13 under a dominant model with high penetrance. These findings identify a Mendelian form of intracranial aneurysm and map the location of the underlying disease locus.

CCM2 Expression Parallels That of CCM1

BACKGROUND AND PURPOSE Mutations in CCM2 (MGC4607 or malcavernin) cause familial cerebral cavernous malformation (CCM), an autosomal dominant neurovascular disease. Both the function of this molecule and the pathogenesis of the disease remain elusive. METHODS We analyzed the mRNA expression of Ccm1 and Ccm2 in the embryonic and postnatal mouse brain by in situ hybridization. Subsequently, we generated CCM2-specific polyclonal antibodies and tested their specificity using transient transfection experiments in various cell lines. We then investigated CCM2 protein expression in cerebral and extracerebral tissues by Western blot analysis as well as immunohistochemistry and compared these results with CCM1 (KRIT1) protein expression. RESULTS In situ analysis shows similar temporal and spatial expression patterns for Ccm1 and Ccm2, although Ccm1 expression appears more widespread. Immunohistochemical analysis shows that CCM2 is expressed in various human organs, most noticeably in the arterial vascular endothelium. As is the case with CCM1, CCM2 is not expressed in other vascular wall elements such as smooth muscle cells or the venous circulation. Within cerebral tissue, it is also expressed in pyramidal neurons, astrocytes, and their foot processes. In extracerebral tissues, CCM2 is present in various epithelial cells necessary for blood-organ barrier formation. CONCLUSIONS CCM1 and CCM2 have similar expression patterns during development and postnatally thereafter. Given the fact that the disease phenotypes caused by mutations in either gene are clinically and pathologically indistinguishable, the significant overlap in expression pattern supports the hypothesis that both molecules are involved in the same pathway important for central nervous system vascular development.

Gamma knife radiosurgery for cranial neurocytomas

Gamma-knife surgery may be an effective alternative for treatment of central neurocytomas owing to its relative safety compared with conventional radiotherapy. In this paper we present results of gamma-knife treatment (GKS) of residual or recurrent neurocytomas. Twenty-two patients (14 female, 8 male) with recurrent or residual neurocytomas who underwent GKS were included. Diagnosis was based on histological findings. The proliferative potential of the tumors was examined by immunostaining with MIB-1 antibody, which is specific for detection of Ki-67 antigen. Tumor volume was determined by using post-gadolinium magnetic resonance images. After GKS treatment, MR imaging was scheduled at three-month intervals in the first year, at six months intervals in the second year, and yearly thereafter. Histopathological diagnoses were: 18 cases of central neurocytomas, two liponeurocytomas, one cerebral neurocytoma and one cerebellar neurocytoma. The MIB1 labeling index (LI) varied from 0 to 5.7%. Marked reduction in tumor volume was seen in 15 patients. In six patients, the tumor volume remained unchanged, and progression was observed for one patient. No complications because of GKS were noted. Shrinking effect on tumor volume increased with increasing duration of follow-up. On the other hand, high MIB labeling index did not seem to have an effect on tumor response to GKS treatment. Findings of this study suggest that GKS is an effective and safe treatment alternative for residual or recurrent neurocytomas. However, its effectiveness should be confirmed with larger studies.

Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations

Background and Purpose— Pathogenesis of cerebral venous malformation (CVM) is unknown. Because of coexistence of CVM and cerebral cavernous malformations (CCM), some studies have suggested that these 2 entities share a common origin and pathogenetic mechanism. Methods— We have identified and ascertained over 200 families with CCM. Among these, 1 unique family was found to have members affected by both disorders. We have performed mutational analysis in all 3 CCM genes, KRIT1, Malcavernin, and PDCD10, to identify the causative gene in the family. Results— Mutational analysis revealed a frameshift mutation affecting exon 19 of the CCM1 gene (KRIT1) in members with CCM, whereas no such mutation was observed in the member with CVM. Conclusions— These findings support the hypothesis that CVM and CCM are 2 distinct entities with different pathogenetic mechanisms. This data further supports the hypothesis that CVM has a distinct biology and clinical behavior when compared to CCM. CVM is a benign developmental anomaly and should be managed separately from CCM.

Outcomes of gamma knife treatment for solid intracranial hemangioblastomas.

The aim of this study was to examine the results of gamma knife radiosurgery for 13 patients with residual/recurrent or newly diagnosed solid hemangioblastomas. The 13 patients had 34 solid hemangioblastomas, and all patients underwent gamma knife radiosurgery. Seven patients had von Hippel-Lindau disease and six had sporadic disease. When individual lesions were considered, the overall mean dose at the tumor periphery was 15.8 Gy (range: 12-25 Gy) and the average maximum tumor dose was 31.6 Gy (range: 24-50 Gy). The mean duration of follow-up with MRI was 50.2 months. At the last follow-up evaluation, growth control was achieved for all tumors (partial remission in three tumors [8.8%] and no change in 31 tumors [91.2%]). No radiation-related complications were encountered. Our findings reinforce the view that gamma knife radiosurgery is effective and safe for the management of solid hemangioblastomas with a diameter less than 3 cm, whether they are sporadic or associated with von Hippel-Lindau disease. The high response rate and lack of any radiation-induced side-effects confirms the suitability of the doses used in the present study.

Ultrastructural analysis of vascular features in cerebral cavernous malformations

OBJECTIVE Investigation of the structure of vascular malformations highlights the pathogenic mechanisms underlying their clinical behavior. One of the vascular malformations is called cerebral cavernous malformation (CCM). However, the ultrastructural features of the vascular malformations are not defined in detail. METHODS We aimed to investigate the ultrastructural features of CCMs using transmission (TEM), scanning (SEM) electron microscopy, and also immunohistochemistry methods with antibodies against CCM proteins such as CCM2 and CCM3. CCM tissues (n=6) microsurgically excised from patients for conventional indications. RESULTS CCM2 and CCM3 were strongly detected in the vascular endothelium. However, there was a very weak immunostaining in stroma. SEM observations revealed that there were ruptures and damages in the luminal endothelium, possibly due to the damage of intercellular junctions. TEM observations also showed a few ruptures and detachments between the endothelium and basal lamina as observed with partially damages and disconnections. The architecture of pericytes showed protrusions and shrinkages. Our results suggest that the thin vessel walls of CCMs were lacking of subendothelial support and intact basal lamina underlying the endothelial cells. CONCLUSION This study is so far the first study attempting to show human CCM lesions with SEM. We believe that an understanding of the ultrastructural features of these lesions by light and electron microscopy techniques would help to understand the pathology of these diseases.

Relationship of angiogenic potential with clinical features in cranial meningiomas: a corneal angiogenesis study.

BACKGROUND: Intracranial meningiomas constitute approximately one fourth of all primary intracranial tumors. The invention of cranial angiographic techniques has led to the recognition of the angiogenic potential of meningiomas, which has been the subject of extensive research. OBJECTIVE: To test the relationship between the angiogenetic potential of intracranial meningiomas and clinical/prognostic features such as World Health Organization (WHO) grade, peritumoral edema, tumor border shape, and recurrence using rat corneal angiogenesis assay. METHODS: Fifteen WHO grade I (typical), 10 WHO grade II (atypical), and 5 WHO grade III (malignant) meningioma samples were implanted in the micropockets formed on rat corneas, and the number of developed vessels were counted on days 5, 10, 15, and 20. Normal brain and glioblastoma multiforme tissues served as negative and positive controls, respectively. Patients were evaluated by magnetic resonance imaging preoperatively and every 6 months thereafter. RESULTS: The angiogenic potential of WHO grade II tumors was significantly lower than that of grade III tumors and higher than that of grade I tumors throughout the experiment. Tumors with a smooth border shape and nonrecurrent tumors exhibited significantly lower angiogenic activity compared with the tumors with irregular border shape and recurrent tumors, respectively. No association was found between angiogenic activity and peritumoral edema. However, multivariate analysis identified WHO grade, recurrence, and peritumoral edema as significant predictors of a high angiogenic potential. CONCLUSION: Our findings, based on a dynamic in vivo model to examine angiogenesis, demonstrate that the angiogenic potential of meningiomas is correlated with WHO grade, recurrence, and possibly with tumor border shape and peritumoral edema. Angiogenesis seems to be an important factor in the natural course of meningiomas, suggesting that inhibition of angiogenesis may be an option, particularly in the treatment of meningiomas with an aggressive course.

A case of primary diffuse leptomeningeal gliomatosis predominantly involving the cervical spinal cord and mimicking chronic meningitis.

Gliomas may rarely arise in the leptomeninges without any evidence of intraaxial involvement. A case of primary diffuse leptomeningeal gliomatosis (PDLG) histologically diagnosed as oligoastrocytoma is presented. A 50-year-old woman presented with nausea, vomiting and headache. Magnetic resonance imaging (MRI) of cranium and cervical region revealed dural thickening starting from the craniocervical junction to the level of C4 without any parenchymal lesions. CSF examination showed an increase in protein and decrease in glucose levels. There were neither any kind of atypical cells nor any kind of growth in bacterial cultures. The patient underwent biopsy at the level of C1 for diagnosis. The specimen was diagnosed as primary diffuse leptomeningeal gliomatosis, with phenotypic features of astrocytoma and oligodendroglioma.

Hereditary spastic paraplegia with recessive trait caused by mutation in KLC4 gene

We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease.