Bernhard Meyer

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas.

OBJECT Navigated transcranial magnetic stimulation (nTMS) is a newly evolving technique. Despite its supposed purpose (for example, preoperative central region mapping), little is known about its accuracy compared with established modalities like direct cortical stimulation (DCS) and functional MR (fMR) imaging. Against this background, the authors performed the current study to compare the accuracy of nTMS with DCS and fMR imaging. METHODS Fourteen patients with tumors in or close to the precentral gyrus were examined using nTMS for motor cortex mapping, as were 12 patients with lesions in the subcortical white matter motor tract. Moreover, preoperative fMR imaging and intraoperative mapping of the motor cortex were performed via DCS, and the outlining of the motor cortex was compared. RESULTS In the 14 cases of lesions affecting the precentral gyrus, the primary motor cortex as outlined by nTMS correlated well with that delineated by intraoperative DCS mapping, with a deviation of 4.4 ± 3.4 mm between the two methods. In comparing nTMS with fMR imaging, the deviation between the two methods was much larger: 9.8 ± 8.5 mm for the upper extremity and 14.7 ± 12.4 mm for the lower extremity. In 13 of 14 cases, the surgeon admitted easier identification of the central region because of nTMS. The procedure had a subjectively positive influence on the operative results in 5 cases and was responsible for a changed resection strategy in 2 cases. One of 26 patients experienced nTMS as unpleasant; none found it painful. CONCLUSIONS Navigated TMS correlates well with DCS as a gold standard despite factors that are supposed to contribute to the inaccuracy of nTMS. Moreover, surgeons have found nTMS to be an additional and helpful modality during the resection of tumors affecting eloquent motor areas, as well as during preoperative planning.

Cellular Pathology of Hilar Neurons in Ammon's Horn Sclerosis

In addition to functionally affected neuronal signaling pathways, altered axonal, dendritic, and synaptic morphology may contribute to hippocampal hyperexcitability in chronic mesial temporal lobe epilepsies (MTLE). The sclerotic hippocampus in Ammons horn sclerosis (AHS)‐associated MTLE, which shows segmental neuronal cell loss, axonal reorganization, and astrogliosis, would appear particularly susceptible to such changes. To characterize the cellular hippocampal pathology in MTLE, we have analyzed hilar neurons in surgical hippocampus specimens from patients with MTLE. Anatomically well‐preserved hippocampal specimens from patients with AHS (n = 44) and from patients with focal temporal lesions (non‐AHS; n = 20) were studied using confocal laser scanning microscopy (CFLSM) and electron microscopy (EM). Hippocampal samples from three tumor patients without chronic epilepsies and autopsy samples were used as controls. Using intracellular Lucifer Yellow injection and CFLSM, spiny pyramidal, multipolar, and mossy cells as well as non‐spiny multipolar neurons have been identified as major hilar cell types in controls and lesion‐associated MTLE specimens. In contrast, none of the hilar neurons from AHS specimens displayed a morphology reminiscent of mossy cells. In AHS, a major portion of the pyramidal and multipolar neurons showed extensive dendritic ramification and periodic nodular swellings of dendritic shafts. EM analysis confirmed the altered cellular morphology, with an accumulation of cytoskeletal filaments and increased numbers of mitochondria as the most prominent findings. To characterize cytoskeletal alterations in hilar neurons further, immunohistochemical reactions for neurofilament proteins (NFP), microtubule‐associated proteins, and tau were performed. This analysis specifically identified large and atypical hilar neurons with an accumulation of low weight NFP. Our data demonstrate striking structural alterations in hilar neurons of patients with AHS compared with controls and non‐sclerotic MTLE specimens. Such changes may develop during cellular reorganization in the epileptogenic hippocampus and are likely to contribute to the pathogenesis or maintenance of temporal lobe epilepsy. J. Comp. Neurol. 414:437–453, 1999.

Minimally invasive transmuscular pedicle screw fixation of the thoracic and lumbar spine.

OBJECTIVE: This study assessed the feasibility and safety of percutaneous posterior pedicle screw fixation for instabilities of the thoracic and lumbar spine, using standard instruments designed for the open approach and fluoroscopy. METHODS: All patients who underwent percutaneous posterior pedicle screw fixation of the thoracic and lumbar spine were studied retrospectively. Charts and operative notes were analyzed for epidemiological data, underlying spinal pathological features, and indications for stabilization, stabilized segments, number of implanted pedicle screws, surgical time, and complications. Postoperative computed tomographic scans were analyzed for screw position. RESULTS: From May 2002 through May 2005, 115 internal fixators were implanted percutaneously in 104 patients. A total of 488 pedicle screws were implanted, stabilizing 1 to 5 spinal motion segments. Median surgical time was 93 minutes. On postoperative computed tomographic scans, 87% of screw positions were rated good, 10% were rated acceptable, and 3% were rated unacceptable. A total of 11 revisions were necessary, 9 for misplaced screws and 2 for loosening of anchor bolts. Only two of the patients experienced new clinical symptoms (i.e., radicular pain) because of screw misplacement. No patients experienced new neurological deficits or other surgery-related morbidity. CONCLUSION: This study shows that percutaneous internal pedicle screw fixation using standard instruments is feasible and safe for posterior stabilization of the thoracic and lumbar spine. It is a straightforward alternative for open approaches or minimally invasive ones using navigation in conjunction with customized instruments. Accuracy of screw placement is similar to that reported for other techniques.

Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator.

We have tested a treatment protocol for intracerebral hemorrhage (ICH), consisting of stereotactic insertion of a catheter into the clot, hematoma lysis by the injection of a fibrinolytic agent, recombinant tissue-plasminogen activator (rt-PA), and closed system drainage of the liquefied clot. Fourteen patients underwent computed tomographically guided stereotactic hematoma puncture and silicone tube insertion within 72 hours of intracerebral hemorrhage. The majority (nine patients) suffered from ganglionic ICH, and the size of the hematoma ranged between 3 x 3 x 4 cm and 7 x 7 x 4 cm (mean, 5.2 x 4 x 3.6 cm). All patients had major neurological deficits with or without an impaired level of consciousness, but without signs of transtentorial herniation. The initial, then daily, dose (in milligrams) of rt-PA administered via the silicone tube equalled the maximal diameter (in centimeters) of the original and remaining clot as measured initially, then daily, by computed tomographic scan. The number of rt-PA injections was four in one patient, three in eight patients, two in four patients, and one in one patient, and the total dose of rt-PA required ranged from 5 to 16 mg (mean, 9.9 mg). After rt-PA injection, the tubing was clamped for 2 hours and then opened to drain spontaneously through a closed system against 0 cm of pressure. At follow-up 6.6 months (mean) after treatment (ranging from 3 to 13 months) and according to the Glasgow outcome score, one patient was Grade V, four were Grade IV, five were Grade III, two were Grade II, and two had died.(ABSTRACT TRUNCATED AT 250 WORDS)

Spondylodiscitis after lumbar discectomy. Incidence and a proposal for prophylaxis.

Study Design. An analysis of the incidence of spondylodiscitis after lumbar disc surgery in 1642 patients. In 508 patients no prophylactic antibiotics were given. In 1134 patients a collagenous sponge containing gentamicin was placed in the cleared disc space. Objectives. To report the incidence of postoperative spondylodiscitis in cases in which no antibiotic prophylaxis was used, and to define the value of a collagenous sponge containing gentamicin in preventing disc space infections. Summary of Background Data. Spondylodiscitis is considered to be a rare complication of lumbar disc surgery. The retrospective design of most studies and the rare use of magnetic resonance imaging for early radiologic diagnosis suggest that the reported incidence rates may be underestimates. Postoperative spondylodiscitis is the result of intraoperative contamination and, theoretically, could be prevented by treating these patients with prophylactic antibiotics. Methods. In 1642 patients, 1712 discectomies were performed. In 508 of these patients no prophylactic antibiotics were given; in 1134 of these patients a collagenous sponge containing gentamicin was placed in the cleared disc space. Clinical reexamination and, in cases of unsatisfactory results, laboratory and radiologic investigations were performed 4‐8 weeks after surgery. Results. In nineteen of the 508 patients who were not treated with antibiotic prophylaxis (3.7%) a postoperative spondylodiscitis developed, whereas none of the 1134 patients who received antibiotic prophylaxis became symptomatic (P < 0.00001). Conclusion. In the current study, a 3.7% incidence of postoperative spondylodiscitis was found in the absence of prophylactic antibiotics. Gentamicin‐containing collagenous sponges placed in the cleared disc space were effective in preventing postoperative spondylodiscitis.

Role of MIF in Inflammation and Tumorigenesis

MIF has been described as a protein that plays an essential role in both innate and acquired immunity. Previous studies have demonstrated that MIF activates lymphocytes, granulocytes and monocytes/macrophages. Furthermore, MIF can counteract the physiological function of steroids, thus playing a role in immune system regulation. Further evidence for a role of MIF in immunity was obtained in mouse models of autoimmune disorders, where the inhibition of MIF resulted in a more benign disease progression. This observation made MIF an attractive therapeutic target for the treatment of these disorders. Moreover, MIF expression was found to be upregulated in a variety of different tumor cells, a finding that further attracted interest. This review provides an overview of the involvement of MIF in both autoimmune disorders and tumorigenesis and summarizes the molecular action of MIF in this context.

An Adaptive Level Set Method for Medical Image Segmentation

An efficient adaptive multigrid level set method for front propagation purposes in three dimensional medical image segmentation is presented. It is able to deal with non sharp segment boundaries. A flexible, interactive modulation of the front speed depending on various boundary and regularization criteria ensure this goal. Efficiency is due to a graded underlying mesh implicitly defined via error or feature indicators. A suitable saturation condition ensures an important regularity condition on the resulting adaptive grid. As a casy study the segmentation of glioma is considered. The clinician interactively selects a few parameters describing the speed function and a few seed points. The automatic process of front propagation then generates a family of segments corresponding to the evolution of the front in time, from which the clinician finally selects an appropriate segment covered by the gliom. Thus, the overall glioma segmentation turns into an efficient, nearly real time process with intuitive and usefully restricted user interaction.

Insular gliomas: the case for surgical management

OBJECT Treatment for insular (paralimbic) gliomas is controversial. In this report the authors summarize their experience with microsurgical resection of insular tumors. METHODS The authors analyzed complications, functional outcomes, and survival in a series of 101 operations performed in 94 patients between 1995 and 2005. RESULTS A > 90% resection was achieved in 42%, and 70-90% tumor removal was accomplished in 51% of cases. Functional outcomes varied considerably between patient subgroups. For example, in neurologically intact patients < or = 40 years of age with WHO Grade I-III tumors, good outcomes (Karnofsky Performance Scale Score 80-100) were seen in 91% of cases. Predictors of an unfavorable functional outcome included histological features of glioblastoma, advanced age, and a low preoperative Karnofsky Performance Scale score. One year after surgery, 76% of patients who had presented with epilepsy were seizure free or experienced only isolated, nondebilitating seizures. Surprisingly good survival rates were seen after surgery for anaplastic gliomas. The median survival for patients with anaplastic astrocytomas (WHO Grade III) was 5 years, and the 5-year survival rate for those with anaplastic oligodendroglial tumors was 80%. Independent predictors of survival included younger age, favorable histological features (WHO Grade I and oligodendroglial tumors), Yaşargil Type 5A/B tumors with frontal extensions, and more extensive resections. CONCLUSIONS Insular tumor surgery carries substantial complication rates. However, surprisingly similar figures have been reported in large unselected craniotomy series and also after alternative treatment regimens. In view of the oncological benefits of resective surgery, our data would therefore argue for microsurgery as the primary treatment for most patients with a presumed WHO Grade I-III tumor. Patients with glioblastomas and/or age > 60 years require a more cautious approach.

Percutaneous Fetoscopic Patch Coverage of Spina Bifida Aperta in the Human – Early Clinical Experience and Potential

Objective: The current operative approach for fetal repair of spina bifida aperta requires maternal laparotomy and hysterotomy. Following technical feasibility studies in sheep, we performed percutaneous fetoscopic patch coverage of this lesion in 3 human fetuses between 23 + 4 and 25 + 3 weeks of gestation. Methods and Results: Whereas the patch detached in the first case 3 weeks after the procedure, it covered the exposed neural tissue in the 2 other fetuses beyond their delivery. Two of the three children survived, but 1 unexpectedly died from a ventilation problem in its 3rd week of life. In 1 of the 2 survivors, ventriculoperitoneal shunt insertion was delayed. Conclusions: Percutaneous fetoscopic patch coverage of spina bifida aperta is feasible in human fetuses and offers a substantial reduction of maternal trauma compared to open fetal repair. Further clinical experience is now required before the efficacy of the new approach to protect the exposed neural tissue from mechanical and chemical damage and to improve hindbrain herniation can be evaluated.