Veit Rohde

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.

OBJECTIVEThe influence of the degree of resection on survival in patients with glioblastoma multiforme is still under discussion. The highly controlled 5-aminolevulinic acid study provided a unique platform for addressing this question as a result of the high frequency of “complete” resections, as revealed by postoperative magnetic resonance imaging scans achieved by fluorescence-guided resection and homogeneous patient characteristics. METHODSTwo hundred forty-three patients with glioblastoma multiforme per protocol from the 5-aminolevulinic acid study were analyzed. Patients with complete and incomplete resections as revealed by early magnetic resonance imaging scans were compared. Prognostic factors that might cause bias regarding resection and influence survival (e.g., tumor size, edema, midline shift, location, age, Karnofsky Performance Scale score, National Institutes of Health Stroke Scale score) were used for analysis of overall survival. Time to reintervention (chemotherapy, reoperation) was analyzed further to exclude bias regarding second-line therapies. RESULTSTreatment bias was identified in patients with complete (n = 122) compared with incomplete resection (n = 121), i.e., younger age and less frequent eloquent tumor location. Other factors, foremost preoperative tumor size, were identical. Patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001). In multivariate analysis, only residual tumor, age, and Karnofsky Performance Scale score were significantly prognostic. To account for distribution bias, patients were stratified for age (>60 or ≤60 yr) and eloquent location. Survival advantages from complete resection remained significant within subgroups, and age/eloquent location were no longer unevenly distributed. Reinterventions occurred marginally earlier in patients with residual tumor (6.7 versus 9.5 mo, P = 0.0582). CONCLUSIONTreatment bias was demonstrated regarding resection and second-line therapies. However, bias and imbalances were controllable in the cohorts available from the 5-aminolevulinic acid study so that the present data now provide Level 2b evidence (Oxford Centre for Evidence-based Medicine) that survival depends on complete resection of enhancing tumor in glioblastoma multiforme.

A microarray-based DNA methylation study of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. The presence of epigenetic lesions, like hypermethylation of known tumor suppressor genes such as MGMT, has been widely described in GBM, but to our knowledge, a genome-wide profile of DNA methylation changes in these lethal tumors is not yet available. In the present analysis, we have quantified the DNA methylation level of 1,505 CpG dinucleotides (807 genes) in 87 consecutive GBMs using universal BeadArrays. Supervised cluster analyses identified 25 and seven genes that were respectively hypermethylated and hypomethylated in more than 20% of the cases studied. The most frequently hypermethylated genes were HOXA11, CD81, PRKCDBP, TES, MEST, TNFRSF10A and FZD9, being involved in more than half of the cases. Studying the biological features of hypermethylated genes, we found that the group of genes hypermethylated in GBM was highly enriched (41%, P

Course of brain shift during microsurgical resection of supratentorial cerebral lesions: limits of conventional neuronavigation.

SummaryBackground. The authors have conducted a prospective study to evaluate the amount and course of brain shift during microsurgical removal of supratentorial cerebral lesions, and to assess factors which potentially influence these shifts. Method. In 61 patients the displacement of 2–3 cortical landmarks on the cerebral surface was dynamically quantified during surgery, i.e. during dissection of the tumour at the estimated half-time of surgery, and at the end of microsurgical removal of the cerebral lesion using the neuronavigation system EasyGuide Neuro™. In 14 of these patients the displacement of a subcortical landmark was additionally analysed. Age of the patients, preoperative midline shift, location of the lesion, lesion volume, depth of the lesion below the cortical surface, presence or absence of oedema, and size of the craniotomy were analysed for potential influence on the amount of brain shift. Correlations were analysed for all patients together and for the subgroups of vault meningiomas (n=10), gliomas (n=30), and nonglial intra-axial lesions (n=21). Findings. The mean displacement of the cortical landmarks ranged between 0.8 and 14.3 mm (mean: 6.1 mm, standard deviation: 3.4 mm) during surgery (10–210 minutes [mean: 50.7 minutes, standard deviation: 34.5 minutes] after dura opening) and between 2.4 and 15.2 mm (mean: 6.6 mm, standard deviation: 3.2 mm) at the end of microsurgical removal of the tumourous cerebral lesions (20–375 minutes [mean: 107.2 minutes, standard deviation: 65.6 minutes] after dura opening). Significant correlations (p<0.01) for the entire patient group were found between brain shift and tumour volume, midline shift, and size of the craniotomy, respectively. For the subgroup of vault meningiomas a significant correlation (p<0.01) between brain shift and patient age was found. For the subgroup of gliomas a significant correlation (p<0.01) between brain shift and tumour volume, midline shift and size of the craniotomy, respectively, was found. For the subgroup of nonglial intra-axial lesions a significant correlation (p<0.01) between brain shift and midline shift and between brain shift and size of the craniotomy was found. The quantity of shared common variance ranged between 10–50%. Performing a discriminant analysis, lesion volume was the only certain factor influencing brain shift intra-operatively as well as at the end of lesion removal. 58.5% of the extent of brain shift could be correctly classified by the tumour volume as the only discriminating variable during dissection of the tumour and at the end of surgery.Comparing superficial with subcortical brain shift over the same time period, a mean superficial shift of 4.6 mm (1.6–10.8 mm, standard deviation: 2.8 mm) and a mean subcortical shift of 3.5 mm (1.0–7.7 mm, standard deviation: 2.3 mm) was found. A highly significant Spearman correlation (Rho: .97, p<0.001) between superficial and subcortical brain shift emerged. Shifting of superficial landmarks exceeded shifting of subcortical structures in all patients. Conclusions. The data demonstrate the dynamics of brain shift and the limits of conventional neuronavigation and add additional support for the unavoidable inaccuracy of contemporary neuronavigational systems once the cranium is opened. Brain shift leads to a significant loss of reliability of neuronavigation systems during microsurgical removal of intracranial lesions and there are differences of the course and the amount of brain shift in relation to special subgroups of supratentorial cerebral lesions. However, because of the heterogeneous nature of lesions neurosurgeons have to remove, the modest quantity of shared common variance, and the differences between superficial and subcortical brain shift, it seems unlikely that the amount and course of brain shift become exactly predictable pre-operatively. Only an intra-operative update of image data should have the capacity to overcome this fundamental problem of modern neuronavigation.

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)

Complications of burr-hole craniostomy and closed-system drainage for chronic subdural hematomas: a retrospective analysis of 376 patients

Abstract.Objective. Burr-hole craniostomy with closed-system drainage (BCD) is the most frequently used neurosurgical treatment of chronic subdural hematomas (cSDH).The surgical and medical complications of BCD have seldom been investigated systematically. The objective of this study was to define the frequency of surgical and medical complications following BCD for cSDH. Methods. The medical records of 376 patients managed by BCD were reviewed with respect to complications during the hospital stay. Results. Seventy-seven surgical complications (20.5%) were encountered . The most frequent minor complication after surgery was seizures (n 51, 13.6%). The most frequent major surgical complications were intracerebral hemorrhage and subdural empyema (n 8, 2.1% each). Four patients with intracerebral hemorrhage died, accounting for a surgical mortality rate of 1.1%. Fifty-nine medical complications (15.7%) occurred during the hospital stay. Pneumonia was the most frequent medical complication (n 29, 7.7%). Medical complications were fatal in 24 patients, accounting for a mortality rate of 6.4%. In 22 patients (5.8%), death was not related to a complication, but to the initial brain damage. The overall mortality rate was 13.3%. Conclusion. The rate of complications in patients with cSDH who underwent the BCD is high. The clinical relevance of medical complications has to be emphasized because of their substantial contribution to overall mortality.

Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage.

A prospective series of 20 patients with moderate to severe intraventricular haemorrhage (IVH) was studied for the effect of intraventricular administration of recombinant tissue plasminogen activator (rt-PA) on reduction of haematoma volume and prognosis. On the day of haemorrhage ventriculostomy was performed and 2 to 5 mg of rt-PA were injected via the external ventricular drainage, followed by drainage closure for two hours. In 14 patients rt-PA treatment was repeated. Computed tomography showed complete clot lysis or substantial reduction of intraventricular haematoma volume in 19 patients within 96 hours; the clearance of the third and fourth ventricle preceded the clearance of the lateral ventricles. Decrease of ventricular enlargement was seen in all but one patient with initial ventricular dilatation. Increase of haematoma volume and ventricular size was found in one patient. Outcome was minor or no neurological deficit in nine patients, disabling neurological deficit in six patients, and vegetative status in four patients. One patient did not survive the IVH. Intraventricular treatment with rt-PA seems effective in rapid lysis of intraventricular haematoma and normalisation of impaired CSF circulation. This treatment may contribute to an improvement in prognosis of moderate to severe IVH.

LONG-TERM RESULTS OF MICROSURGICAL TREATMENT OF LUMBAR SPINAL STENOSIS BY UNILATERAL LAMINOTOMY FOR BILATERAL DECOMPRESSION

OBJECTIVELaminectomy and bilateral laminotomy are the standard procedures for decompression of lumbar spinal stenosis (LSS). With the aim of less invasiveness and better preservation of spinal stability, the technique of unilateral laminotomy for bilateral decompression (ULBD) was developed. However, limited follow-up data exist to determine the efficiency and outcome of ULBD. Therefore, the authors present their 10-year experience with ULBD and postoperative long-term results. METHODSOne hundred thirty-three consecutive patients (73 men and 60 women; mean age, 63 yr) meeting clinical and radiographic criteria for LSS who underwent first-time ULBD between 1994 and 1999 entered the study. The study parameters were set to ensure a follow-up period of at least 4 years. All patients were available for short-term follow-up re-evaluation within 3 months, and 102 (77%) of the 133 patients were available for long-term examination after a mean duration of 5.6 years. The scale of Finneson and Cooper was used for evaluation of the clinical results. RESULTSOne hundred thirty patients (97.7%) improved immediately after surgery. Ninety-four (92.2%) of the 102 patients available for long-term follow-up examination remained improved, and 85.3% had an excellent-to-fair operative result. The incidence of complications was 9.8%. Resurgery for complication was necessary in three patients, for restenosis in seven patients, and for spinal instability in two patients, accounting for a reoperation rate of 11.8%. CONCLUSIONULBD allows achievement of good and long-lasting operative results in patients with LSS. Postoperative deterioration, recurrences, and spinal instability are infrequent. For the authors, ULBD is the preferred technique to treat symptomatic LSS.

Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid

In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.

The C-reactive protein for detection of early infections after lumbar microdiscectomy

SummaryThe tendency for short hospitalization after lumbar microdiscectomy implies the need for early confirmation or disproval of serious postoperative infections such as spondylodiscitis or deep wound infections. The C-reactive protein (CRP) is a well-known screening parameter for monitoring postoperative infectious complications in other fields. Our objective was to establish the diagnostic significance of CRP-in comparison with ESR and WBC-for monitoring infectious complications after lumbar microdiscectomy. Over a 15 months period we studied prospectively a homogeneous group of N = 400 patients with lumbar disc herniations who were operated on a single level for the first time. CRP, ESR and WBC values were determined in all patients pre-operatively, and on postoperative days 1 and 5. Clinical and laboratory findings were correlated and the diagnostic significance of CRP, ESR and WBC calcualted. N = 385 (96%) patients had an uneventful postoperative course. N = 15 (4%) patients developed infectious complications, of which N = 6 (1.5%) were unrelated and N = 9 (2.5%) related to surgery. Evaluation of the laboratory values showed: The CRP baseline is a very individual value of no prognostic relevance. A high postaggression peak is typical and essential as a reference value for only the future time course will disclose any infection. We found 0% false negative and 4% false positive results on day 5. The sensitivity for serial CRP testing was calculated as 100% and specificity as 95.8%. ESR (sensitivity: 78.1%/specificity: 38.1%) and WBC (sensitivity: 21.4%/specificity: 76.8%) both failed to reach such distinct diagnostic significance on day 5. The C-reactive protein has thus proved to be a reliable, simple and economical screening test for infectious complications after lumbar microdiscectomy, superior to classical laboratory parameters.

A Radiologic Score to Distinguish Autoimmune Hypophysitis from Nonsecreting Pituitary Adenoma Preoperatively

BACKGROUND AND PURPOSE: Autoimmune hypophysitis (AH) mimics the more common nonsecreting pituitary adenomas and can be diagnosed with certainty only histologically. Approximately 40% of patients with AH are still misdiagnosed as having pituitary macroadenoma and undergo unnecessary surgery. MR imaging is currently the best noninvasive diagnostic tool to differentiate AH from nonsecreting adenomas, though no single radiologic sign is diagnostically accurate. The purpose of this study was to develop a scoring system that summarizes numerous MR imaging signs to increase the probability of diagnosing AH before surgery. MATERIALS AND METHODS: This was a case-control study of 402 patients, which compared the presurgical pituitary MR imaging features of patients with nonsecreting pituitary adenoma and controls with AH. MR images were compared on the basis of 16 morphologic features besides sex, age, and relation to pregnancy. RESULTS: Only 2 of the 19 proposed features tested lacked prognostic value. When the other 17 predictors were analyzed jointly in a multiple logistic regression model, 8 (relation to pregnancy, pituitary mass volume and symmetry, signal intensity and signal intensity homogeneity after gadolinium administration, posterior pituitary bright spot presence, stalk size, and mucosal swelling) remained significant predictors of a correct classification. The diagnostic score had a global performance of 0.9917 and correctly classified 97% of the patients, with a sensitivity of 92%, a specificity of 99%, a positive predictive value of 97%, and a negative predictive value of 97% for the diagnosis of AH. CONCLUSIONS: This new radiologic score could be integrated into the management of patients with AH, who derive greater benefit from medical as opposed to surgical treatment.