Walter Stummer

Early fatal hemorrhage after endovascular cerebral aneurysm treatment with a flow diverter (SILK-Stent)

A 69-year-old woman presenting with short lasting recent episodes of visual impairment was treated uneventfully with a flow diverter covering the neck of a large paraophthalmic aneurysm. As angiography showed immediate flow reduction we abstained from additional coiling which was initially planned. Eleven days later CT demonstrated nearly complete thrombosis of the aneurysm. Twenty days after treatment the patient suffered a lethal subarachnoid hemorrhage after rupture of the aneurysm. All available data were reviewed and beside hemodynamic factors instability of the intra-aneurysmal thrombus is discussed as a possible cofactor leading to this disastrous event.

5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging.

BACKGROUND: 5-Aminolevulinic acid is used for fluorescence-guided resections. During resection, different macroscopic fluorescence qualities (“strong,” “weak”) can be distinguished that help guide resections. OBJECTIVE: This prospective study was designed to assess the reliability of visible fluorescence qualities by spectrometry, pathology, and imaging. METHODS: Thirty-three patients with malignant gliomas received 5-aminolevulinic acid (20 mg/kg). After debulking surgery, standardized biopsies were obtained from tissues with “weak” and “strong” fluorescence and from nonfluorescing near and distant brain for blinded assessment of cell density and tissue type (necrosis, solid or infiltrating tumor, normal tissue). The positive predictive value was calculated. Unresected fluorescing tissue was navigated for blinded correlation to postoperative magnetic resonance imaging (MRI). Receiver operating characteristic curves were generated for assessing the classification efficiency of spectrometry. RESULTS: “Strong” fluorescence corresponded to greater spectrometric fluorescence, solidly proliferating tumor, and high cell densities, whereas “weak” fluorescence corresponded to lower spectrometric fluorescence, infiltrating tumor, and medium cell densities. The positive predictive value was 100% in strongly fluorescing tissue and 95% in weakly fluorescing tissue. Spectrometric fluorescence was detected in marginal tissue without macroscopic fluorescence. Depending on the threshold, spectrometry displayed greater sensitivity but lower specificity (accuracy 88.4%). Residual MRI enhancement in the tumor bed was detected in 15 of 23 (65%) patients with residual fluorescence, but in none of the patients without residual fluorescence. CONCLUSION: Macroscopic fluorescence qualities predict solid and infiltrating tumor, providing useful information during resection. Fluorescence appears superior to contrast enhancement on MRI for indicating residual tumor. Spectrometry, on the other hand, is more sensitive but less specific, depending on threshold definition. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acid CI, confidence interval gamma-GT, gamma-glutamyl transpeptidase GBM, glioblastoma multiforme NPV, negative predictive value PPIX, protoporphyrin IX PPV, positive predictive value SD, standard deviation WHO, World Health Organization

What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?

The current neurosurgical goal for patients with malignant gliomas is maximal safe resection of the contrast-enhancing tumor. However, a complete resection of the contrast-enhancing tumor is achieved only in a minority of patients. One reason for this limitation is the difficulty in distinguishing viable tumor from normal adjacent brain during surgery at the tumor margin using conventional white-light microscopy. To overcome this limitation, fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) has been introduced in the treatment of malignant gliomas. FGS permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain that is independent of neuronavigation and brain shift. Tissue fluorescence after oral administration of 5-ALA is associated with unprecedented high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue. 5-ALA-induced tumor fluorescence in diffusely infiltrating gliomas with non-significant magnetic resonance imaging contrast-enhancement permits intraoperative identification of anaplastic foci and establishment of an accurate histopathological diagnosis for proper adjuvant treatment. 5-ALA FGS has enabled surgeons to achieve a significantly higher rate of complete resections of malignant gliomas in comparison with conventional white-light resections. Consequently, 5-ALA FGS has become an indispensable surgical technique and standard of care at many neurosurgical departments around the world. We conducted an extensive literature review concerning the surgical benefit of using 5-ALA for FGS of malignant gliomas. According to the literature, there are a number of reasons for the neurosurgeon to perform 5-ALA FGS, which will be discussed in detail in the current review.

Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues

There is unequivocal electrophysiological evidence that spreading depression (SD) can trigger epileptiform field potentials. In vitro experiments on human brain tissues indicated that γ-aminobutyric acid (GABA)-mediated inhibition prevented this process. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent neocortex, hippocampus and amygdala after perfusion of low concentrations of the GABAA antagonist bicuculline and induction of SD by KCl application. Induction of SD in combined amygdala-hippocampus-cortex slices pre-treated with low concentration of bicuculline triggered epileptiform burst discharges in cortical as well as subcortical brain structures. Propagation of SD significantly depolarized the membrane, decreased the amplitude and duration of action potentials (APs) and after-hyperpolarization as well as the neuronal membrane input resistance and the amplitude of threshold potentials. Ten to twenty minutes after induction of SD, the pattern of APs changed from regular firing to a series of APs riding on an underlying paroxysmal depolarization shift before the appearance of typical ictaform activities. Changes of characteristic features of APs occurred after SD persisted during the appearance of epileptiform activities. These results indicate that SD increases neuronal excitability and facilitates synchronization of neuronal discharges in the presence of partial disinhibition of neuronal tissues. Our findings might explain the occurrence of seizures in neurological disorders with partial impairment of inhibitory tone, such as brain ischemia and epilepsy.

Sequential changes in neuronal activity in single neocortical neurons after spreading depression

Background: Cortical spreading depression (CSD) has an important role in migraine with aura. Prolonged neuronal depression is followed by a late excitatory synaptic plasticity after CSD. Method: Intra- and extracellular recordings were performed to investigate the effect of CSD on intracellular properties of mouse neocortical tissues in the late excitatory period. Results: During CSD, changes in the membrane potentials usually began with a relatively short hyperpolarization followed by an abrupt depolarization. These changes occurred roughly at the same time point after CSD as the beginning of the negative extracellular deflection. Forty-five minutes after CSD, neurons showed significantly smaller amplitude of afterhyperpolarization and a reduced input resistance. Depolarization and hyperpolarization of the cells by constant intracellular current injections in this period significantly changed the frequency of the action potentials. Conclusion: These data indicate higher excitability of the neocortical neurons after CSD, which can be assumed to contribute to hyperexcitability of neocortical tissues in patients suffering from migraine.

A Pilot Cost-Effectiveness Analysis of Treatments in Newly Diagnosed High-Grade Gliomas: The Example of 5-Aminolevulinic Acid Compared With White-Light Surgery

BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acid ICER, incremental cost-effectiveness ratio LY, life-year PFLY, progression-free life-year QALY, quality-adjusted life-year

The effects of tetanic stimulation on plasticity of remote synapses in the hippocampus-perirhinal cortex-amygdala network

In the temporal lobe, multiple synaptic pathways reciprocally link different structures. These multiple pathways play an important role in the integrity of the function of the temporal lobe and malfunction in this network has been suggested to underlie some neurological disorders such as epilepsy. To test whether the induction of long‐term potentiation (LTP) in one temporal lobe structure would modulate functional synaptic plasticity in other structures of this network, tetanic stimulation was applied to the white matter of the perirhinal cortex, Schaffer collaterals of the hippocampus, or the external capsule in combined rat amygdala–hippocampus–cortex slices. This tetanic stimulation was accompanied by enhancement of the evoked field potential slope in the third layer of perirhinal cortex, hippocampal CA1 area, and the lateral amygdala. Induction of LTP in each of these structures was concomitant with increased evoked field potentials in the neighboring structures. Surgical disconnection of anatomical pathways between these structures inhibited this concomitant enhancement of theevoked field potential slope. Both NMDA and AMPA glutamate sub‐receptors were involved in changes of synaptic plasticity elicited by induction of LTP in the neighboring structures. The present data indicate a reciprocal control among the perirhinal cortex, the amygdala, and the hippocampus plasticity. This could be important for the formation and retention of the medial temporal lobe‐dependent memory and may play a role in the involvement of all different regions of the temporal lobe in pathological conditions such as epilepsy that affect this brain structure. Synapse 66:965–974, 2012.

Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas

Abstract BACKGROUND: Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy. OBJECTIVE: To perform a double-blinded randomized study comparing 3 different doses of 5-ALA. METHODS: Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet–blue illumination, the surgeons impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content. RESULTS: The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. tmax for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]). CONCLUSION: The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.

Preoperative localization of spinal and peripheral pathologies for surgery by computed tomography-guided placement of a specialized needle system.

OBJECTIVEExact intraoperative localization of pathologies in spinal and peripheral nerve surgery is not easily achieved. In spinal surgery, intraoperative fluoroscopy is the common method for identification of the level affected. It seldom visualizes the pathology itself and is prone to error in identifying anatomic disorders and superimposing structures. In peripheral nerve surgery, intraoperative fluoroscopy is of little value. The present technical study was conducted to evaluate the feasibility of using a preoperative computed tomography–guided needle marking system, which was previously developed for use in gynecology. The goal was to reduce intraoperative localization error and radiation exposure to patients and operating room personnel. METHODSWe used a flexible hooked-wire needle marking system, which has previously been used for preoperative marking of breast lesions, to localize and tag spinal and peripheral nerve pathologies. Marking was carried out under computed tomographic control before surgery. Seven illustrative cases were chosen for this report: 6 patients with disorders of the spine and 1 patient with a peripheral nerve schwannoma. RESULTSNo adverse reactions, aside from minor discomfort, were observed in this study. In all cases, the needle could be used as a reliable guide for the surgical approach and led directly to the pathology. In no case was additional intraoperative fluoroscopy needed. The level of radiation exposure to the patient as a result of computed tomography–based marking was similar to or less than that encountered in conventional intraoperative x-ray localization. Radiation exposure to the operating room personnel was eliminated by this method. CONCLUSIONPreoperative marking of spinal level or peripheral nerve pathologies with a flexible hooked-wire needle marking system is feasible and appears to be safe and useful for neurosurgical spinal and peripheral procedures.

Commentary: Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery: A Histology-Based Evaluation.

T hroughout the past several decades, 3 insights have changed the neurosurgical management of malignant gliomas. The first is the understanding that the extent of resection matters. Themajority of neurosurgeons no longer question this and wearisome demands for randomized studies on the extent of resection (which are not possible anyhow) are abating in the face of many prospective cohorts looking at varying degrees of resection (assessed by early postoperative magnetic resonance imaging [MRI]) and outcome. All are giving the same answers. The second insight is that surgeons have understood that trying to remove amalignant glioma with the help of loupes or the microscope alone is confounded by the fact that contrast-enhancing tumor usually extends well beyond what we consider abnormal based on tissue color and texture alone. The third insight is that maximal resection, which has to be safe, is limited by cortex or tracts that we consider “eloquent,” and surgery should be supported by mapping and monitoring. Major neurological deficits obviate any advantages gained from resection. Among these realizations, confident identification of diseased tissue is the central requisite for performing effective resections, if function allows. The desire to confidently distinguish glioma tissue intraoperatively has consequently spawned the development of several technologies used in the operating room for better identifying diseased tissue than with the conventional surgical microscope. Few of these technologies have, until now, entered routine surgery, the most important being neuronavigation, ultrasound, intraoperative MRI, and intraoperative tumor fluorescence induced by 5-aminolevulinic acid (5-ALA). Understandably, there is curiosity to determine the relative usefulness of each of these tools and whether their combinations offer an additional value, eg, between fluorescence-guided surgery after 5-ALA ingestions and the intraoperative MRI. A number of studies have been devoted to this particular relationship. My understanding of this relationship has been a simple one so far. In the year 2000 we published a first series of 50 patients in the Journal of Neurosurgery. In 17 patients we found no enhancement on early postoperative (1.5 T) MRI despite fluorescing tissue having been left unresected (for concerns regarding function), and our conclusion was that fluorescence shows more than expected from gadolinium (GD) enhancement. Others, as well as ourselves, have recently confirmed this observation. Exploiting this relationship, Aldave et al have recently presented 2 cohorts of patients with glioblastoma multiforme (GBM) (n = 50), both without residual enhancement on early postoperative (1.5 T) MRI, 1 cohort with and 1 cohort without residual fluorescence. The cohort without residual fluorescence survived 10 months longer. Schucht et al have noted that the volume of fluorescing tissue is about double the volume of enhancement on MRI, and Roessler et al found that fluorescence extends even beyond the fluoro-ethyl-tyrosine-positron emission tomography zone of hypermetabolism. It is also now well established that even nonenhancing lowand high-grade gliomas will show fluorescence visible with the modified microscope in about 20% of cases. What kinds of resection rates have been reported with 5-ALA in the hands of users (keeping in mind that resection rates depend on patient selection, neurophysiologicalmonitoring, and many other factors related to the surgeon)? In 2007, we published the data from our 260 patient phase III study, which represented essentially the first 10 patients operated on by study surgeons using fluorescence and thus representing the beginner’s experience. Despite their lack of experience, surgeons achieved 65% complete resections of enhancing tumor in the ALA arm (as evidence by early postoperative Walter Stummer, MD