Christian Ewelt

Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas

PurposeThe aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas.Methods18F-FET positron emission tomography (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumour areas that were positive or negative for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumour to brain ratio ≥1.6 was rated as positive.ResultsOf 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was positive in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was observed in 6 of 21 cases of HGG biopsy samples (3 Gd-positive/5-ALA-negative and 3 Gd-negative/5-ALA-positive). In biopsies corresponding to LGG, 18F-FET was positive in 41% (7/17), while 5-ALA and Gd were negative in all but one instance. All tumour areas with 5-ALA fluorescence were positive on 18F-FET PET.ConclusionThere are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumour tissue especially in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an additional tool in resection planning.

Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence.

OBJECTIVE Diffuse gliomas may harbor anaplastic foci which affect prognosis and determine adjuvant therapies. Such foci are not always detected by contrast-enhancement on MRI. Recently, other modalities have been introduced, such as FET-PET for pre-diagnostic imaging and 5-aminolevulinic derived tumor fluorescence for intraoperative identification of malignant glioma tissue. The relationship between these modalities and their value for guiding biopsies during resection has not yet been elucidated in the group of diffuse gliomas. METHODS FET-PET was performed in 30 consecutive patients with intracerebral lesions suggestive of diffuse gliomas on MRI with or without areas of contrast-enhancement. Prior to surgery patients were given 5-ALA at a dose of 20mg/kg body weight. Areas of FET uptake with a lesion/brain ratio of 1.6 or more were considered indicators of tumor. FET-PET data were corregistered with MRI data before surgery in order to obtain neuronavigated biopsies during resection, which were collected from FET positive and negative areas, analyzed for tumor fluorescence and correlated to contrast-enhancement on MRI. RESULTS 13 of 30 tumors were diagnosed as gliomas WHO Grade II, 15 as gliomas WHO Grade III and 2 as gliomas WHO Grade IV. The mean lesion/brain tissue ratio of FET uptake was significantly greater for high-grade than for low-grade gliomas (averages SD 2.323±0.754 vs. 1.453±0.538 p=0.0014). A match of FET-pos/ALA-pos biopsies was found in 70.6% (12/17) of high-grade gliomas (WHO Grade III/IV) but only in 7.7% (1/13) of low grade gliomas. Gd-neg/FET-neg/ALA-neg biopsies yielded a low-grade tumor in 46.2% (6/13). A mismatch between FET uptake and 5-ALA (FET-pos/ALA-neg) was found in 46.2% (6/13) of the low-grade and in 17.6% (3/17) of the high-grade tumors. The combination of FET-PET- and 5-ALA-positivity yielded a sensitivity for identifying high-grade glioma foci of 70.5% and a specificity of 92.3%. CONCLUSIONS In low grade gliomas 5-ALA fluorescence is the exception and FET PET is more sensitive. High grade areas in diffuse gliomas with anaplastic foci usually fluoresce, if they are FET PET positive. As a result, FET PET appears valuable for pre-operative identification of anaplastic foci and hot spots are strongly predictive for ALA-derived fluorescence, which highlight anaplastic foci during resection.

Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature.

Fluorescent agents, e.g. 5-aminolevulinic acid (5-ALA), fluorescein and indocyanine green (ICG) are in common use in neurosurgery for tumor resection and neurovascular surgery. Protoporphyrine IX (PPIX) as major metabolite of 5-ALA is a strong fluorescent substance accumulated within malignant glioma tissue and a very sensitive and specific tool for visualizing high grade glioma tissue during surgery. Furthermore, 5-ALA or rather PPIX also offers an intratumoral therapeutic option stimulated by laser light in specific wavelength. Fluorescein was demonstrated to show similar fluorescent reactions in neurosurgery, but is controversial in its use, especially in high grade tumor surgery. Intraoperative angiography during resection of arterio-venous malformations, extracranial-intracranial-bypass or aneurysm surgery is supported by ICG fluorescence. Generally ICG will provide beneficial information for both, exposure of the pathology and illustration of healthy structures. This manuscript shows an overview of the literature focussing fluorescence in neurosurgery.

Cordectomy as final treatment option for diffuse intramedullary malignant glioma using 5-ALA fluorescence-guided resection

BACKGROUND We present a case of an anaplastic astrocytoma (WHO-grade III, AA III) in a 27-year-old woman treated by spinal cordectomy. The patient was pretreated by surgery, radiation therapy and temozolomide chemotherapy and repeat surgery at recurrence. Later on, she developed paraplegia and a diffuse severe pain syndrome. MRI demonstrated intramedullar invasion from T12 to T9. To assess tumor invasion intraoperatively, we used tumor fluorescence derived from 5-aminolevulinic acid (5-ALA). PATIENTS COURSE The spinal cord was amputated caudally to the root entry zones of the T10 sensory roots. Additional cordectomy was performed because of tumor infiltration at the cut end to T9 as identified by intraoperative tumor fluorescence, and as verified histologically. The final transected level was between T8 and T9, and the cut end did not reveal any tumor invasion intraoperatively by tumor fluorescence and postoperatively by MRI and with regard to the pathological result. After surgery, the patient was unchanged concerning spasticity, motor and sensory function, and showed complete relief of pain. She refused additional adjuvant therapy. The patient is free of recurrence 15 months after surgery. CONCLUSION Our observation suggests 5-ALA fluorescence-guided resections to be useful in the context of malignant spinal cord gliomas. Furthermore, our particular case indicates that palliative spinal cordectomy with a wide margin and intraoperative resection using fluorescence guidance may be a final option for patients with recurrent spinal malignant glioma presenting with complete deficit below the lesion.

The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors.

BACKGROUND: Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. OBJECTIVE: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [18F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. METHODS: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and 18F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. RESULTS: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and 18F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. CONCLUSION: Age, tumor volume, and 18F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acid CRT, classification and regression tree 18F-FET PET, 18F-fluoroethyl tyrosine positron emission tomography FLAIR, fluid-attenuated inversion recovery GBM, glioblastoma multiforme O6-MGMT, methylguanine DNA methyltransferase ROC, receiver-operating characteristic SUV, standardized uptake value WHO, World Health Organization

Impact of cordectomy as a treatment option for posttraumatic and non-posttraumatic syringomyelia with tethered cord syndrome and myelopathy

OBJECT Spinal cordectomy has recently become more important in the treatment of end-stage posttraumatic or postoperative syringomyelia and arachnopathy as a last resort to manage ascending neurological dysfunction, spasticity, and pain in paraplegic patients. The aim in this study was to confirm a clinical benefit in strict indications for cordectomy. METHODS Between February 2000 and September 2007, 15 spinal cordectomies were performed at the Department of Neurosurgery, Cantonal Hospital, St. Gallen. Indications for treatment were end-stage myelopathies caused by syringomyelia, tethered cord syndrome, and arachnopathy with progressive spasticity and pain or progressive upper-level neurological deficits related to the tethered cord syndrome. All patients had severe motor and sensory deficits with no residual voluntary function below the affected level. RESULTS Fourteen of 15 patients showed stabilization or even an improvement in motor and sensory function. Four patients suffered from progressive spasticity and 3 from deterioration due to pain. There were no other adverse surgical events. CONCLUSIONS Cordectomy can be a useful instrument to preserve functions of the upper extremities and to improve spasticity and pain in patients with severe myelopathy and tethered cord, syringomyelia, or arachnopathy of various etiologies.

Dynamic ICG fluorescence provides better intraoperative understanding of arteriovenous fistulae.

BACKGROUND: Sufficient perfusion is crucial during and after vascular neurosurgical procedures. Intraoperative indocyanine green (ICG) angiography has evolved into a useful tool in aneurysm and arteriovenous malformation surgery. Semiquantitative ICG fluorescence analysis Flow 800 may, in addition, lead to a better understanding of local perfusion. OBJECTIVE: We report the applicability and utility of semiquantitative ICG fluorescence in the surgical treatment of 5 patients with pial or dural arteriovenous fistulae. METHODS: Five patients with pial or dural arteriovenous fistulae were operated on using intraoperative semiquantitative ICG fluorescence Flow 800 (5 mg ICG bolus via central venous line). Before and after occlusion of fistulae, rise time of parenchyma and transit time from artery to parenchyma were measured. RESULTS: The analysis of flow parameters allowed detection of small fistulae and revealed a significant change in flow dynamics in the draining vein after surgical occlusion. ICG “flow” analysis showed rise time and transit time to be significantly shorter comparing pre-occlusion with post-occlusion (P = .025 and P = .039, respectively), leading to a significantly enhanced perfusion of neighboring brain parenchyma. CONCLUSION: In all 5 patients, dynamic analysis of fluorescence revealed a better understanding of intravascular rheology intraoperatively, allowing confident identification and treatment of pathology. Dynamic ICG fluorescence measurements provide additional perfusion information about flow characteristics in the draining vein and tissue perfusion, which facilitates surgical treatment of arteriovenous fistulae. ABBREVIATIONS: AVF, arteriovenous fistula AVM, arteriovenous malformation ICG, indocyanine green ROI, region of interest

Gamma Knife radiosurgery following subtotal resection of vestibular schwannoma

During treatment of large vestibular schwannomas, incomplete resection (IR) followed by Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) possibly offers tumor growth control and good clinical outcome, and is being discussed as an alternative to complete tumor removal with its inherent risks, especially for facial nerve function. However, available data for this concept are limited due to the small number of published studies. To analyze the effects of combined therapy in a larger cohort, we reviewed the currently available data. Six studies comprising 159 patients with a tumor diameter of at least 2 cm were included (median volume 19.95 cm(3) in four studies, n=137). GKS was performed on average 6 months postoperatively with a mean marginal dose of 11.88 Gy (mean target volume 4.42 cm(3), mean diameter 18.45 mm). Preoperatively facial nerve function was serviceable (House and Brackmann Grades I+II) in 158 of 159 patients (99.4%) and in 125 of 151 patients (82.8%, 95% confidence interval [CI] 76-88%) postoperatively. Hearing was serviceable in 29 of 151 patients (19.2%) preoperatively and in 16 of 79 patients postoperatively (20.2%, 95%CI 12-31%). Within a mean follow-up time of 50 months (range 12-102 months), facial nerve function and hearing after IR remained serviceable in 142 of 151 (94.0%, 95%CI 89-97%) and 15 of 129 patients (11.6%, 95%CI 7-18%). Tumor growth control was achieved in 149 of 159 patients (93.8%). Six patients were subjected to repeated therapy. Minimal complications were reported for microsurgery and GKS. Combined therapy was shown to be beneficial regarding both tumor control and adverse side effects among all analyzed studies.

Aquaporin-4 in glioma and metastatic tissues harboring 5-aminolevulinic acid-induced porphyrin fluorescence

INTRODUCTION Aquaporin channels (AQPs) are a group of integral membrane proteins that regulate the transport of water through cell membranes. Previous studies have shown that up-regulation of AQP1 and AQP4, two of the predominant AQPs in the human brain, in high grade glial tumors contribute to cerebral edema. Others link AQPs to the regulation of human glioma cell migration and invasion. The aim of this study was to determine AQPs expression in tumor tissue harboring 5-aminolevulinic acid (ALA)-induced porphyrin fluorescence with flow cytometry and compare it to the expression in normal brain tissue. METHODS Tissue samples were obtained from fluorescing brain tumors of 26 patients treated with ALA prior to surgery (20 mg/kg b.w.). Expression levels of aquaporin channels were measured in primary tissue cultures using a FACS CANTO I flow cytometer. A control group consisted of four non-fluorescing tissue samples, the C6 and the U87 cell line. RESULTS Nineteen gliomas (14 high grade, 5 low grade) and 7 metastases were analyzed. On the 4th post-operative day, expression levels of AQP4 channels, but not of AQP1 channels, were significantly increased in samples from fluorescing tissue compared to non-fluorescing tissue. In addition we could see how ALA induces fluorescence in metastases. CONCLUSION Flow cytometry appears to be an auspicious method for the analysis of porphyrins and AQPs in primary brain cell tumor cultures. ALA fluorescing tissue showed higher AQP4 expression compared to normal brain tissue. The demonstrated expression in a context with ALA could open a targeted therapeutic spectrum, for example to selectively target AQP4.

Dual-labeling with 5–aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note

OBJECTIVE Fluorescence guidance with 5-aminolevulinic acid (5-ALA) helps improve resections of malignant gliomas. However, one limitation is the low intensity of blue light for background illumination. Fluorescein has recently been reintroduced into neurosurgery, and novel microscope systems are available for visualizing this fluorochrome, which highlights all perfused tissues but has limited selectivity for tumor detection. Here, the authors investigate a combination of both fluorochromes: 5-ALA for distinguishing tumor and fluorescein for providing tissue fluorescence of adjacent brain tissue. METHODS The authors evaluated 6 patients who harbored cerebral lesions suggestive of high-grade glioma. Patients received 5-ALA (20 mg/kg) orally 4 hours before induction of anesthesia. Low-dose fluorescein (3 mg/kg intravenous) was injected immediately after anesthesia induction. Pentero microscopes (equipped either with Yellow 560 or Blue 400 filters) were used to visualize fluorescence. To simultaneously visualize both fluorochromes, the Yellow 560 module was combined with external blue light illumination (D-light C System). RESULTS Fluorescein-induced fluorescence created a useful background for protoporphyrin IX (PPIX) fluorescence, which appeared orange to red, surrounded by greenly fluorescent normal brain and edematous tissue. Green brain-tissue fluorescence was helpful in augmenting background. Levels of blue illumination that were too strong obscured PPIX fluorescence. Unspecific extravasation of fluorescein was noted at resection margins, which did not interfere with PPIX fluorescence detection. CONCLUSIONS Dual labeling with both PPIX and fluorescein fluorescence is feasible and gives superior background information during fluorescence-guided resections. The authors believe that this technique carries potential as a next step in fluorescence-guided resections if it is completely integrated into the surgical microscope.