J Neurosurg 139:59–64, 2023
Intraoperative use of the endoscope to assist in visualization of intracranial tumor pathology has expanded with increasing surgeon experience and improved instrumentation. The authors aimed to study how advancements in endoscopic technology have affected the evolution of endoscope use, with particular focus on blue light–filter modification allowing for discrimination of fluorescent tumor tissue following 5-ALA administration.
METHODS A retrospective analysis of patients undergoing craniotomy for tumor resection at a single institution between February 2012 and July 2021 was performed. Patients were included if the endoscope was used for diagnostic tumor cavity inspection or therapeutic assistance with tumor resection following standard craniotomy and microsurgical tumor resection, with emphasis on those cases in which blue light endoscopy was used. Medical records were queried for patient demographics, operative reports describing the use of the endoscope and extent of resection, associations with tumor pathology, and postoperative outcomes. Preoperative and postoperative MR images were reviewed for radiographic extent of resection.
RESULTS A total of 52 patients who underwent endoscope-assisted craniotomy for tumor were included. Thirty patients (57.7%) were men and the average age was 52.6 ± 16.1 years. Standard white light endoscopes were used for assistance with tumor resection in 28 cases (53.8%) for tumors primarily located in the ventricular system, parasellar region, and cerebellopontine angle. A blue light endoscope for detection of 5-ALA fluorescence was introduced into our practice in 2014 and subsequently used for assistance with tumor resection in 24 cases (46.2%) (intraaxial: n = 22, extraaxial: n = 2). Beyond the use of the surgical microscope as the primary visualization source, the blue light endoscope was used to directly perform additional tumor resection in 19/21 cases as a result of improved fluorescence detection as compared to the surgical microscope. No complications were associated with the use of the endoscope or with additional resection performed under white or blue light visualization.
CONCLUSIONS Endoscopic assistance to visualize intracranial tumors had previously been limited to white light, assisting mostly in the visualization of extraaxial tumors confined to intraventricular and cisternal compartments. Blue light– equipped endoscopes provide improved versatility and visualization of 5-ALA fluorescing tissue beyond the capability of the surgical microscope, thereby expanding its use into the realm of intraaxial tumor resections.
J Neurosurg 137:943–952, 2022
Administration of 5-aminolevulinic acid (5-ALA) does not regularly elicit fluorescence in low-grade glioma (LGG) at currently established doses and timing of administration. One explanation may be differences in blood-brain barrier (BBB) integrity compared to high-grade glioma. The authors hypothesized that for a BBB semipermeable to 5-ALA there might be a relationship between plasma 5-ALA concentration and its movement into the brain. A higher dose would elicit more 5-ALA conversion into protoporphyrin IX (PPIX). The authors present a case series of patients harboring LGG who received higher doses of 5-ALA.
METHODS Patients undergoing surgery for indeterminate glioma later diagnosed as LGG were included in this study. 5-ALA was administered at a standard dose of 20 mg/kg body weight (bw) 4 hours prior to induction of anesthesia. A subgroup of patients received a higher dose of 40 mg/kg bw. Fluorescence was evaluated visually and PPIX concentration (cPPIX) was determined ex vivo by hyperspectral measurements in freshly extracted tissue. All adverse events were recorded.
RESULTS A total of 23 patients harboring diffuse low-grade astrocytomas (n = 19) and oligodendrogliomas (n = 4) were analyzed. Thirteen patients received 20 mg/kg bw, and 10 patients received 40 mg/kg bw of 5-ALA. In the 20 mg/ kg group, 30.8% (4 of 13) of tumors harbored areas of visible fluorescence, compared to 60% of cases (n = 6 of 10) with 40 mg/kg bw. The threshold to visibility was 1 μg/ml in both groups. Measured over all biopsies, the mean cPPIX was significantly higher in the double-dose group (1.8 vs 0.45 μg/ml; p < 0.001). In non–visibly fluorescent tissue the mean cPPIX was 0.146 μg/ml in the 20 mg/kg and 0.347 μg/ml in the 40 mg/kg group, indicating an increase of 138% (p < 0.001).
CONCLUSIONS These observations demonstrate different regions with different levels of PPIX accumulation in LGG. With higher 5-ALA doses cPPIX increases, leading to more regions surpassing the visibility threshold of 1 μg/ml. These observations can be explained by the fact that the BBB in LGG is semipermeable to 5-ALA. Higher 5-ALA doses result in more PPIX conversion, an observation with implications for future dosing in LGG.
J Neurosurg 133:1032–1043, 2020
Incomplete neurosurgical resection of brain metastases (BM) due to insufficient intraoperative visualization of tumor tissue is a major clinical challenge and might result in local recurrence. Recently, visible 5-aminolevulinic acid (5-ALA) induced fluorescence was first reported in patients with BM. The aim of this study was thus to investigate, for the first time systematically, the value of 5-ALA fluorescence for intraoperative visualization of BM in a large patient cohort.
METHODS Adult patients (≥ 18 years) with resection of suspected BM after preoperative 5-ALA administration were prospectively recruited at two specialized neurosurgical centers. During surgery, the fluorescence status (visible or no fluorescence); fluorescence quality (strong, vague, or none); and fluorescence homogeneity (homogeneous or heterogeneous) of each BM was investigated. Additionally, these specific fluorescence characteristics of BM were correlated with the primary tumor type and the histopathological subtype. Tumor diagnosis was established according to the current WHO 2016 criteria.
RESULTS Altogether, 157 BM were surgically treated in 154 patients. Visible fluorescence was observed in 104 BM (66%), whereas fluorescence was absent in the remaining 53 cases (34%). In detail, 53 tumors (34%) showed strong fluorescence, 51 tumors (32%) showed vague fluorescence, and 53 tumors (34%) had no fluorescence. The majority of BM (84% of cases) demonstrated a heterogeneous fluorescence pattern. According to primary tumor, visible fluorescence was less frequent in BM of melanomas compared to all other tumors (p = 0.037). According to histopathological subtype, visible fluorescence was more common in BM of ductal breast cancer than all other subtypes (p = 0.008). It is of note that visible fluorescence was observed in the surrounding brain tissue after the resection of BM in 74 (67%) of 111 investigated cases as well.
CONCLUSIONS In this largest series to date, visible 5-ALA fluorescence was detected in two-thirds of BM. However, the characteristic heterogeneous fluorescence pattern and frequent lack of strong fluorescence limits the use of 5-ALA in BM and thus this technique needs further improvements.
J Neurosurg 129:1416–1428, 2018
High invasiveness of malignant gliomas frequently causes early local recurrence of the tumor, resulting in extremely poor outcome. To control such recurrence, novel therapies targeted toward infiltrating glioma cells around the tumor border are required. Here, the authors investigated the antitumor activity of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas to explore the possibility for clinical use of 5-ALA–mediated SDT (5-ALA-SDT).
METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry and TUNEL staining. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined by analysis of the effect of pretreatment with the radical scavenger edaravone. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated.
RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology, inducing cell shrinkage, vacuolization, and swelling. Flow cytometric analysis and TUNEL staining indicated that 5-ALA-SDT induced apoptotic cell death in all gliomas. The 5-ALA-SDT generated significantly higher ROS than in the control group, and inhibition of ROS generation by edaravone completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. The proliferative activity of the entire tumor was markedly decreased. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact.
CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field, whereas the surrounding brain tissue remained normal, resulting in longer survival of the HIFU-treated mice compared with that of untreated mice. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.
J Neurosurg 128:1690–1697, 2018
The objective of this study was to detect 5-aminolevulinic acid (ALA)-induced tumor fluorescence from glioma below the surface of the surgical field by using red-light illumination.
METHODS To overcome the shallow tissue penetration of blue light, which maximally excites the ALA-induced fluorophore protoporphyrin IX (PpIX) but is also strongly absorbed by hemoglobin and oxyhemoglobin, a system was developed to illuminate the surgical field with red light (620–640 nm) matching a secondary, smaller absorption peak of PpIX and detecting the fluorescence emission through a 650-nm longpass filter. This wide-field spectroscopic imaging system was used in conjunction with conventional blue-light fluorescence for comparison in 29 patients undergoing craniotomy for resection of high-grade glioma, low-grade glioma, meningioma, or metastasis.
RESULTS Although, as expected, red-light excitation is less sensitive to PpIX in exposed tumor, it did reveal tumor at a depth up to 5 mm below the resection bed in 22 of 24 patients who also exhibited PpIX fluorescence under blue-light excitation during the course of surgery.
CONCLUSIONS Red-light excitation of tumor-associated PpIX fluorescence below the surface of the surgical field can be achieved intraoperatively and enables detection of subsurface tumor that is not visualized under conventional bluelight excitation. Clinical trial registration no.: NCT02191488 (clinicaltrials.gov)
Neurosurgery 76:552–562, 2015
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, lifeyears, 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.
Neurosurgery 74:310–320, 2014
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.
Neurosurg Rev (2012) 35:381–391 DOI 10.1007/s10143-012-0374-5
Stereotactic biopsies represent a routine neurosurgical procedure for the diagnosis of intracranial lymphomas and selected diffusely infiltrating gliomas. Acquisition of tissue samples that do not allow correct tumor typing and grading is, however, not uncommon. Five-aminolevulinic acid (5-ALA) has been shown to accumulate in malignant tumor tissue. The aim of this study was to prospectively investigate the clinical usability of 5-ALA for intraoperative detection of representative tissue in stereotactic tumor biopsies.
Fifty consecutive patients underwent frameless stereotactic biopsy for a suspected brain tumor. 5-ALA was administered 4 h before anesthesia. Serial biopsy samples were obtained and intraoperatively checked for 5-ALA fluorescence (strong, vague, or none) using a modified neurosurgical microscope. All samples were examined for the presence of representative tumor tissue according to neuroimaging (MRI, positron emission tomography, and/or chemical shift imaging) and histopathological parameters.
Visible 5-ALA fluorescence was observed in 43/50 patients (strong in 39 and vague fluorescence in four cases). At biopsy target, 52/53 samples of glioblastomas, 9/10 samples of gliomas grade III, and 14/16 samples of lymphomas revealed strong 5-ALA fluorescence. Samples with strong 5-ALA fluorescence were only observed at, but not outside the biopsy target. All tissue samples with strong 5-ALA fluorescence were representative according to our neuroimaging and histopathological criteria (positive predictive value of 100%). Our data indicate that strong 5-ALA fluorescence is a reliable and immediately available intraoperative marker of representative tumor tissue of malignant gliomas and intracranial lymphomas in stereotactic biopsies. Thereby, the application of 5- ALA in stereotactic brain tumor biopsies may in future reduce costs for operating room and neuropathology and may decrease procedure-related morbidity.
Acta Neurochir (2012) 154:585–588. DOI 10.1007/s00701-012-1290-8
Frameless stereotactic biopsies are replacing frame-based stereotaxy as a diagnostic approach to brain lesions. In order to avoid a sampling bias or negative histology, multiple specimens are often taken. This in turn increases the risk of hemorrhagic complications.
Objective We present the use of 5-aminolevulinic acid (5- ALA)-induced protoporphyrin IX fluorescence in frameless stereotaxy to improve the procedure duration and yield, and thereby reduce the risk of complications.
Methods Patients with suspected high-grade brain tumors are given 5-ALA 4 h prior to stereotactic biopsy. The biopsy needle is guided to the target using frameless stereotaxy based either on preoperative images or combined with intraoperative MRI sequences. The specimen is illuminated with blue light to look for fluorescence. In case of a positive fluorescence within the tissue sample, no frozen sections are obtained, and no further specimens are taken.
Results The samples of 13 patients revealed a positive fluorescence and were histologically confirmed as malignant or high-grade brain neoplasms. four cases were fluorescence-negative, requiring frozen section confirmation and/or multiple samples. In theses cases histology was either nonspecific gliotic changes or low-grade tumors. There were no complications related to the additional use of 5-ALA.
Conclusion 5-ALA fluorescence in stereotactic biopsies can increase the safety and accuracy of these procedures by reducing sampling errors and eliminating the need for multiple samples and/or frozen section verification, creating a more accurate, faster and safer procedure for cases of suspected malignant or high-grade brain tumors situated in deep or eloquent areas.
J Neurosurg 115:740–748, 2011. DOI: 10.3171/2011.6.JNS11252
Greater extent of resection (EOR) for patients with low-grade glioma (LGG) corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5- ALA)–induced tumor fluorescence is a strategy that can improve EOR in gliomas, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a handheld probe that provides real-time fluorescent imaging at up to 1000× magnification. The authors report a combined approach in which intraoperative confocal microscopy is used to visualize 5-ALA tumor fluorescence in LGGs during the course of microsurgical resection.
Methods. Following 5-ALA administration, patients with newly diagnosed LGG underwent microsurgical resection. Intraoperative confocal microscopy was conducted at the following points: 1) initial encounter with the tumor; 2) the midpoint of tumor resection; and 3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence.
Results. Ten consecutive patients with WHO Grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses.
Conclusions. Intraoperative confocal microscopy can visualize cellular 5-ALA–induced tumor fluorescence within LGGs and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation, and for LGGs in combination with intraoperative confocal microscopy and neuronavigation, a Phase IIIa randomized placebo-controlled trial (BALANCE) is underway at the authors’ institution.
J Neurosurg 114:1410–1413, 2011. DOI: 10.3171/2010.11.JNS10250
The introduction of fluorescence-guided resection of primary malignant brain tumors was a milestone in neurosurgery. Deep-seated malignant brain tumors are often not approachable for microsurgical resection. For diagnosis and therapy, new strategies are recommended. The combination of endoscopy and 5-aminolevulinic acid–induced protoporphyrin IX (5-ALA-induced Pp IX) fluorescence–guided procedures supported by neuronavigation seems an interesting option. Here the authors report on a combined approach for 5-ALA fluorescence–guided biopsy in which they use an endoscopy system based on an Xe lamp (excitation approximately lambda = 407 nm; dichroic filter system lambda = 380–430 nm) to treat a malignant tumor of the thalamus and perform a ventriculostomy and septostomy. The excitation filter and emission filter are adapted to ensure that the remaining visible blue remission is sufficient to superimpose on or suppress the excited red fluorescence of the endogenous fluorochromes. The authors report that the lesion was easily detectable in the fluorescence mode and that biopsy led to histological diagnosis.
J Neurosurg 114:613–623, 2011. DOI: 10.3171/2010.3.JNS097
Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA–induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery.
Methods. Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function.
Results. More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm3, p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036).
Conclusions. Extended resections performed using a tool such as 5-ALA–derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.
Acta Neurochir (2010) 152:1711–1719. DOI 10.1007/s00701-010-0708-4
5-aminolevulinic acid (5-ALA) has gained importance as an intraoperative photodynamic diagnostic agent for the extirpation of malignant gliomas. The application of this technique for resection of meningiomas has barely been explored. The aim of this study was to evaluate the utility of 5-ALA-induced fluorescence as a visual tool in meningioma resection and its correlation with histological findings.
Methods A total of 33 consecutive patients undergoing resection of intracranial meningiomas from December 2007 to August 2009 were included in this study. After confirmation of normal liver function, 5-ALA was administered orally (20 mg/kg) within 3–5 h prior to skin incision. All cases were operated on using standard microsurgical and neuronavigation-guided techniques. Intraoperative 440 nm fluorescence was applied periodically during and at the end of resection in order to detect tumor-infiltrated sites. The fluorescence of the tumor was evaluated intraoperatively by the surgeon and confirmed by subsequent video analysis.
Results A total of 32 (97%) patients presented with benign meningiomas (WHO I–II). In 1 (3%) patient, histological anaplastic signs (WHO III) could be demonstrated. 5-ALAinduced fluorescence of the tumor was confirmed in a total of 31 (94%) patients. The fluorescence did not correlate with the histological findings (n=30 WHO I–II, n=1 WHO grade III) or with preoperative brain edema and administration of steroids. A total resection could be postoperatively demonstrated in 25 (76%) patients. No adverse effects attributable to 5-ALA occurred.
Conclusions 5-ALA-induced fluorescence is a useful and promising intraoperative tool for the visualization of meningioma tissue. The novel findings demonstrated in this study in terms of high fluorescence and poor correlation with histological findings highlight the usefulness of this technique as a routine visual tool to achieve optimal resection of meningiomas.