5 aminolevulinic acid fluorescence guided resection of spinal tumor

Multiple studies have attempted to evaluate the utility of 5-ALA-aided resection of spinal neoplasms.

Wainwright et al., from the Westchester Medical CenterTohoku University Hospital, reviewed the existing literature on the use of 5-ALA and PpIXfluorescence as an aid to resection of primary and secondary spinal neoplasms by searching the PUBMED and EMBASE database for records up to March 2018. Data was abstracted from all studies describing spinal neurosurgical uses in the English language.

In the reviewed studies, the most useful fluorescence was observed in meningiomas, ependymomas, drop metastases from cerebral gliomas, and spinal hemangiopericytoma, which is consistent with applications in cerebral neoplasms.

The available literature is significantly limited by a lack of standardized methods for measurement and quantification of 5-ALA fluorescence. The results of the reviewed studies should guide future development of rational trial protocols for the use of 5-ALA guided resection in spinal neoplasms1).


Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of Protoporphyrin IX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification.

Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy.

In this study, 5-ALA-PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA-induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci 2).


A study included 10 patients who underwent surgical resection of an intramedullary ependymoma. Nine patients were orally administered 5-ALA (20 mg/kg) 2 hours before the induction of anesthesia. 5-ALA fluorescence was visualized with an operating microscope. Tumors were removed in a standardized manner with electrophysiological monitoring. The extent of resection was evaluated on the basis of intraoperative findings and postoperative magnetic resonance imaging. Histopathological diagnosis was established according to World Health Organization 2007 criteria. Cell proliferation was assessed by Ki-67 labeling index.

5-ALA fluorescence was positive in 7 patients (6 grade II and 1 grade III) and negative in 2 patients (grade II). Intraoperative findings were dichotomized: Tumors covered by the cyst were easily separated from the normal parenchyma, whereas tumors without the cyst appeared to be continuous to the spinal cord. In these cases, 5-ALA fluorescence was especially valuable in delineating the ventral and cranial and caudal margins. Ki-67 labeling index was significantly higher in 5-ALA-positive cases compared with 5-ALA-negative cases. All patients improved neurologically or stabilized after surgery.

5-ALA fluorescence was useful for detecting tumor margins during surgery for intramedullary ependymoma. When combined with electrophysiological monitoring, fluorescence-guided resection could help to achieve maximum tumor resection safely 3).

References

1)

Wainwright JV, Endo T, Cooper JB, Tominaga T, Schmidt MH. The role of 5-aminolevulinic acid in spinal tumor surgery: a review. J Neurooncol. 2018 Dec 29. doi: 10.1007/s11060-018-03080-0. [Epub ahead of print] Review. PubMed PMID: 30594965.
2)

Millesi M, Kiesel B, Woehrer A, Hainfellner JA, Novak K, Martínez-Moreno M, Wolfsberger S, Knosp E, Widhalm G. Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors. Neurosurg Focus. 2014 Feb;36(2):E11. doi: 10.3171/2013.12.FOCUS13485. PubMed PMID: 24484249.
3)

Inoue T, Endo T, Nagamatsu K, Watanabe M, Tominaga T. 5-aminolevulinic acid fluorescence-guided resection of intramedullary ependymoma: report of 9 cases. Neurosurgery. 2013 Jun;72(2 Suppl Operative):ons159-68; discussion ons168. doi: 10.1227/NEU.0b013e31827bc7a3. PubMed PMID: 23149963.

Hemifacial spasm etiology

Although classical hemifacial spasm (HFS) has been attributed to an atraumatic pulsatile vascular compression around the root exit zone (REZ) of the facial nerve, rare tumor-related HFS associated with meningiomas, epidermoid tumors, lipomas, and schwannomas in the cerebellopontine angle have been reported. The exact mechanism and the necessity of microvascular decompression for tumor-induced HFS is not clear, especially for vestibular schwannomas.


Imaging data of 341 patients with a HFS who underwent microvascular decompression were reviewed retrospectively and compared with 360 controls. The hemodynamics of typical anatomical variations of the vertebral artery (VA) were analyzed using computational fluid dynamics (CFD) software.

Asymmetry of the left and right VAs was prevalent, and the left VA was the most dominant VA. A dominant VA was more prevalent in the HFS group than in the control group (p=0.026). A Left HFS had a significantly higher proportion of a left dominant VA, and a right HFS had a significantly higher proportion of right dominant VA (p<0.001). CFD models showed that angulation and tortuosity of vessels caused remarkable pressure difference between vascular walls of opposite sides. Dynamic clinical observations showed the mode of vessel transposition coincided with biomechanical characteristics.

Anatomical variations and hemodynamics of the vertebrobasilar arterial system are likely to contribute to vascular compression formation in a HFS1).


Liu et al. retrospectively analyzed 10 patients with vestibular schwannomas out of 5218 cases of hemifacial spasm between 2004 and 2014.

Hemifacial spasm occurred ipsilateral to the vestibular schwannoma in 9 patients and contralateral to the lesion in 1 patient. The mean follow-up period was 86 months (range, 22-140 months). All patients underwent surgery for resection of the vestibular schwannoma. Following the principle of neurovascular compression, offending vessels were found in 7 patients, no offending vessels in 2 patients, and a tumor with the displacement of brain stem contributing to contralateral facial nerve compression in 1 patient. HFS was relieved immediately postoperatively in 9 patients, whereas it improved gradually and then resolved after one month in one patient with a contralateral vestibular schwannoma.

For HFS induced by vestibular schwannomas in this study, the majority of cases are caused by a combination of tumor and vascular co-compression at the REZ. Surgical intervention resulted in resolution of symptoms. For HFS with ipsilateral vestibular schwannoma, exploration of the facial nerve root for vascular compression should be performed routinely after tumor resection. It is critical to check that no vessel is contact with the entire nerve root 2).


During the period from October 1984 to October 2008, Han et al. treated 6,910 HFS patients using a microsurgical procedure. Of these HFS patients, 55 cases were associated with cerebellopontine angle tumors. A small craniectomy was performed in order to excise the tumor. All tumors were found to compress the root exit zone (REZ) of the facial nerve to different extents, but concomitant vascular compression of the facial nerve was observed in a majority of cases, and microvascular decompression of the facial nerve at REZ was conducted in 43 of 55 patients (78.2%) by displacing the co-compressing vasculature away from the REZ and retaining it using a Teflon pad. Intraoperative findings and postoperative pathological examinations suggested that the tumors were epidermoid cysts, meningiomas, and Schwannomas. Follow-up in 48 of 55 patients for 4-230 months after surgery showed that the clinical symptoms of HFS disappeared in 43 cases, improved in two cases, and recurred in three cases. Ten patients had sequelae associated with the operation. They concluded from this study that the majority of cases of tumor-related HFS are caused by combined tumor and vascular co-compression at the REZ, and tumor removal and microvascular decompression are required in order to relieve the symptoms 3).


Kindling-like hyperactivity of the facial motor nucleus induced by constant stimulation of compressing artery is considered as the predominant mechanism underlying the pathogenesis of Hemifacial spasm (HFS).

Trigeminal neuralgia, hemifacial spasm, vestibulocochlear neuralgia and glossopharyngeal neuralgia represent the most common neurovascular compression syndromes.

In nearly all cases, primary hemifacial spasm is related to arterial compression of the facial nerve at root exit zone (REZ). The offending arterial loops originate from the posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), or vertebrobasilar artery (VB). In as many as 40% of the patients, neurovascular conflicts are multiple. The cross-compression is almost always seen on magnetic resonance imagingcombined with magnetic resonance angiography.


Hemifacial spasm (HFS) associated with type 1 Chiari malformation is particularly uncommon and is limited to isolated case report.

Li et al retrospectively evaluated 13 patients who had simultaneously HFS and type 1 Chiari malformation among 675 HFS patients. Clinical features and radiological findings were collected from each patient and analyzed. All these 13 patients were surgically treated with MVD through retro-mastoid microsurgical approach, and postoperative outcomes were evaluated. A review of literature about this association was also provided. In this study, the frequency of type 1 Chiari malformation in HFS patients was 1.9 %. The clinical profile of this series of patients did not differ from typical form of primary HFS. MVD achieved satisfactory results in 11 patients (85 %) in short- and long-term follow-up. There was no mortality or severe complication occurred postoperatively. Although rare, clinician should be aware of the association of HFS and type 1 Chiari malformation and consider MVD as an effective surgical management 4).

References

1)

Wang QP, Yuan Y, Xiong NX, Fu P, Huang T, Yang B, Liu J, Chu X, Zhao HY. Anatomical variation and hemodynamic evolution of vertebrobasilar arterial system may contribute to the development of vascular compression in hemifacial spasm. World Neurosurg. 2018 Dec 26. pii: S1878-8750(18)32897-3. doi: 10.1016/j.wneu.2018.12.074. [Epub ahead of print] PubMed PMID: 30593967.
2)

Liu J, Liu P, Zuo Y, Xu X, Liu H, Du R, Yu Y, Yuan Y. Hemifacial Spasm as Rare Clinical Presentation of Vestibular Schwannomas. World Neurosurg. 2018 Aug;116:e889-e894. doi: 10.1016/j.wneu.2018.05.124. Epub 2018 May 28. PubMed PMID: 29852302.
3)

Han H, Chen G, Zuo H. Microsurgical treatment for 55 patients with hemifacial spasm due to cerebellopontine angle tumors. Neurosurg Rev. 2010 Jul;33(3):335-9; discussion 339-40. doi: 10.1007/s10143-010-0250-0. Epub 2010 Mar 9. PubMed PMID: 20217169.
4)

Li N, Zhao WG, Pu CH, Yang WL. Hemifacial spasm associated with type 1 Chiari malformation: a retrospective study of 13 cases. Neurosurg Rev. 2016 Jul 15. [Epub ahead of print] PubMed PMID: 27422274.

Magnetic resonance perfusion imaging in glioblastoma

Indications

Magnetic resonance perfusion imaging, may:

Provide a noninvasive diagnostic tool for properly grading lesions.

Identifying the most malignant region of a tumor for guiding biopsy

Monitoring response to therapy that may precede conventionally assessed changes in tumor morphology and enhancement characteristics.

May help quantitatively predict recurrent glioblastoma/progression for glioblastomas. The active tumor histological fraction correlated with quantitative radiologic measurements including rCBV and rCBF.

The dominant predictors of OS are normalized perfusion parameters Normalized Relative Tumor Blood Volume (n_rTBV) and Normalized Relative Tumor Blood Flow (n_rTBF). Pre-operative perfusion imaging may be used as a surrogate to predict glioblastoma aggressiveness and survival independent of treatment 1).


For metastases, Perfusion MRI may not be as useful in predicting mean active tumor fraction (AT). Clinicians must be judicious with their use of MRP in predicting tumor recurrence and radiation necrosis 2).

While perfusion MRI is not the ideal diagnostic method for differentiating glioma recurrence from pseudoprogression, it could improve diagnostic accuracy. Therefore, further research on combining perfusion MRI with other imaging modalities is warranted 3).

Perfusion-weighted magnetic resonance imaging (PW-MRI) techniques, such as dynamic contrast-enhanced MRI (DCE-MRI) and dynamic susceptibility contrast-MRI (DSC-MRI), have demonstrated much potential as powerful imaging biomarkers for glioma management as they can provide information of vascular hemodynamics 4) 5) 6).

PW-MRI is now rapidly expanding its application spectrum by noninvasively exploring the relationship between imaging parameters and the molecular characteristics of gliomas 7).


Dynamic contrast enhanced magnetic resonance imaging and Dynamic susceptibility weighted contrast enhanced perfusion imaging represent a widely accepted method to assess glioblastoma (GBM) microvasculature.

The aim of Navone et al. from the Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Postgraduate School in Radiodiagnostics Department of Neuroradiology, Milan, was to investigate the correlation between plasma von Willebrand Factor (VWF):Ag, permeability and perfusion MRI parameters, and examine their potential in predicting GBM patient prognosis.

They retrospectively analysed pre-operative DCE-, DSC-MRI, and VWF:Ag level of 26 GBM patients. They assessed the maximum values of relative cerebral blood flow (rCBF) and volume (rCBV), volume transfer constant Ktrans, plasma volume (Vp) and reflux rate constant between fractional volume of the extravascular space and blood plasma (Kep). Non-parametric Mann-Withney test and Kaplan-Meier survival analyses were conducted and a p-value<0.05 was considered statistically significant.

The median VWF:Ag value was 248 IU/dL and the median follow-up duration was about 13 months. They divided patients according to low- and high-VWF:Ag and found significant differences in the median follow-up duration (19 months vs 10 months, p=0.04) and in Ktrans (0.31 min-1 vs 0.53 min-1, p=0.02), and Kep (1.79 min-1 vs 3.89 min-1, p=0.005) values. The cumulative 1-year survival was significantly shorter in patients with high-VWF:Ag and high-Kep compared to patients with low-VWF:Ag and low-Kep (37.5% vs. 68%, p = 0.05).

These findings, in a small group of patients, suggest a role for VWF:Ag, similar to Ktrans, and Kep as a prognostic indicator of postoperative GBM patient survival 8).

References

1)

Hou BL, Wen S, Katsevman GA, Liu H, Urhie O, Turner RC, Carpenter J, Bhatia S. MRI Parameters and Their Impact on the Survival of Patients with Glioblastoma: Tumor Perfusion Predicts Survival. World Neurosurg. 2018 Dec 26. pii: S1878-8750(18)32908-5. doi: 10.1016/j.wneu.2018.12.085. [Epub ahead of print] PubMed PMID: 30593971.
2)

Shah AH, Kuchakulla M, Ibrahim GM, Dadheech E, Komotar RJ, Gultekin SH, Ivan ME. The utility of Magnetic Resonance Perfusion imaging in quantifying active tumor fraction and radiation necrosis in recurrent intracranial tumors. World Neurosurg. 2018 Oct 9. pii: S1878-8750(18)32288-5. doi: 10.1016/j.wneu.2018.09.233. [Epub ahead of print] PubMed PMID: 30312826.
3)

Wan B, Wang S, Tu M, Wu B, Han P, Xu H. The diagnostic performance of perfusion MRI for differentiating glioma recurrence from pseudoprogression: A meta-analysis. Medicine (Baltimore). 2017 Mar;96(11):e6333. doi: 10.1097/MD.0000000000006333. PubMed PMID: 28296759; PubMed Central PMCID: PMC5369914.
4)

Jain R. Measurements of tumor vascular leakiness using DCE in brain tumors: clinical applications. NMR in Biomedicine. 2013;26(8):1042–1049. doi: 10.1002/nbm.2994.
5)

O’Connor J. P. B., Jackson A., Parker G. J. M., Roberts C., Jayson G. C. Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies. Nature Reviews Clinical Oncology. 2012;9(3):167–177. doi: 10.1038/nrclinonc.2012.2.
6)

Barajas R. F. R., Cha S. Benefits of dynamic susceptibility-weighted contrast-enhanced perfusion MRI for glioma diagnosis and therapy. CNS oncology. 2014;3(6):407–419. doi: 10.2217/cns.14.44.
7)

Chung C., Metser U., Ménard C. Advances in magnetic resonance imaging and positron emission tomography imaging for grading and molecular characterization of glioma. Seminars in Radiation Oncology. 2015;25(3):164–171. doi: 10.1016/j.semradonc.2015.02.002.
8)

Navone SE, Doniselli FM, Summers P, Guarnaccia L, Rampini P, Locatelli M, Campanella R, Marfia G, Costa A. Correlation of preoperative Von Willebrand Factor with MRI perfusion and permeability parameters as predictors of prognosis in glioblastoma. World Neurosurg. 2018 Oct 9. pii: S1878-8750(18)32271-X. doi: 10.1016/j.wneu.2018.09.216. [Epub ahead of print] PubMed PMID: 30312827.
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