Category Archives: Neurooncology

Update: Olea europaea

The olive, known by the botanical name Olea europaea, meaning “European olive”, is a species of small tree in the family Oleaceae, found in the Mediterranean Basin from Portugal to the Levant, the Arabian Peninsula, and southern Asia as far east as China, as well as the Canary Islands and Réunion. The species is cultivated in many places and considered naturalized in all the countries of the Mediterranean coast, as well as in Argentina, Saudi Arabia, Java, Norfolk Island, California, and Bermuda.

Tezcan et al. from the Uludag University , Bursa , Turkey, tested the anti-proliferative activity of Olea europaea (OLE) and the effect of the OLE-TMZ combination in the T98GU138MG and U87 MG GBM cell lines using the cell proliferation reagent WST-1 assay. The mechanism of cell death was analyzed with Annexin A5/fluorescein isothiocyanate (FITC) and TUNEL assays. The effects of OLE on the expression levels of miR-181b, miR-153, miR-145 and miR-137 and potential mRNA targets were analyzed in Glioblastoma stem cell (GSC)s using reverse transcription polymerase chain reaction (RT-qPCR). OLE exhibited anti-proliferative effects via apoptosis and necrosis in the GBM cell lines. In addition, OLE significantly induced the expression of miR-153, miR-145, and miR-137 and decreased the expression of the target genes of these miRNAs in GSCs (p < 0.05). OLE causes cell death in GBM cells with different TMZ responses, and this effect is synergistically increased when the cells are treated with a combination of OLE and TMZ. This is the first study to indicate that OLE may interfere with the pluripotency of GSCs by modulating miRNA expression. Further studies are required, but we suggest that OLE may have a potential for advanced therapeutic cancer drug studies in GBM 1).

OLE (2mg/mL) caused a significant reduction in tumour weight, vascularisation, invasiveness and migration (p=0.0001, p<0.001, p=0.004; respectively) that was associated with reducing the expression of vascular endothelial growth factor A (VEGFA), MMP-2 and MMP-9. This effect was synergistically increased in combination with bevacizumab 2).

Exposure to 1 mg/mL OLE caused a significant induction of CpG island methylation in the MGMT gene using Methyl quantitative PCR assay (P < 0.001). In WST-1 analysis, the use of 350 µM TMZ plus 1 mg/mL OLE significantly increased the TMZ response of MGMT unmethylated cells (P = 0.003). Using the comet assay, the impact of 1 mg/mL OLE plus 350 µM TMZ on the formation of DNA strand breaks was significantly higher than that of 450 µM TMZ alone (P < 0.001) and Western blot analysis revealed that, when cells are treated with 1-mg/mL OLE, the total p53 protein levels tended to decrease. The results presented in this study uniquely demonstrated that OLE synergistically increased the TMZ response of GBM tumors by regulating MGMT gene methylation and p53 expression 3).


Tezcan G, Tunca B, Bekar A, Budak F, Sahin S, Cecener G, Egeli U, Taskapılıoglu MO, Kocaeli H, Tolunay S, Malyer H, Demir C, Tumen G. Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression. Am J Cancer Res. 2014 Sep 6;4(5):572-90. eCollection 2014. PubMed PMID: 25232498; PubMed Central PMCID: PMC4163621.

Tezcan G, Taskapilioglu MO, Tunca B, Bekar A, Demirci H, Kocaeli H, Aksoy SA, Egeli U, Cecener G, Tolunay S. Olea europaea leaf extract and bevacizumab synergistically exhibit beneficial efficacy upon human glioblastoma cancer stem cells through reducing angiogenesis and invasion in vitro. Biomed Pharmacother. 2017 Apr 15;90:713-723. doi: 10.1016/j.biopha.2017.04.022. [Epub ahead of print] PubMed PMID: 28419967.

Tezcan G, Tunca B, Demirci H, Bekar A, Taskapilioglu MO, Kocaeli H, Egeli U, Cecener G, Tolunay S, Vatan O. Olea europaea Leaf Extract Improves the Efficacy of Temozolomide Therapy by Inducing MGMT Methylation and Reducing P53 Expression un Glioblastoma. Nutr Cancer. 2017 Jul 18:1-8. doi: 10.1080/01635581.2017.1339810. [Epub ahead of print] PubMed PMID: 28718668.

Update: GH secreting pituitary adenoma

Growth hormone-secreting functioning pituitary adenoma (GHPA) is a rare, chronic, systemic disease that is associated with premature death and significant morbidity 1).

75 % are > 10 mm at time of diagnosis.


An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH secreting pituitary adenoma2).


The aim of a study was to evaluate the effects of some widely diffused pollutants (i.e. benzene, BZ; bis(2-ethylhexyl) phthalate, DEHP and polychlorinated biphenyls, PCB) on growth hormone secretion, the somatostatin and estrogenic pathways, viability and proliferation of rat GH-producing pituitary adenoma (GH3) cells. All the pollutants induced a statistically significant increase in GH secretion and interfered with cell signaling. They all modulated the expression of SSTR2 and ZAC1, involved in the somatostatin signaling, and the expression of the transcription factor FOXA1, involved in the estrogen receptor signaling. Moreover, all the pollutants increased the expression of the CYP1A1, suggesting AHR pathway activation. None of the pollutants impacted on cell proliferation or viability. Present data demonstrate that exposure to different pollutants, used at in vivo relevant concentrations, plays an important role in the behavior of GH3 pituitary adenoma cells, by increasing GH secretion and modulating several cellular signaling pathways. These observations support a possible influence of different pollutants in vivo on the GH-adenoma aggressiveness and biological behavior 3).


Giant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission 4).

Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done 5).

Clinical Features

Excessive growth hormone (GH) is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults.


It is related to high levels of growth hormone (GH) and insulin-like growth factor-I (IGF-1).


The enhancement was significantly lower in GH secreting pituitary adenoma than in non-secreting ones. 6).

T2 weighted image differentiates GH secreting pituitary adenomas into subgroups with particular behaviors. This raises the question of whether T2-weighted signal could represent a factor in the classification of acromegaly in future studies 7).

In patients with acromegalyT2 weighted image signal intensity at diagnosis correlates with histological features and predicts biochemical outcome of first-line somatostatin analogues (SA) treatment 8).


Each of the biomarkers, Ki-67 and p53, along with patient’s age and mixed GH-prolactin secretion showed a kind of correlation with each of aspects of the clinical, hormonal and radiologic outcome of GH-secreting pituitary adenomas 9).


see Growth hormone secreting pituitary adenoma treatment

Surgery is the first-line therapy.


The resection via a transsphenoidal approach is able to induce a long-term remission of acromegaly, with low risk of recurrence and complications. Endoscopic endonasal transsphenoidal approach is more suitable than microscopic technique in macroadenomas and adenomas with suprasellar extension 10).

Medical therapy

The cost of treatment including medications and the possibility of major side effects represent important limitations of the medical therapy 11) 12).

The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-1 and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly 13)

Current pharmacotherapy includes somatostatin analogs (SAs) and GH receptor antagonist; the former consists of lanreotide Autogel (ATG) and octreotide long-acting release (LAR), and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4-6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits 14).

Somatostatin treatment can induce extensive fibrosis in GH secreting pituitary adenoma 15).


The standardised mortality index (the ratio of observed mortality in the acromegalic population to expected mortality in the general population) ranged from 1.2 to 3.3. If left untreated, patients with acromegaly can die approximately 10 years earlier than the healthy subjects. According to prior studies, approximately 60, 25 and 15% of the patients die from cardiovascular disease, respiratory complications and cancer, respectively 16)17).

Control of serum GH and insulin-like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity.

Remission rates for micro- and macroadenomas were 81.8% and 45.8%, respectively. Patients of older age, with a smaller tumor, lower Knosp grade, lower preoperative GH, and insulinlike growth factor 1 levels were more likely to achieve remission. Remission rate decreased significantly with repeat surgeries. Those patients with adenomas that stained positive for somatostatin receptor subtype 2A were less likely to experience tumor recurrence and more likely to respond to medical treatment with persistent or elevated GH hypersecretion 18).

A retrospective review of 53 patients who had follow up endocrinologic data at least 3 months post-surgery was performed among patients who were treated by EEA between 1998 and 2012. Data were analyzed for remission using GH and IGF-I levels based on 2010 consensus criteria. We also analyzed the outcomes using 2000 consensus criteria for ease in comparison to prior studies of outcomes of surgery for acromegaly. In this series of mostly large (88.2% macroadenomas), invasive (46.9% Hardy-Wilson C, D, E) adenomas, there were 27 patients (50.9%) who achieved remission after EEA only. For patients who had no remission with EEA alone, RS and/or medical therapy were used and 37 patients (69.8 %) achieved remission overall. Statistical analysis showed larger tumor size, Hardy Stages C, D, E and Knosp Scores 3, 4 to be predictive against remission for EEA only and EEA with other modalities. The volume of residual tumor after EEA was not found to be predictive of remission with additional therapies. We used stringent consensus criteria from 2010 in a series which included a high proportion of invasive GH secreting adenomas to show that EEA alone or combined with other modalities results in comparable remission rates to earlier studies which used less strict criteria, while retaining low complication rates 19).

Each of the biomarkers, Ki-67 and p53, along with patient’s age and mixed GH-prolactin secretion showed a kind of correlation with each of aspects of the clinical, hormonal and radiologic outcome of GH-secreting pituitary adenomas in the series of Alimohamadi et al. 20).

Case reports


A 37-year-old woman has presented with complaints of headacheamenorrhea and acromegaly.

Her laboratory studies showed markedly elevated levels of Insulin like Growth Factor 1 (IGF-1), and low levels of follicle stimulating hormone and luteinizing hormone. Computerized tomography has revealed a pituitary tumor without extra-sellar extension. The tumor has completely excised via Endoscopic transsphenoidal approach. Histologically, the tumor has diagnosed as a pituitary adenoma with GH positive cells. The serum IGF1 levels have gradually decreased to the normal range and the patient was symptom free for three and a half years when she has returned with complaint of visual impairment. The brain MRI that time has shown a supra-sellar mass growing independently into the remaining sellar part. Subsequently, surgical operation has performed via trans-nasal endoscopic approach. Histopathological and immunohistochemistry examination have revealed a rare case of growth hormone producing pituitary adenoma with brain invasion and lymphocytic infiltration.

The aim of this publication was to present a rare case of growth hormone producing pituitary adenoma with brain invasion and lymphocytic infiltration 21).


Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab. 2004;89:1613–7.
2) , 3)

Fortunati N, Guaraldi F, Zunino V, Penner F, D’Angelo V, Zenga F, Pecori Giraldi F, Catalano MG, Arvat E. Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells. Environ Res. 2017 Jul 18;158:660-668. doi: 10.1016/j.envres.2017.07.015. [Epub ahead of print] PubMed PMID: 28732322.

Shimon I, Jallad RS, Fleseriu M, Yedinak CG, Greenman Y, Bronstein MD. Giant GH-secreting pituitary adenomas: management of rare and aggressive pituitary tumors. Eur J Endocrinol. 2015 Jun;172(6):707-713. Epub 2015 Mar 19. PubMed PMID: 25792375.

Manuylova E, Calvi LM, Hastings C, Vates GE, Johnson MD, Cave WT Jr, Shafiq I. Late presentation of acromegaly in medically controlled prolactinoma patients. Endocrinol Diabetes Metab Case Rep. 2016;2016. pii: 16-0069. PubMed PMID: 27855229.

Lundin P, Bergström K. Gd-DTPA-enhanced MR imaging of pituitary macroadenomas. Acta Radiol. 1992 Jul;33(4):323-32. PubMed PMID: 1633042.

Potorac I, Petrossians P, Daly AF, Schillo F, Ben Slama C, Nagi S, Sahnoun Fathallah M, Brue T, Girard N, Chanson P, Nasser G, Caron P, Bonneville F, Ravérot G, Lapras V, Cotton F, Delemer B, Higel B, Boulin A, Gaillard S, Luca F, Goichot B, Dietemann J, Beckers A, Bonneville J. Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocr Relat Cancer. 2015 Jan 2. pii: ERC-14-0305. [Epub ahead of print] PubMed PMID: 25556181.

Heck A, Ringstad G, Fougner SL, Casar-Borota O, Nome T, Ramm-Pettersen J, Bollerslev J. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012 Jul;77(1):72-8. doi: 10.1111/j.1365-2265.2011.04286.x. PubMed PMID: 22066905.

Alimohamadi M, Ownagh V, Mahouzi L, Ostovar A, Abbassioun K, Amirjmshidi A. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg. 2014 Jul-Sep;9(3):130-6. doi: 10.4103/1793-5482.142732. PubMed PMID: 25685203; PubMed Central PMCID: PMC4323896.

Lenzi J, Lapadula G, D’amico T, Delfinis CP, Iuorio R, Caporlingua F, Mecca N, Mercuri V, Bassotti G, Rillo M, Santoro F, Tamburrano G, Santoro A, Gargiulo P. Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach. J Neurosurg Sci. 2015 Mar;59(1):11-8. PubMed PMID: 25658052.
11) , 16)

Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Pituitary tumours: Acromegaly. Best Pract Res Clin Endocrinol Metab. 2009;23:555–74.

Gondim JA, Ferraz T, Mota I, Studart D, Almeida JP, Gomes E, et al. Outcome of surgical intrasellar growth hormone tumor performed by a pituitary specialist surgeon in a developing country. Surg Neurol. 2009;72:15–9.

Giustina A, Bronstein MD, Casanueva FF, Chanson P, Ghigo E, Ho KK, Klibanski A, Lamberts S, Trainer P, Melmed S. Current management practices for acromegaly: an international survey. Pituitary. 2011 Jun;14(2):125-33. doi: 10.1007/s11102-010-0269-9. PubMed PMID: 21063787.

Wang JW, Li Y, Mao ZG, Hu B, Jiang XB, Song BB, Wang X, Zhu YH, Wang HJ. Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas. Patient Prefer Adherence. 2014 Jan 6;8:43-51. Review. PubMed PMID: 24421637.

Kerschbaumer J, Pinggera D, Moser P, Hofmann A, Thomé C, Freyschlag CF. Somatostatin treatment can induce extensive fibrosis in growth hormone-producing adenoma. Acta Neurochir (Wien). 2016 Mar;158(3):441-3. doi: 10.1007/s00701-016-2714-7. Epub 2016 Jan 23. PubMed PMID: 26801514.

Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary. 1999;2:29–41.

Sun H, Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Factors associated with biochemical remission after microscopic transsphenoidal surgery for acromegaly. J Neurol Surg B Skull Base. 2014 Feb;75(1):47-52. doi: 10.1055/s-0033-1354578. Epub 2013 Sep 9. PubMed PMID: 24498589; PubMed Central PMCID: PMC3912146.

Shin SS, Tormenti MJ, Paluzzi A, Rothfus WE, Chang YF, Zainah H, Fernandez-Miranda JC, Snyderman CH, Challinor SM, Gardner PA. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary. 2013 Dec;16(4):435-44. doi: 10.1007/s11102-012-0440-6. PubMed PMID: 23179961.

Alimohamadi M, Ownagh V, Mahouzi L, Ostovar A, Abbassioun K, Amirjmshidi A. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg. 2014 Jul-Sep;9(3):130-6. doi: 10.4103/1793-5482.142732. PubMed PMID: 25685203; PubMed Central PMCID: PMC4323896.

Bidari-Zerehpoosh F, Sharifi G, Novin K, Mortazavi N. Invasive Growth Hormone Producing Pituitary Adenoma With Lymphocytic Infiltration: A Case Report and Literature Review. Iran J Cancer Prev. 2015 Dec;8(6):e3504. Epub 2015 Dec 23. PubMed PMID: 26855718.

Update: Navigated transcranial magnetic stimulation for language mapping

In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization.

The expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability 1).

Although language mapping by repetitive navigated transcranial magnetic stimulation (rTMS) gains importance in neuropsychological research and clinical utility, neuroscientists still use different mapping protocols including different stimulation frequencies.

The stimulation frequency has to be adapted to the aim of the rTMS language investigation 2).


Ille et al. performed multimodal language mapping in 35 patients with left-sided perisylvian lesions by using rTMS, fMRI, and DCS. The rTMS mappings were conducted with a picture-to-trigger interval (PTI, time between stimulus presentation and stimulation onset) of either 0 or 300 msec. The error rates (ERs; that is, the number of errors per number of stimulations) were calculated for each region of the cortical parcellation system (CPS). Subsequently, the rTMS mappings were analyzed through different error rate thresholds (ERT; that is, the ER at which a CPS region was defined as language positive in terms of rTMS), and the 2-out-of-3 rule (a stimulation site was defined as language positive in terms of rTMS if at least 2 out of 3 stimulations caused an error). As a second step, the authors combined the results of fMRI and rTMS in a predefined protocol of combined noninvasive mapping. To validate this noninvasive protocol, they correlated its results to DCS during awake surgery.

The analysis by different rTMS ERTs obtained the highest correlation regarding sensitivity and a low rate of false positives for the ERTs of 15%, 20%, 25%, and the 2-out-of-3 rule. However, when comparing the combined fMRI and rTMS results with DCS, the authors observed an overall specificity of 83%, a positive predictive value of 51%, a sensitivity of 98%, and a negative predictive value of 95%.

In comparison with fMRI, rTMS is a more sensitive but less specific tool for preoperative language mapping than DCS. Moreover, rTMS is most reliable when using ERTs of 15%, 20%, 25%, or the 2-out-of-3 rule and a PTI of 0 msec. Furthermore, the combination of fMRI and rTMS leads to a higher correlation to DCS than both techniques alone, and the presented protocols for combined noninvasive language mapping might play a supportive role in the language-mapping assessment prior to the gold-standard intraoperative DCS 3).


nTMS and MEGI were performed on 12 subjects. nTMS yielded 21 positive language disruption sites (11 speech arrest, 5 anomia, and 5 other) while DCS yielded 10 positive sites (2 speech arrest, 5 anomia, and 3 other). MEGI isolated 32 sites of peak activation with language tasks. Positive language sites were most commonly found in the pars opercularis for all three modalities. In 9 instances the positive DCS site corresponded to a positive nTMS site, while in 1 instance it did not. In 4 instances, a positive nTMS site corresponded to a negative DCS site, while 169 instances of negative nTMS and DCS were recorded. The sensitivity of nTMS was therefore 90%, specificity was 98%, the positive predictive value was 69% and the negative predictive value was 99% as compared with intraoperative DCS. MEGI language sites for verb generation and object naming correlated with nTMS sites in 5 subjects, and with DCS sites in 2 subjects. CONCLUSION: Maps of language function generated with nTMS correlate well with those generated by DCS. Negative nTMS mapping also correlates with negative DCS mapping. In our study, MEGI lacks the same level of correlation with intraoperative mapping; nevertheless it provides useful adjunct information in some cases. nTMS may offer a lesion-based method for noninvasively interrogating language pathways and be valuable in managing patients with peri-eloquent lesions 4).

Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system.

Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca’s area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively.

Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology 5).


Krieg SM, Lioumis P, Mäkelä JP, Wilenius J, Karhu J, Hannula H, Savolainen P, Lucas CW, Seidel K, Laakso A, Islam M, Vaalto S, Lehtinen H, Vitikainen AM, Tarapore PE, Picht T. Protocol for motor and language mapping by navigated TMS in patients and healthy volunteers; workshop report. Acta Neurochir (Wien). 2017 Jul;159(7):1187-1195. doi: 10.1007/s00701-017-3187-z. Epub 2017 Apr 29. Review. PubMed PMID: 28456870.

Hauck T, Tanigawa N, Probst M, Wohlschlaeger A, Ille S, Sollmann N, Maurer S, Zimmer C, Ringel F, Meyer B, Krieg SM. Stimulation frequency determines the distribution of language positive cortical regions during navigated transcranial magnetic brain stimulation. BMC Neurosci. 2015 Feb 18;16(1):5. PubMed PMID: 25880838.

Ille S, Sollmann N, Hauck T, Maurer S, Tanigawa N, Obermueller T, Negwer C, Droese D, Zimmer C, Meyer B, Ringel F, Krieg SM. Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation. J Neurosurg. 2015 Jul;123(1):212-25. doi: 10.3171/2014.9.JNS14929. Epub 2015 Mar 6. PubMed PMID: 25748306.

Tarapore PE, Findlay AM, Honma SM, Mizuiri D, Houde JF, Berger MS, Nagarajan SS. Language mapping with navigated repetitive TMS: proof of technique and validation. Neuroimage. 2013 Nov 15;82:260-72. doi: 10.1016/j.neuroimage.2013.05.018. Epub 2013 May 20. PubMed PMID: 23702420; PubMed Central PMCID: PMC3759608.

Picht T, Krieg SM, Sollmann N, Rösler J, Niraula B, Neuvonen T, Savolainen P, Lioumis P, Mäkelä JP, Deletis V, Meyer B, Vajkoczy P, Ringel F. A comparison of language mapping by preoperative navigated transcranial magnetic stimulation and direct cortical stimulation during awake surgery. Neurosurgery. 2013 May;72(5):808-19. doi: 10.1227/NEU.0b013e3182889e01. PubMed PMID: 23385773.

Register Today for This Free Webinar: Strategic Use of BCNU Wafers in Contemporary Care

Register Today for This Free Webinar: Strategic Use
of BCNU Wafers in Contemporary Care

Aug. 23, 2017, at 7 p.m. EDT
Aug. 30, 2017, at 6 p.m. PDT

Register Now >


Lynn Stuart Ashby, MD
Assistant Director, Neuro Oncology Program
Barrow Neurological Institute (BNI)
Phoenix, AZ

Eyas M. Hattab, MD, MBA
AJ Miller Professor and Chair
Pathology and Laboratory Medicine
Louisville, KY

Timothy C. Ryken, MD, MS, FACS, FAANS
Professor and Chief
Section of Neurosurgery
Dartmouth-Hitchcock Medical Center
Lebanon, NH

In this one-hour webinar, participants will receive an overview on the practical use of BCNU Wafers for the treatment of newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation and recurrent glioblastoma multiforme as an adjunct to surgery. Neurooncology, neuropathology and neurosurgery perspectives will be presented in the discussion covering peri-operative considerations for BCNU Wafer implantation as part of a multimodal treatment plan.

Learning Objectives

  • Review historical changes in incidence and survival over recent decades for high grade malignant glioma (HGG) and summarize current FDA approved treatments.
  • Evaluate pivotal evidence for the use of BCNU wafers and indications for newly diagnosed and recurrent HGG setting.
  • Develop strategic approach for integrating BCNU wafers into multimodal standard treatment for patients at diagnosis and relapse of HGG.
  • Discuss prerequisites for successful intraoperative consultation (IOC) outcomes and overcoming challenges in surgical neuropathology.
  • Learn how to bridge the intraoperative gap between pathology and neurosurgery.
  • Identify the best operative and post-operative approaches toward optimizing outcomes following BCNU wafer implantation.

GLIADEL Wafer can cause fetal harm when administered to a pregnant woman. It is recommended that patients receiving GLIADEL Wafer discontinue nursing. Female patients of reproductive potential should receive counseling on pregnancy planning and prevention. Advise male patients of the potential risk of infertility and to seek counseling on fertility and family planning options prior to implantation of GLIADEL Wafer.
Seizures: Seizures occurred in 37% of patients treated with GLIADEL Wafers in the recurrent disease trial. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment-emergent seizures occurred within the first 5 post-operative days. The median time to onset of the first new or worsened post-operative seizure was 4 days. Institute optimal anti-seizure therapy prior to surgery. Monitor patients for seizures postoperatively.
Intracranial Hypertension: Brain edema occurred in 23% of patients treated with GLIADEL Wafers in the initial surgery trial. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation. Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of GLIADEL Wafers or Wafer remnants.
Impaired Neurosurgical Wound Healing: Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgleal, or wound effusions occur with GLIADEL Wafer treatment. In the initial disease trial, 16% of GLIADEL Wafer-treated patients experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In the recurrent disease trial, 14% of GLIADEL Wafer-treated patients experienced wound healing abnormalities. Monitor patients post-operatively for impaired neurosurgical wound healing.
Meningitis: Meningitis occurred in 4% of patients receiving GLIADEL Wafers in the recurrent disease trial. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection.
Wafer Migration: GLIADEL Wafer migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus.
The most common adverse reactions in Newly-Diagnosed High Grade Malignant Glioma patients (incidence >10% and between arm difference ≥4%) are cerebral edema, asthenia, nausea, vomiting, constipation, wound healing abnormalities and depression.
The most common adverse reactions in Recurrent Glioblastoma Multiforme patients (incidence >10% and between arm difference ≥4%) are urinary tract infection, wound healing abnormalities and fever.

Please click here for full Prescribing Information.

Gliadel® is manufactured by Eisai Inc. for Arbor Pharmaceuticals, LLC.
Gliadel® is a registered trademark of Eisai Inc.

Update: Falx Meningioma

Falx or falcine meningioma, as defined by Harvey Williams Cushing, is a meningioma arising from the falx cerebri and completely concealed by the overlying cortex 1).

Not involving the superior sagittal sinus.


Falcine meningiomas account for 9% of all intracranial meningiomas.

Falcine meningioma tends to grow predominately into one cerebral hemisphere but is often bilateral, and in some patients the tumor grows into the inferior edge of the sagittal sinus.

The patients with falcine meningiomas with reference to gender had the following ratio of male:female of 1:2.1 and an average age of 55 years.

In the series of Pires de Aguiar et al 1:6 (men:women) relationship, and the mean age was 55.4 years old 2).


They can be divided into anterior, middle, and posterior types, depending on their origin in the falx 3).

The anterior type extends from the floor of the anterior cranial fossa to the coronal suture, the middle type from the coronal suture to the lambdoid suture, and the posterior type extends from the lambdoid suture to the torcular Herophili.

Falcine meningioma of the anterior third

Falcine meningioma of the middle third

Falcine meningioma of the posterior third.

Yasargil classified falcine meningiomas into outer and inner types. The former arise from the main body of the falx in the frontal (anterior or posterior), central parietal, or occipital regions, whereas inner falcine meningiomas arise in conjunction with the inferior sagittal sinus4).

Zuo et al classified FM into four types, according to tumour growth patterns on coronal MRI: Type I, hemispheroid-shaped tumours invaginating deeply into one hemisphere without shifting the falx (10 patients); Type II, olive-shaped tumours shifting the falx substantially to the contralateral side (six patients); Type IIIA, globular- or dumbbell-shaped tumours extending into both hemispheres, but to different extents (one patient); and Type IIIB, globular- or dumbbell-shaped tumours extending into both hemispheres to approximately equal extent (three patients). An ipsilateral interhemispheric approach was performed for Type I tumours, and a contralateral transfalcine approach for Type II. Type IIIA tumour was approached from the side where the smaller tumour was located. Type IIIB tumours were approached from the non-dominant hemisphere 5).

see also cystic falx meningioma.

Clinical features

Symptoms can vary depending upon the location of these tumors along the falx.

Those located in the frontal section may impair higher levels of brain functioning such as reasoning and memory, while those located in the middle section would be more likely to cause leg weakness.


MRI with and without gadolinium helps better to delineate the tumor in relation to the dural sinus, the tumor interface with the cerebral cortex, presence of significant blood supply, and presence of cysts or other intra-tumoral structures that will add to the complexity and malignant potential of the tumor. Good pre-operative evaluation of falcine meningiomas is also important when integrated with neuronavigation protocols to be utilized in the operating room. Furthermore, the junction between tumor and adjacent brain suggests the presence or absence of an accessible arachnoid plane and enables the surgeon to predict the potential degree of neurologic deficit that may follow surgical removal. Gadolinium-enhanced MRI allows demonstration of tumoral or adjancent dural enhancement. The radiological appearance affords a valid predictor of the degree of dural involvement in the region of the sinus and adjacent falx. This may suggest the presence of syncytium of meningeal cells spreading along the falx from the site of major dural attachment.

Multiplanar MRI is the current standard study for the preoperative evaluation of patients with falcine meningiomas. Coronal, sagittal, and axial T1-weighted gadolinium-enhanced sequences help define the anatomical locations, sizes, and medial hemisphere involvements of these tumors.

MR venography in vertex view can be useful for demonstrating nearby parasagittal draining veins, which must be protected 6) , but MRA alone seems to be inadequate in the lack of venous phase of cerebral vasculature around tumors.

Cerebral angiography

Cerebral angiography is necessary in patients with these meningiomas, and the pericallosal artery is often displaced and may actually be engulfed by the tumor. Arterial phase cerebral or MR angiograms should be studied to determine the relationship between tumor and ACA. Anterior falcine meningiomas are usually supplied by the ACA or by a tentorial branch of the ophthalmic artery. Venous phase cerebral angiography is important because it provides significant information about whether a tumor mass has invaded the sagittal sinus. Moreover, it provides information about the courses of many large drainers around a mass, which must be determined to identify trajectory to a falcine mass and to prevent postoperative venous infarction. It is also useful for determining sinus patency and for delineating the anatomical location of the major cortical draining vein. Signs of venous occlusion include the disappearance of a segment of the superior sagittal sinus (SSS), a delay in venous drainage in the area of obstruction, and failure of the cortical vein to reach the sinus.

Differential diagnosis

There are several tumors that grow near the falx and may mimic the falcine meningiomas. Osteochondromas, chondrosarcomas, solitary fibrous tumor of the meninges, epidermoid tumors and metastasis are the most frequent.

Although rare, marginal zone B-cell lymphoma must be considered in the differential diagnosis of an extra-axial enhancing mass 7).

A 43-year-old man arrived at the emergency department following a syncopal episode. Computed tomography and magnetic resonance images demonstrated a small interhemispheric, anterior parafalcine mass that mimicked a meningioma. Surgical excision and subsequent pathologic evaluation revealed an angioleiomyoma and the patient recovered without incident 8).

see Granulocytic sarcoma


The pure falcine meningiomas (without relation with cortical surface and superior sagittal sinus) and parasagittal falcine meningiomas may arise at any point along the midline, anterior to posterior, and present different technical problems depending on their location and depth.

Cushing and Eisenhardt used a transcortical incision to expose most falcine meningiomas. However, current microsurgical techniques and methods have improved intracranial compliance, including cerebrospinal fluid drainage, mannitolization, and hyperventilation, and a transcortical approach is rarely required 9).

The dura is opened to I to 2 cm from the midline, with the expo­sure planned in relation to the cortical veins draining to the sagittal sinus. Arachnoid and pacchionian granulation attachments are divided. It is only necessary to retract the medial cerebral cortex I to 2 cm from the falx to expose the tumor. In some cases a bridging vein can be freed from the cortex for a few millimeters to give the required exposure without sacrificing the vein. A self­retaining retractor is placed. In the anterior third it is usually possible to take the draining veins and the sagittal sinus if necessary to complete the resection.

The key to the operation is to carry out an extensive internal decompression of the tumor with the ultrasonic aspirator and grad­ually draw the capsule into the area of decompression. Sometimes the tumor is transected parallel to the falx so the capsule can be more easily mobilized. In some patients a bilateral exposure is required. At some point in the operation, depending on the size and configuration of the tumor, the falx is divided well away from the tumor attachment. The inferior sagittal sinus can be occluded. Great care must be taken not to injure the pericallosal and calloso­marginal arteries.

Spektor et al described a purely endoscopic removal of an atypical parasagittal meningioma in a patient who could not undergo standard craniotomy due to severe scalp atrophy following childhood irradiation for tinea capitis 10).

For treating a patient with multiple falcine and parasagittal lesions, Yamaguchi et al. believe that it is beneficial to resect the maximum possible number of lesions during one operation, even if some lesions are asymptomatic. This practice can potentially reduce the total number of operations during a patient’s lifetime 11).


The falcine meningiomas may be present with bleeding as intraparenchymal hematomas, subdural hematomas and subarachnoid hemorrhage, causing a clinical finding of apoplexy in the patients.

Hemorrhages occurring in asymptomatic falcine meningiomas are known beforehand to have been described after the internal use of low-dose aspirin for prolonged period.

During falcine meningioma surgery, we must pay attention to cardiac monitoring due to the risk that the handling of falx and tentorium could provoke cardiac asystole. The mechanical stimulation of the falcine area may result in the hyperactivity of the trigeminal ganglion, thereby triggering TCR.

The dorsal region of the spinal trigeminal tract includes neurons from hypoglossal and vagus nerves, and projections have been seen between the vagus and trigeminal nuclei.


It has been reported that parasagittal meningioma and falx meningiomas recur more frequently than other intracranial meningiomas12).

The rate of recurrence of falx meningiomas significantly increases in cases of non-radical resection of tumor. Aggressive surgical treatment obviously may present several hazards and may carry an increased risk of unsatisfactory outcome; however, the risk of recurrence is significantly decreased 13).

Abou Al-Shaar et al. have utilized brachytherapy as a salvage treatment in two patients with a unique implantation technique. Both patients had recurrence of WHO Grade II falcine meningiomas despite multiple prior surgical and RT treatments. Radioactive I-125 seeds were made into strands and sutured into a mesh implant, with 1 cm spacing, in a size appropriate to cover the cavity and region of susceptible falcine dura. Following resection the vicryl mesh was implanted and fixed to the margins of the falx. Implantation in this interhemispheric space provides good dose conformality with targeting of at-risk tissue and minimal radiation exposure to normal neural tissues. The patients are recurrence free 31 and 10 months after brachytherapy treatment. Brachytherapy was an effective salvage treatment for the recurrent aggressive falcine meningiomas in two patients 14).



Parasagittal and falx meningiomas 1970 by P. C Gautier-Smith (Author)

Publisher: Appleton-Century-Crofts (1970) Language: English ISBN-10: 0407352406 ISBN-13: 978-0407352407.

Case series


Murrone et al. analyzed 95 patients with falcine meningiomas who underwent surgical removal of their lesion at our institution between 2001 and 2014. Surgical management of these patients, focusing on anatomical and clinical features is described. Thus, based on our series, a surgical algorithm, classifying the falcine meningioma into four types, according to location at the falx, and using an ipsilateral interhemispheric approach in supine or prone position, is described. The median length of follow-up was 7.1years (range 1.6-12.3years). Approximately one-third of all patients was asymptomatic, headaches occurred in 27 patients, seizures in 14 cases, and lower-extremity weakness in 9 cases. In this series, the middle third of the falx was the most frequently involved site (55,78%), while the anterior third (26,31%) and the posterior type (17,89%) were less common. The transitional and meningothelial types occurred in 69 of patients and a high grade in only two patients. Compared with previous series in literature, there was no mortality and Gross Total Resection was obtained in 83 (87,5%) cases. Three of 95 patients experienced new or worsened neurological deficits after surgery while other complications were relatively in only 6 cases. This study presents our good results about removal of the tumor while preserving major cortical veins and the sinus using advanced microsurgical tools 15).


68 patients with meningiomas arising from the falx underwent craniotomies. There were 22 male and 46 female patients (1 : 2.1). Mean age was 55 years and ranged from 14 to 77 years. Locations of falcine meningioma were; the anterior third in 33 cases, middle in 20, and falcine meningioma of the posterior third in 15.

Mean tumor volume was 42 cc and ranged from 4 to 140 cc. In 58 of the 68 patients tumors were totally removed. Additional surgery for recurrence was performed in 6 patients over 15 years. Of these 6 patients, only two patients underwent gross total tumor resection at first operation; the other four underwent subtotal tumor resection. Based on pathologic reports, the largest tumor subtype was transitional. There were four patients with a high grade tumor-three atypical and one anaplastic meningioma. Of the 68 patients, 59 achieved a good outcome (no neurological deficit or recurrence), six had temporary complications, two suffered new permanent postoperative deficits, and the remaining one died due to severe brain swelling despite postoperative intensive care. Extent of surgical resection was found to be significantly related to tumor recurrence.

Falcine meningioma accounted for 8.5% of intracranial meningiomas and the transitional meningioma was the most common subtype of falcine meningioma. Gross total resection of tumor was the single most important predictor of an improved surgical outcome 16).


Cushing H, Eisenhardt L. Their Classification, Regional Behavior, Life History, and Surgical End Results: The chiasmal syndrome, in Meningiomas. Suprasellar Meningiomas. 1938:224–49.

2) , 13)

Pires de Aguiar PH, Aires R, Maldaun MV, Tahara A, de Souza Filho AM, Zicarelli CA, Ramina R. Is sagittal sinus resection in falcine meningiomas a factor of bad surgical outcome? Surg Neurol Int. 2010 Oct 25;1:64. doi: 10.4103/2152-7806.71983. PubMed PMID: 21125007; PubMed Central PMCID: PMC2980903.


Al-Mefty O, Becker DP, Lanman TH. Meningiomas. 1991. pp. 345–356.


Yasargil MG. Microneurosurgery. Vol 4. 1996. Meningioma; pp. 134–165.


Zuo FX, Wan JH, Li XJ, Qian HP, Meng XL. A proposed scheme for the classification and surgical planning of falcine meningioma treatment. J Clin Neurosci. 2012 Dec;19(12):1679-83. doi: 10.1016/j.jocn.2012.01.034. Epub 2012 Oct 6. PubMed PMID: 23047062.


Alvernia J, Sindou M. Preoperative neuroimaging findings as a predictor of surgical plane of cleavage : Prospective study of 100 consecutive cases of intracranial meningioma. J Neurosurg. 2004;100:422–430.


Douleh DG, Morone PJ, Forbes JA, Thompson RC. Intracranial Marginal Zone B-Cell Lymphoma Mimicking Meningioma. World Neurosurg. 2016 May 4. pii: S1878-8750(16)30235-2. doi: 10.1016/j.wneu.2016.04.106. [Epub ahead of print] PubMed PMID: 27155383.


Calle S, Louis D, Westmark R, Westmark K. Angioleiomyoma of the falx. J Radiol Case Rep. 2016 Apr 30;10(4):8-15. doi: 10.3941/jrcr.v10i4.2713. eCollection 2016 Apr. PubMed PMID: 27200167; PubMed Central PMCID: PMC4861627.


Chung SB, Kim CY, Park CK, Kim DG, Jung HW. Falx meningiomas: surgical results and lessons learned from 68 cases. J Korean Neurosurg Soc. 2007 Oct;42(4):276-80. doi: 10.3340/jkns.2007.42.4.276. Epub 2007 Oct 20. PubMed PMID: 19096556; PubMed Central PMCID: PMC2588203.


Spektor S, Margolin E, Eliashar R, Moscovici S. Purely endoscopic removal of a parasagittal/falx meningioma. Acta Neurochir (Wien). 2016 Mar;158(3):451-6. doi: 10.1007/s00701-015-2689-9. Epub 2016 Jan 8. PubMed PMID: 26746827.


Yamaguchi J, Watanabe T, Nagatani T. Endoscopic approach via the interhemispheric fissure: the role of an endoscope in a surgical case of multiple falcine lesions. Acta Neurochir (Wien). 2017 Jul;159(7):1243-1246. doi: 10.1007/s00701-017-3129-9. Epub 2017 Mar 11. PubMed PMID: 28283869.


Melamed S, Sahar A, Bellar AJ. The recurrence of intracranial meningiomas. Neurochirurgia. 1979;22:47–51.


Abou Al-Shaar H, Almefty KK, Abolfotoh M, Arvold ND, Devlin PM, Reardon DA, Loeffler JS, Al-Mefty O. Brachytherapy in the treatment of recurrent aggressive falcine meningiomas. J Neurooncol. 2015 Aug 8. [Epub ahead of print] PubMed PMID: 26253325.


Murrone D, De Paulis D, di Norcia V, Di Vitantonio H, Galzio RJ. Surgical management of falcine meningiomas: Experience of 95 patients. J Clin Neurosci. 2017 Mar;37:25-30. doi: 10.1016/j.jocn.2016.11.002. Epub 2016 Nov 22. Review. PubMed PMID: 27884604.


Chung SB, Kim CY, Park CK, Kim DG, Jung HW. Falx meningiomas: surgical results and lessons learned from 68 cases. J Korean Neurosurg Soc. 2007 Oct;42(4):276-80. doi: 10.3340/jkns.2007.42.4.276. Epub 2007 Oct 20. PubMed PMID: 19096556; PubMed Central PMCID: PMC2588203.

Update: Colloid cyst endoscopy

Neuroendoscopy, has been recognised as a viable and safe alternative to microsurgery for the treatment of third ventricle colloid cyst.

Controversy remains as to which is superior 1).

Powell et al. are credited with the first successful endoscopic aspiration of the colloid cysts. 2)

Less invasive endoscopic techniques have employed rigid endoscopes with single or dual working channels.

The increased range of viewing angles of the endoscope within the cylinder of access maintained by the tubular retractor facilitates resection of the cyst through a smaller opening 3).

Entry point and trajectory

An optimal entry point and trajectory for endoscopic colloid cyst (ECC) resection helps to protect important neurovascular structures. There is a large discrepancy in the entry point and trajectory in the neuroendoscopic literature.

The endoscopic approach to colloid cysts of the third ventricle is usually performed through the foramen of Monro. However, this route does not provide adequate visualization of the cyst attachment on the tela choroidea. The combined endoscopic transforaminal-transchoroidal approach (ETTA), providing exposure of the entire cyst and a better visualization of the tela choroidea, could increase the chances of achieving a complete cyst resection 4).

Using a more anterior approach, it is easier to reach the roof of the cyst and its possible adherences with the tela choroidea 5) 6).

Trajectory views from MRI or CT scans used for cranial image guidance in 39 patients who had undergone ECC resection between July 2004 and July 2010 were retrospectively evaluated. A target point of the colloid cyst was extended out to the scalp through a trajectory carefully observed in a 3D model to ensure that important anatomical structures were not violated. The relation of the entry point to the midline and coronal sutures was established. Entry point and trajectory were correlated with the ventricular size. Results The optimal entry point was situated 42.3 ± 11.7 mm away from the sagittal suture, ranging from 19.1 to 66.9 mm (median 41.4 mm) and 46.9 ± 5.7 mm anterior to the coronal suture, ranging from 36.4 to 60.5 mm (median 45.9 mm). The distance from the entry point to the target on the colloid cyst varied from 56.5 to 78.0 mm, with a mean value of 67.9 ± 4.8 mm (median 68.5 mm). Approximately 90% of the optimal entry points are located 40-60 mm in front of the coronal suture, whereas their perpendicular distance from the midline ranges from 19.1 to 66.9 mm. The location of the “ideal” entry points changes laterally from the midline as the ventricles change in size.

The results suggest that the optimal entry for ECC excision be located at 42.3 ± 11.7 mm perpendicular to the midline, and 46.9 ± 5.7 mm anterior to the coronal suture, but also that this point differs with the size of the ventricles. Intraoperative stereotactic navigation should be considered for all ECC procedures whenever it is available. The entry point should be estimated from the patient’s own preoperative imaging studies if intraoperative neuronavigation is not available. An estimated entry point of 4 cm perpendicular to the midline and 4.5 cm anterior to the coronal suture is an acceptable alternative that can be used in patients with ventriculomegaly 7).


Intraventricular extruded colloid fragments can occur after endoscopic resection, with the possible risk demonstrated as cyst hypointensity on preoperative T2-weighted images. The finding does not seem to result in any clinical morbidity, and radiographic involution is the rule. Migratory capacity, however, does exist and justifies a more frequent imaging surveillance schedule and consideration for removal 8).

A patient presented with headaches and was found to have a colloid cyst in the third ventricle and ventriculomegaly. The patient underwent endoscopic colloid cyst resection and third ventriculostomy without incidence. Prior to emergence, a blown right pupil was acutely noted, and bright red blood emanated from the ventricular drain that was routinely placed in the endoscopy tract at the conclusion of the procedure. CT angiography demonstrated active extravasation from the pre-pontine cistern into the third ventricle and subarachnoid space. Emergency DSA confirmed active extravasation from an avulsed thalamoperforator arising from the proximal right P1 posterior cerebral artery, which was immediately embolized without incident 9).

Case series


27 consecutive patients with symptomatic primary and recurrent colloid cysts. All cysts were removed via a neuroendoscope through a rostral transfrontal, transforaminal approach. The endoscope was supported by an additional cannula fixed in the stereotactic frame. Both tools were inserted into one lateral ventricle through two separate burr holes using stereotactic guidance.

The median operating time was 135 minutes. All cysts were removed completely, and no mortality or permanent complications related to surgery occurred. The mean time of observation was 43.5 months (range, 3-78 months), and no clinical or radiologic recurrences were observed. One patient with a history of an infected ventriculoperitoneal shunt did not improve after cyst removal, but improved after subsequent reimplantation of the shunt. In all other cases, symptoms resolved (67%) or decreased (30%). Cognitive functions improved or remained unchanged in all 10 elective cases examined neuropsychologically before and after surgery.

The technique describe for removal of colloid cysts are safe and effective, even for recurrent cases, and they provide 100% total resection, favorable cognitive outcomes, low risk of recurrence, and low risk of morbidity. The disadvantages of this method are a longer time for surgery and the need for more complex instrumentation compared with conventional endoscopic resection 10).


56 patients were reviewed. Surgeries involved an anterolateral neuroendoscopic technique. Patients were followed postoperatively for an average of 14.9 months. Patients were also interviewed regarding their preoperative symptoms, resolution of symptoms postoperatively, and their degree of satisfaction.

The median operative time was 82 minutes, and the median duration of hospital stay was 5 days. During surgery, the ventricles were explored for residual cyst wall or cyst content, and none were encountered. On immediate postoperative imaging, cyst recurrence was not noted for any patient, and only 1 patient has had evidence of recurrence on long-term follow-up. Various preoperative symptoms were described by patients; depending on the specific symptoms, 70%-100% resolution of symptoms was shown after surgery. Along with clinical follow-up, patients were interviewed regarding their perception of surgery and recovery. Of the patients contacted, 100% reported satisfaction with the surgery, and 91% noted satisfaction with their recovery. Reported complications included memory loss, infection, deep vein thrombosis, and postoperative hematoma. There were 2 perioperative deaths (3.5%) related to surgery.

Neuroendoscopic colloid cyst resection can reliably achieve complete lesion removal with short operative times. In addition, there is a high level of reported patient satisfaction. This is till 2014 the largest case series of neuroendoscopic colloid cyst resections from a single surgeon 11).

24 patients with colloid cysts of the third ventricle treated in our department between October 2001 and January 2013 using an endoscopic approach. Clinical presentation, preoperative radiological findings, endoscopic technique employed, and complications were assessed in all patients. The mean length of patient follow-up was 5.16 years. The most common symptom was headache (75%). The average size of the resected colloid cysts was 16.25 mm, the maximum diameter measured in cranial magnetic resonance imaging. Resection was transforaminal in 16 cases (66.7%), transchoroidal in 7 (29.17%), and transseptal in 1; macroscopically complete resection was achieved in 23 of 24 procedures (95.8%). Complications included three intraventricular hemorrhages, four memory deficits (two of them transient), one case of temporary potomania, two soft tissue infections, and one meningitis. There were no statistically significant differences between the route of resection and number of complications. The Glasgow Outcome Scale at 1 year after surgery was 5 in 82.6% of the patients. A transventricular endoscopic approach allows macroscopically complete resection of third ventricle colloid cysts in most cases. The option of opening the choroidal fissure (transventricular-transchoroidal approach) during the procedure can address third ventricle colloid cysts that do not emerge sufficiently through the foramen of Monro without increasing procedure-related morbidity 12).

29 patients who underwent surgery by a variation of the standard worldwide implemented endoscopic technique. Using a more anterior approach, it is easier to reach the roof of the cyst, its possible adherences with the tela choroidea, plexus, and the internal cerebral veins. The described approach has shown to be safe, quick, and very effective with a total cyst removal rate of 86.2% 13).

24 patients.Preoperative computed tomography (CT) scans revealed hydrocephalus in all the patients. Postoperative magnetic resonance imaging (MRI) was done in all cases.

Age ranged from 16 to 57 years. There were 16 male and 8 female patients. The diameter of the cyst varied from 14 to 24 mm. Operating time ranged from 90 to 156 minutes. Total resection was achieved in 21 patients. All patients with subtotal excision underwent coagulation of residual cyst wall. The follow-up period ranged from 6 to 78 months (mean, 37 months). None of the patients developed any symptoms at 26, 31, and 39 months of follow-up. Preoperative symptoms disappeared in all the patients except for memory disorders and seizures in one patient each. No residual cyst was observed on the postoperative MRIs in 21 patients. Hospital stay was 4 to 10 days (median, 6 days). No endoscopic operation was converted into an open resection.

Endoscopic excision of a colloid cyst is an effective and safe alternate method. Although the follow-up time was short, residual cyst wall remained asymptomatic without any evidence of growth after subtotal excision and coagulation of wall 14).


Of 22 patients, near-total resection was obtained in 95%. In 3 cases, a very small, radiographically occult residual was left. Complete cyst wall resection was therefore obtained in 18 (82%). There were no cases of recurrence at follow-up in any patient. No patients required craniotomy or underwent re-resection. Fifteen of 16 (94%) patients with long-term clinical follow-up remained stable or improved.

High rates of complete colloid cyst resection, with low morbidity, are possible with an anterolateral endoscopic approach with dual-instrument technique. These results support the findings of other endoscopists that show how technical modifications to traditional endoscopic approaches can produce favorable results 15).

Sixteen patients (8 female) underwent attempted endoscopic removal of a colloid cyst in the absence of ventriculomegaly. Surgery was technically successful in 15 patients. The cyst was removed completely in 13 of patients. Short-term memory loss was initially present in 3 patients and completely resolved in all but 1 patient who had presented with short-term memory loss. Temporary complications occurred in 2 patients.

Normal-size ventricles are not a contraindication to endoscopic removal of third ventricular colloid cysts. Complication rates are at least comparable to those of patients with ventriculomegaly or to those undergoing open microsurgical resection 16).

Sixty-five consecutive patients and 67 procedures for endoscopic resection of colloid cysts from 1995 to 2011 were reviewed. Degree of resection was based on intraoperative assessment and postoperative magnetic resonance imaging (MRI). Recurrence rates were compared between patients with complete resection those with coagulated cyst remnants.

Data analysis was performed of 56 patients and 58 procedures, with no follow-up in 9 patients. All patients had MRI-defined complete resection. On intraoperative assessment, 9 procedures had coagulated remnants and 45 procedures had complete resection (4 data unknown). The overall recurrence rate was 6.89% (4/58), 33.3% (3/9) with cyst remnants, and 2.2% (1/45) with total resection (P = .0124). Maximum follow-up was 144 months (mean, 40.4 months). Mean follow-up was 66.0 months for cyst remnant cases, and 33.5 months for totally resected cases. There was no mortality or permanent morbidity. Transient morbidity included memory deficit (n = 2), aseptic meningitis (n = 1), and local wound infection (n = 1).

Endoscopic colloid cyst resection results in a low overall recurrence rate. Immediate postoperative MRI was insufficient for assessing degree of resection and was a poor predictor of recurrence. Ablation of cyst remnants rather than total removal is associated with a significantly higher rate of recurrence. The primary goal of endoscopic surgery should, therefore, be removal of all cyst contents and wall remnants 17).


18 patients between 1996 and 2006. All patients were operated through a single burr hole at Kocher’s point using a rigid endoscope with a single working channel. The anatomical variations of the cyst and the foramen of Monro dictated the use of the transforaminal approach, the transseptal interforniceal approach or both.

There were no mortalities or significant morbidities. The operative time ranged between 90 to 240 minutes (with a mean of 133 minutes). Five patients (27.7%) developed remediable postoperative chemical meningitis successfully controlled with steroids. Postoperative transient memory disturbance was observed in 3 patients (16.7%). One patient had a postoperative CSF leak that stopped spontaneously. Aspiration of the cyst’s contents showed variable degrees of resistance to aspiration. The period of follow-up ranged between 5 months to 8 years and 3 months (mean: 4 years and 2 months). None of our patients showed radiological evidence of cyst recurrence during the follow-up period.

Through a single right pre-coronal burr hole at Kocher’s point, several endoscopic manoeuvres can be done. These include aspiration of the contents or its piecemeal removal, combined balloon squeeze and aspiration, foraminoplasty, pellucidotomy, coagulation of cyst capsule and ETV. The choice of the appropriate approach is largely dependent on the location of the cyst and the shape of the foramen of Monro. Coronal MRI may aid in preoperative evaluation of the tucked up retroforaminal growth of the cyst. We had no recurrence in our series with a follow-up reaching more than 8 years. This could be attributed to both the marsupialization and coagulation done for the remaining cyst capsule 18).


Twelve patients underwent 14 endoscopic operations in attempts to treat their colloid cysts. All patients were symptomatic, with headache being the most common complaint (8 of 12 patients). Six patients in this series exhibited enlarged ventricles associated with their colloid cysts. Using rigid endoscopes of < or =3.5-mm diameter, the cysts were inspected and fenestrated. Both hard and soft cyst contents were evacuated, and then the walls of the cysts were coagulated inside and outside. External ventriculostomy tubes were usually placed. Technical obstacles to successful completion of endoscopic colloid cyst surgery are discussed.

For 11 of the 12 patients, the colloid cysts could be treated via an endoscopic approach. The mean follow-up time was 173 weeks, and the median follow-up time was 125 weeks. For the 12th patient, bilateral scarring of the foramina of Monro precluded direct surgery; therefore, a septostomy was performed and a ventriculoperitoneal shunt was placed 19).


Fifteen patients with a radiological diagnosis of colloid cysts were given the option of undergoing either endoscopic surgery or craniotomy. The average tumor size was 1.43 cm. Fourteen patients underwent planned endoscopic resections, and a craniotomy was performed initially in one patient.

Entire tumor resection was achieved with the endoscope in 12 patients (86%). A craniotomy was required for two colloid cysts that could not be resected endoscopically. In total, complete radiographic resections were achieved in 14 patients (93%). There were no permanent complications, although postoperative deficits included short-term memory loss and hemiparesis, each in one patient.

Rigid endoscopy affords good optical resolution, high magnification, and excellent illumination. Total or near total resection of colloid cysts should be the goal for all patients and can be achieved using the rigid endoscope, with little morbidity, shortened operative time, reduced length of stay, and resolution of symptoms. Although long-term follow-up is needed, we think that endoscopy should be considered as a primary treatment for most patients 20).


The presenting symptoms of our patients (10 men and 5 women) were intermittent headache (10 patients), nausea (3 patients), short-term memory loss (4 patients), coma (2 patients), gait disturbance (3 patients), blurred vision (2 patients), and mental status changes (3 patients). The sizes of the cysts ranged from 4 to 50 mm (median, 22.93 mm). Depending on the radiological appearance, the procedure was performed via a right (10 patients) or left (5 patients) precoronal burr hole. A rigid neuroendoscope was used. Initial stereotactic placement of the neuroendoscope was used in two patients who had moderate hydrocephalus. In the other patients, hand-guided endoscopy was performed using an articulated arm. The cysts were perforated with a needle. The opening was enlarged with microscissors. The cyst material was aspirated, and the remaining capsule was coagulated.

The average follow-up was 15.26 months (range, 1-28 mo). Total aspiration of the cysts was achieved in 12 patients, as revealed by normal postoperative magnetic resonance imaging. Control magnetic resonance imaging revealed residual cysts in three patients. One patient presented with an asymptomatic recurrence at 1 year. Resolution of the symptoms was obtained in all patients except for two of the four patients with preoperative memory deficit (improvement without complete recovery). There was no mortality or morbidity.

These results show that endoscopy is a safe and promising percutaneous technique for the treatment of colloid cysts of the third ventricle. Longer follow-up is, however, still required 21).

The surgical technique for the endoscopic evacuation of colloid cysts of the third ventricle in 13 patients is described. The authors conclude that endoscopic resection of these lesions is a useful addition to the current surgical repertoire and a viable alternative to stereotactic aspiration or open craniotomy 22).


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Intraoperative stereovision

Displaying anatomical and physiological information derived from preoperative medical images in the operating room is critical in image guided neurosurgery.

Combination of various intraoperative imaging modalities potentially can reduce error of brain shift estimation during neurosurgical operations.

Preoperative magnetic resonance imaging (pMR) are typically coregistered to provide intraoperative navigation, the accuracy of which can be significantly compromised by brain deformation.

Stereovision is an important intraoperative imaging technique that captures the exposed parenchymal surface noninvasively during open cranial surgery.

Paul et al. presented in 2005 a new approach referred to as augmented virtuality (AV) for displaying intraoperative views of the operative field over three-dimensional (3-D) multimodal preoperative images onto an external screen during surgery. A calibrated stereovision system was set up between the surgical microscope and the binocular tubes. Three-dimensional surface meshes of the operative field were then generated using stereopsis. These reconstructed 3-D surface meshes were directly displayed without any additional geometrical transform over preoperative images of the patient in the physical space. Performance evaluation was achieved using a physical skull phantom. Accuracy of the reconstruction method itself was shown to be within 1 mm (median: 0.76 mm +/- 0.27), whereas accuracy of the overall approach was shown to be within 3 mm (median: 2.29 mm +/- 0.59), including the image-to-physical space registration error.

Paul et al. report the results of six surgical cases where AV was used in conjunction with augmented reality. AV not only enabled vision beyond the cortical surface but also gave an overview of the surgical area. This approach facilitated understanding of the spatial relationship between the operative field and the preoperative multimodal 3-D images of the patient 1).

A surface registration method is presented by Fan et al. to align intraoperative stereovision (iSV) with preoperative magnetic resonance (pMR) images, which utilizes both geometry and texture information to extract tissue displacements as part of the overall process of compensating for intraoperative brain deformation in order to maintain accurate neuronavigational image guidance during surgery.

A sum-of-squared-difference rigid image registration was first executed to detect lateral shift of the cortical surface and was followed by a mutual-information-based block matching method to detect local nonrigid deformation caused by distention or collapse of the cortical surface. Ten (N = 10) surgical cases were evaluated in which an independent point measurement of a dominant cortical surface feature location was recorded with a tracked stylus in each case and compared to its surface-registered counterpart. The full three-dimensional (3D) displacement field was also extracted to drive a biomechanical brain deformation model, the results of which were reconciled with the reconstructed iSV surface as another form of evaluation.

Differences between the tracked stylus coordinates of cortical surface features and their surface-registered locations were 1.94 ± 0.59 mm on average across the ten cases. When the complete displacement map derived from surface registration was utilized, the resulting images generated from mechanical model updates were consistent in terms of both geometry (1-2 mm of model misfit) and texture, and were generated with less than 10 min of computational time. Analysis of the surface-registered 3D displacements indicate that the magnitude of motion ranged from 4.03 to 9.79 mm in the ten patient cases, and the amount of lateral shift was not related statistically to the direction of gravity (p = 0.73 ≫ 0.05) or the craniotomy size (p = 0.48 ≫ 0.05) at the beginning of surgery.

The iSV-pMR surface registration method utilizes texture and geometry information to extract both global lateral shift and local nonrigid movement of the cortical surface in 3D. The results suggest small differences exist in surface-registered locations when compared to positions measured independently with a coregistered stylus and when the full iSV surface was aligned with model-updated MR. The effectiveness and efficiency of the registration method is also minimally disruptive to surgical workflow 2).

Estimating cortical surface shift efficiently and accurately is critical to compensate for brain deformation in the operating room (OR). In a study, Ji et al. present an automatic and robust registration technique based on optical flow (OF) motion tracking to compensate for cortical surface displacement throughout surgery. Stereo images of the cortical surface were acquired at multiple time points after dural opening to reconstruct three-dimensional (3D) texture intensity-encoded cortical surfaces. A local coordinate system was established with its z-axis parallel to the average surface normal direction of the reconstructed cortical surface immediately after dural opening in order to produce two-dimensional (2D) projection images. A dense displacement field between the two projection images was determined directly from OF motion tracking without the need for feature identification or tracking. The starting and end points of the displacement vectors on the two cortical surfaces were then obtained following spatial mapping inversion to produce the full 3D displacement of the exposed cortical surface. We evaluated the technique with images obtained from digital phantoms and 18 surgical cases – 10 of which involved independent measurements of feature locations acquired with a tracked stylus for accuracy comparisons, and 8 others of which 4 involved stereo image acquisitions at three or more time points during surgery to illustrate utility throughout a procedure. Results from the digital phantom images were very accurate (0.05 pixels). In the 10 surgical cases with independently digitized point locations, the average agreement between feature coordinates derived from the cortical surface reconstructions was 1.7-2.1mm relative to those determined with the tracked stylus probe. The agreement in feature displacement tracking was also comparable to tracked probe data (difference in displacement magnitude was <1mm on average). The average magnitude of cortical surface displacement was 7.9 ± 5.7 mm (range 0.3-24.4 mm) in all patient cases with the displacement components along gravity being 5.2 ± 6.0 mm relative to the lateral movement of 2.4 ± 1.6 mm. Thus, our technique appears to be sufficiently accurate and computationally efficiency (typically ∼15 s), for applications in the OR 3).

One of the major challenges impeding advancement in image-guided surgical (IGS) systems is the soft-tissue deformation during surgical procedures. These deformations reduce the utility of the patient’s preoperative images and may produce inaccuracies in the application of preoperative surgical plans. Solutions to compensate for the tissue deformations include the acquisition of intraoperative tomographic images of the whole organ for direct displacement measurement and techniques that combines intraoperative organ surface measurements with computational biomechanical models to predict subsurface displacements. The later solution has the advantage of being less expensive and amenable to surgical workflow. Several modalities such as textured laser scanners, conoscopic holography, and stereo-pair cameras have been proposed for the intraoperative 3D estimation of organ surfaces to drive patient-specific biomechanical models for the intraoperative update of preoperative images. Though each modality has its respective advantages and disadvantages, stereo-pair camera approaches used within a standard operating microscope is the focus of this article. A new method that permits the automatic and near real-time estimation of 3D surfaces (at 1 Hz) under varying magnifications of the operating microscope is proposed. This method has been evaluated on a CAD phantom object and on full-length neurosurgery video sequences (∼1 h) acquired intraoperatively by the proposed stereovision system. To the best of our knowledge, this type of validation study on full-length brain tumor surgery videos has not been done before. The method for estimating the unknown magnification factor of the operating microscope achieves accuracy within 0.02 of the theoretical value on a CAD phantom and within 0.06 on 4 clinical videos of the entire brain tumor surgery. When compared to a laser range scanner, the proposed method for reconstructing 3D surfaces intraoperatively achieves root mean square errors (surface-to-surface distance) in the 0.28-0.81 mm range on the phantom object and in the 0.54-1.35 mm range on 4 clinical cases. The digitization accuracy of the presented stereovision methods indicate that the operating microscope can be used to deliver the persistent intraoperative input required by computational biomechanical models to update the patient’s preoperative images and facilitate active surgical guidance 4)

Mohammadi et al. presented a new combination of surface imaging and Doppler US images proposed to calculate the displacements of cortical surface and deformation of internal vessels in order to estimate the targeted brain shift using a Finite Element Model (FEM). Registration error in each step and the overall performance of the method are evaluated.

The preoperative steps include constructing a FEM from MR images and extracting vascular tree from MR Angiography (MRA). As the first intraoperative step, after the craniotomy and with the dura opened, a designed checkerboard pattern is projected on the cortex surface and projected landmarks are scanned and captured by a stereo camera (Int J Imaging Syst Technol 23(4):294-303, 2013. doi: 10.1002/ima.22064 ). This 3D point cloud should be registered to boundary nodes of FEM in the region of interest. For this purpose, we developed a new non-rigid registration method, called finite element drift that is more compatible with the underlying nature of deformed object. The presented algorithm outperforms other methods such as coherent point drift when the deformation is local or non-coherent. After registration, the acquired displacement vectors are used as boundary conditions for FE model. As the second step, by tracking a 2D Doppler ultrasound probe swept on the parenchyma, a 3D image of deformed vascular tree is constructed. Elastic registration of this vascular point cloud to the corresponding preoperative data results the second series of displacement vector applicable to closest internal nodes of FEM. After running FE analysis, the displacement of all nodes is calculated. The brain shift is then estimated as displacement of nodes in boundary of a deep target, e.g., a tumor. We used intraoperative MR (iMR) images as the references for measuring the performance of the brain shift estimator. In the present study, two set of tests were performed using: (a) a deformable brain phantom with surface data and (b) an alive brain of an approximately big dog with surface data and US Doppler images. In our designed phantom, small tubes connected to an inflatable balloon were considered as displaceable targets and in the animal model, the target was modeled by a cyst which was created by an injection.

In the phantom study, the registration error for the surface points before FE analysis and for the target points after running FE model were <0.76 and 1.4 mm, respectively. In a real condition of operating room for animal model, the registration error was about 1 mm for the surface, 1.9 mm for the vascular tree and 1.55 mm for the target points.

The proposed projected surface imaging in conjunction with the Doppler US data combined in a powerful biomechanical model can result an acceptable performance in calculation of deformation during surgical navigation. However, the projected landmark method is sensitive to ambient light and surface conditions and the Doppler ultrasound suffers from noise and 3D image construction problems, the combination of these two methods applied on a FEM has an eligible performance 5).

In a study Ji et al. evaluated the feasibility of using intraoperative stereovision (iSV) for accurate, efficient, and robust patient registration in an open spinal fusion surgery. Geometrical surfaces of exposed vertebrae were first reconstructed from iSV. A classical multistart registration was then executed between point clouds generated from iSV and preoperative computed tomography images of the spine. With two pairs of feature points manually identified to facilitate the registration, an average registration accuracy of 1.43 mm in terms of surface-to-surface distance error was achieved in eight patient cases using a single iSV image pair sampling 2-3 vertebral segments. The iSV registration error was consistently smaller than the conventional landmark approach for every case (average of 2.02 mm with the same error metric). The large capture ranges (average of 23.8 mm in translation and 46.0° in rotation) found in the iSV patient registration suggest the technique may offer sufficient robustness for practical application in the operating room. Although some manual effort was still necessary, the manually-derived inputs for iSV registration only needed to be approximate as opposed to be precise and accurate for the manual efforts required in landmark registration. The total computational cost of the iSV registration was 1.5 min on average, significantly less than the typical ∼30 min required for the landmark approach. These findings support the clinical feasibility of iSV to offer accurate, efficient, and robust patient registration in open spinal surgery, and therefore, its potential to further increase the adoption of image guidance in this surgical specialty 6).

In a study, Fan et al. generated updated MR images (uMR) in the operating room (OR) to compensate for brain shift due to dural opening, and evaluated the accuracy and computational efficiency of the process.

In 20 open cranial neurosurgical cases, a pair of intraoperative stereovision (iSV) images was acquired after dural opening to reconstruct a 3D profile of the exposed cortical surface. The iSV surface was registered with pMR to detect cortical displacements that were assimilated by a biomechanical model to estimate whole-brain nonrigid deformation and produce uMR in the OR. The uMR views were displayed on a commercial navigation system and compared side by side with the corresponding coregistered pMR. A tracked stylus was used to acquire coordinate locations of features on the cortical surface that served as independent positions for calculating target registration errors (TREs) for the coregistered uMR and pMR image volumes. RESULTS The uMR views were visually more accurate and well aligned with the iSV surface in terms of both geometry and texture compared with pMR where misalignment was evident. The average misfit between model estimates and measured displacements was 1.80 ± 0.35 mm, compared with the average initial misfit of 7.10 ± 2.78 mm between iSV and pMR, and the average TRE was 1.60 ± 0.43 mm across the 20 patients in the uMR image volume, compared with 7.31 ± 2.82 mm on average in the pMR cases. The iSV also proved to be accurate with an average error of 1.20 ± 0.37 mm. The overall computational time required to generate the uMR views was 7-8 minutes.

This study compensated for brain deformation caused by intraoperative dural opening using computational model-based assimilation of iSV cortical surface displacements. The uMR proved to be more accurate in terms of model-data misfit and TRE in the 20 patient cases evaluated relative to pMR. The computational time was acceptable (7-8 minutes) and the process caused minimal interruption of surgical workflow 7).


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Ji S, Fan X, Paulsen KD, Roberts DW, Mirza SK, Lollis SS. Patient Registration Using Intraoperative Stereovision in Image-guided Open Spinal Surgery. IEEE Trans Biomed Eng. 2015 Sep;62(9):2177-86. doi: 10.1109/TBME.2015.2415731. Epub 2015 Mar 26. PubMed PMID: 25826802; PubMed Central PMCID: PMC4545737.

Fan X, Roberts DW, Schaewe TJ, Ji S, Holton LH, Simon DA, Paulsen KD. Intraoperative image updating for brain shift following dural opening. J Neurosurg. 2017 Jun;126(6):1924-1933. doi: 10.3171/2016.6.JNS152953. Epub 2016 Sep 9. PubMed PMID: 27611206.