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Victor E. Staartjes, Anita M. Klukowska, Elena L. Sorba and Marc L. Schröder

OBJECTIVE

Randomized controlled trials (RCTs) form the basis of today’s evidence-based approach to medicine, and play a critical role in guidelines and the drug and device approval process. Conflicts of interest (COIs) are commonplace in medical research, but little is known about their influence. The authors aimed to evaluate the extent and influence of COIs in recent RCTs published in core neurosurgical journals using a cross-sectional analysis.

METHODS

Through review of 6 general neurosurgical journals, all interventional RCTs published from January 2009 to January 2019 were identified. Because it is difficult to objectively assess study outcome, the authors opted for a strict rating approach based on the statistical significance of unambiguously reported primary endpoints, and the reported statistical protocol.

RESULTS

A total of 129 RCTs met the inclusion criteria. During the study period, the Journal of Neurosurgery published the largest number of RCTs (n = 40, 31%). Any potential COI was disclosed by 57%, and a mean of 12% of authors had a personal COI. Nonfinancial industry involvement was reported in 10%, while 31% and 20% received external support and sponsoring, respectively. Study registration was reported by 56%, while 51% of studies were blinded. Registration showed an increasing trend from 17% to 76% (p < 0.001). The median randomized sample size was 92 (interquartile range 50–153), and 8% were designed to investigate noninferiority or equality. Sixty-three RCTs (49%) unambiguously reported a primary endpoint, of which 13% were composite primary endpoints. In 43%, study outcome was positive, which was associated with a noninferiority design (31% vs 3%, p = 0.007) and a composite primary endpoint (46% vs 9%, p = 0.002). Potential COIs were not significantly associated with study positivity (69% vs 59%, p = 0.433). In the multivariate analysis, only a composite primary endpoint remained predictive of a positive study outcome (odds ratio 6.34, 95% confidence interval 1.51–33.61, p = 0.017).

CONCLUSIONS

This analysis provides an overview of COIs and their potential influence on recent trials published in core neurosurgical journals. Reporting of primary endpoints, study registration, and uniform disclosure of COIs are crucial to ensure the quality of future neurosurgical randomized trials. COIs do not appear to significantly influence the outcome of randomized neurosurgical trials.

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Andrea Franzini, Giuseppe Messina, Vincenzo Levi, Antonio D’Ammando, Roberto Cordella, Shayan Moosa, Francesco Prada and Angelo Franzini

OBJECTIVE

Central poststroke neuropathic pain is a debilitating syndrome that is often resistant to medical therapies. Surgical measures include motor cortex stimulation and deep brain stimulation (DBS), which have been used to relieve pain. The aim of this study was to retrospectively assess the safety and long-term efficacy of DBS of the posterior limb of the internal capsule for relieving central poststroke neuropathic pain and associated spasticity affecting the lower limb.

METHODS

Clinical and surgical data were retrospectively collected and analyzed in all patients who had undergone DBS of the posterior limb of the internal capsule to address central poststroke neuropathic pain refractory to conservative measures. In addition, long-term pain intensity and level of satisfaction gained from stimulation were assessed. Pain was evaluated using the visual analog scale (VAS). Information on gait improvement was obtained from medical records, neurological examination, and interview.

RESULTS

Four patients have undergone the procedure since 2001. No mortality or morbidity related to the surgery was recorded. In three patients, stimulation of the posterior limb of the internal capsule resulted in long-term pain relief; in a fourth patient, the procedure failed to produce any long-lasting positive effect. Two patients obtained a reduction in spasticity and improved motor capability. Before surgery, the mean VAS score was 9 (range 8–10). In the immediate postoperative period and within 1 week after the DBS system had been turned on, the mean VAS score was significantly lower at a mean of 3 (range 0–6). After a mean follow-up of 5.88 years, the mean VAS score was still reduced at 5.5 (range 3–8). The mean percentage of long-term pain reduction was 38.13%.

CONCLUSIONS

This series suggests that stimulation of the posterior limb of the internal capsule is safe and effective in treating patients with chronic neuropathic pain affecting the lower limb. The procedure may be a more targeted treatment method than motor cortex stimulation or other neuromodulation techniques in the subset of patients whose pain and spasticity are referred to the lower limbs.

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John D. Nerva, Peter S. Amenta and Aaron S. Dumont

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Pierluigi Longatti, Alessandro Fiorindi, Paolo Peruzzo, Luca Basaldella and Francesca Maria Susin

OBJECTIVE

In the last 20 years, researchers have debated cerebrospinal fluid (CSF) dynamics theories, commonly based on the classic bulk flow perspective. New hypotheses do not consider a possible hydraulic impact of the ventricular morphology. The present study investigates, by means of a mathematical model, the eventual role played by the geometric shape of the “third ventricle–aqueduct–fourth ventricle” complex in CSF circulation under the assumption that the complex behaves like a diffuser/nozzle (DN) pump.

METHODS

DN pumps are quite recent devices introduced as valveless micropumps in various industrial applications given their property of driving net flow when subjected to rhythmic pulsations. A novel peculiar DN pump configuration was adopted in this study to mimic the ventricular complex, with two reservoirs (the ventricles) and one tube provided with a conical reach (the aqueduct–proximal fourth ventricle). The flow was modeled according to the classic equations of laminar flow, and the external rhythmic pulsations forcing the system were reproduced as a pulsatile pressure gradient between the chambers. Several physiological scenarios were implemented with the integration of data acquired by MRI in 10 patients with no known pathology of CSF dynamics, and a quantitative analysis of the effect of geometric and hydraulic parameters (diverging angle, sizes, frequency of pulsations) on the CSF net flow was performed.

RESULTS

The results showed a craniocaudal net flow in all the given values, consistent with the findings of cine MRI studies. Moreover, the net flow estimated for the analyzed cohort of patients ranged from 0.221 to 0.505 ml/min, remarkably close to the values found on phase contrast cine MRI in healthy subjects. Sensitivity analysis underlines the pivotal role of the DN configuration, as well as of the frequency of forcing pressure, which promotes a relevant net flow considering both the heart and respiration rate.

CONCLUSIONS

This work suggests that the geometry of the third ventricle–aqueduct–fourth ventricle complex, which resembles a diverter, appears to be functional in the generation of a net craniocaudal flow and potentially has an impact on CSF dynamics. These conclusions can be drawn by observing the analogies between the shape of the ventricles and the geometry of DN pumps and by recognizing the basis of the mathematical model of the simplified third ventricle–aqueduct–fourth ventricle complex proposed.

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Gautam U. Mehta and Gregory P. Lekovic

Although most widely known as the birthplace of neuro-otology, the House Clinic in Los Angeles has been the site of several major contributions to the field of neurosurgery. From the beginning of the formation of the Otologic Medical Group in 1958 (later renamed the House Ear Clinic), these contributions have been largely due to the innovative and collaborative work of neurosurgeon William E. Hitselberger, MD, and neuro-otologist William F. House, MD, DDS. Together they were responsible for the development and widespread adoption of the team approach to skull-base surgery. Specific neurosurgical advances accomplished at the House Clinic have included the first application of the operative microscope to neurosurgery, the application of middle fossa and translabyrinthine approaches for vestibular schwannoma, and the development of combined petrosal, retrolabyrinthine, and other alternative petrosal approaches and of hearing preservation surgery for vestibular schwannoma. The auditory brainstem implant, invented at the House Clinic in 1979, was the first ever successful application of central nervous system neuromodulation for restoration of function. Technological innovations at the House Clinic have also advanced neurosurgery. These include the first video transmission of microsurgery, the first suction irrigator, the first debulking instrument for tumors, and the House-Urban retractor for middle fossa surgery.

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Nagore I. Marín-Ramos, Marta Pérez-Hernández, Anson Tam, Stephen D. Swenson, Hee-Yeon Cho, Thu Zan Thein, Florence M. Hofman and Thomas C. Chen

OBJECTIVE

Glioblastoma (GBM) is the most aggressive type of brain tumor with a high rate of tumor recurrence, and it often develops resistance over time to current standard of care chemotherapy. Its highly invasive nature plays an essential role in tumor progression and recurrence. Glioma stem cells (GSCs) are a subpopulation of glioma cells highly resistant to treatments and are considered responsible for tumor recurrence.

METHODS

Patient-derived populations of GSCs were analyzed by western blot, MTT, and cytoplasmic calcium labeling to determine the cytotoxicity of NEO100. High-performance liquid chromatography was used to evaluate the levels of NEO100 in the cell culture supernatants. The effects of the compound on GSC motility were studied using Boyden chamber migration, 3D spheroid migration and invasion assays, and an mRNA expression PCR array. A RhoA activation assay, western blot, and immunofluorescence techniques were employed to confirm the signaling pathways involved. Intracranial implantation of GSCs in athymic mice was used to evaluate the effects of NEO100 in vivo on tumor progression and overall survival.

RESULTS

Here, the authors show how NEO100, a highly purified guanosine monophosphate–quality form of perillyl alcohol, is cytotoxic for different subtypes of GSCs, regardless of the mechanisms of DNA repair present. At doses similar to the IC50 (half maximal inhibitory concentration) values, NEO100 induces ER stress and activates apoptotic pathways in all GSC populations tested. At subcytotoxic doses in the micromolar range, NEO100 blocks migration and invasion of GSCs. These results correlate with a decrease in calpain-1 expression and an increase in RhoA activation, leading to enhanced contractility of the GSCs. In addition, NEO100 blocks the activation of the kinases Src, p42/44 MAPK, Akt, and Stat3, all related to cell proliferation and migration. Intranasal administration of NEO100 in mice with GSC-derived intracranial tumors led to a decrease in tumor progression and a 32% increase in overall survival. Immunostaining studies showed that NEO100 induces apoptosis and reduces GSC invasion in vivo.

CONCLUSIONS

NEO100 could have significant value targeting GSCs and could be used for GBM therapy as either monotherapy or a coadjuvant therapy during temozolomide rest cycles.

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Cameron A. Elliott, Hayden Danyluk, Keith E. Aronyk, Karolyn Au, B. Matt Wheatley, Donald W. Gross, Tejas Sankar and Christian Beaulieu

OBJECTIVE

Diffusion tensor imaging (DTI) tractography is commonly used in neurosurgical practice but is largely limited to the preoperative setting. This is due primarily to image degradation caused by susceptibility artifact when conventional single-shot (SS) echo-planar imaging (EPI) DTI (SS-DTI) is acquired for open cranial, surgical position intraoperative DTI (iDTI). Readout-segmented (RS) EPI DTI (RS-DTI) has been reported to reduce such artifact but has not yet been evaluated in the intraoperative MRI (iMRI) environment. The authors evaluated the performance of RS versus SS EPI for DTI of the human brain in the iMRI setting.

METHODS

Pre- and intraoperative 3-T 3D T1-weighted and 2D multislice RS-iDTI (called RESOLVE [readout segmentation of long variable echo-trains] on the Siemens platform) and SS-iDTI images were acquired in 22 adult patients undergoing intraaxial iMRI resections for suspected low-grade glioma (14; 64%), high-grade glioma (7; 32%), or focal cortical dysplasia. Regional susceptibility artifact, anatomical deviation relative to T1-weighted imaging, and tractographic output for surgically relevant tracts were compared between iDTI sequences as well as the intraoperative tract shifts from preoperative DTI.

RESULTS

RS-iDTI resulted in qualitatively less regional susceptibility artifact (resection cavity, orbitofrontal and anterior temporal cortices) and mean anatomical deviation in regions most prone to susceptibility artifact (RS-iDTI 2.7 ± 0.2 vs SS-iDTI 7.5 ± 0.4 mm) compared to SS-iDTI. Although tract reconstruction success did not significantly differ by DTI method, susceptibility artifact–related tractography failure (of at least 1 surgically relevant tract) occurred for SS-iDTI in 8/22 (36%) patients, and in 5 of these 8 patients RS-iDTI permitted successful reconstruction. Among cases with successful tractography for both sequences, maximal intersequence differences were substantial (mean 9.5 ± 5.7 mm, range −27.1 to 18.7 mm).

CONCLUSIONS

RS EPI enables higher quality and more accurate DTI for surgically relevant tractography of major white matter tracts in intraoperative, open cranium neurosurgical applications at 3 T.

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Giorgio Lofrese, Francesco Cultrera, Jacopo Visani, Nicola Nicassio, Walid Ibn Essayed, Roberto Donati, Michele Alessandro Cavallo and Pasquale De Bonis

Vertebral artery injury (VAI) is a potential catastrophic complication of Goel and Harms C1–C2 posterior arthrodesis. Meticulous study of preoperative spinal CT angiography together with neuronavigation plays a fundamental role in avoiding VAI. Doppler ultrasonography may be an additional intraoperative tool, providing real-time identification of the vertebral artery (VA) and thus helping its preservation.

Thirty-three consecutive patients with unstable odontoid fractures underwent Goel and Harms C1–C2 posterior arthrodesis. Surgery was performed with the aid of lateral fluoroscopic control in 16 cases (control group) that was supplemented by Doppler ultrasonography in 17 cases (Doppler group). Two patients in each group had a C1 ponticulus posticus. In the Doppler group, Doppler probing was performed during lateral subperiosteal muscle dissection, stepwise drilling, and tapping. Blood flow velocity in the V3 segment of the VA was recorded before and after posterior arthrodesis. All patients had a 12-month outpatient follow-up, and outcome was assessed using the Smiley-Webster Pain Scale. Neither VAI nor postoperative neurological impairments were observed in the Doppler group. In the control group, VAIs occurred in the 2 patients with C1 ponticulus posticus. In the Doppler group, 1 patient needed intra- and postoperative blood transfusions, and no difference in terms of Doppler signal or VA blood flow velocity was detected before and after C1–C2 posterior arthrodesis. In the control group, 3 patients needed intra- and postoperative blood transfusions.

Useful in supporting fluoroscopy-assisted procedures, intraoperative Doppler may play a significant role even during surgeries in which neuronavigation is used, reducing the chance of a mismatch between the view on the neuronavigation screen and the actual course of the VA in the operative field and supplying the additional data of blood flow velocity.

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Eung Koo Yeon, Young Dae Cho, Dong Hyun Yoo, Su Hwan Lee, Hyun-Seung Kang, Jeong Eun Kim, Won-Sang Cho, Hyun Ho Choi and Moon Hee Han

OBJECTIVE

The authors conducted a study to ascertain the long-term durability of coiled aneurysms completely occluded at 36 months’ follow-up given the potential for delayed recanalization.

METHODS

In this retrospective review, the authors examined 299 patients with 339 aneurysms, all shown to be completely occluded at 36 months on follow-up images obtained between 2011 and 2013. Medical records and radiological data acquired during the extended monitoring period (mean 74.3 ± 22.5 months) were retrieved, and the authors analyzed the incidence of (including mean annual risk) and risk factors for delayed recanalization.

RESULTS

A total of 5 coiled aneurysms (1.5%) occluded completely at 36 months showed recanalization (0.46% per aneurysm-year) during the long-term surveillance period (1081.9 aneurysm-years), 2 surfacing within 60 months and 3 developing thereafter. Four showed minor recanalization, with only one instance of major recanalization. The latter involved the posterior communicating artery as an apparent de novo lesion, arising at the neck of a firmly coiled sac, and was unrelated to coil compaction or growth. Additional embolization was undertaken. In a multivariate analysis, a second embolization for a recurrent aneurysm (HR = 22.088, p = 0.003) independently correlated with delayed recanalization.

CONCLUSIONS

Almost all coiled aneurysms (98.5%) showing complete occlusion at 36 months postembolization proved to be stable during extended observation. However, recurrent aneurysms were predisposed to delayed recanalization. Given the low probability yet seriousness of delayed recanalization and the possibility of de novo aneurysm formation, careful monitoring may be still considered in this setting but at less frequent intervals beyond 36 months.

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Andrew B. Boucher and Joshua J. Chern