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Yona Goldshmit, Evgeni Banyas, Nicole Bens, Alex Yakovchuk and Angela Ruban

OBJECTIVE

Excitotoxicity due to neuronal damage and glutamate release is one of the first events that leads to the progression of neuronal degeneration and functional impairment. This study is based on a paradigm shift in the therapeutic approach for treating spinal cord injury (SCI). The authors tested a new treatment targeting removal of CNS glutamate into the blood circulation by injection of the blood glutamate scavengers (BGSs) recombinant enzyme glutamate-oxaloacetate transaminase (rGOT1) and its cosubstrate oxaloacetic acid (OxAc). Their primary objective was to investigate whether BGS treatment, followed by treadmill exercises in mice with SCI, could attenuate excitotoxicity, inflammation, scarring, and axonal degeneration and, at a later time point, improve functional recovery.

METHODS

A pharmacokinetic experiment was done in C57BL/6 naive mice to verify rGOT1/OxAc blood activity and to characterize the time curve of glutamate reduction in the blood up to 24 hours. The reduction of glutamate in CSF after BGS administration in mice with SCI was confirmed by high-performance liquid chromatography. Next, SCI (left hemisection) was induced in the mice, and the mice were randomly assigned to one of the following groups at 1 hour postinjury: control (underwent SCI and received PBS), treadmill exercises, rGOT1/OxAc treatment, or rGOT1/OxAc treatment followed by treadmill exercises. Treatment started 1 hour postinjury with an injection of rGOT1/OxAc and continued for 5 consecutive days. Starting 1 week after SCI, the exercises and the combined treatment groups recommenced the treadmill exercise regimen 5 days a week for 3 months. Locomotor function was assessed for 3 months using the horizontal grid walking test and CatWalk. Axonal anterograde and wallerian degenerations were evaluated using tetramethylrhodamine dextran. Tissue sections were immunofluorescently stained for Iba1, GFAP, GAP-43, synaptophysin, and NeuN.

RESULTS

BGS treatment decreased the CSF glutamate level up to 50%, reduced axonal wallerian degeneration, and increased axonal survival and GAP-43 expression in neuronal cells. Combined treatment reduced inflammation, scarring, and lesion size. Additionally, the combination of BGS treatment and exercises increased synapses around motor neurons and enhanced axonal regeneration through the lesion site. This resulted in motor function improvement 3 months post-SCI.

CONCLUSIONS

As shown by biochemical, immunohistochemical, and functional analysis, BGSs exhibit a substantial neuroprotective effect by reducing excitotoxicity and secondary damage after SCI. Furthermore, in combination with exercises, they reduced axonal degeneration and scarring and resulted in improved functional recovery.

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Yosef Ellenbogen, Karanbir Brar, Kaiyun Yang, Yung Lee and Olufemi Ajani

OBJECTIVE

Pediatric hydrocephalus is a significant contributor to infant morbidity and mortality, particularly in developing countries. The mainstay of treatment has long been shunt placement for CSF diversion, but recent years have seen the rise of alternative procedures such as endoscopic third ventriculostomy (ETV), which provides similar efficacy in selected patients. The addition of choroid plexus cauterization (CPC) to ETV has been proposed to increase efficacy, but the evidence of its utility is limited. This systematic review and meta-analysis aimed to determine the efficacy and safety of ETV+CPC in comparison to ETV alone for the treatment of pediatric all-cause hydrocephalus.

METHODS

MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and ICRCTN databases were searched from conception through to October 2018 for comparative studies including both ETV+CPC and ETV in a pediatric population. The primary outcome was success rate, defined as no secondary procedure required for CSF diversion; secondary outcomes included time to failure, mortality, and complications. Data were pooled using random-effects models of meta-analysis, and relative risk (RR) was calculated.

RESULTS

Five studies were included for final qualitative and quantitative analysis, including 2 prospective and 3 retrospective studies representing a total of 963 patients. Overall, there was no significant difference in success rates between ETV and ETV+CPC (RR 1.24, 95% CI 0.88–1.75, p = 0.21). However, a subgroup analysis including the 4 studies focusing on African cohorts demonstrated a significant benefit of ETV+CPC (RR 1.38, 95% CI 1.08–1.78, p = 0.01). There were no notable differences in complication rates among studies.

CONCLUSIONS

This systematic review and meta-analysis failed to find an overall benefit to the addition of CPC to ETV; however, a subgroup analysis showed efficacy in sub-Saharan African populations. This points to the need for future randomized clinical trials investigating the efficacy of ETV+CPC versus ETV in varied patient populations and geographic locales.

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Monica Mureb, Danielle Golub, Carolina Benjamin, Jason Gurewitz, Ben A. Strickland, Gabriel Zada, Eric Chang, Dušan Urgošík, Roman Liščák, Ronald E. Warnick, Herwin Speckter, Skyler Eastman, Anthony M. Kaufmann, Samir Patel, Caleb E. Feliciano, Carlos H. Carbini, David Mathieu, William Leduc, DCS, Sean J. Nagel, Yusuke S. Hori, Yi-Chieh Hung, Akiyoshi Ogino, Andrew Faramand, Hideyuki Kano, L. Dade Lunsford, Jason Sheehan and Douglas Kondziolka

OBJECTIVE

Trigeminal neuralgia (TN) is a chronic pain condition that is difficult to control with conservative management. Furthermore, disabling medication-related side effects are common. This study examined how stereotactic radiosurgery (SRS) affects pain outcomes and medication dependence based on the latency period between diagnosis and radiosurgery.

METHODS

The authors conducted a retrospective analysis of patients with type I TN at 12 Gamma Knife treatment centers. SRS was the primary surgical intervention in all patients. Patient demographics, disease characteristics, treatment plans, medication histories, and outcomes were reviewed.

RESULTS

Overall, 404 patients were included. The mean patient age at SRS was 70 years, and 60% of the population was female. The most common indication for SRS was pain refractory to medications (81%). The median maximum radiation dose was 80 Gy (range 50–95 Gy), and the mean follow-up duration was 32 months. The mean number of medications between baseline (pre-SRS) and the last follow-up decreased from 1.98 to 0.90 (p < 0.0001), respectively, and this significant reduction was observed across all medication categories. Patients who received SRS within 4 years of their initial diagnosis achieved significantly faster pain relief than those who underwent treatment after 4 years (median 21 vs 30 days, p = 0.041). The 90-day pain relief rate for those who received SRS ≤ 4 years after their diagnosis was 83.8% compared with 73.7% in patients who received SRS > 4 years after their diagnosis. The maximum radiation dose was the strongest predictor of a durable pain response (OR 1.091, p = 0.003). Early intervention (OR 1.785, p = 0.007) and higher maximum radiation dose (OR 1.150, p < 0.0001) were also significant predictors of being pain free (a Barrow Neurological Institute pain intensity score of I–IIIA) at the last follow-up visit. New sensory symptoms of any kind were seen in 98 patients (24.3%) after SRS. Higher maximum radiation dose trended toward predicting new sensory deficits but was nonsignificant (p = 0.075).

CONCLUSIONS

TN patients managed with SRS within 4 years of diagnosis experienced a shorter interval to pain relief with low risk. SRS also yielded significant decreases in adjunct medication utilization. Radiosurgery should be considered earlier in the course of treatment for TN.

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Lelio Guida, Kevin Beccaria, Sandro Benichi, Anaïs Chivet, Timothée de Saint Denis, Syril James, Giovanna Paternoster, Michel Zerah, Stéphanie Puget and Thomas Blauwblomme

OBJECTIVE

Pediatric patients with long-term shunts may experience specific complications related to the segregation of the supra- and infratentorial spaces along with different pressure regimens, leading to either mesencephalic syndromes during shunt dysfunction or isolated fourth ventricle (IFV). An accepted treatment to reestablish normal CSF pathways and reequilibrate the transtentorial pressures is endoscopic aqueductal stenting (EAS) to avoid restenosis. In the present paper, the authors studied children treated with EAS during the last decade for both IFV and obstructive hydrocephalus, evaluated its impact on the course of the disease, and identified prognostic factors for EAS success.

METHODS

A noninterventional retrospective study of routinely acquired data was performed, including all hydrocephalic children undergoing EAS between 2011 and 2019 at Hôpital Necker, Paris, France. The following variables were analyzed: etiology of hydrocephalus; number of surgeries before and after stent placement; indication for EAS; type of stent connection (i.e., connected or not to a ventriculoperitoneal shunt); and the stent position. Stent failure was defined as the need to perform further shunt revision. Univariate and multivariate analyses were run to identify factors associated with stent failure.

RESULTS

Seventeen patients with a mean age at stent placement of 6 years (SD 6.5 years, range 1 month–18 years) and with a mean follow-up after EAS of 47.5 months (SD 33.7 months, range 5–120 months) were included in the analysis. The etiology of hydrocephalus was as follows: obstructive tumoral (41%), posthemorrhagic (35%), postinfectious (12%), and dysraphism related (12%). The indication for EAS was IFV (47%), rostral midbrain dysfunction syndrome (35%), prevention of secondary aqueductal stenosis after debulking surgery (12%), or primary aqueductal stenosis (6%). No transient or permanent neurological deficits related to the procedure were observed. After EAS, 10 patients did not require further surgeries (59%), and for the others the number of hydrocephalus-related surgeries significantly decreased after stenting. In univariate analysis posthemorrhagic etiology and prevention of aqueductal stenosis were identified as predictors of a good outcome, whereas in multivariate analysis posthemorrhagic hydrocephalus was found to predict a favorable outcome.

CONCLUSIONS

The results confirm EAS as a first-line treatment for IFV and suggest its efficacy in changing the history of hydrocephalic patients who have undergone multiple operations and who experience rostral midbrain dysfunction syndrome, as well as efficacy in the prevention of aqueductal stenosis in selected cases of obstructive tumoral hydrocephalus.

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Jacob D. Bond, Zhaoyang Xu and Ming Zhang

OBJECTIVE

The extradural neural axis compartment (EDNAC) is an adipovenous zone that is located between the meningeal (ML) and endosteal (EL) layers of the dura mater and has been minimally investigated in the jugular foramen (JF) region. In this study, the authors aimed to explore the fine architecture of the EDNAC within the JF and evaluate whether the EDNAC can be used as a component for JF compartmentalization.

METHODS

A total of 46 cadaveric heads (31 male, 15 female; age range 54–96 years) and 30 dry skulls were examined in this study. Twelve of 46 cadaveric heads were plastinated as a series of transverse (7 sets), coronal (3 sets), and sagittal (2 sets) slices and examined using stereomicroscopy and confocal microscopy. The dural entry points of the JF cranial nerves were recorded in 34 cadaveric skulls. The volumes of the JF, intraforaminal EDNAC, and internal jugular vein (IJV) were quantified.

RESULTS

Based on constant osseous landmarks, the JF was subdivided into preforaminal, intraforaminal, and subforaminal segments. The ML-derived fascial sheath along the anteromedial wall of the IJV demarcated the “venous portion” and the “EDNAC portion” of the bipartite JF. The EDNAC did not surround the intraforaminal IJV and comprised an ML-derived dural fibrous network and an adipose matrix. A fibrovenous curtain subdivided the intraforaminal EDNAC into a small anterior column containing cranial nerve (CN) IX and the anterior condylar venous plexus and a large posterior adipose column containing CNs X and XI. In the intraforaminal segment, the IJV occupied a slightly larger space in the foramen (57%; p < 0.01), whereas in the subforaminal segment it occupied a space of similar size to that of the EDNAC.

CONCLUSIONS

Excluding the IJV, the neurovascular structures in the JF traverse the dural fibrous network that is dominant in the foraminal EDNAC. The results of this study will contribute to anatomical knowledge of the obscure yet crucially important JF region, increase understanding of foraminal tumor growth and spread patterns, and facilitate the planning and execution of surgical interventions.

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Yu-Cheng Ren, Bin-Jie Zhao, Zhi-Yi Xie, Guang-Yu Ying, Fang Shen and Yong-Jian Zhu

Bead-like schwannomas at the cauda equina are rare but benign intraspinal tumors. They can involve multiple nerve roots and spread within the spinal canal, and open resection would cause significant trauma. The authors have successfully applied a novel minimally invasive technique for the total removal of such schwannomas. A 68-year-old woman presented with a 1-month history of left waist and leg pain. MRI demonstrated multiple intraspinal lesions located from L1 to S1. The diagnosis was bead-like schwannomas at the cauda equina. Two incisions were made at the T12 and L5 levels. A flexible endoscope was introduced into the spinal canal following hemisemilaminectomy under a microscope to identify the relationship between the tumors and the carrying nerves. After dissecting both cranial and caudal ends of the carrying nerve, the string of bead-like tumors was gently pulled out from the caudal end as a whole. The endoscope was reintroduced into the spinal canal to ensure complete tumor removal. The patient recovered quickly, and no tumor residual was found at postoperative MRI. Flexible endoscope–assisted visualization plus microscopic hemisemilaminectomy via 2 incisions is a feasible minimally invasive approach for selected patients with bead-like schwannomas at the cauda equina.

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Heidi J. Nurmonen, Terhi Huttunen, Jukka Huttunen, Arttu Kurtelius, Satu Kotikoski, Antti Junkkari, Timo Koivisto, Mikael von und zu Fraunberg, Olli-Pekka Kämäräinen, Maarit Lång, Helena Isoniemi, Juha E. Jääskeläinen and Antti E. Lindgren

OBJECTIVE

The authors set out to study whether autosomal dominant polycystic kidney disease (ADPKD), an established risk factor for intracranial aneurysms (IAs), affects the acute course and long-term outcome of aneurysmal subarachnoid hemorrhage (aSAH).

METHODS

The outcomes of 32 ADPKD patients with aSAH between 1980 and 2015 (median age 43 years; 50% women) were compared with 160 matched (age, sex, and year of aSAH) non-ADPKD aSAH patients in the prospectively collected Kuopio Intracranial Aneurysm Patient and Family Database.

RESULTS

At 12 months, 75% of the aSAH patients with ADPKD versus 71% of the matched-control aSAH patients without ADPKD had good outcomes (Glasgow Outcome Scale score 4 or 5). There was no significant difference in condition at admission. Hypertension had been diagnosed before aSAH in 69% of the ADPKD patients versus 27% of controls (p < 0.001). Multiple IAs were present in 44% of patients in the ADPKD group versus 25% in the control group (p = 0.03). The most common sites of ruptured IAs were the anterior communicating artery (47% vs 29%, p = 0.05) and the middle cerebral artery bifurcation (28% vs 31%), and the median size was 6.0 mm versus 8.0 mm (p = 0.02). During the median follow-up of 11 years, a second aSAH occurred in 3 of 29 (10%) ADPKD patients and in 4 of 131 (3%) controls (p = 0.11). A fatal second aSAH due to a confirmed de novo aneurysm occurred in 2 (6%) of the ADPKD patients but in none of the controls (p = 0.027).

CONCLUSIONS

The outcomes of ADPKD patients with aSAH did not differ significantly from those of matched non-ADPKD aSAH patients. ADPKD patients had an increased risk of second aSAH from a de novo aneurysm, warranting long-term angiographic follow-up.

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Olivia Foesleitner, Benjamin Sigl, Victor Schmidbauer, Karl-Heinz Nenning, Ekaterina Pataraia, Lisa Bartha-Doering, Christoph Baumgartner, Susanne Pirker, Doris Moser, Michelle Schwarz, Johannes A. Hainfellner, Thomas Czech, Christian Dorfer, Georg Langs, Daniela Prayer, Silvia Bonelli and Gregor Kasprian

OBJECTIVE

Epilepsy surgery is the recommended treatment option for patients with drug-resistant temporal lobe epilepsy (TLE). This method offers a good chance of seizure freedom but carries a considerable risk of postoperative language impairment. The extremely variable neurocognitive profiles in surgical epilepsy patients cannot be fully explained by extent of resection, fiber integrity, or current task-based functional MRI (fMRI). In this study, the authors aimed to investigate pathology- and surgery-triggered language organization in TLE by using fMRI activation and network analysis as well as considering structural and neuropsychological measures.

METHODS

Twenty-eight patients with unilateral TLE (16 right, 12 left) underwent T1-weighted imaging, diffusion tensor imaging, and task-based language fMRI pre- and postoperatively (n = 15 anterior temporal lobectomy, n = 11 selective amygdalohippocampectomy, n = 2 focal resection). Twenty-two healthy subjects served as the control cohort. Functional connectivity, activation maps, and laterality indices for language dominance were analyzed from fMRI data. Postoperative fractional anisotropy values of 7 major tracts were calculated. Naming, semantic, and phonematic verbal fluency scores before and after surgery were correlated with imaging parameters.

RESULTS

fMRI network analysis revealed widespread, bihemispheric alterations in language architecture that were not captured by activation analysis. These network changes were found preoperatively and proceeded after surgery with characteristic patterns in the left and right TLEs. Ipsilesional fronto-temporal connectivity decreased in both left and right TLE. In left TLE specifically, preoperative atypical language dominance predicted better postoperative verbal fluency and naming function. In right TLE, left frontal language dominance correlated with good semantic verbal fluency before and after surgery, and left fronto-temporal language laterality predicted good naming outcome. Ongoing seizures after surgery (Engel classes ID–IV) were associated with naming deterioration irrespective of seizure side. Functional findings were not explained by the extent of resection or integrity of major white matter tracts.

CONCLUSIONS

Functional connectivity analysis contributes unique insight into bihemispheric remodeling processes of language networks after epilepsy surgery, with characteristic findings in left and right TLE. Presurgical contralateral language recruitment is associated with better postsurgical language outcome in left and right TLE.

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Yongqin Xiong, Jianfeng He and Xin Lou