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Daniel Lubelski, Andrew T. Healy, Prasath Mageswaran, Robb Colbrunn and Richard P. Schlenk

OBJECTIVE

Lateral mass fixation stabilizes the cervical spine while causing minimal morbidity and resulting in high fusion rates. Still, with 2 years of follow-up, approximately 6% of patients who have undergone posterior cervical fusion have worsening kyphosis or symptomatic adjacent-segment disease. Based on the length of the construct, the question of whether to extend the fixation system to undisrupted levels has not been answered for the cervical spine. The authors conducted a study to quantify the role of construct length and the terminal dorsal ligamentous complex in the adjacent-segment kinematics of the subaxial cervical spine.

METHODS

In vitro flexibility testing was performed using 6 human cadaveric specimens (C2–T8), with the upper thoracic rib cage and osseous and ligamentous integrity intact. An industrial robot was used to apply pure moments and to measure segmental motion at each level. The authors tested the intact state, followed by 9 postsurgical permutations of laminectomy and lateral mass fixation spanning C2 to C7.

RESULTS

Constructs spanning a single level exerted no significant effects on immediate adjacent-segment motion. The addition of a second immobilized segment, however, created significant changes in flexion-extension range of motion at the supradjacent level (+164%). Regardless of construct length, resection of the terminal dorsal ligaments did not greatly affect adjacent-level motion except at C2–3 and C7–T1 (increasing by +794% and +607%, respectively).

CONCLUSIONS

Dorsal ligamentous support was found to contribute significant stability to the C2–3 and C7–T1 segments only. Construct length was found to play a significant role when fixating two or more segments. The addition of a fused segment to support an undisrupted cervical level is not suggested by the present data, except potentially at C2–3 and C7–T1. The study findings emphasize the importance of the C2–3 segment and its dorsal support.

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Darryl Lau, Anthony M. DiGiorgio, Andrew K. Chan, Cecilia L. Dalle Ore, Michael S. Virk, Dean Chou, Erica F. Bisson and Praveen V. Mummaneni

OBJECTIVE

Understanding what influences pain and disability following anterior cervical discectomy and fusion (ACDF) in patients with degenerative cervical spine disease is critical. This study examines the timing of clinical improvement and identifies factors (including spinal alignment) associated with worse outcomes.

METHODS

Consecutive adult patients were enrolled in a prospective outcomes database from two academic centers participating in the Quality Outcomes Database from 2013 to 2016. Demographics, surgical details, radiographic data, arm and neck pain (visual analog scale [VAS] scores), and disability (Neck Disability Index [NDI] and EQ-5D scores) were reviewed. Multivariate analysis was used.

RESULTS

A total of 186 patients were included, and 48.4% were male. Their mean age was 55.4 years, and 45.7% had myelopathy. Preoperative cervical sagittal vertical axis (cSVA), cervical lordosis (CL), and T1 slope values were 24.9 mm (range 0–55 mm), 10.4° (range −6.0° to 44°), and 28.3° (range 14.0°–51.0°), respectively. ACDF was performed at 1, 2, and 3 levels in 47.8%, 42.0%, and 10.2% of patients, respectively. Preoperative neck and arm VAS scores were 5.7 and 5.4, respectively. NDI and EQ-5D scores were 22.1 and 0.5, respectively. There was significant improvement in all outcomes at 3 months (p < 0.001) and 12 months (p < 0.001). At 3 months, neck VAS (3.0), arm VAS (2.2), NDI (12.7), and EQ-5D (0.7) scores were improved, and at 12 months, neck VAS (2.8), arm VAS (2.3), NDI (11.7), and EQ-5D (0.8) score improvements were sustained. Improvements occurred within the first 3-month period; there was no significant difference in outcomes between the 3-month and 12-month mark. There was no correlation among cSVA, CL, or T1 slope with any outcome endpoint. The most consistent independent preoperative factors associated with worse outcomes were high neck and arm VAS scores and a severe NDI result (p < 0.001). Similar findings were seen with worse NDI and EQ-5D scores (p < 0.001). A significant linear trend of worse NDI and EQ-5D scores at 3 and 12 months was associated with worse baseline scores. Of the 186 patients, 171 (91.9%) had 3-month follow-up data, and 162 (87.1%) had 12-month follow-up data.

CONCLUSIONS

ACDF is effective in improving pain and disability, and improvement occurs within 3 months of surgery. cSVA, CL, and T1 slope do not appear to influence outcomes following ACDF surgery in the population with degenerative cervical disease. Therefore, in patients with relatively normal cervical parameters, augmenting alignment or lordosis is likely unnecessary. Worse preoperative pain and disability were independently associated with worse outcomes.

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Nataliya Smith, Debra Saunders, Randy L. Jensen and Rheal A. Towner

OBJECTIVE

High-grade gliomas, such as glioblastoma (GBM), are devastating tumors with a very poor prognosis. Previously the authors have found that the nitrone compound OKN-007 (OKlahoma Nitrone 007; or disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is effective against high-grade gliomas in various GBM rodent and human xenograft models. The purpose of the present study was to assess the levels of the lipopolysaccharide-binding protein (LBP) in rodent gliomas treated with OKN-007 as well as determine the expression of LBP in human gliomas.

METHODS

Microarray analysis was done to assess altered gene expression following OKN-007 administration in an F98 glioma model. An enzyme-linked immunosorbent assay was incorporated to assess LBP levels in glioma tissues, as well as blood serum, comparing results in OKN-007–treated and untreated tumor-bearing animals. Immunohistochemistry was used to assess LBP levels in varying grades of human glioma tissue sections.

RESULTS

Upon further assessment of gene expression fold changes in F98 gliomas in rats that received or did not receive OKN-007, it was found that the gene for LBP was significantly downregulated by OKN-007. Further investigation was done to see whether levels of LBP were affected by OKN-007 treatment in F98 gliomas. It was found that LBP could be detected not only in glioma tissue but also in blood serum of F98 glioma-bearing rats and that OKN-007 decreased the levels of LBP. It was also found that LBP levels are highly expressed in human high-grade glioma tissues.

CONCLUSIONS

LBP could potentially be used as a serum diagnostic marker of treatment response in high-grade gliomas.

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Takahiro Makino, Shota Takenaka, Gensuke Okamura, Yusuke Sakai, Hideki Yoshikawa and Takashi Kaito

Dorsal spinal cord herniation is reportedly a rare condition. Here, the authors report an unusual case of dorsal spinal cord herniation at the thoracolumbar junction presenting with scalloping of ossification of the ligamentum flavum (OLF). A 75-year-old woman with a 2-year history of bilateral leg dysesthesia presented with progressive gait ataxia. Neurological examination showed bilateral patellar tendon hyperreflexia with loss of vibratory sensation and proprioception in her bilateral lower extremities. CT myelography revealed a posterior kink and dorsal herniation of the spinal cord at T11–12, with OLF between T10–11 and T12–L1. In addition, scalloping of the OLF was observed at T11–12 at the site of the herniated spinal cord. This scalloping was first noted 9 years previously and had been gradually progressing. The patient underwent surgical repair of the spinal cord herniation. Subsequently, her spinal cord herniation and vibratory sensation and proprioception in both legs partly improved, but gait ataxia remained unchanged. Dorsal spinal cord herniation reportedly occurs under conditions of vulnerability of the dorsal dura mater. In this case, acquired vulnerability of the dorsal dura mater owing to previous epidural catheter placement into the thoracolumbar space may have resulted in dorsal spinal cord herniation.

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Hironobu Sakaura, Daisuke Ikegami, Takahito Fujimori, Tsuyoshi Sugiura, Yoshihiro Mukai, Noboru Hosono and Takeshi Fuji

OBJECTIVE

Cortical bone trajectory (CBT) screw insertion through a caudomedial starting point provides advantages in limiting dissection of the superior facet joints and reducing muscle dissection and the risk of superior-segment facet violation by the screw. These advantages of the cephalad CBT screw can result in lower rates of early cephalad adjacent segment degeneration (ASD) after posterior lumbar interbody fusion (PLIF) with CBT screw fixation (CBT-PLIF) than those after PLIF using traditional trajectory screw fixation (TT-PLIF). Here, the authors investigated early cephalad ASD after CBT-PLIF and compared these results with those after TT-PLIF.

METHODS

The medical records of all patients who had undergone single-level CBT-PLIF or single-level TT-PLIF for degenerative lumbar spondylolisthesis (DLS) and with at least 3 years of postsurgical follow-up were retrospectively reviewed. At 3 years postoperatively, early cephalad radiological ASD changes (R-ASD) such as narrowing of disc height (> 3 mm), anterior or posterior slippage (> 3 mm), and posterior opening (> 5°) were examined using lateral radiographs of the lumbar spine. Early cephalad symptomatic adjacent segment disease (S-ASD) was diagnosed when clinical symptoms such as leg pain deteriorated during postoperative follow-up and the responsible lesion suprajacent to the fused segment was confirmed on MRI.

RESULTS

One hundred two patients underwent single-level CBT-PLIF for DLS and were followed up for at least 3 years (CBT group). As a control group, age- and sex-matched patients (77) underwent single-level TT-PLIF for DLS and were followed up for at least 3 years (TT group). The total incidence of early cephalad R-ASD was 12.7% in the CBT group and 41.6% in the TT group (p < 0.0001). The incidence of narrowing of disc height, anterior slippage, and posterior slippage was significantly lower in the CBT group (5.9%, 2.0%, and 4.9%) than in the TT group (16.9%, 13.0%, and 14.3%; p < 0.05). Early cephalad S-ASD developed in 1 patient (1.0%) in the CBT group and 3 patients (3.9%) in the TT group; although the incidence was lower in the CBT group than in the TT group, no significant difference was found between the two groups.

CONCLUSIONS

CBT-PLIF, as compared with TT-PLIF, significantly reduced the incidence of early cephalad R-ASD. One of the main reasons may be that cephalad CBT screws reduced the risk of proximal facet violation by the screw, which reportedly can increase biomechanical stress and lead to destabilization at the suprajacent segment to the fused segment.

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Alexander Lilja-Cyron, Morten Andresen, Jesper Kelsen, Trine Hjorslev Andreasen, Lonnie Grove Petersen, Kåre Fugleholm and Marianne Juhler

OBJECTIVE

Decompressive craniectomy (DC) is an emergency neurosurgical procedure used in cases of severe intracranial hypertension or impending intracranial herniation. The procedure is often lifesaving, but it exposes the brain to atmospheric pressure in the subsequent rehabilitation period, which changes intracranial physiology and probably leads to complications such as hydrocephalus, hygromas, and “syndrome of the trephined.” The objective of the study was to study the effect of cranioplasty on intracranial pressure (ICP), postural ICP changes, and intracranial pulse wave amplitude (PWA).

METHODS

The authors performed a prospective observational study including patients who underwent DC during a 12-month period. Telemetric ICP sensors were implanted in all patients at the time of DC. ICP was evaluated before and after cranioplasty during weekly measurement sessions including a standardized postural change program.

RESULTS

Twelve of the 17 patients enrolled in the study had cranioplasty performed and were included in the present investigation. Their mean ICP in the supine position increased from –0.5 ± 4.8 mm Hg the week before cranioplasty to 6.3 ± 2.5 mm Hg the week after cranioplasty (p < 0.0001), whereas the mean ICP in the sitting position was unchanged (–1.2 ± 4.8 vs –1.1 ± 3.6 mm Hg, p = 0.90). The difference in ICP between the supine and sitting positions was minimal before cranioplasty (1.1 ± 1.8 mm Hg) and increased to 7.4 ± 3.6 mm Hg in the week following cranioplasty (p < 0.0001). During the succeeding 2 weeks of the follow-up period, the mean ICP in the supine and sitting positions decreased in parallel to, respectively, 4.6 ± 3.0 mm Hg (p = 0.0003) and –3.9 ± 2.7 mm Hg (p = 0.040), meaning that the postural ICP difference remained constant at around 8 mm Hg. The mean intracranial PWA increased from 0.7 ± 0.7 mm Hg to 2.9 ± 0.8 mm Hg after cranioplasty (p < 0.0001) and remained around 3 mm Hg throughout the following weeks.

CONCLUSIONS

Cranioplasty restores normal intracranial physiology regarding postural ICP changes and intracranial PWA. These findings complement those of previous investigations on cerebral blood flow and cerebral metabolism in patients after decompressive craniectomy.

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Benjamin Davidson, Nathan Schoen, Shaina Sedighim, Renée Haldenby, Blythe Dalziel, Sara Breitbart, Darcy Fehlings, Golda Milo-Manson, Unni G. Narayanan, James M. Drake and George M. Ibrahim

OBJECTIVE

Cerebral palsy (CP) is the most common childhood physical disability. Historically, children with hypertonia who are nonambulatory (Gross Motor Function Classification System [GMFCS] level IV or V) were considered candidates for intrathecal baclofen (ITB) therapy to facilitate care and mitigate discomfort. Selective dorsal rhizotomy (SDR) was often reserved for ambulant children to improve gait. Recently, case series have suggested SDR as an alternative to ITB in selected children functioning at GMFCS level IV/V. The objective for this study was to systematically review the evidence for ITB and SDR in GMFCS level IV or V children.

METHODS

Medline, Embase, Web of Science, and Cochrane databases were systematically searched. Articles were screened using the following inclusion criteria: 1) peer-reviewed articles reporting outcomes after SDR or ITB; 2) outcomes reported using a quantifiable scale or standardized outcome measure; 3) patients were < 19 years old at the time of operation; 4) patients had a diagnosis of CP; 5) patients were GMFCS level IV/V or results were reported based on GMFCS status and included some GMFCS level IV/V patients; 6) article and/or abstract in English; and 7) primary indication for surgery was hypertonia. Included studies were assessed with the Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I) tool.

RESULTS

Twenty-seven studies met inclusion criteria. The most commonly reported outcomes were spasticity (on the Mean Ashworth Scale) and gross motor function (using the Gross Motor Function Measure), although other outcomes including frequency of orthopedic procedures and complications were also reported. There is evidence from case series that suggests that both ITB and SDR can lower spasticity and improve gross motor function in this nonambulatory population. Complication rates are decidedly higher after ITB due in part to the ongoing risk of device-related complications. The heterogeneity among study design, patient selection, outcome selection, and follow-up periods was extremely high, preventing meta-analysis. There are no comparative studies, and meaningful health-related quality of life outcomes such as care and comfort are lacking. This review is limited by the high risk of bias among included studies. Studies of SDR or ITB that did not clearly describe patients as being GMFCS level IV/V or nonambulatory were excluded.

CONCLUSIONS

There is a lack of evidence comparing the outcomes of ITB and SDR in the nonambulatory CP population. This could be overcome with standardized prospective studies using more robust methodology and relevant outcome measures.

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Ahmed N. Ibrahim, Daisuke Yamashita, Joshua C. Anderson, Moaaz Abdelrashid, Amr Alwakeal, Dagoberto Estevez-Ordonez, Svetlana Komarova, James M. Markert, Violaine Goidts, Christopher D. Willey and Ichiro Nakano

OBJECTIVE

Despite significant recent efforts applied toward the development of efficacious therapies for glioblastoma (GBM) through exploration of GBM’s genome and transcriptome, curative therapeutic strategies remain highly elusive. As such, novel and effective therapeutics are urgently required. In this study, the authors sought to explore the kinomic landscape of GBM from a previously underutilized approach (i.e., spatial heterogeneity), followed by validation of Bruton’s tyrosine kinase (BTK) targeting according to this stepwise kinomic-based novel approach.

METHODS

Twelve GBM tumor samples were obtained and characterized histopathologically from 2 patients with GBM. PamStation peptide-array analysis of these tissues was performed to measure the kinomic activity of each sample. The Ivy GBM database was then utilized to determine the intratumoral spatial localization of BTK activity by investigating the expression of BTK-related transcription factors (TFs) within tumors. Genetic inhibition of BTK family members through lentiviral short hairpin RNA (shRNA) knockdown was performed to determine their function in the core-like and edge-like GBM neurosphere models. Finally, the small-molecule inhibitor of BTK, ONO/GS-4059, which is currently under clinical investigation in nonbrain cancers, was applied for pharmacological inhibition of regionally specified newly established GBM edge and core neurosphere models.

RESULTS

Kinomic investigation identified two major subclusters of GBM tissues from both patients exhibiting distinct profiles of kinase activity. Comparatively, in these spatially defined subgroups, BTK was the centric kinase differentially expressed. According to the Ivy GBM database, BTK-related TFs were highly expressed in the tumor core, but not in edge counterparts. Short hairpin RNA–mediated gene silencing of BTK in previously established edge- and core-like GBM neurospheres demonstrated increased apoptotic activity with predominance of the sub-G1 phase of core-like neurospheres compared to edge-like neurospheres. Lastly, pharmacological inhibition of BTK by ONO/GS-4059 resulted in growth inhibition of regionally derived GBM core cells and, to a lesser extent, their edge counterparts.

CONCLUSIONS

This study identifies significant heterogeneity in kinase activity both within and across distinct GBM tumors. The study findings indicate that BTK activity is elevated in the classically therapy-resistant GBM tumor core. Given these findings, targeting GBM’s resistant core through BTK may potentially provide therapeutic benefit for patients with GBM.