Comparison of Prognostic Scoring Systems to Predict Durable Pain Relief After Microvascular Decompression for Trigeminal Neuralgia.

BACKGROUND: Microvascular decompression (MVD) is an effective treatment for trigeminal neuralgia, but pain recurs in a substantial minority of patients. Two recently published scoring systems by Hardaway et al. and Panczykowski et al. use simple preoperative clinical and imaging features to predict durable pain relief following MVD, but their predictive performance has not been independently validated. This study aimed to compare predictive performance of the Hardaway et al. score (HS) and Panczykowski et al. score (PS) for 1-year, 3-year, and long-term pain-free outcomes after MVD for trigeminal neuralgia. METHODS: HS and PS were computed for a retrospective, single-institution cohort of 68 patients with trigeminal neuralgia who underwent MVD. Primary outcome was pain recurrence after MVD. Predictive performance of HSs and PSs was evaluated with area under the curve sensitivity analysis and regression models for survival analyses at 1 year, 3 years, and last follow-up. RESULTS: Area under the curve for predicting pain-free outcome was higher for PS versus HS at 1 year (0.873 vs. 0.775) and 3 years (0.793 vs. 0.704). Cox proportional hazard models showed that PS better predicted long-term pain-free outcomes compared with HS (P < 0.05). One-year pain-free outcome was best predicted by pain type; longer-term outcomes were better predicted by presence and degree of neurovascular compression on preoperative imaging. CONCLUSIONS: PS is superior to HS in predicting pain-free outcomes after MVD, which may aid in patient selection and counseling. Overall, more significant neurovascular compression of the trigeminal nerve root, and to a lesser extent classical paroxysmal pain, are good predictors of durable pain relief after MVD.

The thalamus in trigeminal neuralgia: structural and metabolic abnormalities, and influence on surgical response.

BACKGROUND: Medically-refractory trigeminal neuralgia (TN) can be treated successfully with operative intervention, but a significant proportion of patients are non-responders despite undergoing technically successful surgery. The thalamus is a key component of the trigeminal sensory pathway involved in transmitting facial pain, but the role of the thalamus in TN, and its influence on durability of pain relief after TN surgery, are relatively understudied. We aimed to test the hypothesis that variations in thalamic structure and metabolism are related to surgical non-response in TN. METHODS: We performed a longitudinal, peri-operative neuroimaging study of the thalamus in medically-refractory TN patients undergoing microvascular decompression or percutaneous balloon compression rhizotomy. Patients underwent structural MRI and MR spectroscopy scans pre-operatively and at 1-week following surgery, and were classified as responders or non-responders based on 1-year post-operative pain outcome. Thalamus volume, shape, and metabolite concentration (choline/creatine [Cho/Cr] and N-acetylaspartate/creatine [NAA/Cr]) were evaluated at baseline and 1-week, and compared between responders, non-responders, and healthy controls. RESULTS: Twenty healthy controls and 23 patients with medically-refractory TN treated surgically (17 responders, 6 non-responders) were included. Pre-operatively, TN patients as a group showed significantly larger thalamus volume contralateral to the side of facial pain. However, vertex-wise shape analysis showed significant contralateral thalamus volume reduction in non-responders compared to responders in an axially-oriented band spanning the outer thalamic circumference (peak p = 0.019). Further, while pre-operative thalamic metabolite concentrations did not differ between responders and non-responders, as early as 1-week after surgery, long-term non-responders showed a distinct decrease in contralateral thalamic Cho/Cr and NAA/Cr, irrespective of surgery type, which was not observed in responders. CONCLUSIONS: Atrophy of the contralateral thalamus is a consistent feature across patients with medically-refractory TN. Regional alterations in preoperative thalamic structure, and very early post-operative metabolic changes in the thalamus, both appear to influence the durability of pain relief after TN surgery.

Clinical Uncertainty and Equipoise in the Management of Recurrent Glioblastoma.

BACKGROUND: A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. METHODS: We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years' experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. RESULTS: The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years' experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. CONCLUSION: There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

Hippocampal and trigeminal nerve volume predict outcome of surgical treatment for trigeminal neuralgia.

BACKGROUND: Many medically-refractory trigeminal neuralgia patients are non-responders to surgical treatment. Few studies have explored how trigeminal nerve characteristics relate to surgical outcome, and none have investigated the relationship between subcortical brain structure and treatment outcomes. METHODS: We retrospectively studied trigeminal neuralgia patients undergoing surgical treatment with microvascular decompression. Preoperative magnetic resonance imaging was used for manual tracing of trigeminal nerves and automated segmentation of hippocampus, amygdala, and thalamus. Nerve and subcortical structure volumes were compared between responders and non-responders and assessed for ability to predict postoperative pain outcome. RESULTS: In all, 359 trigeminal neuralgia patients treated surgically from 2005-2018 were identified. A total of 34 patients met the inclusion criteria (32 with classic and two with idiopathic trigeminal neuralgia). Across all patients, thalamus volume was reduced ipsilateral compared to contralateral to the side of pain. Between responders and non-responders, non-responders exhibited larger contralateral trigeminal nerve volume, and larger ipsilateral and contralateral hippocampus volume. Through receiver-operator characteristic curve analyses, contralateral hippocampus volume correctly classified treatment outcome in 82% of cases (91% sensitive, 78% specific, p = 0.008), and contralateral nerve volume correctly classified 81% of cases (91% sensitive, 75% specific, p < 0.001). Binomial logistic regression analysis showed that contralateral hippocampus and contralateral nerve volumes together classified outcome with 84% accuracy (Nagelkerke R2 = 65.1). CONCLUSION: Preoperative hippocampal and trigeminal nerve volume, measured on standard clinical magnetic resonance images, may predict early non-response to surgical treatment for trigeminal neuralgia. Treatment resistance in medically refractory trigeminal neuralgia may depend on the structural features of both the trigeminal nerve and structures involved in limbic components of chronic pain.

Development of a Competence-Based Spine Surgery Fellowship Curriculum Set of Learning Objectives in Canada.

STUDY DESIGN: Modified-Delphi expert consensus method. OBJECTIVE: The aim of this study was to develop competence-based spine fellowship curricula as a set of learning goals through expert consensus methodology in order to provide an educational tool for surgical educators and trainees. Secondarily, we aimed to determine potential differences among specialties in their rating of learning objectives to defined curriculum documents. SUMMARY OF BACKGROUND DATA: There has been recent interest in competence-based education in the training of future surgeons. Current spine fellowships often work on a preceptor-based model, and recent studies have demonstrated that graduating spine fellows may not necessarily be exposed to key cognitive and procedural competencies throughout their training that are expected of a practicing spine surgeon. METHODS: A consensus group of 32 spine surgeons from across Canada was assembled. A modified-Delphi approach refined an initial fellowship-level curriculum set of learning objectives (108 cognitive and 84 procedural competencies obtained from open sources). A consensus threshold of 70% was chosen with up to 5 rounds of blinded voting performed. Members were asked to ratify objectives into either a general comprehensive or focused/advanced curriculum. RESULTS: Twenty-eight of 32 consultants (88%) responded and participated in voting rounds. Seventy-eight (72%) cognitive and 63 (75%) procedural competency objectives reached 70% consensus in the first round. This increased to 82 cognitive and 73 procedural objectives by round 4. The final curriculum document evolved to include a general comprehensive curriculum (91 cognitive and 53 procedural objectives), a focused/advanced curriculum (22 procedural objectives), and a pediatrics curriculum (22 cognitive and 9 procedural objectives). CONCLUSION: Through a consensus-building approach, the study authors have developed a competence-based curriculum set of learning objectives anticipated to be of educational value to spine surgery fellowship educators and trainees. To our knowledge, this is one of the first nationally based efforts of its kind that is also anticipated to be of interest by international colleagues.

Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas.

Tumor immune microenvironment has been gradually recognized as a key contributor to tumor development, progression, and control. Immune cell infiltrates in brain tumors have been increasingly studied, but few have published on immune cell infiltrates in pituitary adenomas. We quantitatively assessed the infiltration of macrophages and lymphocytes in 35 pituitary adenomas, including 9 densely granulated growth hormone (DG-GH), 9 sparsely granulated growth hormone (SG-GH), 9 null cell (NC), and 8 adrenocorticotropic hormone (ACTH) adenomas. All the adenomas showed varying degrees of CD68+ macrophage infiltration. While SG-GH adenomas were significantly larger in size than DG-GH and ACTH adenomas, the infiltration of CD68+ macrophages was significantly greater in SG-GH than in DG-GH and ACTH adenomas. Similarly, NC adenomas that were significantly larger than DG-GH and ACTH adenomas had significantly greater infiltration of CD68+ macrophages than DG-GH and ACTH adenomas. The numbers of CD68+ macrophages were positively correlated with the tumor sizes and Knosp classification grades for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but GH adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. Both DG-GH and SG-GH adenomas had significantly more CD4+ cells than ACTH adenomas and significantly more CD8+ cells than NC adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in the pituitary adenoma size and invasiveness. Our observation contributes to understanding the growth environment of pituitary adenomas, for which adjuvant immunotherapy may help to constrain the tumor enlargement and invasiveness.

Olfactory and sinonasal outcomes in endoscopic transsphenoidal skull-base surgery.

BACKGROUND: Endoscopic anterior skull-base surgery has been previously suggested to cause a significant deterioration in olfactory function. Given the impact on quality of life, the objective of this study was to determine the effect of a unilateral middle-turbinate-sacrificing approach on olfactory function and sinonasal outcome. METHODS: Prospective cohort study comparing olfactory and sinonasal outcomes pre- and post-transsphenoidal skull-base surgery. Olfaction was the primary outcome and was measured prospectively using the University of Pennsylvania Smell Identification Test (SIT). Sinonasal symptoms were assessed subjectively via sinonasal-specific questions from the 22-item Sino-Nasal Outcome Test (SNOT-22), and objectively via the Lund-Kennedy Endoscopic Scoring system (LKES). RESULTS: Twenty-two patients met study inclusion criteria and completed all data acquisition. The mean preoperative SIT score was 34.8 and the mean postoperative SIT value was 35.1 (p = 0.37). The average change in score (delta) was an increase of 0.3, with changes ranging from -3 to +4. When examined categorically, 91% of patients maintained their preoperative olfactory function classification. There was no significant difference in mean pre- and postoperative symptom scores. A small increase in the LKES was noted, from a mean of 0.6 to 2.5 (p = 0.001) in the early postoperative period. CONCLUSION: Olfactory function, as measured by the SIT test, was preserved with a middle-turbinate-sacrificing skull-base approach. Subjective sinonasal symptom scores were unaffected, but a slight worsening of objective endoscopic appearance was noted.

Radial forearm free flap with titanium mesh sandwich reconstruction in complex anterior skull base defects.

BACKGROUND: Skull base reconstruction presents a number of challenges from anatomical and functional perspectives. This is especially the case with large anterior skull base defects with compromised recipient beds from repeated infection, multiple surgeries, or previous radiation. The purpose of the study was to demonstrate the use of the titanium mesh/radial forearm free flap (RFFF) mesh sandwich for reconstruction of large anterior skull base defects with a poor recipient bed or excessive bony defect. METHODS: Retrospective case series of 3 patients with complex anterior skull base defects reconstructed with a titanium mesh/RFFF mesh sandwich technique. RESULTS: Reconstruction of 3 cases using the titanium mesh/RFFF sandwich technique resulted in definitive treatment with no recurrent cerebral spinal fluid leaks, meningitis, or complications. CONCLUSIONS: The titanium mesh/RFFF sandwich is an excellent reconstructive option for large anterior skull base defects with a poor recipient bed. This approach is facilitated using a combined open and endonasal endoscopic approach in a multidisciplinary team composed of head and neck surgery, rhinology, and neurosurgery.

A pilot study of magnetic resonance imaging-guided closed reduction of cervical spine fractures.

STUDY DESIGN: We report on a prospective selective case series of 17 patients with cervical fracture-dislocations treated with closed reduction under MRI guidance. OBJECTIVE: To demonstrate the safe and effective use of in-line axial traction in the reduction of cervical fracture-dislocations using MRI guidance. SUMMARY OF BACKGROUND DATA: Closed reduction of the cervical spine for acute fracture-dislocations has been a traditional technique used for restoring vertebral alignment and providing neural element decompression. The safety of this technique has been questioned, with concerns of disc migration and overdistraction causing neurologic worsening cited as reasons to choose operative reduction and decompression as a safer option in some circumstances. METHODS: Seventeen patients with fracture-dislocations of the subaxial cervical spine were given a trial of traction under MRI guidance between 1999 and 2003. The incidence of posteriorly herniated disc material was noted, and the diameter of the spinal canal at the injured level was recorded before and after traction. RESULTS: All patients tolerated traction without neurologic worsening. Pretraction disc disruption was found in 15 of 17 (88.2%) of patients, with posterior herniation in 4 of 17 (23.5\%). Traction caused a return of herniated disc material toward the disc space in all cases. Canal dimensions improved in 11 of 17 patients, with canal diameter increasing by a factor of 1.1 to 3.0, with a mean improvement of 1.73. The process of reduction was observed to be a gradual one, with progressive, significant improvement in canal dimensions occurring before anatomic realignment. As distracting force was increased, sequential MRIs showed that canal dimensions did not diminish at any time in any patient. CONCLUSIONS: MRI monitoring in closed cervical reduction is a useful research tool for this technique. Closed reduction appears to be safe as used in this preliminary study and is effective in achieving immediate spinal cord decompression.

An adult with childhood medical trauma treated with psychoanalytic psychotherapy and EMDR: a case study.

PROBLEM: Adverse childhood experiences have been found to be a strong predictor of emotional and physical problems in adulthood. However, the long-term sequelae for children who have suffered critical illness and exposure to invasive medical procedures are less well documented. METHODS: This is a case study of an adult client who sought treatment for depression and attention deficit disorder. The psychotherapy treatment is discussed and the use of eye movement desensitization and reprocessing (EMDR) is described targeting a memory of a medical trauma resulting from a tonsillectomy when the client was 8 years old. CONCLUSIONS: Significant healing outcomes were attained as a result of the therapy, i.e., decreased depression, less hypervigilance, and increased ability to concentrate, which resulted in the discontinuation of medication for depression and ADHD as well as significant improvement in overall functioning.

Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway.

Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies. Although HDAC inhibitors induce cell death through an apoptotic process, little is known about the molecular events that control their effectiveness. In this study, we demonstrate that HDAC inhibitors are limited in their ability to induce apoptosis in non-small cell lung cancer (NSCLC) cell lines despite their ability to effectively inhibit deacetylase activity. Because the anti-apoptotic transcription factor NF-kappa B has been shown to be under the control of HDAC-mediated repression, we analyzed whether HDAC inhibitors activated NF-kappa B in NSCLC cells. HDAC inhibitors effectively stimulated endogenous NF-kappa B-dependent gene expression by up-regulating IL-8, Bcl-XL, and MMP-9 transcripts. The ability of HDAC inhibitors to increase NF-kappa B transcriptional activity was not associated with signaling events that stimulated nuclear translocation, but rather modulated the transactivation potential of the RelA/p65 subunit of NF-kappa B. The inhibition of HDAC activity was associated with the recruitment of the p300 transcriptional co-activator to chromatin in an Akt-dependent manner. Moreover, Akt directly phosphorylated p300 in vitro and was required for stimulating the transactivation potential of the co-activator following the addition of HDAC inhibitors. Selective inhibition of either the phosphoinositide 3-kinase/Akt pathway, or NF-kappa B itself blocked the ability of HDAC inhibitors to activate NF-kappa B and dramatically sensitized NSCLC cells to apoptosis following of the addition of HDAC inhibitors. Our study indicates that the ineffectiveness of HDAC inhibitors to induce apoptosis in NSCLC cancer cells is associated with the ability of these molecules to stimulate NF-kappa B-dependent transcription and cell survival.