Stephen T. Magill

microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus

Newborn neurons in the dentate gyrus of the adult hippocampus rely upon cAMP response element binding protein (CREB) signaling for their differentiation into mature granule cells and their integration into the dentate network. Among its many targets, the transcription factor CREB activates expression of a gene locus that produces two microRNAs, miR-132 and miR-212. In cultured cortical and hippocampal neurons, miR-132 functions downstream from CREB to mediate activity-dependent dendritic growth and spine formation in response to a variety of signaling pathways. To investigate whether miR-132 and/or miR-212 contribute to the maturation of dendrites in newborn neurons in the adult hippocampus, we inserted LoxP sites surrounding the miR-212/132 locus and specifically targeted its deletion by stereotactically injecting a retrovirus expressing Cre recombinase. Deletion of the miR-212/132 locus caused a dramatic decrease in dendrite length, arborization, and spine density. The miR-212/132 locus may express up to four distinct microRNAs, miR-132 and -212 and their reverse strands miR-132* and -212*. Using ratiometric microRNA sensors, we determined that miR-132 is the predominantly active product in hippocampal neurons. We conclude that miR-132 is required for normal dendrite maturation in newborn neurons in the adult hippocampus and suggest that this microRNA also may participate in other examples of CREB-mediated signaling.

Long-term outcome following ilioinguinal neurectomy for chronic pain.

OBJECT Ilioinguinal neuralgia is one cause of chronic groin pain following inguinal hernia repair, and it affects approximately 10% of patients. Selective ilioinguinal neurectomy is one proposed treatment option for carefully selected patients. The goal of this study was to determine the long-term outcome of patients who underwent selective ilioinguinal neurectomy for chronic post-hernia pain. METHODS The authors retrospectively reviewed the clinical assessment, surgical treatment, and long-term outcome in 26 patients with ilioinguinal neuralgia who underwent selective ilioinguinal neurectomy performed by the senior author (K.J.B.) at Oregon Health & Science University between 1998 and 2008. Data were collected from patient charts and a follow-up telephone questionnaire. RESULTS Twenty-six patients (14 men and 12 women) had a clinical diagnosis of ilioinguinal neuralgia based on a history of radiating neuropathic groin, medial thigh, and genitalia pain. One patient had bilateral disease (therefore there were 27 surgical cases). A selective nerve block was performed in 21 (81%) of 26 patients and was positive in 20 (77%) of the 26. In all but 2 patients, pain onset followed abdominal surgery (for hernia repair in 18 patients), and was immediate in 16 (67%) of 24 patients. The mean patient age was 48.7 years, and the mean duration of pain prior to neurosurgical consultation was 3.9 years. Surgery was performed after induction of local or general anesthesia in 17 and 10 cases, respectively. The ilioinguinal nerve was identified in 25 cases, and the genitofemoral nerve in 2, either entrapped in mesh, scar, or with obvious neuroma (22 of 27 cases). The identified nerve was doubly ligated, cut, and buried in muscle at its most proximal point. At the 2-week follow-up evaluations, 14 (74%) of 19 patients noted definite pain improvement. Nineteen (73%) of the 26 patients were contacted by telephone and agreed to participate in completing long-term follow-up questionnaires. The mean follow-up duration was 34.78 months. Return of pain was reported by 13 (68%) of 19 patients. Using a verbal numerical rating scale (0-10), pain was completely relieved in 27.8%, better in 38.9%, no better in 16.7%, and worse in 16.7% of patients. CONCLUSIONS Ilioinguinal neurectomy is an effective and appropriate treatment for selected patients with iatrogenic ilioinguinal neuralgia following abdominal surgery. Although a high proportion of patients reported some long-term recurrence of pain, complete or partial pain relief was achieved in 66.7% of the patients observed.

Seizures in supratentorial meningioma: a systematic review and meta-analysis.

OBJECT Meningioma is the most common benign intracranial tumor, and patients with supratentorial meningioma frequently suffer from seizures. The rates and predictors of seizures in patients with meningioma have been significantly under-studied, even in comparison with other brain tumor types. Improved strategies for the prediction, treatment, and prevention of seizures in patients with meningioma is an important goal, because tumor-related epilepsy significantly impacts patient quality of life. METHODS The authors performed a systematic review of PubMed for manuscripts published between January 1980 and September 2014, examining rates of pre- and postoperative seizures in supratentorial meningioma, and evaluating potential predictors of seizures with separate meta-analyses. RESULTS The authors identified 39 observational case series for inclusion in the study, but no controlled trials. Preoperative seizures were observed in 29.2% of 4709 patients with supratentorial meningioma, and were significantly predicted by male sex (OR 1.74, 95% CI 1.30-2.34); an absence of headache (OR 1.77, 95% CI 1.04-3.25); peritumoral edema (OR 7.48, 95% CI 6.13-9.47); and non-skull base location (OR 1.77, 95% CI 1.04-3.25). After surgery, seizure freedom was achieved in 69.3% of 703 patients with preoperative epilepsy, and was more than twice as likely in those without peritumoral edema, although an insufficient number of studies were available for formal meta-analysis of this association. Of 1085 individuals without preoperative epilepsy who underwent resection, new postoperative seizures were seen in 12.3% of patients. No difference in the rate of new postoperative seizures was observed with or without perioperative prophylactic anticonvulsants. CONCLUSIONS Seizures are common in supratentorial meningioma, particularly in tumors associated with brain edema, and seizure freedom is a critical treatment goal. Favorable seizure control can be achieved with resection, but evidence does not support routine use of prophylactic anticonvulsants in patients without seizures. Limitations associated with systematic review and meta-analysis should be considered when interpreting these results.

Memory formation and retention are affected in adult miR-132/212 knockout mice.

The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6-month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wild-type controls in general locomotor activity in an open-field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases.

Thalamotomy as a Treatment Option for Tremor after Ineffective Deep Brain Stimulation

Background: As the number of deep brain stimulation (DBS) surgeries increases, complications from malpositioned electrodes, tolerance to stimulation and loss of efficacy have also increased. Our objective was to assess thalamotomy as a salvage treatment option after ineffective DBS. Methods: A retrospective chart analysis of patients who underwent ipsilateral stereotactic thalamotomy after an ineffective ventrointermediate nucleus DBS procedure was undertaken. Patient outcome was based on follow-up visit chart notes, and a nonvalidated patient telephone questionnaire to assess patients’ perception of tremor and functional ability after thalamotomy. Results: Six patients with essential tremor and 1 with tremor-predominant Parkinson’s disease met our inclusion criteria. Thalamotomies were undertaken for ineffective DBS due to dysarthria and paresthesias with programming in 2 patients, tremor that failed to respond to increased DBS despite a lack of side effects in 2 patients, malpositioned electrode in 2 patients, and sudden loss of DBS efficacy following eye surgery in 1 patient. Following thalamotomy, 3 patients reported improvement in symptoms and function, 3 patients reported improvement in symptoms that were not reflected in functional improvement, and 1 patient reported no improvement in symptoms or function. Conclusion: Thalamotomy may provide a viable salvage solution in patients who fail to respond to DBS due to complications such as malpositioned electrodes, tolerance to stimulation or loss of efficacy.

Neurogenic thoracic outlet syndrome: current diagnostic criteria and advances in MRI diagnostics.

Neurogenic thoracic outlet syndrome (nTOS) is caused by compression of the brachial plexus as it traverses from the thoracic outlet to the axilla. Diagnosing nTOS can be difficult because of overlap with other complex pain and entrapment syndromes. An nTOS diagnosis is made based on patient history, physical exam, electrodiagnostic studies, and, more recently, interpretation of MR neurograms with tractography. Advances in high-resolution MRI and tractography can confirm an nTOS diagnosis and identify the location of nerve compression, allowing tailored surgical decompression. In this report, the authors review the current diagnostic criteria, present an update on advances in MRI, and provide case examples demonstrating how MR neurography (MRN) can aid in diagnosing nTOS. The authors conclude that improved high-resolution MRN and tractography are valuable tools for identifying the source of nerve compression in patients with nTOS and can augment current diagnostic modalities for this syndrome.

Differentiating intrathecal catheter tip granulomas from normal magnetic resonance image distortion caused by metallic catheter tips

OBJECTIVETo characterize the normal image distortion produced by metallic intrathecal catheter tips and define features that differentiate them from a catheter tip granuloma. METHODSThree Medtronic Inc. (Minneapolis, MN) intrathecal catheter models (M8709, M8711, and M8731) were placed in a water-filled phantom, which was secured with a spinal coil and scanned with a 1.5-T magnetic resonance imaging (MRI) scanner. MRI scans from two patients receiving intrathecal opiate therapy without a granuloma and one patient with a granuloma were analyzed for comparison. RESULTSAll three catheter models produced a metallic susceptibility artifact, which distorted the local tissue image. The tip appeared as a round, dark void sandwiched between two bright bands in the sagittal plane. Axial views produced an oval-shaped, dark central void completely surrounded by a bright rim. On MRI scans, catheter tip diameter varied from 2.3 to 6.7 mm and tip length varied from 4.0 to 7.5 mm, which is a 74 to 480% increase over their actual size. The catheter tip appearance in the phantom correlated with the tip appearance in MRI scans from patients with intrathecal catheters. Images from a tip granuloma show a bright rim surrounding the catheter tip in the sagittal plane with or without contrast as well as postcontrast enhancement of the whole granuloma, and the catheter tip appeared greater than 5 mm in diameter and length. CONCLUSIONWhen evaluating possible granuloma development around an intrathecal catheter tip, it is important to take into account the characteristic metallic susceptibility artifact and increased size of normal metallic catheter tips on MRI scans.

Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68−, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68− expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68− was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Preoperative magnetic resonance imaging in Type 2 trigeminal neuralgia: Clinical article

OBJECT Trigeminal neuralgia (TN) is a neuropathic pain syndrome that is often associated with neurovascular compression of the trigeminal nerve and may be effectively treated with microvascular decompression (MVD). The authors used high-resolution MR imaging with 3D reconstruction in patients with constant facial pain (Type 2 TN) to determine the presence/absence of neurovascular compression and thus a potential MVD benefit. They retrospectively contacted patients to evaluate outcome. METHODS All patients who reported spontaneous onset of constant facial pain (Type 2 TN), which occurred at least 50% of the time, who had undergone high-resolution 3-T MR imaging with 3D reconstruction were retrospectively selected for this study. Clinical history, facial pain questionnaire data, physical examination findings, and results from 3-T 3D MR imaging reconstruction were recorded for all patients. Intraoperative findings and clinical pain outcome were recorded for all patients who underwent MVD. RESULTS Data obtained in 27 patients were assessed. On the basis of history and 3D MR imaging reconstruction findings, 13 patients were selected for MVD (Group A) and 14 underwent conservative treatment (Group B). Typical or suspected artery- or vein-induced neurovascular compression was predicted preoperatively in 100% of Group A patients and in 0% of Group B patients. At the time of MVD, definitive neurovascular compression was confirmed in 11 (84.6%) of 13 Group A patients. Following MVD, facial pain was completely relieved in 3 (23%), improved in 7 (53.8%), and no better in 3 (23%) of 13 Group A patients. A history of episodic (Type 1 TN) pain at any time was reported in 100 and 50% of Group A and Group B patients, respectively. A Type 1 TN pain component was reportedly improved/relieved in all Group A patients, but the Type 2 TN pain component was improved in only 7 (53.8%) of 13 patients. The mean postoperative follow-up duration was 13 months. CONCLUSIONS High-resolution 3D MR imaging reconstruction in patients with constant facial pain (Type 2 TN) can help determine the presence/absence of neurovascular compression. Surgical selection based on both clinical and radiological criteria has the potential to improve surgical outcome in patients with Type 2 TN who may potentially benefit from MVD. However, even in such selected patients, pain relief is likely to be incomplete.

Factors Associated With Pre- and Postoperative Seizures in 1033 Patients Undergoing Supratentorial Meningioma Resection

BACKGROUND Risk factors for pre- and postoperative seizures in supratentorial meningiomas are understudied compared to other brain tumors. OBJECTIVE To report seizure frequency and identify factors associated with pre- and postoperative seizures in a large single-center population study of patients undergoing resection of supratentorial meningioma. METHODS Retrospective chart review of 1033 subjects undergoing resection of supratentorial meningioma at the authors institution (1991-2014). Multivariate regression was used to identify variables significantly associated with pre- and postoperative seizures. RESULTS Preoperative seizures occurred in 234 (22.7%) subjects. At 5 years postoperative, probability of seizure freedom was 89.9% among subjects without preoperative seizures and 62.2% with preoperative seizures. Multivariate analysis identified the following predictors of preoperative seizures: presence of  ≥1 cm peritumoral edema (odds ratio [OR]: 4.45, 2.55-8.50), nonskull base tumor location (OR: 2.13, 1.26-3.67), greater age (OR per unit increase: 1.03, 1.01-1.05), while presenting symptom of headache (OR: 0.50, 0.29-0.84) or cranial nerve deficit (OR: 0.36, 0.17-0.71) decreased odds of preoperative seizures. Postoperative seizures after discharge were associated with preoperative seizures (OR: 5.70, 2.57-13.13), in-hospital seizure (OR: 4.31, 1.28-13.67), and among patients without preoperative seizure, occurrence of medical or surgical complications (OR 3.39, 1.09-9.48). Perioperative anti-epileptic drug use was not associated with decreased incidence of postoperative seizures. CONCLUSIONS Nonskull base supratentorial meningiomas with surrounding edema have the highest risk for preoperative seizure. Long-term follow-up showing persistent seizures in meningioma patients with preoperative seizures raises the possibility that these patients may benefit from electrocorticographic mapping of adjacent cortex and resection of noneloquent, epileptically active cortex.