Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

Strategies to improve surgical technical competency: a systematic review.

BACKGROUND: A cornerstone of surgical residency training is an educational program that produces highly skilled and effective surgeons. Training structures are constantly being revised due to evolving program structures, shifting workforces, and variability in the clinical environment. This has resulted in significant heterogeneity in all surgical resident education, training tools utilized, and measures of training efficacy. METHODS: We systematically reviewed educational interventions for technical skills in neurosurgery published across PubMed, Embase, and Web of Science over four decades. We extracted general characteristics of each surgical training tool while categorizing educational interventions by modality and neurosurgical application. RESULTS: We identified 626 studies which developed surgical training tools across eight different training modalities: textbooks and literature (11), online resources (53), didactic teaching and one-on-one instruction (7), laboratory courses (50), cadaveric models (63), animal models (47), mixed reality (166), and physical models (229). While publication volume has grown exponentially, a majority of studies were cited with relatively low frequency. Most training programs were published in the development and validation phase with only 2.1% of tools implemented long-term. Each training modality expressed unique strengths and limitations, with limited data reported on the educational impact connected to each training tool. CONCLUSIONS: Numerous surgical training tools have been developed and implemented across residency training programs. Though many creative and cutting-edge tools have been devised, evidence supporting educational efficacy and long-term application is lacking. Increased utilization of novel surgical training tools will require validation of metrics used to assess the training outcomes and optimized integration with clinical practice.

Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway.

Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Does minimally invasive spine surgery improve outcomes in the obese population? A retrospective review of 1442 degenerative lumbar spine surgeries.

OBJECTIVE: The effect of obesity on outcomes in minimally invasive surgery (MIS) approaches to posterior lumbar surgery is not well characterized. The authors aimed to determine if there was a difference in operative variables and complication rates in obese patients who underwent MIS versus open approaches in posterior spinal surgery, as well as between obese and nonobese patients undergoing MIS approaches. METHODS: A retrospective review of all consecutive patients who underwent posterior lumbar surgery from 2013 to 2016 at a single institution was performed. The primary outcome measure was postoperative complications. Secondary outcome measures included estimated blood loss (EBL), operative time, the need for revision, and hospital length of stay (LOS); readmission and disposition were also reviewed. Obese patients who underwent MIS were compared with those who underwent an open approach. Additionally, obese patients who underwent an MIS approach were compared with nonobese patients. Bivariate and multivariate analyses were carried out between the groups. RESULTS: In total, 423 obese patients (57.0% decompression and 43.0% fusion) underwent posterior lumbar MIS. When compared with 229 obese patients (56.8% decompression and 43.2% fusion) who underwent an open approach, patients in both the obese and nonobese groups who underwent MIS experienced significantly decreased EBL, LOS, operative time, and surgical site infections (SSIs). Of the nonobese patients, 538 (58.4% decompression and 41.6% fusion) underwent MIS procedures. When compared with nonobese patients, obese patients who underwent MIS procedures had significantly increased LOS, EBL, operative time, revision rates, complications, and readmissions in the decompression group. In the fusion group, only LOS and disposition were significantly different. CONCLUSIONS: Obese patients have poorer outcomes after posterior lumbar MIS when compared with nonobese patients. The use of an MIS technique can be of benefit, as it decreased EBL, operative time, LOS, and SSIs for posterior decompression with or without instrumented fusion in obese patients.

Comparison of Clinical and Radiographic Outcomes After Standalone Versus Cage and Plate Constructs for Anterior Cervical Discectomy and Fusion.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) has conventionally been performed using an allograft cage with a plate-and-screw construct. Recently, standalone cages have gained popularity due to theorized decreases in operative time and postoperative dysphagia. Few studies have compared these outcomes. Here, we directly compare the outcomes of plated versus standalone ACDF constructs. METHODS: A single-center retrospective review of patients undergoing ACDF after June 2011 with at least 6 months of follow up was conducted. Clinical outcomes were analyzed and compared between standalone and plated constructs. Multivariate regression analysis of the primary outcome, need for revision surgery, as well as several secondary outcomes, procedure duration, estimated blood loss (EBL), length of hospital stay, disposition, and incidence of dysphagia, hoarseness, or surgical site infection, was completed. RESULTS: A total of 321 patients underwent ACDF and met inclusion-exclusion criteria, with mean follow-up duration of 20 months. Forty-six (14.3%) patients received standalone constructs, while 275 (85.7%) received plated constructs. Fourteen (4.4%) total revisions were necessary, 4 in the standalone group and 10 in the plated group, yielding revision rates of 8.7% and 3.6%, respectively (P = .125). Mean EBL was 98 mL in the standalone group and 63 mL in the plated group (P = .001). Mean procedure duration was 147 minutes in the standalone group and 151 minutes in the plated group (P = .800). Mean hospital stay was 3.6 days in the standalone group and 2.5 days in the plated group (P = .270). There was no significant difference in incidence of dysphagia (P = .700) or hoarseness (P = .700). CONCLUSIONS: Standalone ACDF demonstrates higher, but not statistically significant, revision rates than plate-and-screw constructs, without the hypothesized decreased incidence of dysphagia or hoarseness and without decreased procedure duration or EBL. Surgeons may consider limiting use of these constructs to cases of adjacent segment disease. Larger studies with longer follow up are necessary to make more definitive conclusions. LEVEL OF EVIDENCE: 4. CLINICAL RELEVANCE: This study will help spine surgeons decide between using standalone or cage-and-plate constructs for ACDF.

Does minimally invasive spine surgery reduce the rate of perioperative medical complications? A retrospective single-center experience of 1435 degenerative lumbar spine surgeries.

PURPOSE: It is unclear if minimally invasive techniques reduce the rate of perioperative complications when compared to traditional open approaches to the lumbar spine. Our aim was to evaluate perioperative complications in patients that underwent MIS and conventional open techniques for degenerative lumbar pathology. METHODS: A retrospective review of a prospectively collected database identified 1435 patients that underwent surgery for degenerative lumbar pathology from January 2013-2016. We evaluated the rates of deep vein thrombosis, pulmonary embolism, urinary tract infection, and pneumonia. Groups were analyzed based on decompression alone as compared with decompression and fusion for both MIS and traditional open techniques. RESULTS: Patients that underwent traditional open lumbar decompression surgery were more likely to develop a DVT (P = .01) than those undergoing MIS decompression. There was no significant difference in rates of PE (P = .99), UTI (P = .24), or pneumonia (P = .56). Patients that underwent traditional open lumbar fusion surgery compared to MIS fusion were also more likely to have a PE (P = .03). There was no significant difference in rates of DVT (P = .22), UTI (P = .43), or pneumonia (P = .24). CONCLUSION: Minimally invasive spinal surgery was found to reduce the rate of DVT for decompression surgeries and reduce the rate of PE for fusion surgeries.

Spontaneous Occlusion of a Complex Brain Arteriovenous Malformation Following Partial Embolization.

BACKGROUND: Curative embolization for cerebral arteriovenous malformation (AVM) cannot always be achieved. Rather, embolization plays a role in AVM treatment as an adjuvant therapy before radiosurgery and microsurgery. Curative embolization for large, complex AVMs is not commonly seen. CASE DESCRIPTION: A man in his 30s with an unruptured left cerebral AVM underwent radiosurgery in 2014 and was lost to follow-up. He presented with intracerebral hemorrhage in 2019, and diagnostic cerebral angiography demonstrated a large, complex AVM. The patient was scheduled for 2-stage embolization in preparation for microsurgical resection. Initial embolization targeted and occluded 20% of the AVM nidus involving primarily the anteroinferior portion. A cerebral angiogram obtained 5 weeks following initial embolization revealed spontaneous occlusion of the remaining AVM. CONCLUSIONS: There are few reported cases of spontaneous occlusion of a large, complex AVM following embolization with previous radiation therapy. The spontaneous occlusion in this case suggests that at least some AVMs that receive embolization after radiation, rather than before, may have a potential for spontaneous, curative thrombosis.

Reoperation, Readmission, and Discharge Disposition for Patients With Degenerative Lumbar Pathology Treated With Either Open or Minimally Invasive Techniques: A Single-Center Retrospective Review of 1435 Cases.

BACKGROUND: Spine surgery has been transformed by the growth of minimally invasive surgery (MIS) procedures. Previous studies agree that MIS has shorter hospitalization and faster recovery time when compared to conventional open surgery. However, the reoperation and readmission rates between the 2 techniques have yet to be well characterized. OBJECTIVE: To evaluate the rate of subsequent revision between MIS and open techniques for degenerative lumbar pathology. METHODS: A total of 1435 adult patients who underwent lumbar spine surgery between 2013 and 2016 were included in this retrospective analysis. The rates of need for subsequent reoperation, 30- and 90-d readmission, and discharge to rehabilitation were recorded for both MIS and traditional open techniques. Groups were divided into decompression alone and decompression with fusion. RESULTS: The rates of subsequent reoperation following MIS and open surgery were 10.4% and 12.2%, respectively (P = .32), which were maintained when subdivided into decompression and decompression with fusion. MIS and open 30-d readmission rates were 7.9% and 7.2% (P = .67), while 90-d readmission rates were 4.3% and 3.6% (P = .57), respectively. Discharge to rehabilitation was significantly lower for patients under 60 yr of age undergoing MIS (1.64% vs 5.63%, P = .04). CONCLUSION: The use of minimally invasive techniques for the treatment of lumbar spine pathology does not result in increased reoperation or 30- and 90-d readmission rates when compared to open approaches. Patients under the age of 60 yr undergoing MIS procedures were less likely to be discharged to rehab.

The incidence of symptomatic postoperative epidural hematoma after minimally invasive lumbar decompression: A single institution retrospective review.

OBJECTIVE: Postoperative epidural hematoma (PEDH) after minimally invasive lumbar laminectomy (MILL) can lead to significant morbidity and healthcare cost. The incidence is not well characterized in the literature as compared with traditional open techniques. Our aim was to define the incidence of PEDH after MIS lumbar decompression procedures and evaluate strategies for reduction of PEDH. PATIENTS AND METHODS: A retrospective review of a prospectively collected database was queried from January 2013 to September 2018 for all patients that underwent a minimally invasive lumbar laminectomy or laminotomy, with or without discectomy, for which the goal was decompression alone. Charts were reviewed to see the operation type and whether the patient developed a postoperative epidural hematoma. RESULTS: 1004 cases were identified and reviewed. The overall PEDH rate was 1.4 % (14/1004). 78.5 % (11/14) of cases involved at least a single level laminectomy. 21.4 % (3/14) involved a laminotomy alone or with discectomy. 64.3 % (9/14) of patients presented with a neurological deficit. CONCLUSIONS: The rate of PEDH after MIS lumbar decompression procedures is 1.4 %. A majority of patients presented with a neurological deficit.

Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis.

Loss-of-function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinson's disease termed Kufor-Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinson's disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Parkinson's disease and Gaucher's disease, a lysosomal storage disorder. Mutations in ATP13A2 are generally thought to be loss of function; however, the lack of human autopsy tissue has prevented the field from determining the pathological consequences of losing functional ATP13A2. We and others have previously neuropathologically characterized mice completely lacking murine Atp13a2, demonstrating the presence of lipofuscinosis within the brain - a key feature of NCL, one of the diseases to which ATP13A2 mutations have been linked. To determine if loss of one functional Atp13a2 allele can serve as a risk factor for disease, we have now assessed heterozygous Atp13a2 knockout mice for key features of NCL. In this report, we demonstrate that loss of one functional Atp13a2 allele leads to both microgliosis and astrocytosis in multiple brain regions compared to age-matched controls; however, levels of lipofuscin were only modestly elevated in the cortex of heterozygous Atp13a2 knockout mice over controls. This data suggests the possibility that partial loss of ATP13A2 causes inflammatory changes within the brain which appear to be independent of robust lipofuscinosis. This study suggests that heterozygous loss-of-function mutations in ATP13A2 are likely harmful and indicates that glial involvement in the disease process may be an early event that positions the CNS for subsequent disease development.

The diagnosis and natural history of Huntington disease.

Huntington disease (HD) is an autosomal-dominant disorder resulting from CAG triplet repeats, which leads to an expanded polyglutamine sequence in the HTT (Huntingtin) protein. Accumulation of the Huntingtin protein ultimately leads to neurodegeneration and negative effects in multiple clinical domains, including motor function, cognition, and behavior. HD is a disorder governed by genetics, and the ability to quantify the CAG triplet repeats can provide important insight regarding clinical onset, severity, and disease progression. HD affects generations of family members and can typically span several decades. Understanding HD is invaluable for the advancement in therapeutics for other prevalent neurodegenerative disorders caused by the accumulation of misfolded proteins such as Parkinson disease, Alzheimer disease, and Lewy body dementia.

Studies of alternative isoforms provide insight into TDP-43 autoregulation and pathogenesis.

TDP-43 is a soluble, nuclear protein that undergoes cytoplasmic redistribution and aggregation in the majority of cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 autoregulates the abundance of its own transcript TARDBP by binding to an intron in the 3' untranslated region, although the mechanisms underlying this activity have been debated. Herein, we provide the most extensive analysis of TARDBP transcript yet undertaken. We detail the existence of a plethora of complex splicing events and alternative poly(A) use and provide data that explain the discrepancies reported to date regarding the autoregulatory capacity of TDP-43. Additionally, although many splice isoforms emanating from the TARDBP locus contain the regulated intron in the 3' UTR, we find only evidence for autoregulation of the transcript encoding full-length TDP-43. Finally, we use a novel cytoplasmic isoform of TDP to induce disease-like loss of soluble, nuclear TDP-43, which results in aberrant splicing and up-regulation of endogenous TARDBP. These results reveal a previously underappreciated complexity to TDP-43 regulated splicing and suggest that loss of TDP-43 autoregulatory capacity may contribute to the pathogenesis of ALS.

Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling.

The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy.