Spinal cord high-grade infiltrating gliomas in adults: clinico-pathological and molecular evaluation.

Primary high-grade infiltrating gliomas of the spinal cord are rare, with prior series including limited numbers of cases and reporting poor outcomes. Additionally, the molecular profile of high-grade infiltrating gliomas of the spinal cord has not been well characterized. We identified 13 adult patients whose surgery had been performed at our institution over a 26-year-period. Radiologically, nine cases harbored regions of post-contrast enhancement. Existing slides were reviewed, and when sufficient tissue was available, immunohistochemical stains (IDH1-R132H, H3-K27M, H3K27-me3, ATRX, p53 and BRAF-V600E), and a targeted 150-gene neuro-oncology next-generation sequencing panel were performed. The 13 patients included 11 men and 2 women with a median age of 38 years (range = 18-69). Histologically, all were consistent with an infiltrating astrocytoma corresponding to 2016 WHO grades III (n = 5) and IV (n = 8). By immunohistochemistry, six cases were positive for H3K27M, all showing concomitant loss of H3K27-me3. Next-generation sequencing was successfully performed in ten cases. Next-generation sequencing studies were successfully performed in four of the cases positive for H3K27M by immunohistochemistry, and all were confirmed as H3F3A K27M-mutant. Additional recurrent mutations identified included those of TERT promoter (n = 3), TP53 (n = 5), PPM1D (n = 3), NF1 (n = 3), ATRX (n = 2), and PIK3CA (n = 2). No HIST1H3B, HIST1H3C, IDH1, IDH2, or BRAF mutations were detected. Ten patients have died since first surgery, with a median survival of 13 months and 1 year of 46%. Median survival was 48.5 months for H3K27M-positive cases, compared to 1 month for those with TERT promoter mutation and 77 months for those harboring neither (p = 0.019). Median survival for cases with TP53 mutations was 11.5 months and for those with PPM1D mutations was 84 months. Our findings suggest that high-grade infiltrating gliomas of the spinal cord in adults represent a heterogeneous group of tumors, with variable outcomes possibly related to their molecular profiles.

Drug-resistant focal epilepsy in women of childbearing age: Reproduction and the effect of epilepsy surgery.

OBJECTIVE: Women with epilepsy (WWE) have lower birth rates than expected. The reasons for this are multifactorial and involve a complex interaction between reproductive endocrine and psychosocial factors. The effect of epilepsy surgery on reproduction in women with drug-resistant focal epilepsy has not previously been studied. METHODS: Adult women of childbearing age (18-45years old) with drug-resistant focal epilepsy who had undergone a focal cortical resection between 1997 and 2008 at the Mayo Clinic in Rochester, MN were included in the study. Patients who had a history of hysterectomy or tubal ligation or who were menopausal at the time of surgery were excluded. Data on prior pregnancies and births, epilepsy history, surgical treatment, hormonal dysfunction, and socioeconomic status were obtained using a retrospective chart review. Associations between various clinical and demographic variables with changes in pregnancies and births from pre- to postsurgery were assessed using Chi-square or Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. All tests were 2-sided, and p-values less than 0.05 were considered statistically significant. All analyses were performed using SAS software version 9.2 (SAS INC, Cary NC). RESULTS: One hundred and thirteen women (average age: 30.5years) were included in the study. Average length of follow-up was 5.7years (SD-3.90). Sixty-four patients (57.5%) were nulliparous at the time of surgery. Sixty-one patients (54%) had never been married. Average number of pregnancies per patient prior to surgery was 0.93, and average number of births prior to surgery was 0.73. After surgery, a total of 17 women had a total of 35 pregnancies and 25 births. The average number of pregnancies and births after surgery was 1.27 and 0.96, respectively. Infertility was reported in one patient postoperatively. Patients who were younger at the time of surgery experienced a greater change in the number of pregnancies and births after surgery (p=0.0036 and 0.0060, respectively). Patients who received fewer antiepileptic drug medication trials by the time of surgery also had a greater change in the number of births after surgery (p=0.0362). Seizure onset localization and lateralization, presurgical seizure frequency, age at seizure onset, duration of epilepsy, and postoperative seizure outcome were not statistically significant factors. CONCLUSION: The present retrospective observational study provides additional evidence for the importance of early surgical treatment in women with drug-resistant focal epilepsy. Patients who had received fewer medications prior to surgery were more likely to experience an increase in births following surgery. The significance of these findings requires further investigation but may support a role for earlier surgical intervention in the management of drug-resistant focal epilepsy.

Predicting long-term outcomes after microvascular decompression for hemifacial spasm according to lateral spread response and immediate postoperative outcomes: a cohort study.

OBJECTIVE: Microvascular decompression (MVD) is a well-established and highly effective treatment option for hemifacial spasm (HFS). Lateral spread response (LSR) has been used as an intraoperative indicator of HFS resolution, with controversial reliability. The purpose of this study was to determine long-term outcomes of MVD for HFS and the role of LSR and other preoperative predictors. METHODS: The authors conducted a cohort study of all patients treated with MVD for HFS at a single institution from January 1, 1998, to December 31, 2019. In addition to a retrospective chart review, all patients were contacted at the time of the study to provide informed consent and responded to a telephone survey to ascertain their current disease and medication status. Patients with at least 12 months of postoperative follow-up were included. Statistical testing included a Student t-test, Fisher's exact test, logistic regression, and Cox proportional hazards analysis. RESULTS: One hundred nineteen patients met study criteria; 41 (34%) had at least 10 years of clinical follow-up. HFS fully resolved in 93 (78%), symptoms subjectively improved in 11 (9%) and were unchanged in 15 (13%). Immediate postoperative HFS status did not correlate with long-term outcome (p = 0.13). Changes in LSR were not associated with outcome. Patients receiving neuromodulating agents had significantly longer preoperative duration of symptoms and were more likely to show persistent LSR intraoperatively. HFS recurrence was associated with younger age at the time of surgery but not with intraoperative LSR resolution. CONCLUSIONS: This study demonstrated that MVD for HFS is highly effective for most patients. Neither intraoperative LSR change nor immediate postoperative status was predictive of long-term outcomes.

Plasma extracellular vesicles as a source of biomarkers in traumatic brain injury.

OBJECTIVE: The objective of this study was to isolate extracellular vesicles (EVs) from plasma in a cohort of patients with traumatic brain injury (TBI) and analyze their contents for novel biomarkers that could prove useful for rapid diagnosis and classification of brain injury during initial evaluation. METHODS: Plasma EVs were isolated by serial ultracentrifugation from patients with TBI (n = 15) and healthy controls (n = 5). Samples were obtained from the TRACK-TBI biorepository (2010-present). Size and concentration were determined by nanoparticle tracking. Glial fibrillary acidic protein (GFAP) concentration was determined in EV protein. EV RNA was isolated and deep sequencing of short noncoding RNA was performed. RESULTS: Plasma EVs are physically similar but contained approximately 10 times more GFAP in TBI patients with altered consciousness than patients and controls with normal consciousness. Eleven highly differentially expressed microRNAs (miRNAs) were identified between these groups. Genes targeted by these miRNAs are highly associated with biologically relevant cellular pathways, including organismal injury, cellular development, and organismal development. Multiple additional coding and noncoding RNA species with potential biomarker utility were identified. CONCLUSIONS: Isolating plasma EVs in patients with TBI is feasible. Increased GFAP concentration-a validated plasma TBI marker-in EVs from TBI patients with altered consciousness, along with differential expression of multiple miRNAs targeting TBI-relevant pathways, suggests that EVs may be a useful source of TBI biomarkers. Additional evaluation in larger patient cohorts is indicated.

Perceptions of overlapping surgery in neurosurgery based on practice volume: A multi-institutional survey.

OBJECTIVE: Overlapping surgery, accepted by many as two distinct operations occurring at the same time but without coincident critical portions, has been said to improve patient access to surgical care. With recent controversy, some are opposed to this practice due to concerns regarding its safety. In this manuscript, we sought to investigate the perceptions of overlapping surgery among neurosurgical leadership and the association of these perceptions with neurosurgical case volume. PATIENTS AND METHODS: We conducted a self-administered survey of neurosurgery department chair and residency program directors of institutions participating in the Vizient Clinical Database/Resource (CDB/RM), an administrative database of 117 United States (US) medical centers and their 300 affiliated hospitals. We queried participants regarding yearly departmental case-volume, frequency of overlapping surgery in daily practice and the degree of overlapping they find acceptable. RESULTS: Of the 236 surveys disseminated, a total of 70 responses were received with a response rate of 29.7.%, which is comparable to previously reported response rates among neurosurgeons and other physicians. Our respondents consisted of 43 of 165 chairs (26.1.%) and 27 of 66 program directors (40.0.%) representing 64 unique hospitals/institutions out of 216 (29.6.%). Based on the responses to question involving case volume, we divided our responders into high volume hospitals (HVH) (n = 44; > 2000 cases per year) and low volume hospitals (LVH) (N = 26). More HVH were found to have frequent occurrence of overlapping surgery (50% weekly and 20.9.% daily vs LVH's 26.9.% weekly and 3.8.% daily, p = 0.003) and considered two overlapping surgeries without overlap of critical portion as acceptable (38.6.% vs 26.9.%, p = 0.10). CONCLUSIONS: Our survey results showed that neurosurgical departments with high-volume practices were more likely to practice overlapping surgery on a regular basis and to view it as an acceptable practice. The association between overlapping surgery and the volume-outcome relationship should be further evaluated.

Central nervous system tumors.

Central nervous system tumors are relatively common in the United States, with more than 40,000 cases annually. Although more than half of these tumors are benign, they can cause substantial morbidity. Malignant primary brain tumors are the leading cause of death from solid tumors in children and the third leading cause of death from cancer in adolescents and adults aged 15 to 34 years. Common presenting symptoms include headache, seizures, and altered mental status. Whereas magnetic resonance imaging helps define the anatomic extent of tumor, biopsy is often required to confirm the diagnosis. Treatment depends on the histologic diagnosis. Benign tumors are usually curable with surgical resection or radiation therapy including stereotactic radiation; however, most patients with malignant brain tumors benefit from chemotherapy either at the time of initial diagnosis or at tumor recurrence. Metastases to the brain remain a frequent and morbid complication of solid tumors but are frequently controlled with surgery or radiation therapy. Unfortunately, the mortality rate from malignant brain tumors remains high, despite initial disease control. This article provides an overview of current diagnostic and treatment approaches for patients with primary and metastatic brain tumors.

Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma.

Cushing's disease is caused by functional corticotroph adenomas of the pituitary, mostly noninvasive microadenomas. Classic Crooke's cells are nonneoplastic corticotrophs with cytoplasmic accumulation of cytokeratin filaments in response to glucocorticoid excess. Corticotroph adenomas exhibiting Crooke's change are rare and incompletely understood. We intend to define more clearly the clinicopathological features of Crooke's cell adenomas (CCA). Thirty-six CCAs were retrieved from the files of Mayo Clinic and from our (B.W.S., K.K.) consultation files. The number of informative cases varied for different criteria. Clinical follow-up was obtained in 31 cases. The 27 females and 9 males were 18 to 81 years of age (mean 46 years). At presentation, Cushing's disease was evident in 22/34 (65%); 81% were macroadenomas and 72% were invasive. All were initially treated by transsphenoidal resection. Twenty-five patients were followed for more than 1 year (mean 6.7 years). Of these, 15 (60%) developed recurrent tumor, and 6 (24%) had multiple recurrences. Lastly, 3 of these 25 patients (12%) died of tumor: 1 after multiple local recurrences and 2 from pituitary carcinoma. Compared with typical corticotroph adenomas, CCAs are aggressive. Most are functional adenomas occurring in middle-aged women and are invasive macroadenomas prone to recurrence. Morbidity and mortality rates are substantial. CCAs represent a distinct entity that should be separated from corticotroph adenomas without Crooke's hyaline change.

Prognostic importance of risk factors for temporal lobe epilepsy in patients undergoing surgical treatment.

OBJECTIVE: To investigate the prognostic importance of an identified putative underlying risk factor in patients undergoing surgery for intractable temporal lobe epilepsy (TLE). PATIENTS AND METHODS: A retrospective study of 400 consecutive patients who underwent TLE surgery between December 21, 1987, and September 11, 1996, was performed. Demographic characteristics, history of remote symptomatic neurologic disease, preoperative evaluation, and postoperative outcome data were extracted. Individuals without any risk factors were considered controls. Magnetic resonance imaging findings were used to identify mesial temporal sclerosis (MTS) before surgery. Seizure outcome was classified by a modified Engel classification. RESULTS: Two hundred eighty-one patients had a potential underlying etiology, and 143 patients had more than 1 risk factor. One hundred nineteen patients had no evidence of a putative symptomatic neurologic illness. There was a statistically significant association (P<.05) between the presence of MTS and a favorable operative outcome (odds ratio, 4.28; 95% CI, 2.67-6.87). A history of remote symptomatic neurologic disease was not of prognostic importance unless associated with the development of MTS. CONCLUSION: These results indicate that the preoperative identification of MTS by neuroimaging is the most important predictor of a favorable operative outcome in patients with TLE. These findings may be useful in the identification and counseling of potential candidates for epilepsy surgery.

Awake craniotomy, electrophysiologic mapping, and tumor resection with high-field intraoperative MRI.

BACKGROUND: Awake craniotomy and electrophysiologic mapping (EPM) is an established technique to facilitate the resection of near eloquent cortex. Intraoperative magnetic resonance imaging (iMRI) is increasingly used to aid in the resection of intracranial lesions. Standard draping protocols in high-field iMRI units make awake craniotomies challenging, and only two groups have previously reported combined EPM and high-field iMRI. METHODS: We present an illustrative case describing a simple technique for combining awake craniotomy and EPM with high-field iMRI. A movable platter is used to transfer the patient from the operating table to a transport trolley and into the adjacent MRI and still maintaining the patient's surgical position. This system allows excess drapes to be removed, facilitating awake craniotomy. RESULTS: A 57-year-old right-handed man presented with new onset seizures. Magnetic resonance imaging demonstrated a large left temporal mass. The patient underwent an awake, left frontotemporal craniotomy. The EPM demonstrated a single critical area for speech in his inferior frontal gyrus. After an initial tumor debulking, the scalp flap was loosely approximated, the wound was covered with additional drapes, and the excess surrounding drapes were trimmed. An iMRI was obtained. The image-guidance system was re-registered and the patient was redraped. Additional resection was performed, allowing extensive removal of what proved to be an anaplastic astrocytoma. The patient tolerated this well without any new neurological deficits. CONCLUSIONS: Standard protocols for positioning and draping in high-field iMRI units make awake craniotomies problematic. This straightforward technique for combined awake EPM and iMRI may facilitate safe removal of large lesions in eloquent cortex.

Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization.

BACKGROUND AND PURPOSE: Placenta growth factor (PlGF) mediates angiogenesis and inflammation, but its role in human atherosclerosis is unknown. This study was designed to test the hypothesis that PlGF-expression in human atherosclerotic carotid plaques is related to inflammation, vascularization and clinical plaque instability. METHODS: The expression of PlGF, C-reactive protein (CRP) and CD40L was analyzed with Western blots in carotid plaques of 60 patients. Cellular infiltration (CD68, CD3) and vascularization (von-Willebrand-factor) was assessed by immunohistochemistry. RESULTS: Symptomatic patients showed higher levels of PlGF than asymptomatic patients (115.4+/-8.2 versus 83.6+/-10.5 densitometric units (DU), p<0.05) and higher grading for inflammatory cells and microvessels (CD3: 2.3+/-0.1 versus 0.6+/-0.1, p<0.001, CD68: 2.4+/-0.1 versus 0.8+/-0.1, p<0.001, microvessels: 2.3+/-0.1 versus 1.5+/-0.1, p<0.01). PlGF-expression showed a positive correlation to the expression of CRP (r=0.5, p<0.001) and CD40L (r=0.4, p<0.01). CONCLUSIONS: PlGF-expression within human atherosclerotic lesions is associated with plaque inflammation and microvascular density, suggesting a role for PlGF in plaque destabilization and, thus, in clinical manifestation of the disease.

Functional profile of activated dendritic cells in unstable atherosclerotic plaque.

BACKGROUND: Unstable atherosclerotic plaque typically contains an infiltrate of activated macrophages and activated T cells. This study established a functional profile of plaque-residing dendritic cells (DC) to examine whether they can function as Ag-presenting cells to facilitate in situ T-cell activation. METHODS: Carotid artery plaque tissues were collected from 19 asymptomatic and 38 symptomatic patients undergoing endarterectomy. Matched samples of normal coronary artery wall, stable nonruptured plaque, and eroded unstable plaque were harvested from patients with fatal myocardial infarction. Quantitative PCR and immunohistochemistry were used to analyze the tissues for markers of DC activation (CD83, CD86, CCL19,CCL21) and correlate them with T-cell activation (IFN-gamma,TNF-alpha). RESULTS: Carotid artery plaques from patients with ischemic symptoms compared to asymptomatic patients were characterized by the presence of high amount of T-cells (P<0.01) and tissue production of high levels of the T-cell cytokines IFN-gamma (P=0.001) and TNF-alpha (P=0.006). Plaque tissues from patients with ischemic complications contained elevated levels of CD83 (P<0.001), a marker of DC activation, and the DC chemokines CCL19 (P=0.001) and CCL21 (P<0.02). Unstable coronary artery plaques were similarly correlated compared to carotid plaques from symptomatic patients with the accumulation of T cells (P=0.001) and the production of T cell chemokines IFN-gamma (P=0.001) and TNF-alpha (P=0.002). Immunohistochemistry confirmed the presence of CD83(+) DC in the shoulder region of unstable plaques, where they produced the T cell-attracting chemokines CCL19 and CCL21. Mapping of activated DC demonstrated close contact between mature DC and T cells expressing the activation marker CD40 ligand (CD40L). CONCLUSION: Activated and fully mature DC are represented in the inflammatory infiltrate characteristic for unstable carotid and coronary atheroma. Such DC produce chemokines, and thus can regulate the cell traffic into the lesion. Through the expression of the costimulatory ligand CD86, plaque-residing DC can augment T-cell stimulation and provide optimal stimulation conditions for T lymphocytes, resembling the microenvironment in organized lymphoid tissues.

Angiogenesis in patients with craniopharyngiomas: correlation with treatment and outcome.

BACKGROUND: Craniopharyngiomas are histologically benign epithelial neoplasms of the sellar region that often exhibit aggressive and invasive growth. The authors hypothesized that tumor proliferation, spread, and recurrence are angiogenesis dependent and investigated the significance of vascularization relative to biologic behavior. To the authors' knowledge, angiogenesis for patients with craniopharyngiomas has not been examined to date. METHODS: The authors measured microvessel densities in resected, histologically proven craniopharyngiomas using immunostains for CD-34, a monoclonal antibody that selectively recognizes endothelial cells. Both histologic types of craniopharyngiomas, adamantinomatous and papillary, were included in the study. In addition, the cellular distribution of vascular endothelial growth factor (VEGF), a strong stimulator of new vessel formation, was assessed by both immunohistochemistry and in situ hybridization for VEGF receptor 2 (VEGFR-2) mRNA expression. RESULTS: Histologically, small numbers of capillaries were identified in temporal stroma but not in their epithelial components. Immunohistochemistry revealed strong, conclusive cytoplasmic immunoreactivity for VEGF in the epithelial cells of both adamantinomatous craniopharyngiomas and papillary craniopharyngiomas. In situ hybridization showed that VEGFR-2 mRNA was expressed widely, not only in neoplastic epithelium but also in capillary endothelium. CONCLUSIONS: Tumors with greater microvessel density regrow more frequently compared with tumors that have lower microvessel density, suggesting that the extent of angiogenesis is of prognostic value in patients with craniopharyngioma. VEGFR-2 may act as a key modulator of VEGF activity in endothelial cells and nonendothelial cells, indicating that VEGF plays an important role in the behavior of craniopharyngiomas.

Focal ictal beta discharge on scalp EEG predicts excellent outcome of frontal lobe epilepsy surgery.

PURPOSE: To determine whether a focal beta-frequency discharge at seizure onset on scalp EEG predicts outcome of frontal lobe epilepsy (FLE) surgery. METHODS: We identified 54 consecutive patients with intractable FLE who underwent epilepsy surgery between December 1987 and December 1996. A blind review of EEGs and magnetic resonance images (MRIs) was performed. Lesional epilepsy is defined as presence of an underlying structural abnormality on MRI. RESULTS: Overall, 28 (52%) patients were seizure free, with a mean follow-up of 46.5 months. Presence of a focal beta-frequency discharge at seizure onset on scalp EEG predicted seizure-free outcome in lesional (p = 0.02) and non-lesional (p = 0.01) epilepsy patients. At least 90% of patients who had either lesional or non-lesional epilepsy were seizure free if scalp EEG revealed a focal beta discharge at ictal onset. Moreover, logistic regression analysis showed that focal ictal beta pattern and completeness of lesion resection were independently predictive of seizure-free outcome. Ictal onset with lateralized EEG activity of any kind and postresection electrocorticographic spikes did not predict surgical outcome (p > 0.05). CONCLUSIONS: Only about 25% of FLE surgical patients have a focal beta-frequency discharge at seizure onset on scalp EEG. However, its presence is highly predictive of excellent postsurgical seizure control in either lesional or non-lesional FLE surgical patients.