Publications by authors named "Iyan Younus"

25 Publications

  • Page 1 of 1

The slope of the learning curve in 600 consecutive endoscopic transsphenoidal pituitary surgeries.

Acta Neurochir (Wien) 2020 10 1;162(10):2361-2370. Epub 2020 Jul 1.

Department of Neurosurgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.

Background: Endonasal endoscopic transsphenoidal surgery (EETS) for pituitary adenoma has become a mainstay of treatment over the last two decades and it is generally accepted that once this learning curve is achieved, a plateau is reached with little incremental improvement.

Objective: The objective of this study was to assess the slope of the learning curve over a long period of time for a variety of outcomes measures.

Methods: We examined outcomes and complications in a consecutive series of 600 EETS for pituitary adenoma grouped into quartiles based on date of surgery.

Results: GTR significantly increased across quartiles from 55 to 79% in the last quartile (p < 0.005). The rate of intraoperative CSF leak significantly decreased from 60% in the first quartile to 33% in the last quartile and the rate of lumbar drain placement from 28% in the first quartile to 6% in the last quartile (p < 0.005). Hormonal remission for secreting adenomas increased from 68% in the first quartile to 90% in the last quartile (p < 0.05). The rate of post-operative CSF leak trended lower (3% in first quartile to 0.7% in last two quartiles). The greatest improvement in outcome occurred between the first and second quartiles (19.9%), but persistent improvement occurred between the second and third (6.7%) and third and fourth quartiles (8.0%).

Conclusion: Although the slope of the learning curve is steeper earlier in a surgeon's experience, the slope does not plateau and continues to increase even over more than a decade.
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http://dx.doi.org/10.1007/s00701-020-04471-xDOI Listing
October 2020

Medical Student Concerns Relating to Neurosurgery Education During COVID-19.

World Neurosurg 2020 07 16;139:e836-e847. Epub 2020 May 16.

Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA. Electronic address:

Background: The coronavirus disease 2019 (COVID-19) pandemic has created significant obstacles within medical education. For medical students interested in pursuing neurosurgery as a specialty, the educational policies surrounding COVID-19 have resulted in unique challenges. The present study used a nationwide survey to identify the concerns of medical students interested in pursuing neurosurgery during the COVID-19 pandemic.

Methods: Students who had previously registered for medical student neurosurgery training camps were sent an online Qualtrics survey requesting them to assess how the COVID-19 pandemic was affecting their neurosurgical education. The Pearson χ test and post hoc pairwise Fisher exact test were used for analysis of categorical variables, and the 2-tailed paired Student t test was used for continuous variables.

Results: The survey was distributed to 852 medical students, with 127 analyzed responses. Concerns regarding conferences and networking opportunities (63%), clinical experience (59%), and board examination scores (42%) were most frequently cited. Of the third-year medical students, 76% reported ≥1 cancelled or postponed neurosurgery rotation. On average, students were more likely to take 1 year off from medical school after than before the start of the COVID-19 pandemic, measured from 0 to 100 (25.3 ± 36.0 vs. 39.5 ± 37.5; P = 0.004). Virtual mentorship pairing was the highest rated educational intervention suggested by first- and second-year medical students. The third- and fourth-year medical students had cited virtual surgical skills workshops most frequently.

Conclusions: The results from the present nationwide survey have highlighted the concerns of medical students regarding their neurosurgery education during the COVID-19 pandemic. With these findings, neurosurgery organizations can consider targeted plans for students of each year to continue their education and development.
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http://dx.doi.org/10.1016/j.wneu.2020.05.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229732PMC
July 2020

Medical Students' Perceived Interests and Concerns for a Career in Neurosurgery.

World Neurosurg 2020 07 6;139:e203-e211. Epub 2020 Apr 6.

Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA.

Objective: The factors that attract and concern medical students about a career in neurosurgery have never been clearly characterized or delineated in a large nationwide cohort of medical students intending to pursue a career in neurosurgery. The objective of the present study was to characterize the factors that influence medical student interest in neurosurgery and assess the effects of a formal neurosurgery training course on participants' perceptions of a career in neurosurgery.

Methods: Before the Medical Student Neurosurgery Training Camp for subinternship preparation, registered students were surveyed about their interest level in neurosurgery, factors that attracted or concerned them about a career in neurosurgery, attendance at a national neurosurgery conference or course, formal clinical neurosurgery exposure in medical school, and whether they had a resident or attending mentor in neurosurgery. At the end of the course, all the participants completed the surveyed again. P < 0.05 was considered significant on Pearson's χ and Fisher's exact tests for categorical variables and 2-tailed paired Student's t tests for continuous variables.

Results: Of the training camp attendees, >95% completed both pre- and postcourse surveys, including 41 first-year, 19 second-year, 30 third-year, and 5 fourth-year medical school students. The most common factors that concerned students about a career in neurosurgery were work-life balance (76%) and competitiveness (56%). All factors of concern were decreased in the postcourse survey, except for competitiveness. A small cohort (8.4%) of students had no concerns about a career in neurosurgery; this cohort had doubled to 17% after the course (P < 0.05). The students that indicated no concern had a greater postcourse interest level in neurosurgery (95.8 ± 8.7 vs. 86.7 ± 20.5; P < 0.05). Student reasons for an interest in neurosurgery included intellectually stimulating work (94%), interest in neurosciences (93%), effect on patients (84%), innovation and new technology (80%), research opportunities (77%), and prestige (24%). All reasons increased after the course, with the exception of prestige, which decreased to 22%.

Conclusion: A training camp for students pursuing a neurosurgery subinternship was effective in providing transparency and positively influencing the factors that attract and concern students about a career in neurosurgery. Characterization of medical student perceptions of neurosurgery from a large, nationwide cohort of students pursuing a subinternship has provided novel data and could help identify factors protecting against burnout later in life.
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http://dx.doi.org/10.1016/j.wneu.2020.03.169DOI Listing
July 2020

Impact of Medicaid insurance on outcomes following endoscopic transsphenoidal pituitary surgery.

J Neurosurg 2020 Mar 20:1-6. Epub 2020 Mar 20.

Departments of2Neurosurgery.

Objective: Despite the rise of studies in the neurosurgical literature suggesting that patients with Medicaid insurance have inferior outcomes, there remains a paucity of data on the impact of insurance on outcomes after endonasal endoscopic transsphenoidal surgery (EETS). Given the increasing importance of complications in quality-based healthcare metrics, the objective of this study was to assess whether Medicaid insurance type influences outcomes in EETS for pituitary adenoma.

Methods: The authors analyzed a prospectively acquired database of EETS for pituitary adenoma from 2005 to 2018 at NewYork-Presbyterian Hospital, Weill Cornell Medicine. All patients with Medicaid insurance were identified. As a control group, the clinical, socioeconomic, and radiographic data of all other patients in the series with non-Medicaid insurance were reviewed. Statistical significance was determined with an alpha < 0.05 using Pearson chi-square and Fisher's exact tests for categorical variables and the independent-samples t-test for continuous variables.

Results: Of 584 patients undergoing EETS for pituitary adenoma, 57 (10%) had Medicaid insurance. The maximum tumor diameter was significantly larger for Medicaid patients (26.1 ± 12 vs 23.1 ± 11 mm for controls, p < 0.05). Baseline comorbidities including diabetes mellitus, hypertension, smoking history, and BMI were not significantly different between Medicaid patients and controls. Patients with Medicaid insurance had a significantly higher rate of any complication (14% vs 7% for controls, p < 0.05) and long-term cranial neuropathy (5% vs 1% for controls, p < 0.05). There were no statistically significant differences in endocrine outcome or vision outcome. The mean postoperative length of stay was significantly longer for Medicaid patients compared to the controls (9.4 ± 31 vs 3.6 ± 3 days, p < 0.05). This difference remained significant even when accounting for outliers (5.6 ± 2.5 vs 3.0 ± 2.7 days for controls, p < 0.05). The most common causes of extended length of stay greater than 1 standard deviation for Medicaid patients were management of perioperative complications and disposition challenges. The rate of 30-day readmission was 7% for Medicaid patients and 4.4% for controls, which was not a statistically significant difference.

Conclusions: The authors found that larger tumor diameter, longer postoperative length of stay, higher rate of complications, and long-term cranial neuropathy were significantly associated with Medicaid insurance. There were no statistically significant differences in baseline comorbidities, apoplexy, endocrine outcome, vision outcome, or 30-day readmission.
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http://dx.doi.org/10.3171/2020.1.JNS192707DOI Listing
March 2020

How long is the tail end of the learning curve? Results from 1000 consecutive endoscopic endonasal skull base cases following the initial 200 cases.

J Neurosurg 2020 Feb 7:1-11. Epub 2020 Feb 7.

Departments of2Neurosurgery.

Objective: Endoscopic endonasal approaches (EEAs) to the skull base have evolved over the last 20 years to become an essential component of a comprehensive skull base practice. Many case series show a learning curve from the earliest cases, in which the authors were inexperienced or were not using advanced closure techniques. It is generally accepted that once this learning curve is achieved, a plateau is reached with little incremental improvement. Cases performed during the early steep learning curve were eliminated to examine whether the continued improvement exists over the "tail end" of the curve.

Methods: A prospectively acquired database of all EEA cases performed by the senior authors at Weill Cornell Medicine/NewYork-Presbyterian Hospital was reviewed. The first 200 cases were eliminated and the next 1000 consecutive cases were examined to avoid the bias created by the early learning curve.

Results: Of the 1000 cases, the most common pathologies included pituitary adenoma (51%), meningoencephalocele or CSF leak repair (8.6%), meningioma (8.4%), craniopharyngioma (7.3%), basilar invagination (3.1%), Rathke's cleft cyst (2.8%), and chordoma (2.4%). Use of lumbar drains decreased from the first half to the second half of our series (p <0.05) as did the authors' use of fat alone (p <0.005) or gasket alone (p <0.005) for dural closure, while the use of a nasoseptal flap increased (p <0.005). Although mean tumor diameter was constant (on average), gross-total resection (GTR) increased from 60% in the first half to 73% in the second half (p <0.005). GTR increased for all pathologies but most significantly for chordoma (56% vs 100%, p <0.05), craniopharyngioma (47% vs 0.71%, p <0.05) and pituitary adenoma (67% vs 75%, p <0.05). Hormonal cure for secreting adenomas also increased from 83% in the first half to 89% in the second half (p <0.05). The rate of any complication was unchanged at 6.4% in the first half and 6.2% in the latter half of cases, and vascular injury occurred in only 0.6% of cases. Postoperative CSF leak occurred in 2% of cases and was unchanged between the first and second half of the series.

Conclusions: This study demonstrates that contrary to popular belief, the surgical learning curve does not plateau but can continue for several years depending on the complexity of the endpoints considered. These findings may have implications for clinical trial design, surgical education, and patient safety measures.
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http://dx.doi.org/10.3171/2019.12.JNS192600DOI Listing
February 2020

Long-term outcomes after endoscopic endonasal surgery for nonfunctioning pituitary macroadenomas.

J Neurosurg 2020 Jan 31:1-12. Epub 2020 Jan 31.

Departments of1Neurosurgery.

Objective: Nonfunctioning pituitary adenomas are benign, slow-growing tumors. After gross-total resection (GTR) or subtotal resection (STR), tumors can recur or progress and may ultimately require additional intervention. A greater understanding of long-term recurrence and progression rates following complete or partial resection and the need for further intervention will help clinicians provide meaningful counsel for their patients and assist data-driven decision-making.

Methods: The authors retrospectively analyzed their institutional database for patients undergoing endoscopic endonasal surgery (EES) for nonfunctioning pituitary macroadenomas (2003-2014). Only patients with follow-up of at least 5 years after surgery were included. Tumor volumes were measured on pre- and postoperative MRI. Tumor recurrence was defined as the presence of a 0.1-cm3 tumor volume after GTR, and tumor progression was defined as a 25.0% increase in residual tumor after STR.

Results: A total of 190 patients were included, with a mean age of 63.8 ± 13.2 years; 79 (41.6%) were female. The mean follow-up was 75.0 ± 18.0 months. GTR was achieved in 127 (66.8%) patients. In multivariate analysis, age (p = 0.04), preoperative tumor volume (p = 0.03), Knosp score (p < 0.001), and Ki-67 (p = 0.03) were significant predictors of STR. In patients with GTR, the probability of recurrence at 5 and 10 years was 3.9% and 4.7%, and the probability of requiring treatment for recurrence was 0.79% and 1.6%, respectively. In 63 patients who underwent STR, 6 (9.5%) received early postoperative radiation and did not experience progression, while the remaining 57 (90.5%) were observed. Of these, the probability of disease progression at 5 and 10 years was 21% and 24.5%, respectively, and the probability of requiring additional treatment for progression was 17.5% and 21%. Predictors of recurrence or progression in the entire group were Knosp score (p < 0.001) and elevated Ki-67 (p = 0.03). Significant predictors of progression after STR in those who did not receive early radiotherapy were cavernous sinus location (p < 0.05) and tumor size > 1.0 cm3 (p = 0.005).

Conclusions: Following GTR for nonfunctioning pituitary adenomas, the 10-year chance of recurrence is low and the need for treatment even lower. After STR, although upfront radiation therapy may prevent progression, even without radiotherapy, the need for intervention at 10 years is only approximately 20% and a period of observation may be warranted to prevent unnecessary prophylactic radiation therapy. Tumor volume > 1 cm3, Knosp score ≥ 3, and Ki-67 ≥ 3% may be useful metrics to prompt closer follow-up or justify early prophylactic radiation therapy.
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http://dx.doi.org/10.3171/2019.11.JNS192457DOI Listing
January 2020

Endoscopic transorbital approach to the infratemporal fossa and parapharyngeal space: a cadaveric study.

J Neurosurg 2019 Nov 1:1-12. Epub 2019 Nov 1.

1Department of Neurosurgery, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York.

Objective: The infratemporal fossa (ITF) and parapharyngeal space are anatomical regions that can be challenging to access without the use of complex, cosmetically disfiguring approaches. With advances in endoscopic techniques, a new group of surgical approaches to access the intracranial space through the orbit has been recently referred to as transorbital neuroendoscopic surgery (TONES). The objective of this study was to establish a transorbital endoscopic approach utilizing the inferior orbital fissure (IOF) to gain access to the ITF and parapharyngeal space and provide a detailed endoscopic anatomical description of this approach.

Methods: Four cadaveric heads (8 sides) were dissected using a TONES approach through the IOF to reach the ITF and parapharyngeal space, providing stepwise dissection with detailed anatomical findings and a description of each step.

Results: An inferior eyelid approach was made with subperiosteal periorbital dissection to the IOF. The zygomatic and greater wing of the sphenoid were drilled, forming the boundaries of the IOF. The upper head of the lateral pterygoid muscle in the ITF and parapharyngeal space was removed, and 7 distinct planes were described, each with its own anatomical contents. The second part of the maxillary artery was mainly found in plane 1 between the temporalis laterally and the lateral pterygoid muscle in plane 2. The branches of the mandibular nerve (V3) and middle meningeal artery (MMA) were identified in plane 3. Plane 4 was formed by the fascia of the medial pterygoid muscle (MTM) and the tensor veli palatini muscle. The prestyloid segment, found in plane 5, was composed mainly of fat and lymph nodes. The parapharyngeal carotid artery in the poststyloid segment, found in plane 7, was identified after laterally dissecting the styloid diaphragm, found in plane 6. V3 and the origin of the levator and tensor veli palatini muscles serve as landmarks for identification of the parapharyngeal carotid artery.

Conclusions: The transorbital endoscopic approach provides excellent access to the ITF and parapharyngeal space compared to previously described complex and morbid transfacial or transcranial approaches. Using the IOF is an important and useful landmark that permits a wide exposure.
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http://dx.doi.org/10.3171/2019.7.JNS191743DOI Listing
November 2019

Readmission after endoscopic transsphenoidal pituitary surgery: analysis of 584 consecutive cases.

J Neurosurg 2019 Sep 27:1-6. Epub 2019 Sep 27.

Departments of2Neurosurgery.

Objective: Hospital readmission is a key component in value-based healthcare models but there are limited data about the 30-day readmission rate after endonasal endoscopic transsphenoidal surgery (EETS) for pituitary adenoma. The objective of this study was to determine the incidence and identify factors associated with 30-day readmission after EETS for pituitary adenoma.

Methods: The authors analyzed a prospectively acquired database of patients who underwent EETS for pituitary adenoma from 2005 to 2018 at NewYork-Presbyterian Hospital, Weill Cornell Medicine. Clinical, socioeconomic, and radiographic data were reviewed for cases of unplanned readmission within 30 days of surgery and, as a control group, for all other patients in the series who were not readmitted. Statistical significance was determined with an alpha < 0.05 using Pearson's chi-square and Fisher's exact tests for categorical variables and the independent-samples t-test for continuous variables.

Results: Of 584 patients undergoing EETS for pituitary adenoma, 27 (4.6%) had unplanned readmission within 30 days. Most readmissions occurred within the first week after surgery, with a mean time to readmission of 6.6 ± 3.9 days. The majority of readmissions (59%) were for hyponatremia. These patients had a mean sodium level of 120.6 ± 4.6 mEq/L at presentation. Other causes of readmission were epistaxis (11%), spinal headache (11%), sellar hematoma (7.4%), CSF leak (3.7%), nonspecific headache (3.7%), and pulmonary embolism (3.7%). The postoperative length of stay was significantly shorter for patients who were readmitted than for the controls (2.7 ± 1.0 days vs 3.9 ± 3.2 days; p < 0.05). Patients readmitted for hyponatremia had an initial length of stay of 2.6 ± 0.9 days, the shortest of any cause for readmission. The mean BMI was significantly lower for readmitted patients than for the controls (26.4 ± 3.9 kg/m2 vs 29.3 ± 6.1 kg/m2; p < 0.05).

Conclusions: Readmission after EETS for pituitary adenoma is a relatively rare phenomenon, with delayed hyponatremia being the primary cause. The study results demonstrate that shorter postoperative length of stay and lower BMI were associated with 30-day readmission.
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http://dx.doi.org/10.3171/2019.7.JNS191558DOI Listing
September 2019

Incidence and risk factors associated with reoperation for sellar hematoma following endoscopic transsphenoidal pituitary surgery.

J Neurosurg 2019 Aug 23:1-7. Epub 2019 Aug 23.

Departments of2Neurosurgery.

Objective: Postoperative sellar hematoma is an uncommon complication of endonasal endoscopic transsphenoidal surgery (EETS) for pituitary adenoma that often requires emergency surgical evacuation. Sellar hematomas can cause mass effect and compress parasellar structures, leading to clinically significant symptoms such as visual impairment and severe headache. The objective of this study was to determine the incidence and risk factors associated with reoperation for postoperative hematoma after EETS for pituitary adenoma.

Methods: The authors reviewed a prospectively acquired database of EETS for pituitary adenoma over 13 years at Weill Cornell Medicine, NewYork-Presbyterian Hospital and identified cases that required reoperation for confirmed hematoma. They also reviewed clinical and radiographic data of a consecutive series of patients undergoing EETS for pituitary adenoma who did not have postoperative hematoma, which served as the control group. Demographic data and risk factors were compared between the groups using univariate and multivariate analyses via binary logistic regression.

Results: Among a cohort of 583 patients undergoing EETS for pituitary adenoma, 9 patients (1.5%) required operation for sellar hematoma evacuation. All 9 patients with reoperation for sellar hematoma presented with worsening in their vision, and severe headache was present in 67%. New postoperative endocrine dysfunction developed in 78%. Clot evacuation improved vision in 88%. The mean time to hematoma evacuation was 4.5 days. The median length of stay for patients with sellar hematoma was 8 days (range 4-210 days) compared with a median length of stay of 3 days (range 1-32 days) for the control patients (p < 0.005). Significant risk factors in univariate analysis were tumor diameter ≥ 30 mm (p < 0.005), suprasellar extension (p < 0.005), tumor volume (p < 0.005), cavernous sinus invasion (p < 0.05), gonadotroph histology (p < 0.05), antiplatelet use (p < 0.05), and elevated BMI (p < 0.05). On multivariate analysis, tumor diameter ≥ 30 mm (OR 4.555, CI 1.30-28.90; p < 0.05) and suprasellar extension (OR 1.048, CI 1.01-1.10; p < 0.05) were found to be the only independent predictors of sellar hematoma. The incidence of hematoma in tumors ≥ 30 mm was 5% (7/139).

Conclusions: Postoperative sellar hematoma requiring reoperation is a rare phenomenon after transsphenoidal surgery, often presenting with visual loss and headache. Clot evacuation results in improvement in vision, but long-term endocrinopathy often ensues. Tumor diameter ≥ 30 mm and suprasellar extent are the most reliable risk factors. Close postoperative scrutiny should be given to patients at high risk.
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http://dx.doi.org/10.3171/2019.6.JNS191169DOI Listing
August 2019

Medical Student Neurosurgery Training Camp: Updates Following 2019 Course Expansion.

World Neurosurg 2019 10 25;130:561-563. Epub 2019 Jul 25.

American Association of Neurological Surgeons Medical Student Chapter, Weill Cornell Medical College, New York, New York, USA.

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http://dx.doi.org/10.1016/j.wneu.2019.07.157DOI Listing
October 2019

Neurosurgery Training Camp for Sub-Internship Preparation: Lessons From the Inaugural Course.

World Neurosurg 2019 Jul 1;127:e707-e716. Epub 2019 Apr 1.

Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA.

Objective: Historically, medical student education in neurological surgery has generally limited student involvement to assisting in research projects with minimal formal clinical exposure before starting sub-internships and application for the neurosurgery match. Consequently, students have generally had little opportunity to acquire exposure to clinical neurosurgery and attain minimal proficiency. A medical student training camp was created to improve the preparation of medical students for the involvement in neurological surgery activities and sub-internships.

Methods: A 1-day course was held at Weill Cornell Medicine, which consisted of a series of morning lectures, an interactive resident lunch panel, and afternoon hands-on laboratory sessions. Students completed self-assessment questionnaires regarding their confidence in several areas of clinical neurosurgery before the start of the course and again at its end.

Results: A significant increase in self-assessed confidence was observed in all skill areas surveyed. Overall, rising fourth year students who were starting sub-internships in the subsequent weeks reported a substantial increase in their preparedness for the elective rotations in neurosurgery.

Conclusions: The preparation of medical students for clinical neurosurgery can be improved. Single-day courses such as the described training camp are an effective method for improving knowledge and skill gaps in medical students entering neurosurgical careers. Initiatives should be developed, in addition to this annual program, to increase the clinical and research skills throughout medical student education.
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http://dx.doi.org/10.1016/j.wneu.2019.03.246DOI Listing
July 2019

Identification of Preoperative Language Tracts for Intrinsic Frontotemporal Diseases: A Pilot Reconstruction Algorithm in a Middle-Income Country.

World Neurosurg 2019 05 5;125:e729-e742. Epub 2019 Feb 5.

Department of Neurological Surgery, Fundación Universitaria de Ciencias de la Salud, Hospital Infantil Universitario de San José, Bogotá, Colombia.

Objective: Diffusion tensor imaging (DTI) tractography provides useful information that can be used to optimize surgical planning and help avoid injury during subcortical dissection of eloquent tracts. The objective is to provide a safe, timely, and affordable algorithm for preoperative DTI language reconstruction for intrinsic frontotemporal diseases.

Methods: We reviewed a prospectively acquired database of preoperative DTI reconstruction for resection of left frontotemporal lesions over 3 years at Hospital de San José and Hospital Infantil Universitario San José, Fundación Universitaria de Ciencias de la Salud, Bogota, Colombia. Preoperative and postoperative clinical and radiographic features were determined from retrospective chart review. A comprehensive review of the structural and functional anatomy of the language tracts was performed. Separate reconstruction of both ventral (semantic) and dorsal (phonologic) stream pathways is described: arcuate fasciculus, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, and inferior longitudinal fasciculus.

Results: Between January 2015 and January 2018, 44 tumor cases were found to be resected with preoperative fiber tracking planning and neuronavigation-guided surgery. Ten patients (7 women, 3 men) aged 28-65 years underwent resection of an intrinsic frontotemporal lesion with preoperative DTI tractography reconstruction of language tracts. Eight cases (80%) were high-grade gliomas and 2 (20%) were cavernous malformations. In 5 cases (50%), the lesion was in the frontal lobe and in 5 (50%), it was in the temporal lobe. The extent of resection was classified as gross total resection (100%), subtotal resection (>90%), or partial resection (<90%). Gross total resection was achieved in 5 cases (50%), subtotal resection was achieved in 4 cases (40%), and partial resection in the remaining case (10%). Compromised tracts included superior longitudinal fasciculus in 7 (70%), inferior longitudinal fasciculus in 4 (40%), the arcuate fasciculus in 3 (30%), and uncinate fasciculus in 1 (10%). Language function was unchanged or improved in 90% of patients. New-onset postoperative language decline occurred in 1 patient, who recovered transient phonemic paraphasias 1 month after resection. The mean follow-up time was 7 months (range, 4-12 months). Residual tumors were treated with radiation and/or with chemotherapy as indicated in an outpatient setting.

Conclusions: We present a safe and efficacious preoperative DTI language reconstruction algorithm that could be used as a feasible treatment strategy in a challenging subset of tumors in low- to middle-income countries.
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http://dx.doi.org/10.1016/j.wneu.2019.01.163DOI Listing
May 2019

Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy.

Int J Mol Sci 2019 Jan 8;20(1). Epub 2019 Jan 8.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA.

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.
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http://dx.doi.org/10.3390/ijms20010220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337422PMC
January 2019

Recovery of consciousness after a brainstem cavernous malformation hemorrhage: A descriptive study of preserved reticular activating system with tractography.

J Clin Neurosci 2019 Jan 24;59:372-377. Epub 2018 Oct 24.

Department of Neurological Surgery, Fundación Universitaria de Ciencias de la Salud, Hospital Infantil Universitario de San José, Bogotá, Colombia.

The aim of this study is to describe the imaging features, the relevant anatomy, and the fractional anisotropy (FA) values in diffusion tensor tractography (DTT) of the ascending reticular activating system (ARAS) fiber tracts in 2 patients who recovered from initial altered consciousness after presenting with a brainstem cavernous malformation (BSCM) hemorrhage. A DTT was performed in 2 patients with impaired consciousness after a brainstem cavernous malformation hemorrhage. A 1.5 T scanner was used to obtain the axial tensors. Post-processing was performed and the mean FA values were recorded. The FA maps were used to seed the following regions of interest: the ventromedial midbrain, the anterior thalamus bilaterally, and the hypothalamus bilaterally. The first case presented with posterior displacement of the dorsal raphè fiber tracts, with preservation of all the ascending reticular activating fiber tracts and spontaneous recovery of consciousness after 20 days. The second case presented with no destruction but also had posterior displacement of the inferior dorsal raphè fiber tracts, with recovery of consciousness 1 month after resection surgery. Described in this study are affected fibers of the ARAS, as well as the FA value abnormalities in 2 patients, with recovery of a transient disorder of consciousness after a BSCM hemorrhage.
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http://dx.doi.org/10.1016/j.jocn.2018.10.074DOI Listing
January 2019

Endonasal endoscopic transsphenoidal resection of intrinsic third ventricular craniopharyngioma: surgical results.

J Neurosurg 2018 Nov 1:1-11. Epub 2018 Nov 1.

1Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.

OBJECTIVEIntrinsic third ventricular craniopharyngiomas (IVCs) have been reported by some authors to "pose the greatest surgical challenge" of all craniopharyngiomas (CPAs). A variety of open microsurgical approaches have historically been used for resection of these tumors. Despite increased utilization of the endoscopic endonasal approach (EEA) for resection of CPAs in recent years, many authors continue to recommend against use of the EEA for resection of IVCs. In this paper, the authors present the largest series to date utilizing the EEA to remove IVCs.METHODSThe authors reviewed a prospectively acquired database of the EEA for resection of IVCs over 14 years at Weill Cornell Medical College, NewYork-Presbyterian Hospital. Preoperative MR images were examined independently by two neurosurgeons and a neuroradiologist to identify IVCs. Pre- and postoperative endocrinological, ophthalmological, radiographic, and other morbidities were determined from retrospective chart review and volumetric radiographic analysis.RESULTSBetween January 2006 and August 2017, 10 patients (4 men, 6 women) ranging in age from 26 to 67 years old, underwent resection of an IVC utilizing the EEA. Preoperative endocrinopathy was present in 70% and visual deterioration in 60%. Gross-total resection (GTR) was achieved in 9 (90%) of 10 patients, with achievement of near-total (98%) resection in the remaining patient. Pathology was papillary in 30%. Closure incorporated a "gasket-seal" technique with nasoseptal flap coverage and either lumbar drainage (9 patients) or a ventricular drain (1 patient). Postoperatively, complete anterior and posterior pituitary insufficiency was present in 90% and 70% of patients, respectively. In 4 patients with normal vision prior to surgery, 3 had stable vision following tumor resection. One patient noted a new, incongruous, left inferior homonymous quadrantanopsia postoperatively. In the 6 patients who presented with compromised vision, 2 reported stable vision following surgery. Each of the remaining 4 patients noted significant improvement in vision after tumor resection, with complete restoration of normal vision in 1 patient. Aside from the single case (10%) of visual deterioration referenced above, there were no instances of postoperative neurological decline. Postoperative CSF leakage occurred in 1 morbidly obese patient who required reoperation for revision of closure. After a mean follow-up of 46.8 months (range 4-131 months), tumor recurrence was observed in 2 patients (20%), one of whom was treated with radiation and the other with chemotherapy. Both of these patients had previously undergone GTR of the IVC.CONCLUSIONSThe 10 patients described in this report represent the largest number of patients with IVC treated using EEA for resection to date. EEA for resection of IVC is a safe and efficacious operative strategy that should be considered a surgical option in the treatment of this challenging subset of tumors.
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http://dx.doi.org/10.3171/2018.5.JNS18198DOI Listing
November 2018

BRAF V600E mutant papillary craniopharyngiomas: a single-institutional case series.

Pituitary 2018 Dec;21(6):571-583

Department of Neurosurgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68th St., Box #99, New York, NY, 10065, USA.

Purpose: To describe the clinical, radiographic and surgical outcomes in a cohort of patients with BRAF V600E mutant papillary craniopharyngiomas.

Methods: A retrospective review was performed to identify all patients with a histological diagnosis of CP operated upon at a single institution between 2005 and 2017. All cases with adequate material were sequenced to confirm the presence of BRAF V600E mutation.

Results: Sixteen patients were included in the present study. Approach was endoscopic endonasal (EEA) in 14 and transcranial (TCA) in 2. All patients were adult with an average age of 50 years (24-88). Radiographic review demonstrated that the majority (93.7%) were suprasellar and twelve (75%) had third ventricular involvement. No tumor showed evidence of calcifications and 68.7% were mixed solid-cystic. All patients had some evidence of hypopituitarism and 62.5% had hypothalamic disturbances. GTR was achieved in 11/14 (78.6%) EEA and 0/2 (0%) TCA (p < 0.05). The mean length of stay was 17.5 days in the TCA group and 7.6 days in the EEA group (p < 0.05). There were no CSF leaks. Post-operatively, eleven (68.7%) developed new DI or new hypopituitarism. Nine increased their BMI with a mean increase of 12.3%, whereas six patients lost weight with a mean decrease of 5.3%.

Conclusions: BRAF V600E mutant papillary tumors represent a clearly distinct clinical-pathological entity of craniopharyngiomas. These are generally non-calcified suprasellar tumors that occur in adults. These distinct characteristics may someday lead to upfront chemotherapy. When surgery is necessary, EEA may be preferred over TCA.
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http://dx.doi.org/10.1007/s11102-018-0909-zDOI Listing
December 2018

Radiation therapy rather than prior surgery reduces extent of resection during endonasal endoscopic reoperation for craniopharyngioma.

Acta Neurochir (Wien) 2018 07 25;160(7):1425-1431. Epub 2018 May 25.

Department of Otolaryngology, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.

Objective: Radiation therapy is often advocated for residual or recurrent craniopharyngioma following surgical resection to prevent local recurrence. However, radiation therapy is not always effective and may render tumors more difficult to remove. If this is the case, patients may benefit more from reoperation if gross total resection can be achieved. Nevertheless, there is little data on the impact of radiation on reoperations for craniopharyngioma. In this study, we sought to analyze whether a history of previous radiation therapy (RT) affected extent of resection in patients with recurrent craniopharyngiomas subsequently treated with reoperation via endoscopic endonasal approach (EEA).

Methods: The authors reviewed a prospectively acquired database of EEA reoperations of craniopharyngiomas over 13 years at Weill Cornell, NewYork-Presbyterian Hospital. All procedures were performed by the senior author. The operations were separated into two groups based on whether the patient had surgery alone (group A) or surgery and RT (group B) prior to recurrence.

Results: A total of 24 patients (16 male, 8 female) who underwent surgery for recurrent craniopharyngioma were identified. The average time to recurrence was 7.64 ± 4.34 months (range 3-16 months) for group A and 16.62 ± 12.1 months (range 6-45 months) for group B (p < 0.05). The average tumor size at recurrence was smaller in group A (1.85 ± 0.72 cm; range 0.5-3.2) than group B (2.59 ± 0.91 cm; range 1.5-4.6; p = 0.00017). Gross total resection (GTR) was achieved in 91% (10/11) of patients in group A and 54% (7/13) of patients in group B (p = 0.047). There was a near significant trend for higher average Karnofsky performance status (KPS) score at last follow-up for group A (83 ± 10.6) compared with group B (70 ± 16.3, p = 0.056).

Conclusions: While RT for residual or recurrent craniopharyngioma may delay time to recurrence, ability to achieve GTR with additional surgery is reduced. In the case of recurrent craniopharyngioma, if GTR can be achieved, consideration should be given to endonasal reoperation prior to the decision to irradiate residual or recurrent tumor.
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http://dx.doi.org/10.1007/s00701-018-3567-zDOI Listing
July 2018

Predictors of postoperative motor function in rolandic meningiomas.

J Neurosurg 2018 May 1:1-6. Epub 2018 May 1.

Departments of1Neurological Surgery.

OBJECTIVEResection of supratentorial meningiomas is generally considered a low-risk procedure, but tumors involving the rolandic cortex present a unique challenge. The rate of motor function deterioration associated with resecting such tumors is not well described in the literature. Thus, the authors sought to report the rates and predictors of postoperative motor deficit following the resection of rolandic meningiomas to assist with patient counseling and surgical decision-making.METHODSAn institution's pathology database was screened for meningiomas removed between 2000 and 2017, and patients with neuroradiological evidence of rolandic involvement were identified. Parameters screened as potential predictors included patient age, sex, preoperative motor severity, tumor location, tumor origin (falx vs convexity), histological grade, FLAIR signal (T2-weighted MRI), venous involvement (T1-weighted MRI with contrast), intratumoral hemorrhage, embolization, and degree of resection (Simpson grade). Variables of interest included preoperative weakness and postoperative motor decline (novel or worsened permanent deficit). The SPSS univariate and bivariate analysis functions were used, and statistical significance was determined with alpha < 0.05.RESULTSIn 89 patients who had undergone resection of convexity (80.9%) or parasagittal (19.1%) rolandic meningiomas, a postoperative motor decline occurred in 24.7%. Of 53 patients (59.6%) with preoperative motor deficits, 60.3% improved, 13.2% were unchanged, and 26.4% worsened following surgery. Among the 36 patients without preoperative deficits, 22.2% developed new weakness. Predictors of preoperative motor deficit included tumor size (41.6 vs 33.2 cm3, p = 0.040) and presence of FLAIR signal (69.8% vs 50.0%, p = 0.046). Predictors of postoperative motor decline were preoperative motor deficit (47.2% vs 22.2%, p = 0.017), minor (compared with severe) preoperative weakness (25.6% vs 21.4%, p < 0.001), and preoperative embolization (54.5% vs 20.5%, p = 0.014). Factors that trended toward significance included parafalcine tumor origin (41.2% vs 20.8% convexity, p = 0.08), significant venous involvement (44.4% vs 23.5% none, p = 0.09), and Simpson grade II+ (34.2% vs 17.6% grade I, p = 0.07).CONCLUSIONSResection of rolandic area meningiomas carries a high rate of postoperative morbidity and deserves special preoperative planning. Large tumor size, peritumoral edema, preoperative embolization, parafalcine origin, and venous involvement may further increase the risk. Alternative surgical strategies, such as aggressive internal debulking, may prevent motor decline in a subset of high-risk patients.
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http://dx.doi.org/10.3171/2017.12.JNS172423DOI Listing
May 2018

Decision-making algorithm for minimally invasive approaches to anterior skull base meningiomas.

Neurosurg Focus 2018 04;44(4):E7

Departments of1Neurological Surgery.

OBJECTIVE Anterior skull base meningiomas are benign lesions that cause neurological symptoms through mass effect on adjacent neurovascular structures. While traditional transcranial approaches have proven to be effective at removing these tumors, minimally invasive approaches that involve using an endoscope offer the possibility of reducing brain and nerve retraction, minimizing incision size, and speeding patient recovery; however, appropriate case selection and results in large series are lacking. METHODS The authors developed an algorithm for selecting a supraorbital keyhole minicraniotomy (SKM) for olfactory groove meningiomas or an expanded endoscopic endonasal approach (EEA) for tuberculum sella (TS) or planum sphenoidale (PS) meningiomas based on the presence or absence of olfaction and the anatomical extent of the tumor. Where neither approach is appropriate, a standard transcranial approach is utilized. The authors describe rates of gross-total resection (GTR), olfactory outcomes, and visual outcomes, as well as complications, for 7 subgroups of patients. Exceptions to the algorithm are also discussed. RESULTS The series of 57 patients harbored 57 anterior skull base meningiomas; the mean tumor volume was 14.7 ± 15.4 cm (range 2.2-66.1 cm), and the mean follow-up duration was 42.2 ± 37.1 months (range 2-144 months). Of 19 patients with olfactory groove meningiomas, 10 had preserved olfaction and underwent SKM, and preservation of olfaction in was seen in 60%. Of 9 patients who presented without olfaction, 8 had cribriform plate invasion and underwent combined SKM and EEA (n = 3), bifrontal craniotomy (n = 3), or EEA (n = 2), and one patient without both olfaction and cribriform plate invasion underwent SKM. GTR was achieved in 94.7%. Of 38 TS/PS meningiomas, 36 of the lesions were treated according to the algorithm. Of these 36 meningiomas, 30 were treated by EEA and 6 by craniotomy. GTR was achieved in 97.2%, with no visual deterioration and one CSF leak that resolved by placement of a lumbar drain. Two patients with tumors that, based on the algorithm, were not amenable to an EEA underwent EEA nonetheless: one had GTR and the other had a residual tumor that was followed and removed via craniotomy 9 years later. CONCLUSIONS Utilizing a simple algorithm aimed at preserving olfaction and vision and based on maximizing use of minimally invasive approaches and selective use of transcranial approaches, the authors found that excellent outcomes can be achieved for anterior skull base meningiomas.
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http://dx.doi.org/10.3171/2018.1.FOCUS17734DOI Listing
April 2018

A resurging boom in new drugs for epilepsy and brain disorders.

Expert Rev Clin Pharmacol 2018 Jan 23;11(1):27-45. Epub 2017 Oct 23.

a Department of Neuroscience and Experimental Therapeutics, College of Medicine , Texas A&M Health Science Center , Bryan , TX , USA.

Introduction: Epilepsy is one of the most common neurological diseases affecting approximately 50 million people worldwide. Despite many advances in epilepsy research, nearly a third of patients with epilepsy have refractory or pharmacoresistant epilepsy. Despite the approval of a dozen antiepileptic drugs (AEDs) over the past decade, there are no agents that halt the development of epilepsy. Thus, newer and better AEDs that can prevent refractory seizures and modify the disease are needed for curing epilepsy. Areas covered: In this article, we highlight the recent advances and emerging trends in new and innovative drugs for epilepsy and seizure disorders. We review in detail top new drugs that are currently in clinical trials or agents that are under development and have novel mechanisms of action. Expert commentary: Among the new agents under clinical investigation, the majority were originally developed for treating other neurological diseases (everolimus, fenfluramine, nalutozan, bumetanide, and valnoctamide); several have mechanisms of action similar to those of conventional AEDs (AP, ganaxolone, and YKP3089); and some new agents represent novel mechanisms of actions (huperzine-A, cannabidiol, tonabersat, and VX-765).
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http://dx.doi.org/10.1080/17512433.2018.1386553DOI Listing
January 2018

Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy.

Pharmacol Ther 2017 Sep 6;177:108-122. Epub 2017 Mar 6.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA. Electronic address:

This article highlights the emerging therapeutic potential of specific epigenetic modulators as promising antiepileptogenic or disease-modifying agents for curing epilepsy. Currently, there is an unmet need for antiepileptogenic agents that truly prevent the development of epilepsy in people at risk. There is strong evidence that epigenetic signaling, which exerts high fidelity regulation of gene expression, plays a crucial role in the pathophysiology of epileptogenesis and chronic epilepsy. These modifications are not hard-wired into the genome and are constantly reprogrammed by environmental influences. The potential epigenetic mechanisms, including histone modifications, DNA methylation, microRNA-based transcriptional control, and bromodomain reading activity, can drastically alter the neuronal gene expression profile by exerting their summative effects in a coordinated fashion. Such an epigenetic intervention appears more rational strategy for preventing epilepsy because it targets the primary pathway that initially triggers the numerous downstream cellular and molecular events mediating epileptogenesis. Among currently approved epigenetic drugs, the majority are anticancer drugs with well-established profiles in clinical trials and practice. Evidence from preclinical studies supports the premise that these drugs may be applied to a wide range of brain disorders. Targeting histone deacetylation by inhibiting histone deacetylase enzymes appears to be one promising epigenetic therapy since certain inhibitors have been shown to prevent epileptogenesis in animal models. However, developing neuronal specific epigenetic modulators requires rational, pathophysiology-based optimization to efficiently intercept the upstream pathways in epileptogenesis. Overall, epigenetic agents have been well positioned as new frontier tools towards the national goal of curing epilepsy.
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http://dx.doi.org/10.1016/j.pharmthera.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565684PMC
September 2017

Seizure facilitating activity of the oral contraceptive ethinyl estradiol.

Epilepsy Res 2016 Mar 27;121:29-32. Epub 2016 Jan 27.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA. Electronic address:

Contraceptive management is critical in women with epilepsy. Although oral contraceptives (OCs) are widely used by many women with epilepsy, little is known about their impact on epileptic seizures and epileptogenesis. Ethinyl estradiol (EE) is the primary component of OC pills. In this study, we investigated the pharmacological effect of EE on epileptogenesis and kindled seizures in female mice using the hippocampus kindling model. Animals were stimulated daily with or without EE until generalized stage 5 seizures were elicited. EE treatment significantly accelerated the rate of epileptogenesis. In acute studies, EE caused a significant decrease in the afterdischarge threshold and increased the incidence and severity of seizures in fully-kindled mice. In chronic studies, EE treatment caused a greater susceptibility to kindled seizures. Collectively, these results are consistent with moderate proconvulsant-like activity of EE. Such excitatory effects may affect seizure risk in women with epilepsy taking OC pills.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771519PMC
March 2016

Neurostereology protocol for unbiased quantification of neuronal injury and neurodegeneration.

Front Aging Neurosci 2015 31;7:196. Epub 2015 Oct 31.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine Bryan, TX, USA.

Neuronal injury and neurodegeneration are the hallmark pathologies in a variety of neurological conditions such as epilepsy, stroke, traumatic brain injury, Parkinson's disease and Alzheimer's disease. Quantification of absolute neuron and interneuron counts in various brain regions is essential to understand the impact of neurological insults or neurodegenerative disease progression in animal models. However, conventional qualitative scoring-based protocols are superficial and less reliable for use in studies of neuroprotection evaluations. Here, we describe an optimized stereology protocol for quantification of neuronal injury and neurodegeneration by unbiased counting of neurons and interneurons. Every 20th section in each series of 20 sections was processed for NeuN(+) total neuron and parvalbumin(+) interneuron immunostaining. The sections that contain the hippocampus were then delineated into five reliably predefined subregions. Each region was separately analyzed with a microscope driven by the stereology software. Regional tissue volume was determined by using the Cavalieri estimator, as well as cell density and cell number were determined by using the optical disector and optical fractionator. This protocol yielded an estimate of 1.5 million total neurons and 0.05 million PV(+) interneurons within the rat hippocampus. The protocol has greater predictive power for absolute counts as it is based on 3D features rather than 2D images. The total neuron counts were consistent with literature values from sophisticated systems, which are more expensive than our stereology system. This unbiased stereology protocol allows for sensitive, medium-throughput counting of total neurons in any brain region, and thus provides a quantitative tool for studies of neuronal injury and neurodegeneration in a variety of acute brain injury and chronic neurological models.
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http://dx.doi.org/10.3389/fnagi.2015.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628120PMC
November 2015

Antiseizure Activity of Midazolam in Mice Lacking δ-Subunit Extrasynaptic GABA(A) Receptors.

J Pharmacol Exp Ther 2015 Jun 17;353(3):517-28. Epub 2015 Mar 17.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas

Midazolam is a benzodiazepine anticonvulsant with rapid onset and short duration of action. Midazolam is the current drug of choice for acute seizures and status epilepticus, including those caused by organophosphate nerve agents. The antiseizure activity of midazolam is thought to result from its allosteric potentiation of synaptic GABA(A) receptors in the brain. However, there are indications that benzodiazepines promote neurosteroid synthesis via the 18-kDa cholesterol transporter protein (TSPO). Therefore, we investigated the role of neurosteroids and their extrasynaptic GABA(A) receptor targets in the antiseizure activity of midazolam. Here, we used δ-subunit knockout (DKO) mice bearing a targeted deletion of the extrasynaptic receptors to investigate the contribution of the extrasynaptic receptors to the antiseizure activity of midazolam using the 6-Hz and hippocampus kindling seizure models. In both models, midazolam produced rapid and dose-dependent protection against seizures (ED50, 0.4 mg/kg). Moreover, the antiseizure potency of midazolam was undiminished in DKO mice compared with control mice. Pretreatment with PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide], a TSPO blocker, or finasteride, a 5α-reductase neurosteroid inhibitor, did not affect the antiseizure effect of midazolam. The antiseizure activity of midazolam was significantly reversed by pretreatment with flumazenil, a benzodiazepine antagonist. Plasma and brain levels of the neurosteroid allopregnanolone were not significantly greater in midazolam-treated animals. These studies therefore provide strong evidence that neurosteroids and extrasynaptic GABA(A) receptors are not involved in the antiseizure activity of midazolam, which mainly occurs through synaptic GABA(A) receptors via direct binding to benzodiazepine sites. This study reaffirms midazolam's use for controlling acute seizures and status epilepticus.
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http://dx.doi.org/10.1124/jpet.114.222075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429675PMC
June 2015