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Martin H. Weiss, Gabriel Zada, John D. Carmichael and William T. Couldwell

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Monica Mureb, Danielle Golub, Carolina Benjamin, Jason Gurewitz, Ben A. Strickland, Gabriel Zada, Eric Chang, Dušan Urgošík, Roman Liščák, Ronald E. Warnick, Herwin Speckter, Skyler Eastman, Anthony M. Kaufmann, Samir Patel, Caleb E. Feliciano, Carlos H. Carbini, David Mathieu, William Leduc, DCS, Sean J. Nagel, Yusuke S. Hori, Yi-Chieh Hung, Akiyoshi Ogino, Andrew Faramand, Hideyuki Kano, L. Dade Lunsford, Jason Sheehan and Douglas Kondziolka

OBJECTIVE

Trigeminal neuralgia (TN) is a chronic pain condition that is difficult to control with conservative management. Furthermore, disabling medication-related side effects are common. This study examined how stereotactic radiosurgery (SRS) affects pain outcomes and medication dependence based on the latency period between diagnosis and radiosurgery.

METHODS

The authors conducted a retrospective analysis of patients with type I TN at 12 Gamma Knife treatment centers. SRS was the primary surgical intervention in all patients. Patient demographics, disease characteristics, treatment plans, medication histories, and outcomes were reviewed.

RESULTS

Overall, 404 patients were included. The mean patient age at SRS was 70 years, and 60% of the population was female. The most common indication for SRS was pain refractory to medications (81%). The median maximum radiation dose was 80 Gy (range 50–95 Gy), and the mean follow-up duration was 32 months. The mean number of medications between baseline (pre-SRS) and the last follow-up decreased from 1.98 to 0.90 (p < 0.0001), respectively, and this significant reduction was observed across all medication categories. Patients who received SRS within 4 years of their initial diagnosis achieved significantly faster pain relief than those who underwent treatment after 4 years (median 21 vs 30 days, p = 0.041). The 90-day pain relief rate for those who received SRS ≤ 4 years after their diagnosis was 83.8% compared with 73.7% in patients who received SRS > 4 years after their diagnosis. The maximum radiation dose was the strongest predictor of a durable pain response (OR 1.091, p = 0.003). Early intervention (OR 1.785, p = 0.007) and higher maximum radiation dose (OR 1.150, p < 0.0001) were also significant predictors of being pain free (a Barrow Neurological Institute pain intensity score of I–IIIA) at the last follow-up visit. New sensory symptoms of any kind were seen in 98 patients (24.3%) after SRS. Higher maximum radiation dose trended toward predicting new sensory deficits but was nonsignificant (p = 0.075).

CONCLUSIONS

TN patients managed with SRS within 4 years of diagnosis experienced a shorter interval to pain relief with low risk. SRS also yielded significant decreases in adjunct medication utilization. Radiosurgery should be considered earlier in the course of treatment for TN.

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Shane Shahrestani, Alexander M. Ballatori, Xiao T. Chen, Andy Ton, Ben A. Strickland, Andrew Brunswick and Gabriel Zada

OBJECTIVE

Pituitary adenomas (PAs) are among the most common intracranial tumors. Understanding the clinical effects of various modifiable risk factors (MRFs) and nonmodifiable risk factors (NMRFs) is important in guiding proper treatment, yet there is limited evidence outlining the influence of MRFs and NMRFs on outcomes of PA resection. The aim of this study was to analyze MRFs and NMRFs in patients undergoing resection for PAs.

METHODS

Using the 2016 and 2017 National Readmission Database, the authors identified a cohort of 9472 patients undergoing microscopic or endoscopic resection of a PA. Patients with nonoverlapping MRFs and NMRFs were analyzed for length of stay (LOS), hospital cost, readmission rates, and postoperative complications. From the original cohort, a subset of 373 frail patients (as defined by the Johns Hopkins Frailty Index) were identified and propensity matched to nonfrail patients. Statistical analysis included 1-way ANOVA, Tukey multiple comparisons of means, odds ratios, Wald testing, and unpaired Welch 2-sample t-tests to compare complications, outcomes, and costs between each cohort. Perioperative outcomes and hospital readmission rates were tracked, and predictive algorithms were developed to establish precise relationships between relevant risk factors and neurosurgical outcomes.

RESULTS

Malnourished patients had significantly longer LOSs when compared to nonmalnourished patients (p < 0.001). There was a significant positive correlation between the number of MRFs and readmission at 90 days (p = 0.012) and 180 days (p = 0.020). Obese patients had higher rates of postoperative neurological injury at the 30-day follow-up (p = 0.048) compared to patients with normal BMI. Within this NMRF cohort, frail patients were found to have significantly increased hospital LOS (p < 0.001) and total inpatient costs compared to nonfrail patients (p < 0.001). Predictive analytics showed that frail patients had significantly higher readmission rates at both 90-day (p < 0.001) and 180-day follow-ups (p < 0.001). Lastly, rates of acute postsurgical infection were higher in frail patients compared to nonfrail patients (p < 0.001).

CONCLUSIONS

These findings suggest that both MRFs and NMRFs negatively affect the perioperative outcomes following PA resection. Notable risk factors including malnutrition, obesity, elevated lipid panels, and frailty make patients more prone to prolonged LOS, higher inpatient costs, and readmission. Further prospective research with longitudinal data is required to precisely pinpoint the effects of various risk factors on the outcomes of pituitary surgery.

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Martin J. Rutkowski, Ki-Eun Chang, Tyler Cardinal, Robin Du, Ali R. Tafreshi, Daniel A. Donoho, Andrew Brunswick, Alexander Micko, Chia-Shang J. Liu, Mark S. Shiroishi, John D. Carmichael and Gabriel Zada

OBJECTIVE

Pituitary adenoma (PA) consistency, or texture, is an important intraoperative characteristic that may dictate operative dissection techniques and/or instruments used for tumor removal during endoscopic endonasal approaches (EEAs). The impact of PA consistency on surgical outcomes has yet to be elucidated.

METHODS

The authors developed an objective 5-point grading scale for PA consistency based on intraoperative characteristics, including ease of tumor debulking, manipulation, and instrument selection, ranging from cystic/hemorrhagic tumors (grade 1) to calcified tumors (grade 5). The proposed grading system was prospectively assessed in 306 consecutive patients who underwent an EEA for PAs, and who were subsequently analyzed for associations with surgical outcomes, including extent of resection (EOR) and complication profiles.

RESULTS

Institutional database review identified 306 patients who underwent intraoperative assessment of PA consistency, of which 96% were macroadenomas, 70% had suprasellar extension, and 44% had cavernous sinus invasion (CSI). There were 214 (69.9%) nonfunctional PAs and 92 functional PAs (31.1%). Distribution of scores included 15 grade 1 tumors (4.9%), 112 grade 2 tumors (36.6%), 125 grade 3 tumors (40.8%), 52 grade 4 tumors (17%), and 2 grade 5 tumors (0.7%). Compared to grade 1/2 and grade 3 PAs, grade 4/5 PAs were significantly larger (22.5 vs 26.6 vs 27.4 mm, p < 0.01), more likely to exhibit CSI (39% vs 42% vs 59%, p < 0.05), and trended toward nonfunctionality (67% vs 68% vs 82%, p = 0.086). Although there was no association between PA consistency and preoperative headaches or visual dysfunction, grade 4/5 PAs trended toward preoperative (p = 0.058) and postoperative panhypopituitarism (p = 0.066). Patients with preoperative visual dysfunction experienced greater improvement if they had a grade 1/2 PA (p < 0.05). Intraoperative CSF leaks were noted in 32% of cases and were more common with higher-consistency-grade tumors (p = 0.048), although this difference did not translate to postoperative CSF leaks. Gross-total resection (%) was more likely with lower PA consistency score as follows: grade 1/2 (60%), grade 3 (50%), grade 4/5 (44%; p = 0.045). Extracapsular techniques were almost exclusively performed in grade 4/5 PAs. Assignment of scores showed low variance and high reproducibility, with an intraclass correlation coefficient of 0.905 (95% CI 0.815–0.958), indicating excellent interrater reliability.

CONCLUSIONS

These findings demonstrate clinical validity of the proposed intraoperative grading scale with respect to PA subtype, neuroimaging features, EOR, and endocrine complications. Future studies will assess the relation of PA consistency to preoperative MRI findings to accurately predict consistency, thereby allowing the surgeon to tailor the exposure and prepare for varying resection strategies.

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Tyler Cardinal, Martin J. Rutkowski, Alexander Micko, Mark Shiroishi, Chia-Shang Jason Liu, Bozena Wrobel, John Carmichael and Gabriel Zada

OBJECTIVE

Acromegaly is a disease of acral enlargement and elevated serum levels of insulin-like growth factor–1 (IGF-1) and growth hormone (GH), usually caused by a pituitary adenoma. A lack of consensus on factors that reliably predict outcomes in acromegalic patients following endoscopic endonasal transsphenoidal surgery (EETS) warrants additional investigation.

METHODS

The authors identified 52 patients with acromegaly who underwent an endoscopic endonasal approach (EEA) for resection of a GH-secreting pituitary adenoma. Preoperative and postoperative tumor and endocrinological characteristics such as tumor size, invasiveness, and GH/IGF-1 levels were evaluated as potential indicators of postoperative hormonal remission. Endocrinological remission was defined as postoperative IGF-1 levels at or below the age- and sex-normalized values.

RESULTS

The 52 patients had a mean age of 50.7 ± 13.4 years and a mean follow-up duration of 24.4 ± 19.1 months. Ten patients (19%) had microadenomas and 42 (81%) had macroadenomas. Five patients (9.6%) had giant adenomas. Forty-four tumors (85%) had extrasellar extension, with 40 (77%) exhibiting infrasellar invasion, 18 (35%) extending above the sella, and 7 (13%) invading the cavernous sinuses. Thirty-six patients (69%) underwent gross-total resection (GTR; mean maximal tumor diameter 1.47 cm), and 16 (31%) underwent subtotal resection (STR; mean maximal tumor diameter 2.74 cm). Invasive tumors were significantly larger, and Knosp scores were negatively correlated with GTR. Thirty-eight patients (73%) achieved hormonal remission after EEA resection alone, which increased to 87% with adjunctive medical therapy. Ninety percent of patients with microadenomas and 86% of patients with macroadenomas achieved hormonal remission. Preoperative IGF-1 and postoperative day 1 (POD1) GH levels were inversely correlated with hormonal remission. Postoperative CSF leakage occurred in 2 patients (4%), and none experienced vision loss, death, or injury to internal carotid arteries or cranial nerves.

CONCLUSIONS

Endoscopic transsphenoidal resection of GH-secreting pituitary adenomas is a safe and highly effective treatment for achieving hormonal remission and tumor control in up to 87% of patients with acromegaly when combined with postoperative medical therapy. Patients with lower preoperative IGF-1 and POD1 GH levels, with less invasive pituitary adenomas, and who undergo GTR are more likely to achieve postoperative biochemical remission.

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Gabriel Zada, Henry W. S. Schroeder, Andrew S. Little and Edward R. Laws Jr.

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Sepideh Amin-Hanjani, Nicholas C. Bambakidis, Fred G. Barker II, Bob S Carter, Kevin M. Cockroft, Rose Du, Justin F. Fraser, Mark G. Hamilton, Judy Huang, John A. Jane Jr., Randy L. Jensen, Michael G. Kaplitt, Anthony M. Kaufmann, Julie G. Pilitsis, Howard A. Riina, Michael Schulder, Michael A. Vogelbaum, Lynda J. S. Yang and Gabriel Zada

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Janelle Cyprich, Dhiraj J. Pangal, Martin Rutkowski, Daniel A. Donoho, Mark Shiroishi, Chia-Shang Jason Liu, John D. Carmichael and Gabriel Zada

OBJECTIVE

Sociodemographic disparities in health outcomes are well documented, but the effects of such disparities on preoperative presentation of pituitary adenomas (PA) and surgical outcomes following resection are not completely understood. In this study the authors sought to compare the preoperative clinical characteristics and postoperative outcomes in patients undergoing PA resection at a private hospital (PH) versus a safety-net hospital (SNH).

METHODS

The authors conducted a retrospective review over a 36-month period of patients with PAs who underwent endoscopic endonasal transsphenoidal surgery performed by the same attending neurosurgeon at either a PH or an SNH at a single academic medical institution.

RESULTS

A total of 92 PH patients and 69 SNH patients were included. SNH patients were more likely to be uninsured or have Medicaid (88.4% vs 10.9%, p < 0.0001). A larger percentage of SNH patients were Hispanic (98.7% vs 32.6% p < 0.0001), while PH patients were more likely to be non-Hispanic white (39.1% vs 4.3%, p < 0.0001). SNH patients had a larger mean PA diameter (26.2 vs 22.4 mm, p = 0.0347) and a higher rate of bilateral cavernous sinus invasion (13% vs 4.3%, p = 0.0451). SNH patients were more likely to present with headache (68.1% vs 45.7%, p = 0.0048), vision loss (63.8% vs 35.9%, p < 0.0005), panhypopituitarism (18.8% vs 4.3%, p = 0.0031), and pituitary apoplexy (18.8% vs 7.6%, p = 0.0334). Compared to PH patients, SNH patients were as likely to undergo gross-total resection (73.9% vs 76.1%, p = 0.7499) and had similar rates of postoperative improvement in headache (80% vs 89%, p = 0.14) and vision (82% vs 84%, p = 0.74), but had higher rates of postoperative panhypopituitarism (23% vs 10%, p = 0.04) driven by preoperative endocrinopathies. Although there were no differences in tumor recurrence or progression, loss to follow-up was seen in 7.6% of PH versus 18.6% (p = 0.04) of SNH patients.

CONCLUSIONS

Patients presenting to the SNH were more often uninsured or on Medicaid and presented with larger, more advanced pituitary tumors. SNH patients were more likely to present with headaches, vision loss, and apoplexy, likely translating to greater improvements in headache and vision observed after surgery. These findings highlight the association between medically underserved populations and more advanced disease states at presentation, and underscore the likely role of academic tertiary multidisciplinary care teams and endoscopic PA resection in somewhat mitigating sociodemographic factors known to portend poorer outcomes, though longer-term follow-up is needed to confirm these findings.

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Charles Ashton, Suhn K. Rhie, John D. Carmichael and Gabriel Zada

OBJECTIVE

Prior profiling of the human pituitary adenoma (PA) DNA methylome showed the potassium channel subunit–encoding gene KCNAB2 to be highly differentially methylated between nonfunctional PAs (NFPAs) and growth hormone (GH)–secreting PAs, with greater KCNAB2 methylation detected in secretory PAs. KCNAB2 encodes an aldo-keto reductase that, among other things, negatively regulates members of the voltage-gated potassium channel (Kv) family. In this study, the authors aimed to determine whether modulation of Kcnab2 expression would alter GH secretion in the GH3 mammosomatotroph rat cell line. In addition, they examined whether dosing GH3 cells with the antiarrhythmic drug quinidine, a known inhibitor of Kv and voltage-gated sodium channels, would affect hormonal secretion.

METHODS

Previously generated RNA-seq data were reanalyzed to compare KCNAB2 expression levels in human NFPAs and GH-secreting PAs. Kcnab2 was overexpressed in GH3 cells using plasmid transfection and knocked down using shRNA, with confirmation by quantitative polymerase chain reaction (qPCR). GH concentrations in cell culture supernatants collected 24 hours after cell seeding were measured using enzyme-linked immunosorbent assay (ELISA). Separately, quinidine was administered to GH3 cells at graduated doses. GH and prolactin concentrations in supernatants collected 48 hours after quinidine treatment were measured by fluorometric immunoassay.

RESULTS

Modulation of expression at the transcript level in GH3 cells resulted in proportionate changes in the expression of GH mRNA and secretion of GH peptide, as confirmed by qPCR and ELISA. Specifically, partial knockdown of Kcnab2 was associated with fewer GH RNA transcripts and less GH secretion compared with controls, while augmentation of Kcnab2 expression was associated with more GH transcripts and secretion than the controls. Administration of quinidine (≥ 50 µM) reduced both GH and prolactin secretion in a dose-dependent fashion (p ≤ 0.05).

CONCLUSIONS

GH secretion in a somatotroph cell line is partially dependent on KCNAB2 gene expression and may be mitigated in vitro by quinidine. These results collectively suggest a potential new target and pharmacological candidate to be considered in the development of clinical therapeutics for acromegaly.

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Kyohei Itamura, Ki-Eun Chang, Joshua Lucas, Daniel A. Donoho, Steven Giannotta and Gabriel Zada

OBJECTIVE

The present study aims to assess the clinical utility of a previously validated intraoperative meningioma consistency grading scale and its association with extent of resection (EOR) and various surgical outcomes.

METHODS

The previously validated grading system was prospectively assessed in 127 consecutive patients undergoing open craniotomy for meningioma by multiple neurosurgeons at two high-volume academic hospitals from 2013 to 2016. Consistency grading scores ranging from 1 (soft) to 5 (firm/calcified) were retrospectively analyzed to test for association with surgical outcomes and EOR, categorized as gross-total resection (GTR) or subtotal resection, defined by postoperative MRI.

RESULTS

One hundred twenty-seven patients were included in the analysis with a tumor consistency distribution as follows: grade 1, 3.1%; grade 2, 14.2%; grade 3, 44.1%; grade 4, 32.3%; and grade 5, 6.3%. The mean tumor diameter was 3.6 ± 1.7 cm. Tumor consistency grades were grouped into soft (grades 1 and 2), average (grade 3), and firm (grades 4 and 5) groups for statistical analysis with distributions of 17.3%, 44.1%, and 38.6%, respectively. There was no association between meningioma consistency and maximal tumor diameter, or location. Mean duration of surgery was longer for tumors with higher consistency: grades 1 and 2, 186 minutes; grade 3, 219 minutes; and grades 4 and 5, 299 minutes (p = 0.000028). There was a trend toward higher perioperative complication rates for tumors of increased consistency: grades 1 and 2, 4.5%; grade 3, 7.0%; and grades 4 and 5, 20.8% (p = 0.047). The proportion of GTR for each consistency group was as follows: grades 1 and 2, 77%; grade 3, 68%; and grades 4 and 5, 43% (p = 0.0062).

CONCLUSIONS

In addition to other important meningioma characteristics such as invasiveness, tumor consistency is a key determinant of surgical outcomes, including operative duration and EOR. Future studies predicting tumor consistency based on preoperative neuroimaging will help considerably with preoperative planning for meningiomas.