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Cushing's disease: current medical therapies and molecular insights guiding future therapies

Darryl Lau, Caleb Rutledge, and Manish K. Aghi

OBJECT

Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD.

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A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase “(name of agent) and Cushing's” was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review.

RESULTS

A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%–100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth.

CONCLUSIONS

Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.

InNeurosurgical Focus Volume 38 (2015): Issue 2 (Feb 2015): Cushing's Disease: Diagnosis and Management

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Incidence, classification, and treatment of angiographically occult intracranial aneurysms found during microsurgical aneurysm clipping of known aneurysms

Jan-Karl Burkhardt, Michelle H. Chua, Ethan A. Winkler, W. Caleb Rutledge, and Michael T. Lawton

OBJECTIVE

During the microsurgical clipping of known aneurysms, angiographically occult (AO) aneurysms are sometimes found and treated simultaneously to prevent their growth and protect the patient from future rupture or reoperation. The authors analyzed the incidence, treatment, and outcomes associated with AO aneurysms to determine whether limited surgical exploration around the known aneurysm was safe and justified given the known limitations of diagnostic angiography.

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An AO aneurysm was defined as a saccular aneurysm detected using the operative microscope during dissection of a known aneurysm, and not detected on preoperative catheter angiography. A prospective database was retrospectively reviewed to identify patients with AO aneurysms treated microsurgically over a 20-year period.

RESULTS

One hundred fifteen AO aneurysms (4.0%) were identified during 2867 distinct craniotomies for aneurysm clipping. The most common locations for AO aneurysms were the middle cerebral artery (60 aneurysms, 54.1%) and the anterior cerebral artery (20 aneurysms, 18.0%). Fifty-six AO aneurysms (50.5%) were located on the same artery as the known saccular aneurysm. Most AO aneurysms (95.5%) were clipped and there was no attributed morbidity. The most common causes of failed angiographic detection were superimposition of a large aneurysm (type 1, 30.6%), a small aneurysm (type 2, 18.9%), or an adjacent normal artery (type 3, 36.9%). Multivariate analysis identified multiple known aneurysms (odds ratio [OR] 3.45, 95% confidence interval [CI] 2.16–5.49, p < 0.0001) and young age (OR 0.981, 95% CI 0.965–0.997, p = 0.0226) as independent predictors of AO aneurysms.

CONCLUSIONS

细致的检查常见的动脉瘤网站智慧hin the surgical field will identify AO aneurysms during microsurgical dissection of another known aneurysm. Simultaneous identification and treatment of these additional undiagnosed aneurysms can spare patients later rupture or reoperation, particularly in those with multiple known aneurysms and a history of subarachnoid hemorrhage. Limited microsurgical exploration around a known aneurysm can be performed safely without additional morbidity.

In开云手机版app下载安装最新版神经外科杂志》卷132开云体育app官方网站下载入口:问题2(Feb 2020)

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Suboccipital craniectomy with bilateral cerebellomedullary fissure dissection for resection of a ruptured tonsillar/vermian AVM occupying the roof of the fourth ventricle in a pregnant patient

Daniel M. S. Raper, Kunal P. Raygor, Caleb Rutledge, Todd B. Dubnicoff, and Adib A. Abla

Posterior fossa arteriovenous malformations (AVMs) in pregnant patients can present unique considerations for surgical treatment, including positioning to minimize pressure on the fetus, minimization of radiation exposure, and ethical considerations regarding emergency surgery. This video outlines surgical treatment of a ruptured tonsillar/vermian AVM performed in a staged fashion after emergent suboccipital craniotomy with posterior fossa decompression in the setting of a life-threatening infratentorial hemorrhage. Later, bilateral cerebellomedullary fissure dissection, exposure and dissection of the tela choroidea and inferior medullary velum, and disconnection of arterial feeders from the posterior inferior cerebellar artery (PICA) allowed resection of this AVM occupying the roof of the fourth ventricle.

This study was approved by the UCSF Human Research Protection Program IRB no. 18-26938.

The video can be found here:https://youtu.be/rTYUGanopUE

InNeurosurgical Focus: Video Volume 4: Issue null (Jan 2021): Posterior Fossa Arteriovenous Malformations

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The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs

Adib A. Abla, Jeffrey Nelson, W. Caleb Rutledge, William L. Young, Helen Kim, and Michael T. Lawton

Object

颅后窝动静脉malfor患者mations (AVMs) are more likely to present with hemorrhage than those with supratentorial AVMs. Observed patients subject to the AVM natural history should be informed of the individualized effects of AVM characteristics on the clinical course following a new, first-time hemorrhage. The authors hypothesize that the debilitating effects of first-time bleeding from an AVM in a previously intact patient with an unruptured AVM are more pronounced when AVMs are located in the posterior fossa.

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加州大学旧金山prospective registry of brain AVMs was searched for patients with a ruptured AVM who had a pre-hemorrhage modified Rankin Scale (mRS) score of 0 and a post-hemorrhage mRS score obtained within 2 days of the hemorrhagic event. A total of 154 patients met the inclusion criteria for this study. Immediate post-hemorrhage presentation mRS scores were dichotomized into nonsevere outcome (mRS ≤ 3) and severe outcome (mRS > 3). There were 77 patients in each group. Univariate and multivariate logistic regression analyses using severe outcome as the binary response were run. The authors also performed a logistic regression analysis to measure the effects of hematoma volume and AVM location on severe outcome.

Results

Posterior fossa location was a significant predictor of severe outcome (OR 2.60, 95% CI 1.20–5.67, p = 0.016) and the results were strengthened in a multivariate model (OR 4.96, 95% CI 1.73–14.17, p = 0.003). Eloquent location (OR 3.47, 95% CI 1.37–8.80, p = 0.009) and associated arterial aneurysms (OR 2.58, 95% CI 1.09, 6.10; p = 0.031) were also significant predictors of poor outcome. Hematoma volume for patients with a posterior fossa AVM was 10.1 ± 10.1 cm3compared with 25.6 ±28.0 cm3in supratentorial locations (p = 0.003). A logistic analysis (based on imputed hemorrhage volume values) found that posterior fossa location was a significant predictor of severe outcome (OR 8.03, 95% CI 1.20–53.77, p = 0.033) and logarithmic hematoma volume showed a positive, but not statistically significant, association in the model (p = 0.079).

Conclusions

Patients with posterior fossa AVMs are more likely to have severe outcomes than those with supratentorial AVMs based on this natural history study. Age, sex, and ethnicity were not associated with an increased risk of severe outcome after AVM rupture, but posterior fossa location, associated aneurysms, and eloquent location were associated with poor post-hemorrhage mRS scores. Posterior fossa hematomas are poorly tolerated, with severe outcomes observed even with smaller hematoma volumes. These findings support an aggressive surgical posture with respect to posterior fossa AVMs, both before and after rupture.

InNeurosurgical Focus Volume 37 (2014): Issue 3 (Sep 2014): AVMs: Strategies for Management and Outcome

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Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution

W. Caleb Rutledge, Adib A. Abla, Jeffrey Nelson, Van V. Halbach, Helen Kim, and Michael T. Lawton

Object

Management of unruptured arteriovenous malformations (AVMs) is controversial. In the first randomized trial of unruptured AVMs (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [ARUBA]), medically managed patients had a significantly lower risk of death or stroke and had better outcomes. The University of California, San Francisco (UCSF) was one of the participating ARUBA sites. While 473 patients were screened for eligibility, only 4 patients were enrolled in ARUBA. The purpose of this study is to report the treatment and outcomes of all ARUBA-eligible patients at UCSF.

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The authors compared the treatment and outcomes of ARUBA-eligible patients using prospectively collected data from the UCSF brain AVM registry. Similar to ARUBA, they compared the rate of stroke or death in observed and treated patients and used the modified Rankin Scale to grade outcomes.

Results

74名患者,61收到了干预和13所示were observed. Most treated patients had resection with or without preoperative embolization (43 [70.5%] of 61 patients). One of the 13 observed patients died after AVM hemorrhage. Nine of the 61 treated patients had a stroke or died. There was no significant difference in the rate of stroke or death (HR 1.34, 95% CI 0.12–14.53, p = 0.81) or clinical impairment (Fisher’s exact test, p > 0.99) between observed and treated patients.

Conclusions

The risk of stroke or death and degree of clinical impairment among treated patients was lower than reported in ARUBA. The authors found no significant difference in outcomes between observed and treated ARUBA-eligible patients at UCSF. Results in ARUBA-eligible patients managed outside that trial led to an entirely different conclusion about AVM intervention, due to the primary role of surgery, judicious surgical selection with established outcome predictors, and technical expertise developed at high-volume AVM centers.

InNeurosurgical Focus Volume 37 (2014): Issue 3 (Sep 2014): AVMs: Strategies for Management and Outcome

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Indirect and direct revascularization ofACTA2cerebral arteriopathy: feasibility of the superficial temporal artery to anterior cerebral artery bypass with posterior auricular artery interposition graft: case report

W. Caleb Rutledge, Omar Choudhri, Brian P. Walcott, Arnau Benet, Christine K. Fox, Nalin Gupta, and Michael T. Lawton

Mutations in the smooth muscle–specific isoform of alpha actin (ACTA2) cause smooth muscle dysfunction in arteries. This rare loss-of-function mutation may cause a diffuse occlusive cerebral arteriopathy, resulting in stroke. WhileACTA2arteriopathy is often described as moyamoya-like, it has a distinct phenotype characterized by dilation of the proximal internal carotid artery (ICA) and occlusion of the terminal ICA and proximal middle cerebral artery. Intracranial arteries have an abnormally straight course, often with small aneurysms. There is limited experience with revascularization procedures forACTA2arteriopathy, and the safety and efficacy of these procedures are unknown. In this paper the authors present a symptomatic 6-year-old patient withACTA2cerebral arteriopathy who underwent both indirect revascularization and direct cerebrovascular bypass. Postoperatively, the patient suffered an ischemic infarct in a neighboring vascular territory. While direct cerebrovascular bypass is technically feasible, patients withACTA2arteriopathy may be at increased risk for perioperative stroke compared with patients with moyamoya disease.

InJournal of Neurosurgery: Pediatrics Volume 18 (2016): Issue 3 (Sep 2016)

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Socioeconomic factors associated with pediatric moyamoya disease hospitalizations: a nationwide cross-sectional study

Kunal P. Raygor, Ryan R. L. Phelps, Caleb Rutledge, Daniel M. S. Raper, Annette Molinaro, Christine K. Fox, Nalin Gupta, and Adib A. Abla

OBJECTIVE

Healthcare disparities are widely described in adults, but barriers affecting access to care for pediatric patients with moyamoya disease (MMD) are unknown. Understanding socioeconomic factors impacting hospital access and outcomes is necessary to address pediatric healthcare disparities.

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In this cross-sectional observational study, the Kids’ Inpatient Database was used to identify patients admitted with a primary diagnosis of MMD from 2003 to 2016. Patients ≤ 18 years with a primary diagnosis of MMD based onInternational Classification of Diseases(ICD) codes were included. Hospital admissions were queried for use of cerebral revascularization based on ICD procedure codes.

RESULTS

Query of the KID yielded 1449 MMD hospitalizations. After multivariable regression, Hispanic ethnicity (OR 0.52 [95% CI 0.33–0.81], p = 0.004) was associated with lack of surgical revascularization. Private insurance (OR 1.56 [95% CI 1.15–2.13], p = 0.004), admissions at medium- and high-volume centers (OR 2.01 [95% CI 1.42–2.83], p < 0.001 and OR 2.84 [95% CI 1.95–4.14], p < 0.001, respectively), and elective hospitalization (OR 3.37 [95% CI 2.46–4.64], p < 0.001) were positively associated with revascularization. Compared with Caucasian race, Hispanic ethnicity was associated with increased mean (± SEM) length of stay by 2.01 ± 0.70 days (p = 0.004) and increased hospital charges by $24,333.61 ± $7918.20 (p = 0.002), despite the decreased utilization of surgical revascularization. Private insurance was associated with elective admission (OR 1.50 [95% CI 1.10–2.05], p = 0.01) and admission to high-volume centers (OR 1.90 [95% CI 1.26–2.88], p = 0.002). African American race was associated with the development of in-hospital complications (OR 2.52 [95% CI 1.38–4.59], p = 0.003).

CONCLUSIONS

Among pediatric MMD hospitalizations, multiple socioeconomic factors were associated with access to care, whether surgical treatment is provided, and whether in-hospital complications occur. These results suggest that socioeconomic factors are important drivers of healthcare disparities in children with MMD and warrant further study.

InJournal of Neurosurgery: Pediatrics Volume 29: Issue 6 (Jun 2022)

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Arteriovenous malformations in the optic apparatus: systematic literature review and report of four cases

Visish M. Srinivasan, Phiroz E. Tarapore, Stefan W. Koester, Joshua S. Catapano, Caleb Rutledge, Kunal P. Raygor, and Michael T. Lawton

OBJECTIVE

Rare arteriovenous malformations (AVMs) of the optic apparatus account for < 1% of all AVMs. The authors conducted a systematic review of the literature for cases of optic apparatus AVMs and present 4 cases from their institution. The literature is summarized to describe preoperative characteristics, surgical technique, and treatment outcomes for these lesions.

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A comprehensive search of the English-language literature was performed in accordance with established Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all published cases of AVM in the optic apparatus in the PubMed, Web of Science, and Cochrane databases. The authors also searched their prospective institutional database of vascular malformations for such cases. Data regarding the clinical and radiological presentation, visual acuity, visual fields, extent of resection, and postoperative outcomes were gathered.

RESULTS

九个病人在文学和4个病人the authors’ single-surgeon series who fit the inclusion criteria were identified. The median age at presentation was 29 years (range 8–39 years). Among these patients, 11 presented with visual disturbance, 9 with headache, and 1 with multiple prior subarachnoid hemorrhages; the AVM in 1 case was found incidentally. Four patients described prior symptoms of headache or visual disturbance consistent with sentinel events. Visual acuity was decreased from baseline in 10 patients, and 11 patients had visual field defects on formal visual field testing. The most common visual field defect was temporal hemianopia, found in one or both eyes in 7 patients. The optic chiasm was affected in 10 patients, the hypothalamus in 2 patients, the optic nerve (unilaterally) in 8 patients, and the optic tract in 2 patients. Six patients underwent gross-total resection; 6 patients underwent subtotal resection; and 1 patient underwent craniotomy, but no resection was attempted. Postoperatively, 9 of the patients had improved visual function, 1 had no change, and 3 had worse visual acuity. Eight patients demonstrated improved visual fields, 1 had no change, and 4 had narrowed fields.

CONCLUSIONS

AVMs of the optic apparatus are rare lesions. Although they reside in a highly eloquent region, surgical outcomes are generally good; the majority of patients will see improvement in their visual function postoperatively. Microsurgical technique is critical to the successful removal of these lesions, and preservation of function sometimes requires subtotal resection of the lesion.

InJournal of Neurosurgery Volume 136: Issue 2 (Feb 2022)

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A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection

Adib A. Abla, William Caleb Rutledge, Zachary A. Seymour, Diana Guo, Helen Kim, Nalin Gupta, Penny K. Sneed, Igor J. Barani, David Larson, Michael W. McDermott, and Michael T. Lawton

OBJECT

The surgical treatment of many large arteriovenous malformations (AVMs) is associated with substantial risks, and many are considered inoperable. Furthermore, AVMs larger than 3 cm in diameter are not usually treated with conventional single-session radiosurgery encompassing the entire AVM volume. Volume-staged stereotactic radiosurgery (VS-SRS) is an option for large AVMs, but it has mixed results. The authors report on a series of patients with high-grade AVMs who underwent multiple VS-SRS sessions with resultant downgrading of the AVMs, followed by resection.

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A cohort of patients was retrieved from a single-institution AVM patient registry consisting of prospectively collected data. VS-SRS was performed as a planned intentional treatment. Surgery was considered as salvage therapy in select patients.

RESULTS

Sixteen AVMs underwent VS-SRS followed by surgery. Four AVMs presented with rupture. The mean patient age was 25.3 years (range 13–54 years). The average initial Spetzler-Martin grade before any treatment was 4, while the average supplemented Spetzler-Martin grade (Spetzler-Martin plus Lawton-Young) was 7.1. The average AVM size in maximum dimension was 5.9 cm (range 3.3–10 cm). All AVMs were supratentorial in location and all except one were in eloquent areas of the brain, with 7 involving primary motor cortex. The mean number of VS-SRS sessions was 2.7 (range 2–5 sessions). The mean interval between first VS-SRS session and resection was 5.7 years. There were 4 hemorrhages that occurred after VS-SRS. The average Spetzler-Martin grade was reduced to 2.5 (downgrade, −1.5) and the average supplemented Spetzler-Martin grade was reduced to 5.6 (downgrade, −1.5). The maximum AVM size was reduced to an average of 3.0 cm (downsize = −2.9 cm). The mean modified Rankin Scale (mRS) scores were 1.2, 2.3, and 2.2 before VS-SRS, before surgery, and at last follow-up, respectively (mean follow-up, 6.9 years). Fifteen AVMs were cured after surgery. Ten patients had good outcomes at last follow-up (7 with mRS Score 0 or 1, and 3 with mRS Score 2). There were 2 deaths (both mRS Score 1 before treatment) and 4 patients with mRS Score 3 outcome (from mRS Scores 0, 1, and 2 [n = 2]).

CONCLUSIONS

Volume-staged SRS can downgrade AVMs, transforming high-grade AVMs (initially considered inoperable) into operable AVMs with acceptable surgical risks. This treatment paradigm offers an alternative to conservative observation for young patients with unruptured AVMs and long life expectancy, where the risk of hemorrhage is substantial. Difficult AVMs were cured in 15 patients. Surgical morbidity associated with downgraded AVMs is reduced to that of postradiosurgical/preoperative supplemented Spetzler-Martin grades, not their initial AVM grades.

InJournal of Neurosurgery Volume 122 (2015): Issue 2 (Feb 2015)

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External validation of the Lawton brainstem cavernous malformation grading system in a cohort of 277 microsurgical patients

Joshua S. Catapano, Caleb Rutledge, Kavelin Rumalla, Kunal P. Raygor, Visish M. Srinivasan, Stefan W. Koester, Anna R. Kimata, Kevin L. Ma, Mohamed A. Labib, Robert F. Spetzler, and Michael T. Lawton

OBJECTIVE

The brainstem cavernous malformation (BSCM) grading system predicts neurological outcomes associated with microsurgical resection and assists neurosurgeons in selecting patients for treatment. The predictive accuracy of the BSCM grading system should be validated in a large cohort from high-volume centers to generalize its use.

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An external validation cohort comprised patients with a BSCM resected by the senior author (M.T.L.) since the publication of the BSCM grading system and those resected by another neurosurgeon (R.F.S.) over a 16-year period. Size, crossing the axial midpoint, the presence of a developmental venous anomaly, patient age, and timing of last hemorrhage were used to assign BSCM grades from 0 to VII. Poor neurological outcomes were recorded as modified Rankin Scale scores > 2 at last follow-up examination.

RESULTS

A total of 277 patients were included in the study. The average BSCM grade was 3.9, and the majority of BSCMs (181 patients, 65%) were intermediate grade (grades III–V). Outcomes were predicted by BSCM grade, with good outcomes observed in 47 of 54 patients (87%) with low-grade BSCMs, in 135 of 181 patients (75%) with intermediate-grade BSCMs, and in 21 of 42 patients (50%) with high-grade BSCMs. Conversely, proportions of patients with neurological deterioration increased with increasing BSCM grade, with worsening observed in 2 of 54 patients (4%) with low-grade BSCMs, in 29 of 181 patients (16%) with intermediate-grade BSCMs, and in 17 of 42 patients (40%) with high-grade BSCMs. In the chi-square analysis, high-grade BSCMs were associated with increased odds of neurological worsening compared to low- and intermediate-grade BSCMs (OR 5.0, 95% CI 2.4–10.4; p < 0.001). The receiver operating characteristic analysis demonstrated acceptable discrimination for predicting unfavorable functional outcomes (modified Rankin Scale score > 2) with an area under the curve of 0.74 (95% CI 0.68–0.80; p < 0.001).

CONCLUSIONS

This study validates the BSCM grading system in a large cohort of patients from two high-volume surgeons. BSCM grade predicted neurological outcomes with accuracy comparable to that of other grading systems in widespread use. The BSCM grading system establishes categories of low-, intermediate-, and high-grade BSCMs and a boundary or cutoff for surgery at BSCM grade V. BSCM grading guides the analysis of a particular patient’s condition, but treatment recommendations must be individualized, and neurosurgeons must calibrate BSCM grading to their own outcome results, unique abilities, and practices.

InJournal of Neurosurgery Volume 136: Issue 5 (May 2022)

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