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Martin J. Rutkowski, Sandeep Kunwar, Lewis Blevins, and Manish K. Aghi

OBJECTIVE

Pituitary apoplexy is a clinical syndrome consisting of neurological and endocrine abnormalities secondary to hemorrhage or ischemia of an underlying pituitary adenoma. The authors investigated whether there was a significant difference in neurological, endocrine, and nonneuroendocrine outcomes for patients with pituitary apoplexy, based on the time between symptom onset and surgical intervention.

METHODS

The authors retrospectively analyzed the medical records of 32 patients who had presented to their institution with acute pituitary apoplexy and subsequently undergone endonasal transsphenoidal resection in the period from 2003 to 2014. All patients had undergone preoperative MRI demonstrating evidence of apoplexy in the form of intratumoral hemorrhage, ischemia, and necrosis. Neurological deficits, partial or complete endocrinopathy, and nonneuroendocrine abnormalities were analyzed both pre- and postoperatively.

RESULTS

Preoperatively, neurological deficits including visual loss and cranial nerve palsies were found in 31 (97%) of the 32 patients, endocrinopathy in the form of partial or panhypopituitarism was seen in 28 patients (88%), and nonneuroendocrine signs and symptoms were seen in 32 patients (100%). Thirteen patients (41%) underwent surgery within 72 hours of symptom onset (“early”), whereas 19 patients (59%) underwent surgery more than 72 hours from symptom onset (“delayed”). Early versus delayed resection did not appear to significantly improve visual deficits, total visual loss, resolution of oculomotor palsy, recovery from hypopituitarism, or nonneuroendocrine signs and symptoms such as headache and encephalopathy. Overall, visual improvement was seen in 77% of patients, complete restoration of normal vision in 38% of patients, and resolution of preoperative oculomotor palsies in 81% of patients. Only 6 (21%) of 28 patients showed evidence of partial hormone recovery following preoperative hypopituitarism. An absence of benefit for early surgery held true even when considering time to surgery from symptom onset as a continuous variable.

CONCLUSIONS

Neurological deficits such as visual loss and cranial neuropathies show moderate improvement following surgical decompression, as does preoperative hypopituitarism. The timing of surgical intervention relative to the onset of symptoms does not appear to significantly affect the resolution of neurological or endocrinological deficits.

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Martin J. Rutkowski, Patrick M. Flanigan, and Manish K. Aghi

After transsphenoidal surgery, Cushing's disease (CD) shows excellent long-term remission rates, but it may recur and pose a therapeutic challenge. Findings in recent published reports on the treatment of recurrent adrenocorticotropic hormone (ACTH)–secreting tumors suggest that repeat resection, radiation-based therapies such as Gamma Knife surgery and proton-beam radiosurgery, pharmacotherapy, and bilateral adrenalectomy all have important roles in the treatment of recurrent CD. Each of these interventions has inherent risks and benefits that should be presented to the patient during counseling on retreatment options. Radiation-based therapies increasingly appear to have efficacies similar to those of repeat resection in achieving biochemical remission and tumor control. In addition, an expanding retinue of medication-based therapies, several of which are currently being evaluated in clinical trials, has shown some promise as tertiary adjunctive therapies. Lastly, bilateral adrenalectomy may offer durable control of refractory recurrent CD. An increasing number of published studies with long-term patient outcomes highlight the evolving treatment patterns in the management of recurrent CD.

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Lauren E. Rotman, T. Brooks Vaughan, James R. Hackney, and Kristen O. Riley

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Anna Jackanich, Sherwin Tavakol, Ben A. Strickland, Martin Rutkowski, Dina Kamel, John D. Carmichael, Martin Weiss, and Gabriel Zada

OBJECTIVE

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a well-documented complication of transsphenoidal craniotomy (TSC) for sellar lesions. The authors aimed to assess their multidisciplinary approach to the diagnosis and treatment of postoperative hypocortisolemia utilizing conservative screening methods.

METHODS

The authors performed a retrospective review of 257 patients who underwent TSC for pituitary adenoma (PA) or Rathke cleft cyst (RCC) at the University of Southern California between 2012 and 2017. Patients with preoperative adrenal insufficiency, Cushing’s disease, or < 3 months of postoperative follow-up were excluded. Patient demographics, pathology, tumor characteristics, and complications were recorded. Postoperative day 1 (POD1) morning serum cortisol was assessed in all patients. Hypocortisolemia on POD1 (serum cortisol < 5 μg/dl) prompted a 7 am cortisol level measurement on POD 2 (POD2). Clinical signs and symptoms of hypocortisolemia were consistently monitored. After two serum cortisol levels < 5 μg/dl, or one serum level < 5 μg/dl plus a high clinical suspicion for HPA dysfunction, high-risk patients received glucocorticoid supplementation.

RESULTS

Data on 165 patients were included in the analysis; there were 101 women (61.2%) and 64 men (38.7%). Preoperative diagnoses included nonfunctional adenoma (n = 97, 58.7%), growth hormone–secreting adenoma (n = 37, 22.4%), RCC (n = 18, 10.9%), prolactinoma (n = 8, 4.8%), and other (n = 5, 3.0%). One hundred thirty-eight patients (63.0%) had either suprasellar extension or cavernous sinus invasion. POD1 hypocortisolemia was diagnosed in 8 patients (4.8%). Of these patients, 2 (1.2%) were clinically asymptomatic and had normalized POD2 cortisol levels. Six patients (3.6%) had clinical symptoms and POD2 cortisol levels confirming HPA axis deficiency. Of these 6 patients treated with early glucocorticoid replacement, 2 patients recovered HPA axis function during follow-up, making the incidence of new, permanent HPA axis deficiency 2.5%.

CONCLUSIONS

In the authors’ institutional review, all patients warranting postoperative glucocorticoid replacement had both complicated surgical courses and associated clinical symptoms of hypocortisolemia. The authors’ algorithm of withholding steroids until patients demonstrate clear evidence of postoperative hypocortisolemia is safe and clinically efficacious. Their data further suggest that routine postoperative cortisol screening may not be necessary following an uncomplicated operative resection, with gland preservation and the absence of clinical symptoms indicative of HPA dysfunction.

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Michael E. Sughrue, Martin J. Rutkowski, Derick Aranda, Igor J. Barani, Michael W. McDermott, and Andrew T. Parsa

Object

Definitive data allowing clinicians to predict which meningioma patients will fail to respond to conservative management are lacking. To address this need, the authors systematically reviewed the published literature regarding the natural history of small, untreated meningiomas.

Methods

The authors performed a systematic review of the existing literature on untreated meningiomas that were followed with serial MR imaging. They summarize the published linear rates of tumor growth, and the risk factors for development of new or worsened symptoms during follow-up by using a stratified chi-square test.

Results

The search methods identified 22 published studies reporting on 675 patients with untreated meningiomas followed by serial MR imaging. Linear growth rates varied significantly: no growth was the most common rate, although reports of more aggressive tumors noted growth rates of up to a 93% linear increase in size per year. The authors found that few patients with initial tumor diameters < 2 cm went on to develop new or worsened symptoms over a median follow-up period of 4.6 years. Patients with initial tumor diameters of 2–2.5 cm demonstrated a marked difference in the rate of symptom progression if their tumors grew > 10% per year, compared with those tumors growing ≤ 10% per year (42% vs 0%; p < 0.001, chi-square test). Patients with tumors between > 2.5 and 3 cm in initial size went on to develop new or worsened symptoms 17% of the time.

Conclusions

This systematic review of the literature regarding the clinical behavior of untreated meningiomas suggests that most meningiomas ≤ 2.5 cm in diameter do not proceed to cause symptoms in the approximately 5-year period following their discovery. Those that do cause symptoms can usually be predicted with close radiographic follow-up. Based on these findings, the authors suggest the importance of observation in the early course of treatment for small asymptomatic meningiomas, especially those with an initial diameter < 2 cm.

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Michael E. Sughrue, Andrea H. Yeung, Martin J. Rutkowski, Steven W. Cheung, and Andrew T. Parsa

Vestibular schwannomas (VSs) are benign tumors arising from the sheath of cranial nerve VIII. The pathogenesis underlying most familial and sporadic VSs has been linked to a mutation in a single gene, the neurofibromin 2 (NF2) gene located on chromosome 22, band q11–13.1. In this review, the authors summarized what is known about the epidemiology of NF2 mutations and patients with VSs. The authors also discuss the function of the NF2 gene product, merlin, and describe the known and hypothetical effects of genetic mutations that lead to merlin dysfunction on a broad variety of cellular and histological end points. A better understanding of the molecular pathobiology of VSs may lead to novel therapeutics to augment current modalities of treatment while minimizing morbidity.

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Editorial

Cavernous sinus meningiomas

Atul Goel and Manu Kothari

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Michael E. Sughrue, Ari J. Kane, Gopal Shangari, Martin J. Rutkowski, Michael W. McDermott, Mitchel S. Berger, and Andrew T. Parsa

Object

In 1957, Simpson published a seminal paper defining the risk factors for recurrence following surgical treatment of intracranial meningiomas. Given that Simpson's study was published more than 50 years ago, preceding image guidance technology and MR imaging, the authors reviewed their own experience with surgical treatment of Grade I meningiomas to determine if Simpson's grading scale is still relevant to modern neurosurgical practice.

Methods

From this cohort, the authors evaluated all patients undergoing craniotomy for resection of a histologically proven WHO Grade I meningioma as their initial therapy. Clinical information was retrospectively reconstructed using patient medical records and radiological data. Recurrence analysis was performed using the Kaplan-Meier method.

Results

The 5-year recurrence/progression-free survival for all patients receiving a Simpson Grade I, II, III, or IV resection was 95, 85, 88, and 81%, respectively (p = not significant, log-rank test). Kaplan-Meier analysis revealed no significant difference in recurrence-free survival between patients receiving a Simpson Grade I, II, III, or IV resection. Analysis limited to meningiomas arising from the skull base (excluding the cavernous sinus) similarly found no significant benefit to Simpson Grade I or II resection, and the survival curves were nearly superimposed.

Conclusions

In this study of a cohort of patients undergoing surgery for WHO Grade I meningiomas, the authors demonstrate that the benefit of more aggressive attempts to resect the tumor with dura and underlying bone was negligible compared with simply removing the entire tumor, or even leaving small amounts of tumor attached to critical structures. The authors believe that these data reflect an evolution in the nature of meningioma surgery over the past 2 decades, and bring into question the relevance of using Simpson's grading system as the sole predictor of recurrence.

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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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Martin J. Rutkowski, Harjus S. Birk, Matthew D. Wood, Arie Perry, Theodore Nicolaides, Christopher P. Ames, and Nalin Gupta

The authors report the case of a 5-year-old boy in whom extraneural metastases developed 5 years after he underwent an occipitocervical fusion and transoral approach to treat a clival chordoma without local recurrence. Following primary resection, the patient's postoperative course was complicated by recurrent meningitis secondary to CSF leak, which responded to antibiotics, and communicating hydrocephalus, for which a ventriculoperitoneal shunt was placed. The patient then underwent postoperative proton beam radiotherapy. Five years following his initial presentation, surveillance imaging revealed a new asymptomatic lung mass for which the patient underwent thoracotomy and resection of the mass. Histological examination of the lung mass revealed findings consistent with a de-differentiated chordoma, confirming extraneural metastasis from the original tumor without evidence of local recurrence. Chest wall and scalp metastases subsequently developed, and the patient was started on an adjuvant chemotherapy regimen that included imatinib and rapamycin followed by subsequent nivolumab and an EZH2 inhibitor for recurrent, disseminated disease. Despite this patient's remote and distant metastases, primary gross-total resection for chordoma remains a critical treatment objective, followed by proton beam radiotherapy. This case illustrates the importance of interval posttreatment imaging and the emerging potential to treat chordoma with molecularly targeted therapies.