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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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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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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, Rajwant Kaur, Martin J. Rutkowski, Ari J. Kane, Gurvinder Kaur, Isaac Yang, Lawrence H. Pitts and Andrew T. Parsa

Object

With limited studies available, the correlation between the extent of resection and tumor recurrence in vestibular schwannomas (VSs) has not been definitively established. In this prospective study, the authors evaluated 772 patients who underwent microsurgical resection of VSs to analyze the association between total tumor resection and the tumor recurrence rate.

Methods

The authors selected all cases from a prospectively collected database of patients who underwent microsurgical resection as their initial treatment for a histopathologically confirmed VS. Recurrence-free survival was analyzed using Kaplan-Meier analysis. The authors studied the impact of possible confounders such as patient age and tumor size using stepwise Cox regression to calculate the proportional hazard ratio of recurrence while controlling for other cofounding variables.

Results

The authors analyzed data obtained in 571, 89, and 112 patients in whom gross-total, near-total, and subtotal resections, respectively, were performed. A gross-total resection was achieved in 74% of the patients, and the overall recurrence rate in these patients 8.8%. There was no significant relation between the extent of resection and the rate of tumor recurrence (p = 0.58). As expected, the extent of resection was highly correlated with patient age, tumor size, and surgical approach (p < 0.0001). Using Cox regression, the authors found that the approach used did not significantly affect tumor control when the extent of resection was controlled for.

Conclusions

While complete tumor removal is ideal, the results presented here suggest that there is no significant relationship between the extent of resection and tumor recurrence.

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Ari J. Kane, Michael E. Sughrue, Martin J. Rutkowski, Derick Aranda, Stephen A. Mills, Mandeep Lehil, Shanna Fang and Andrew T. Parsa

Object

The literature, at present, provides limited information about extraventricular neurocytomas (EVNs) and is almost exclusively composed of case reports or small case series. Treatment for EVNs has largely been guided by results from central neurocytoma outcome studies. The authors present an analysis of all reported intracranial EVN cases to establish if tumor histopathological features can substratify EVN into groups with differing prognosis and help guide treatment decisions.

Methods

The authors identified studies reporting histology, treatment modality, and outcomes for patients with intracranial EVN. The rates of recurrence and survival for patients were compared using Kaplan-Meier analysis. Atypical tumors, defined by MIB-1 labeling index exceeding 3% or atypical histological features, were compared with typical tumors, and patients 50 years of age or older were compared with those younger than 50 years of age.

Results

Eighty-five patients met the inclusion criteria, and 27% of them had an atypical histology. Typical EVNs had a better prognosis than atypical EVNs after primary treatment, with a 5-year recurrence rate of 36% compared with 68% (p < 0.001), and a 5-year mortality rate of 4% compared with 44%, respectively (p < 0.001). Age younger 50 years was associated with a better prognosis than age equal to or greater than 50 years, with a 5-year recurrence rate of 33% and 74%, respectively (p < 0.001), and a 5-year mortality rate of 4% and 52%, respectively (p < 0.001). Multivariate analysis demonstrated that atypical EVNs carried significantly increased risk for recurrence (hazard ratio [HR] 4.91, p < 0.001) and death (HR 22.91, p < 0.01). Gross-total resection was superior to subtotal resection (STR) alone in tumor control rates for typical EVNs (95% and 68%, p < 0.05), and there was a trend for adjuvant external-beam radiotherapy to benefit STR. There was suggestion of similar trends in patients with atypical EVNs.

Conclusions

There are at least 2 distinct histological subtypes of EVN, with different prognostic significances. Atypia or MIB-1 labeling index greater than 3% is a significant predictor of poor prognosis for EVNs. Complete resection or more aggressive attempts at providing adjuvant therapy following STR appear to improve the prognosis for patients with EVNs. Although the authors' results are informative, there are limitations to their analysis. Given the relatively modest total number of cases reported, as well as the nature of the disaggregated analysis, the authors were not able to use formal meta-analytical methods to limit the impact of between center heterogeneity. Additionally, they were not able to control for individual differences in data analysis and presentation across the different studies included in their analysis.

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Editorial

Cavernous sinus meningiomas

Atul Goel and Manu Kothari

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

Object

Although there is a considerable volume of literature available on the treatment of patients with cavernous sinus meningiomas (CSMs), most of the data regarding tumor control and survival come from case studies or single-institution series. The authors performed a meta-analysis of reported tumor control and survival rates of patients described in the published literature, with an emphasis on specific prognostic factors.

Methods

The authors systematically analyzed the published literature and found more than 3000 patients treated for CSMs. Separate meta-analyses were performed to calculate pooled rates of recurrence and cranial neuropathy after 1) gross-total resection, 2) subtotal resection without adjuvant postoperative radiotherapy or radiosurgery, and 3) stereotactic radiosurgery (SRS) alone. Results were expressed as pooled proportions, and random-effects models were used to incorporate any heterogeneity present to generate a pooled proportion. Individual studies were weighted using the inverse variance method, and 95% CIs for each group were calculated from the pooled proportions.

Results

A total of 2065 nonduplicated patients treated for CSM met inclusion criteria for the analysis. Comparisons of the 95% CIs for recurrence of these 3 cohorts revealed that SRS-treated patients experienced improved rates of recurrence (3.2% [95% CI 1.9–4.5%]) compared with either gross-total resection (11.8% [95% CI 7.4–16.1%]) or subtotal resection alone (11.1% [95% CI 6.6–15.7%]) (p < 0.01). The authors found that the pooled mixed-effects rate of cranial neuropathy was markedly higher in patients undergoing resection (59.6% [95% CI 50.3–67.5%]) than for those undergoing SRS alone (25.7% [95% CI 11.5–38.9%]) (p < 0.05).

Conclusions

Radiosurgery provided improved rates of tumor control compared with surgery alone, regardless of the subjective extent of resection.

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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.