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Gautam U. Mehta, Kamran D. Bakhtian and Edward H. Oldfield

Object

Primary empty sella syndrome (ESS) results from herniation of arachnoid mater into the pituitary fossa. It has been suggested to have a negative effect on pituitary surgery; however, outcomes in this cohort have not been defined. This study was performed to determine the effect of ESS on immediate and long-term biochemical outcome after pituitary surgery for Cushing's disease (CD).

Methods

Using a matched cohort study design, the authors followed patients treated with pituitary surgery for CD with and without ESS. Complete ESS was defined as pituitary gland height ≤ 2 mm, whereas partial ESS was defined as pituitary gland height > 2 mm but less than three-quarters of the total sellar depth. The primary end points were immediate and long-term biochemical outcome. Cerebrospinal fluid leaks were recorded as a secondary end point.

Results

Seventy-eight patients with CD and primary ESS were identified and matched with 78 patients with CD without ESS. After surgical management, immediate biochemical remission was achieved in 69 patients (88%) with ESS and 75 controls (96%, p = 0.10). Long-term remission was achieved in most patients in both groups (5-year cure: 85% vs 92%, p = 0.10). Among patients with ESS, the presence of complete ESS predicted a worse long-term outcome (p = 0.04). Intraoperative CSF leaks were significantly more frequent with ESS (54% vs 24%, p < 0.001), and despite sellar floor repair, the rate of postoperative CSF leaks was also increased (6% vs 3%, p = 0.27).

Conclusions

Biochemical outcome after pituitary surgery for CD was worse in patients with complete ESS, and the risk of a CSF leak was increased with both partial and complete ESS. However, as outcome remains superior to those following alternative therapies and the biology of these tumors is unchanged in the setting of ESS, pituitary surgery should remain the initial treatment of choice.

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Robert Dallapiazza, Aaron E. Bond, Yuval Grober, Robert G. Louis, Spencer C. Payne, Edward H. Oldfield and John A. Jane Jr.

Object

The object of this study was to compare surgical outcomes and complications in a contemporaneous series of patients undergoing either microscopic or endoscopic transsphenoidal surgery for nonfunctioning pituitary macroadenomas without imaging evidence of cavernous sinus invasion.

Methods

This is a retrospective analysis of a prospectively collected database from a single institution. Data were collected from patients whose surgery had occurred in the period from June 2010 to January 2013. Patients who underwent microscopic or endoscopic surgery for Knosp Grade 0, 1, or 2 nonfunctioning pituitary macroadenomas were included in the study. Patients who had clinically secreting or Knosp Grade 3 or 4 tumors and patients who were undergoing revision surgery were excluded from analysis. Eligible patient records were analyzed for outcomes and complications. Statistical analyses were performed on tumor volume, intraoperative factors, postoperative complications, and degree of resection on 1-year postoperative MRI. The results were used to compare the outcomes after microscopic and endoscopic approaches.

Results

Forty-three patients underwent microscopic transsphenoidal surgery, and 56 underwent endoscopic transsphenoidal surgery. There were no statistical differences in the intraoperative extent of resection or endocrinological complications. There were significantly more intraoperative CSF leaks in the endoscopic group (58% vs 16%); however, there was no difference in the incidence of postoperative CSF rhinorrhea (12% microscopic vs 7% endoscopic). Length of hospitalization was significantly shorter in patients undergoing an endoscopic approach (3.0 days vs 2.4 days). Two-month follow-up imaging was available in 95% of patients, and 75% of patients had 1-year follow-up imaging. At 2 months postprocedure, there was no evidence of residual tumor in 79% (31 of 39) and 85% (47 of 55) of patients in the microscopic and endoscopic groups, respectively. At 1 year postprocedure, 83% (25 of 30) of patients in the microscopic group had no evidence of residual tumor and 82% (36 of 44) of those in the endoscopic group had no evidence of residual tumor.

Conclusions

The microscopic and endoscopic techniques provide similar outcomes in the surgical treatment of Knosp Grades 0–2 nonfunctioning pituitary macroadenomas.

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Russell R. Lonser, John A. Butman, Kristin Huntoon, Ashok R. Asthagiri, Tianxia Wu, Kamran D. Bakhtian, Emily Y. Chew, Zhengping Zhuang, W. Marston Linehan and Edward H. Oldfield

Object

The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined.

Methods

Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data.

Results

At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9).

Conclusions

Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability. Clinical trial registration no.: NCT00005902 (ClinicalTrials.gov).

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Edward H. Oldfield, Johanna J. Loomba, Stephen J. Monteith, R. Webster Crowley, Ricky Medel, Daryl R. Gress, Neal F. Kassell, Aaron S. Dumont and Craig Sherman

Object

Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion.

Methods

In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter.

Results

In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14.

Conclusions

Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm. Clinical trial registration no.: NCT00873015 (ClinicalTrials.gov).

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Edward R. Laws Jr., Kenneth de los Reyes and Jordina Rincon-Torroella

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John D. Heiss, Giancarlo Suffredini, Kamran D. Bakhtian, Malisa Sarntinoranont and Edward H. Oldfield

Object

Chiari malformation Type I (CM-I) is characterized by hindbrain deformity. We investigated the effects of craniocervical decompression surgery on the anatomical features of hindbrain deformity with a prospective MRI study of patients with CM-I.

Methods

A prospective longitudinal study was conducted in 48 patients with CM-I (39 with syringomyelia) treated with craniocervical decompression. Clinical examinations and cervical MRI were performed before surgery and 1 week, 3–6 months, and annually after surgery. Hindbrain deformity was defined by tonsillar ectopia, pointed cerebellar tonsils, and/or cervicomedullary protuberance. The length of the clivus, basiocciput (sphenooccipital synchondrosis to basion), supraocciput (internal occipital protuberance to opisthion), and anteroposterior (AP) width of CSF pathways at the foramen magnum were measured and compared with those from 18 healthy volunteers (control group).

Results

Before surgery, the patients' posterior fossa bones were short and their CSF pathways were narrow. All patients had tonsillar ectopia (mean [± SD] 12.3 ± 5.1 mm; normal 0.3 ± 1.0). The majority of patients had pointed tonsils and more than two-thirds exhibited a cervicomedullary protuberance. Clivus and basiocciput lengths were significantly shorter than the values obtained in the control group. However, the supraocciput length did not differ significantly from control measurements. The mean bulbopontine sulcus distance superior to the basion was 9.5 ± 2.6 mm (vs 13.6 ± 2.8 mm in controls; p < 0.0001). The AP widths of the CSF pathways at the level of the foramen magnum were significantly narrowed. After surgery, CSF pathways significantly expanded both ventrally and dorsally. By 3–6 months after surgery, pointed tonsils became round, cervicomedullary protuberance disappeared, and tonsillar ectopia diminished by 51% (to 6.0 ± 3.3 mm; p < 0.0001).

Conclusions

The cerebellar tonsils and brainstem assumed a normal appearance within 6 months after craniocervical decompression. These findings support the concept that the CM-I is not a congenital malformation of the neural elements but rather an acquired malformation that arises from pulsatile impaction of the cerebellar tonsils into the foramen magnum. Clinical trial registration no.: NCT00001327.

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John D. Heiss, Kendall Snyder, Matthew M. Peterson, Nicholas J. Patronas, John A. Butman, René K. Smith, Hetty L. DeVroom, Charles A. Sansur, Eric Eskioglu, William A. Kammerer and Edward H. Oldfield

Object

The pathogenesis of syringomyelia in patients with an associated spinal lesion is incompletely understood. The authors hypothesized that in primary spinal syringomyelia, a subarachnoid block effectively shortens the length of the spinal subarachnoid space (SAS), reducing compliance and the ability of the spinal theca to dampen the subarachnoid CSF pressure waves produced by brain expansion during cardiac systole. This creates exaggerated spinal subarachnoid pressure waves during every heartbeat that act on the spinal cord above the block to drive CSF into the spinal cord and create a syrinx. After a syrinx is formed, enlarged subarachnoid pressure waves compress the external surface of the spinal cord, propel the syrinx fluid, and promote syrinx progression.

Methods

To elucidate the pathophysiology, the authors prospectively studied 36 adult patients with spinal lesions obstructing the spinal SAS. Testing before surgery included clinical examination; evaluation of anatomy on T1-weighted MRI; measurement of lumbar and cervical subarachnoid mean and pulse pressures at rest, during Valsalva maneuver, during jugular compression, and after removal of CSF (CSF compliance measurement); and evaluation with CT myelography. During surgery, pressure measurements from the SAS above the level of the lesion and the lumbar intrathecal space below the lesion were obtained, and cardiac-gated ultrasonography was performed. One week after surgery, CT myelography was repeated. Three months after surgery, clinical examination, T1-weighted MRI, and CSF pressure recordings (cervical and lumbar) were repeated. Clinical examination and MRI studies were repeated annually thereafter. Findings in patients were compared with those obtained in a group of 18 healthy individuals who had already undergone T1-weighted MRI, cine MRI, and cervical and lumbar subarachnoid pressure testing.

Results

In syringomyelia patients compared with healthy volunteers, cervical subarachnoid pulse pressure was increased (2.7 ± 1.2 vs 1.6 ± 0.6 mm Hg, respectively; p = 0.004), pressure transmission to the thecal sac below the block was reduced, and spinal CSF compliance was decreased. Intraoperative ultrasonography confirmed that pulse pressure waves compressed the outer surface of the spinal cord superior to regions of obstruction of the subarachnoid space.

Conclusions

These findings are consistent with the theory that a spinal subarachnoid block increases spinal subarachnoid pulse pressure above the block, producing a pressure differential across the obstructed segment of the SAS, which results in syrinx formation and progression. These findings are similar to the results of the authors' previous studies that examined the pathophysiology of syringomyelia associated with obstruction of the SAS at the foramen magnum in the Chiari Type I malformation and indicate that a common mechanism, rather than different, separate mechanisms, underlies syrinx formation in these two entities. Clinical trial registration no.: NCT00011245.

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Dueng-Yuan Hueng, Hsin-I Ma and Chien-Min Chen

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Gautam U. Mehta and Edward H. Oldfield

Object

Cerebrospinal fluid leakage is a major complication of transsphenoidal surgery. An intraoperative CSF leak, which occurs in up to 50% of pituitary tumor cases, is the only modifiable risk factor for postoperative leaks. Although several techniques have been described for surgical repair when an intraoperative leak is noted, none has been proposed to prevent an intraoperative CSF leak. The authors postulated that intraoperative CSF drainage would diminish tension on the arachnoid, decrease the rate of intraoperative CSF leakage during surgery for larger tumors, and reduce the need for surgical repair of CSF leaks.

Methods

The results of 114 transsphenoidal operations for pituitary macroadenoma performed without intraoperative CSF drainage were compared with the findings from 44 cases in which a lumbar subarachnoid catheter was placed before surgery to drain CSF at the time of dural exposure and tumor removal.

Results

Cerebrospinal fluid drainage reduced the rate of intraoperative CSF leakage from 41% to 5% (p < 0.001). This reduction occurred in macroadenomas with (from 57% to 5%, p < 0.001) and those without suprasellar extension (from 29% to 0%, p = 0.31). The rate of postoperative CSF leakage was similar (5% vs 5%), despite the fact that intraoperative CSF drainage reduced the need for operative repair (from 32% to 5%, p < 0.001). There were no significant catheter-related complications.

Conclusions

Cerebrospinal fluid drainage during transsphenoidal surgery for macroadenomas reduces the rate of intraoperative CSF leaks. This preventative measure obviated the need for surgical repair of intraoperative CSF leaks using autologous fat graft placement, other operative techniques, postoperative lumbar drainage, and/or reoperation in most patients and is associated with minimal risks.