Hetty L. DeVroom

Surgical management of cerebellar hemangioblastomas in patients with von Hippel–Lindau disease

OBJECT Despite the frequency of cerebellar hemangioblastomas in von Hippel-Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas. METHODS Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8+/-10.3 years, follow-up duration 96.0+/-60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed. RESULTS Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8+/-1.9 cm; volume 2.8+/-3.4 cm3; p<0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p<0.05) than asymptomatic tumors (diameter 1.1+/-0.9 cm; volume 0.7+/-0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p<0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5+/-15.0 months) revealed no recurrences. CONCLUSIONS Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.

Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease

OBJECT Many patients with Cushing disease still have active or recurrent disease after pituitary surgery. The histological pseudocapsule of a pituitary adenoma is a layer of compressed normal anterior lobe that surrounds the adenoma and can be used during surgery to identify and guide removal of the tumor. In this study the authors examined the results of using the pseudocapsule as a surgical capsule in the resection of adenomas in patients with Cushing disease. METHODS The authors reviewed a prospective database of data obtained in patients with Cushing disease who underwent surgery. The analysis included all cases in which a lesion was identified during surgery and in which the lesion was believed to be confined to the pituitary gland in patients with Cushing disease between January 1990 and March 2007. Since the objective was to determine the success of using the pseudocapsule as a surgical capsule, patients with invasive tumors and patients in whom no lesion was identified during surgery-challenging cases for surgical success-were excluded from analysis. RESULTS In 261 patients an encapsulated adenoma was identified at surgery. Tumor was visible on MR imaging in 135 patients (52%); in 126 patients (48%) MR imaging detected no tumor. The range of tumor size overlapped considerably in the groups with positive and negative MR imaging results, indicating that in addition to size other features of the adenoma influence the results of MR imaging. In 252 patients hypercortisolism resolved after the first operation, whereas in 9 patients (3 with positive MR imaging and 6 with negative MR imaging) early reoperation was required. Hypercortisolism resolved in all 261 patients (256 with hypocortisolism and 5 with eucortisolism) before hospital discharge. Forty-six patients (18%) had postoperative electrolyte abnormalities (30 with hyponatremia and 16 with diabetes insipidus), but only 2 patients required treatment at discharge. The mean clinical follow-up duration was 84 months (range 12-215 months). Six patients (2%) had recurrence of hypercortisolism, all of whom were treated successfully with reoperation. CONCLUSIONS Because of their small size, adenomas can be challenging to identify in patients with Cushing disease. Use of the histological pseudocapsule of an adenoma allows accurate identification of the tumor and helps guide its complete excision. With this approach the overall remission rate is high and the rate of complications is low.

Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers

Background Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. Methodology Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. Findings The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. Conclusion Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. Clinical Trial Registration Information http://www.clinicaltrials.gov; NCT00103025

Outcome of Surgical Treatment of 200 Children With Cushing's Disease

CONTEXT Factors influencing the outcome of surgical treatment of pediatric Cushings disease (CD) have not been fully established. OBJECTIVE The aim of this study was to examine features influencing the outcome of surgery for pediatric CD. DESIGN In this prospective observational study, the clinical, imaging, endocrinological, and operative outcomes were analyzed in consecutive patients treated at the National Institutes of Health (NIH) from 1982 through 2010. SETTING The study was conducted in a tertiary referral center. RESULTS Two hundred CD patients (106 females, 94 males) were included. Mean age at symptom development was 10.6 ± 3.6 years (range, 4.0 to 19.0 y). Mean age at NIH operation was 13.7 ± 3.7 years. Twenty-seven patients (13%) had prior surgery at another institution. Magnetic resonance imaging identified adenomas in 97 patients (50%). When positive, magnetic resonance imaging accurately defined a discrete adenoma in 96 of the 97 patients (99%), which was more accurate than the use of ACTH ratios during inferior petrosal sinus sampling to determine adenoma lateralization (accurate in 72% of patients without prior surgery). A total of 195 of the 200 patients (98%) achieved remission after surgery (189 [97%] were hypocortisolemic; 6 [3%] were eucortisolemic postoperatively). Factors associated with initial remission (P < .05) included identification of an adenoma at surgery, immunohistochemical ACTH-producing adenoma, and noninvasive ACTH adenoma. Younger age, smaller adenoma, and absence of cavernous sinus wall or other dural invasion were associated with long-term remission (P < .05). A minimum morning serum cortisol of less than 1 μg/dl after surgery had a positive predictive value for lasting remission of 96%. CONCLUSIONS With rare disorders, such as pediatric CD, enhanced outcomes are obtained by evaluation and treatment at centers with substantial experience. Resection of pituitary adenomas in pediatric CD in that setting can be safe, effective, and durable. Early postoperative endocrine testing predicts lasting remission. Because lasting remission is associated with younger age at surgery, smaller adenomas, and lack of dural invasion, early diagnosis should improve surgical outcome.

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVE The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.

The Lateralization Accuracy of Inferior Petrosal Sinus Sampling in 501 Patients With Cushing's Disease

CONTEXT It is often difficult to find an adenoma in patients with Cushings disease (CD) whose preoperative magnetic resonance imaging (MRI) is normal. Better localizing modalities are needed. OBJECTIVE The aim of this study was to determine the accuracy of inferior petrosal sinus sampling (IPSS) in predicting adenoma lateralization. DESIGN AND SETTING We conducted a prospective observational study at a tertiary care clinical research center. PATIENTS A total of 501 consecutive patients (363 female) with confirmed ACTH adenomas and IPSS were included. MAIN OUTCOME MEASURE We measured the accuracy of IPSS to predict the intrasellar location of an adenoma. RESULTS IPSS confirmed a pituitary source of ACTH secretion in 491 patients (98%). All 10 patients with false-negative results had peak IPSS ACTH concentrations (before or after CRH) of < 400 pg/ml. Interpetrosal (side-to-side) ratios were ≥ 1.4 in 491 patients (98%). This ratio correctly predicted lateralization in 273 of 396 patients (positive predictive value = 69%) with a lateral adenoma. Left-sided IPSS lateralization (P = .008) and consistent lateralization before and after CRH administration (P = .02) were associated with enhanced accuracy. When positive, preoperative MRI correlated with adenoma location in 171 of 201 patients (positive predictive value = 86%). CONCLUSIONS Potential false-negative results, the most common type of diagnostic error with IPSS for the differential diagnosis of CS, can be identified by peak IPSS ACTH values < 400 pg/ml. When MRI is normal, IPSS can be used to guide surgical exploration in patients with negative preoperative imaging. However, because of the limited accuracy of lateralization, thorough exploration of the pituitary gland is required when an adenoma is not readily discovered based on predicted location.

Pathophysiology of persistent syringomyelia after decompressive craniocervical surgery. Clinical article.

OBJECT Craniocervical decompression for Chiari malformation Type I (CM-I) and syringomyelia has been reported to fail in 10%-40% of patients. The present prospective clinical study was designed to test the hypothesis that in cases in which syringomyelia persists after surgery, craniocervical decompression relieves neither the physiological block at the foramen magnum nor the mechanism of syringomyelia progression. METHODS The authors prospectively evaluated and treated 16 patients with CM-I who had persistent syringomyelia despite previous craniocervical decompression. Testing before surgery included the following: 1) clinical examination; 2) evaluation of the anatomy using T1-weighted MR imaging; 3) assessment of the syrinx and CSF velocity and flow using cine phase-contrast MR imaging; and 4) appraisal of the lumbar and cervical subarachnoid pressures at rest, during a Valsalva maneuver, during jugular compression, and following the removal of CSF (CSF compliance measurement). During surgery, ultrasonography was performed to observe the motion of the cerebellar tonsils and syrinx walls; pressure measurements were obtained from the intracranial and lumbar intrathecal spaces. The surgical procedure involved enlarging the previous craniectomy and performing an expansile duraplasty with autologous pericranium. Three to 6 months after surgery, clinical examination, MR imaging, and CSF pressure recordings were repeated. Clinical examination and MR imaging studies were then repeated annually. RESULTS Before reexploration, patients had a decreased size of the CSF pathways and a partial blockage in CSF transmission at the foramen magnum. Cervical subarachnoid pressure and pulse pressure were abnormally elevated. During surgery, ultrasonographic imaging demonstrated active pulsation of the cerebellar tonsils, with the tonsils descending during cardiac systole and concomitant narrowing of the upper pole of the syrinx. Three months after reoperation, patency of the CSF pathways was restored and pressure transmission was improved. The flow of syrinx fluid and the diameter of the syrinx decreased after surgery in 15 of 16 patients. CONCLUSIONS Persistent blockage of the CSF pathways at the foramen magnum resulted in increased pulsation of the cerebellar tonsils, which acted on a partially enclosed cervical subarachnoid space to create elevated cervical CSF pressure waves, which in turn affected the external surface of the spinal cord to force CSF into the spinal cord through the Virchow-Robin spaces and to propel the syrinx fluid caudally, leading to syrinx progression. A surgical procedure that reestablished the CSF pathways at the foramen magnum reversed this pathophysiological mechanism and resolved syringomyelia. Elucidating the pathophysiology of persistent syringomyelia has implications for its primary and secondary treatment.

A method to record, store, and analyze multiple physiologic pressure recordings

To investigate the pathophysiology of syringomyelia, we developed a system to simultaneously record arterial, central venous, airway, cervical subarachnoid and intrathecal pressures. In addition, our system records electrocardiograms (ECGs) and provides us with the means to analyze all pressures during individual and averaged cardiac cycles. During the described study, flow magnetic resonance imaging and cardiac-gated ultrasound images were also used. To compare our pressure readings with these images, we needed to account for the low-frequency changes in the recorded pressures resulting from normal respiration. We therefore wrote a program to derive mean pressure waves during the cardiac cycle that averaged out the pressure effects of the respiratory cycle. Simultaneous cerebrospinal pressure, hemodynamic pressure and ECG were plotted. This allowed us to establish the simultaneous relationship between pressures, syrinx size and cerebellar tonsil pulsation during the cardiac cycle. This system may prove valuable to other researchers investigating the interactions between multiple physiological parameters during the cardiac cycle.