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Alan R. Cohen, David Leifer, Marc Zechel, Daniel P. Flaningan, Jonathan S. Lewin and W. David Lust

The purpose of this study was to elucidate the pathophysiology of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine, transforming growth factor-ß1 (TGFß1), in the central nervous system (CNS).

Galbreath and colleagues generated transgenic mice that overexpressed TGFß1 in the CNS in an effort to examine the role of this cytokine in the astrocytic response to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that were heterozygous for the transgene with wild-type females.

One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, which was characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and ultimately death. The presence of the TGFß1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample cuts of tail. The animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develope hydrocephalus.

Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemistry. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls, and it demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFß1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the TGFß1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed the occurrence of overexpression of the TGFß1 cytokine in brain, cerebrospinal fluid, and plasma.

The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFß1 in the CNS causes hyrdocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and additionally, should help in the search for novel treatment strategies.

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Alan R. Cohen, David W. Leifer, Marc Zechel, Daniel P. Flaningan, Jonathan S. Lewin and W. David Lust

Object. The purpose of this study was to elucidate the pathophysiological characteristics of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine transforming growth factor—β1 (TGFβ1) in the central nervous system (CNS).

Methods. Galbreath and colleagues generated transgenic mice that overexpressed TGFβ1 in the CNS in an effort to examine the role of this cytokine in the response of astrocytes to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors have perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that are heterozygous for the transgene with wild-type females.

One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and, ultimately, death. The presence of the TGFβ1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample tail slices. Animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develop hydrocephalus.

Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemical studies. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls and demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFβ1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase—PCR analysis demonstrated tissue-specific expression of the TGFβ1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed overexpression of the TGFβ1 cytokine in brain, cerebrospinal fluid, and plasma.

Conclusions. The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFβ1 in the CNS causes hydrocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and should also help in the search for new treatment strategies.

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Bert W. O'Malley Jr., M. Sean Grady, Brandon C. Gabel, Marc A. Cohen, Gregory G. Heuer, Jared Pisapia, Leif-Erik Bohman and Jason M. Leibowitz

Object

The endoscopic endonasal approach for resection of pituitary lesions is an effective surgical option for tumors of the sella turcica. In this study the authors compared outcomes after either purely endoscopic resection or traditional microscope-aided resection. They also attempted to determine the learning curve associated with a surgical team converting to endoscopic techniques.

Methods

Retrospective data were collected on patients who were surgically treated for a pituitary lesion at the Hospital of the University of Pennsylvania between July 2003 and May 2008. Age, sex, race, presenting symptoms, length of hospital stay, surgical approach, duration of surgery, tumor pathological features, gross-total resection (GTR) of tumor, recurrence of the lesion, and intraoperative and postoperative complications were noted. All procedures were performed by the same senior neurosurgeon, who was initially unfamiliar with the endoscopic endonasal approach.

Results

A total of 25 patients underwent microscopic resection and 25 patients underwent endoscopic resection performed by a single skull base team consisting of the same senior neurosurgeon and otorhinolaryngologist (M.S.G. and B.W.O.). In the microscopically treated cohort, there were 8 intra- or postoperative complications, 6 intraoperative CSF leaks, 17 (77%) of 22 patients had GTR on postoperative imaging, 5 patients underwent ≥ 2 operations, and 10 (59%) of 17 patients reported total symptom resolution at follow-up. The endoscopically treated group had 7 intraor postoperative complications and 7 intraoperative CSF leaks. Of the patients who had pre- and postoperative imaging studies, 14 (66%) of 21 endoscopically treated patients had GTR; 4 patients had ≥ 2 operations, and 10 (66%) of 15 patients reported complete symptom resolution at follow-up. The first 9 patients who were treated endoscopically had a mean surgical time of 3.42 hours and a mean hospital stay of 4.67 days. The next 8 patients treated had a mean surgical time of 3.11 hours and a mean hospital stay of 3.13 days. The final 8 patients treated endoscopically had a mean surgical time of 2.22 hours and a mean hospital stay of 3.88 days. The difference in length of operation between the first 9 and the last 8 patients treated endoscopically was significantly different. There was a trend toward decreased CSF leaks and other complications from the first 2 groups compared with the third group.

Conclusions

In this subset of patients, the use of endoscopic endonasal resection results in a similar complication and symptom resolution rate compared with traditional techniques. The authors postulate that the learning curve for endoscopic resection can be ≤ 17 procedures.

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Marc S. Schwartz, James I. Cohen, Toby Meltzer, Michael J. Wheatley, Sean O. McMenomey, Michael A. Horgan, Jordi X. Kellogg and Johnny B. Delashaw Jr.

Object. Reconstruction of the cranial base after resection of complex lesions requires creation of both a vascularized barrier to cerebrospinal fluid (CSF) leakage and tailored filling of operative defects. The authors describe the use of radial forearm microvascular free-flap grafts to reconstruct skull base lesions, to fill small tissue defects, and to provide an excellent barrier against CSF leakage.

Methods. Ten patients underwent 11 skull base procedures including placement of microvascular free-flap grafts harvested from the forearm and featuring the radial artery and its accompanying venae comitantes. Operations included six craniofacial, three lateral skull base, and two transoral procedures for various diseases. Excellent results were obtained, with no persistent CSF leaks, no flap failures, and no operative infections. One temporary CSF leak was easily repaired with flap repositioning, and at one flap donor site minor wound breakdown was observed. One patient underwent a second procedure for tumor recurrence and CSF leakage at a site distant from the original operation.

Conclusions. Microvascular free tissue transfer reconstruction of skull base defects by using the radial forearm flap provides a safe, reliable, low-morbidity method for reconstructing the skull base and is ideally suited to “low-volume” defects.

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Rupa G. Juthani, Anne S. Reiner, Ankur R. Patel, Aimee Cowan, Marie Roguski, Katherine S. Panageas, Eliza B. Geer, Sasan Karimi, Marc A. Cohen and Viviane Tabar

OBJECTIVE

The utility and safety of intraoperative MRI (iMRI) for resection of pituitary adenomas is not clearly established in the context of advances in endoscopic approaches. The goal in this study was to evaluate the safety and efficacy of iMRI for pituitary adenoma resection, with endoscopic transsphenoidal (ETS) versus microscopic transsphenoidal (MTS) approaches.

METHODS

Radiographic and clinical outcomes of all pituitary adenomas resected using iMRI between 2008 and 2017 at a single institution were retrospectively evaluated.

RESULTS

Of 212 tumors treated, 131 (62%) underwent further resection based on iMRI findings, resulting in a significant increase in gross-total resection on postoperative MRI compared with iMRI (p = 0.0001) in both ETS and MTS groups. iMRI increased rates of gross-total resection for cavernous sinus invasion Knosp grades 1 and 2, but not in Knosp ≥ 3 across treatment groups (p < 0.0001). The extent of resection on postoperative MRI was significantly correlated with increased progression-free survival (p < 0.0001). Initial hormone remission off medical therapy was achieved in 64%, with a significantly higher rate of remission in tumors resected via the ETS approach (81%) compared with the MTS approach (55%) (p = 0.02). The rate of persistent new hormone deficit was low at 8%, including a 2.8% rate of permanent diabetes insipidus, and 45% of patients had improvement in preoperative hormone deficit following surgery. Serious postoperative complications including CSF leaks requiring reoperation were rare at 1%, with no postoperative infections.

CONCLUSIONS

These results suggest that iMRI is a safe and effective method of increasing the extent of resection for pituitary adenomas while preserving hormone function. When paired with the endoscope, iMRI may offer the ability to tailor more aggressive removal of tumors while optimizing pituitary function, resulting in high rates of secretory hormone remission. Secretory tumors and adenomas with Knosp grade < 3 cavernous sinus invasion may benefit most from the use of iMRI.

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Gregory G. Heuer, Heather Kiefer, Alexander R. Judkins, Jean Belasco, Jaclyn A. Biegel, Eric M. Jackson, Marc Cohen, Bert W. O'Malley Jr. and Phillip B. Storm

The authors present the case of en bloc resection of a clival-C2 atypical teratoid/rhabdoid tumor. These aggressive lesions of early childhood generally occur in the cerebellum or cerebral hemispheres. This 7-year-old boy presented with pain on turning his head and was found to have a clival-C2 mass. A metastatic workup was negative for disseminated disease. A transoral biopsy procedure revealed an atypical teratoid/rhabdoid tumor on histological examination. The tumor was resected via a transoral approach, and the patient's spine was stabilized with posterior instrumented fusion from the occiput to C-5. Postoperatively, the patient underwent 16 months of chemotherapy along with 6 weeks of overlapping radiation therapy. Twenty-seven months after the initial surgery he presented with leg pain and was found to have a solitary metastatic lesion at the conus medullaris. There was no local recurrence at the clivus. The conus tumor was resected and found to be consistent with the primary tumor. Several months later the patient presented with disseminated intrathecal disease and ultimately died 42 months after the initial resection.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010