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Delayed Cerebrospinal Fluid Rhinorrhea After Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
Accepted Manuscript Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology Avital Perry, MD, Christopher S. Graffeo, MD, William R. Copeland, III, MD, Kathryn M. Van Abel, Matthew L. Carlson, MD, Bruce E. Pollock, MD, Michael J. Link, MD PII:
S1878-8750(17)30009-8
DOI:
10.1016/j.wneu.2017.01.001
Reference:
WNEU 5098
To appear in:
World Neurosurgery
Received Date: 30 July 2016 Revised Date:
31 December 2016
Accepted Date: 2 January 2017
Please cite this article as: Perry A, Graffeo CS, Copeland III WR, Van Abel KM, Carlson ML, Pollock BE, Link MJ, Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology, World Neurosurgery (2017), doi: 10.1016/ j.wneu.2017.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1,3, Michael J Link MD1,2 ORIGINATING INSTITUTION: Department of Neurologic Surgery1, Department of Otolaryngology-Head and Neck Surgery2 and Department of Radiation Oncology3, Mayo Clinic, Rochester MN Michael J. Link, MD Department of Neurologic Surgery – Mayo Clinic 200 First St SW Rochester, MN, USA 55905
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CORRESPONDING AUTHOR:
Telephone: 507-284-4871 Fax: 507-284-5206 Email: [email protected]
FINANCIAL MATERIAL & SUPPORT: None
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CONFLICT(S) OF INTEREST TO DECLARE: None KEYWORDS: Cerebrospinal fluid leak, gamma knife, transsphenoidal surgery, acromegaly, late outcomes
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RUNNING HEADER: Delayed CSF Rhinorrhea
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PREVIOUS PRESENTATION: Components of this research were presented at the North American Skull Base Society 2016 annual meeting WORD COUNT: 2,693
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ABSTRACT Background: Skull base cerebrospinal fluid (CSF) leak after gamma knife radiosurgery (GKRS) is a very rare complication. In patients who were treated with both GKRS and transsphenoidal resection (TSR) for pituitary lesions, early CSF leak occurs at a comparable rate to the general
therapy, is exceedingly rare.
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Methods: Retrospective chart review and review of the literature
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TSR population (4%). Delayed CSF leak occurring more than a year after TSR, GKRS, or dual
Results: We present two cases of delayed CSF leak following GKRS to treat pituitary adenoma.
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One patient developed CSF rhinorrhea 16 years following GKRS for growth hormone producing pituitary adenoma. She had previously undergone TSR surgery 7 years prior to GKRS without complication. Additionally, a 55-year-old man developed high flow CSF rhinorrhea 2 years following GKRS for a prolactinoma that failed dopamine agonist therapy. Both patients underwent a complicated clinical course following presentation, requiring multiple revisions for
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definitive CSF leak repair.
Conclusion: Delayed CSF leak is a rare but serious complication after GKRS independent of TSR status; urgent repair is the treatment of choice. Based on our experience, these leaks have the potential to be refractory, and we recommend aggressive reconstruction, preferably with a
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vascularized flap, and potentially supplemented by placement of a lumbar drain and acetazolamide. Current evidence is scant and provides little insight regarding an underlying
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mechanism, which may include bony destruction by the tumor, delayed radiation necrosis, or a secondary empty sella syndrome.
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INTRODUCTION Cerebrospinal fluid (CSF) leak is perhaps the most common and troublesome postoperative complication after pituitary surgery, with a widely quoted incidence of 3.9% following
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transsphenoidal resection (TSR)—although other reports have published rates ranging from 0.515%.5,8,10-12,29,33,34 A potential advantage of Gamma Knife radiosurgery (GKRS) treatment for pituitary tumors is very low risk of CSF leak.15,27,31
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CSF leak after GKRS without preceding TSR or dopamine agonist therapy is exceedingly rare, with preceding large series reporting zero cases, and one case report appearing in the
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literature.13 Although early CSF leak rates may occur after TSR for pituitary adenomas, delayed leaks—even following resection of large tumors—are uncommon, with <1% occurring in the 30to-90 day window, and exceedingly rare cases documenting CSF leaks beyond the six-month threshold after surgery.12,19,28,29,32,39
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We report two cases of delayed CSF leak occurring years after TSR and GKRS. Notably, ours is also only the second reported case of a leak occurring more than ten years after either
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TSR or GKRS for any pathology.13,29
CASE HISTORIES
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Case 1
A 74-year-old woman initially presented in 1984 to an outside institution with signs of acromegaly and imaging findings consistent with pituitary macroadenoma. She underwent sublabial transsphenoidal resection of the tumor; gross total resection was achieved, and her endocrinologic derangements resolved. Pathology confirmed pituitary adenoma.
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In 1991, the patient presented again to an outside institution with symptoms and imaging findings concerning for tumor recurrence. She was treated with external beam radiation therapy (dose/fractionation records not available), which halted tumor progression, but also precipitated
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pan-hypopituitarism requiring long-term supplementation with hydrocortisone and levothyroxine.
In 1998, the patient presented to our facility with new complaints of headache, and
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surveillance MRI revealed an enlargement of the known sellar mass (Figure 1A). She
subsequently underwent GKRS 14 years after initial TSR, receiving 30 Gy to the 50% isodose
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line covering a volume of 0.9 cc. Follow-up including annual MRI scans and serum IGF-1 levels, showed stable tumor regression and no biochemical evidence of recurrent acromegaly (Figure 1B).
In November 2014, the patient sneezed and experienced immediate, copious, drainage of
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clear fluid from her nose. Over the course of several hours, she developed headache, lethargy, and confusion, prompting presentation to an outside emergency department. Head CT revealed severe pneumocephalus, and the patient was transferred to our facility for further work-up and
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treatment (Figure 1C). Repeat head CT acquired preoperatively demonstrated a large bony defect of the sellar floor with clear communication between the clivus and intracranial space
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(Figure 1D).
The patient was taken emergently to the operating theater for exploration and repair of a
presumed CSF leak. A lumbar drain was placed in the L3-4 interspace, and 0.25mL of 10% fluorescein mixed in 20mL of sterile saline was injected into the thecal sac. A nasoseptal flap was raised, and the sphenoid sinus was then explored using endoscopic technique. An obvious defect of the sellar floor was noted with frank drainage of fluorescein-stained CSF. The bony
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margins of the defect were demucosalized and debrided, and further exploration revealed that the diaphragm sella had herniated into the sella turcica, and was overlying the defect intracranially. The sella was packed with abdominal fat wrapped in rectus fascia, followed by additional fat and
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fascial tissue within the bony tract. A Valsalva maneuver was performed, and no egress of CSF was observed. The nasoseptal flap was then positioned on top of the bony defect, covered with polymer sealant and secured with bioresorbable intranasal dressing.
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The patient returned to her neurologic baseline within 24 hours. Broad-spectrum
antibiotics were maintained throughout her admission, lumbar drainage was continued at a rate
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of 10mL every two hours for six days, and the patient underwent an unremarkable recovery, with no symptoms concerning for complications including meningitis or diabetes insipidus. She was discharged home on postoperative day seven in stable condition; head CT prior to hospital dismissal showed a marked improvement in pneumocephalus.
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On postoperative day 26, the patient presented again to our emergency department, complaining of clear, salty nasal drainage, and worsening headaches for three days. Head CT showed significant recurrent pneumocephalus, and a sample of nasal fluid tested positive for
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beta-2 transferrin. The patient was taken again to the operating theater, and a lumbar drain was placed for injection of fluorescein dye. Endoscopic exploration demonstrated minimal drainage
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of fluorescein from around the nasoseptal flap, which was carefully lifted and temporarily reflected into the choana. The face of the sella was further demucosalized, and the fascia and fat used to pack the initial defect were removed. A collagen matrix graft was placed within the sella, covering the site of the CSF leak along the posterior diaphragm. New abdominal fat and fascia lata were packed within the sella and the bony defect, and the nasoseptal flap was repositioned and covered with polymer sealant. No CSF leak was observed on Valsalva, and the repair was
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covered with layers of oxidized cellulose hemostat, compressed gelatin sponge, and petroleum gauze. Lumbar drainage, 10cc every 2 hours, was again used for three days, and acetazolamide (250mg BID by mouth) was also employed to decrease pressure exerted on the repair by the CSF
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compartment.
The patient again returned to her neurologically intact pre-leak baseline, and serial imaging studies demonstrated progressive decrease in pneumocephalus, which resolved
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completely by dismissal (Figure 1E). Five days following admission, the patient was discharged in stable condition, without evidence of on-going CSF leak, on a one-month course of
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acetazolamide. She was seen in follow-up at one, three, and twelve months, with no findings concerning for recurrent CSF leak; nasal endoscopy demonstrated a healthy nasoseptal flap and robust healing at the defect site, without evidence of dehiscence.
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Case 2
A 55-year-old man initially presented to an outside institution in 1999 with erectile dysfunction, loss of libido, gynecomastia with galactorrhea, and visual changes, leading to the diagnosis of
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pituitary prolactinoma. He was initiated on cabergoline, resulting in improvement but incomplete resolution of his symptoms. He presented to our institution in 2002, reporting significant
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dissatisfaction with his symptomatic control. MRI at that time demonstrated encasement of the right intracavernous carotid artery; correspondingly, the patient was treated with GKRS (25Gy to the 50% isodose line; volume: 3.4cc) and continued on cabergoline (Figure 2A). Following treatment, the patient noted marked, progressive improvement in all of his
symptoms, follow-up imaging demonstrated expected post-radiation changes, tumor necrosis, and regression, and laboratory studies showed a moderate decrease in serum prolactin from
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39ng/mL on cabergoline alone to 20ng/mL (Figure 2B). In 2004, the patent experienced an episode of unprovoked clear fluid drainage from the nose, prompting him to present for outpatient evaluation. Laboratory analysis was positive for beta-2 transferrin, and a bony defect
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of the right sphenoid sinus was demonstrated on maxillofacial CT (Figure 2C). An endoscopicassisted microscopic repair was carried out, and the bony defect was identified in the posterior sphenoid wall, with an underlying dural defect. The bony margins were demucosalized, and the
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repair was carried out in layers, using fat and muscle to pack the defect, followed by an
autologous fascia lata onlay graft secured with polymer sealant, bone graft, additional fat and
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muscle, compressed gelatin sponge, and reticulated polyvinyl alcohol sponge. The patient had an uneventful recovery and was dismissed home at his neurologic and endocrine baseline. Ten months later, he presented again, with intermittent clear nasal drainage over several weeks. Repeat maxillofacial CT showed a more prominent bony defect in the sellar
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floor (Figure 2D-F), and CSF leak was confirmed by nuclear cisternography, following which the patient underwent a second operative repair. Fluorescein dye was used to localize a pinpoint tear in the mucosal layer overlying a pulsatile pituitary mass bulging into the sphenoid sinus. The
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mucosa was elevated, and the defect was packed with abdominal fat, local mucosal graft, polymer sealant, and a right superior turbinate rotational flap, which was fixed in place with
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additional polymer sealant, abdominal fat, and reticulated polyvinyl alcohol sponge. The patient again recovered without issue, and close clinical follow up disclosed no additional signs or symptoms concerning for recurrent CSF leak over five years.
DISCUSSION
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Delayed CSF leak is an exceedingly rare complication after any neurosurgical intervention for pituitary pathology. CSF leak following TSR is relatively rare and almost always occurs in the early postoperative period, with almost no cases presenting beyond the six-month threshold. CSF
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leak after GKRS in neurosurgery-naïve patients is exquisitely rare outside the context of
dopamine agonist therapy. Ours is the second reported case of CSF leak more than ten years after multi-modality initial therapy in a patient who underwent both TSR and GKRS, with one
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additional case documenting a leak beyond the ten-year threshold after GKRS monotherapy.13,29 The overall CSF leak rate after TSR for pituitary pathology is frequently approximated at
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3.9%, although various reports have demonstrated incidences ranging from 0.5-15%.3,12,33 Some disagreement exists regarding risk factors, with prior evidence demonstrating associations with both micro- and macroadenomas, ACTH-producing tumors, prolactinomas, history of multiple transsphenoidal operations, history of radiotherapy of any modality, or an observed
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intraoperative leak—an occurrence that is thought to increase the risk of a postoperative leak by more than three-fold.2,12,21,28,32,39
Timing of CSF leak after TSR is heavily skewed towards the early postoperative period.
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In a large, contemporary series of 607 pituitary operations in 592 patients, the overall leak rate of 4.4% occurred a mean time of 23.1 days after initial surgery, with no presentations beyond six
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months.12 Another series of 152 cases demonstrated a 3.3% leak rate, with a mean presentation time of 43.6 days—which was skewed in part due to one case presenting at 90 days.39 The same study also observed an 8.1% leak rate after combined TSR and radiotherapy, as compared to 1.7% after TSR alone. Still another series of 168 consecutive pituitary adenoma operations documented a 3% overall leak rate; 80% of leaks occurred within one week of surgery, with one
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patient developing symptoms at 90 days after TSR for a nonfunctioning macroadenoma that had been previously treated with GKRS.28 Rare case reports have documented delayed leaks, including Kudo’s case report seven
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months after TSR for a growth hormone (GH)-secreting adenoma, and Ogawa’s report at ten years after combined TSR and GKRS for prolactinoma—notably, in a patient with a history of bromocriptine therapy.19,29 When our own cases are incorporated into this brief review, multi-
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modality therapy stands out as a significant component of most patient histories, potentially marking an important risk factor for this rare complication. GKRS without TSR precipitating a
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CSF leak is all but unheard of, with Hongmei reporting a lone case 11 years after GKRS for a GH-secreting tumor.13
Several preceding authors have posited a relationship between empty sella syndrome (ESS) and CSF leak after GKRS—including Hongmei, who documented radiographic
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development of ESS in the patient who ultimately went on to leak 11 years post-treatment.13 This possibility is supported by the rationale that both idiopathic and tumor-associated ESS can precipitate CSF leak, as well as the association between ESS and postoperative CSF leak after
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TSR.17,23,35,36,40 Notwithstanding, as Hongmei also points out, the association is far from universal, with parallel cases demonstrating similar development of frank ESS post-GKRS for
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pituitary adenoma, but without CSF leak over more than five years of follow-up.13,14,17 Taken together, these findings suggest that ESS likely bears a small increase in risk of CSF leak postGKRS; further study is required to confirm and characterize this potential association. Dopamine agonist therapy for prolactinoma is a significant exception to the general
paradigm of CSF leak being rare in the absence of recent TSR. Overall, 37 cases of dopamine agonist-induced CSF leak have been documented, with a mean onset time of 3.3 months
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following initiation of therapy, and isolated presentations at up to 18 months.20 In addition to a long history of cases and short series, two longer retrospective reviews of 114 and 41 macroprolactinoma patients documented non-neurosurgical rhinorrhea rates of 6.1% and 7%
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within the first year of medical treatment—more than double the typical rate observed after TSR.22,37 Mechanistically, the drug has been demonstrated to produce substantial tumor
shrinkage, which is thought to precipitate dehiscence of the sellar floor, or perhaps “unplug”
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bony defects formed by tumor invasion—resulting in open channels for CSF flow following tumor regression.1,18,20,30,37 A similar pattern was observed in the one reported case of CSF leak
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after somatostatin analog therapy—although interpretation of the drug effect in this case is complicated by a history of both TSR and GKRS.38
Spontaneous CSF leak presents a final etiology for CSF rhinorrhea in the setting of pituitary adenoma. An additional 14 tumors have been reported as presenting with spontaneous
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CSF rhinorrhea, without compelling evidence for a clear trend.20 One of these cases involved a GH-secreting adenoma, although the overwhelming majority were prolactinomas or nonfunctioning macroadenomas.20,41 The invasive nature of prolactinomas and GH-secreting
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adenomas is thought to underlie this propensity for spontaneous leakage—a theory that finds further support in the finding of a 2.6% incidence of spontaneous leak among prolactinomas that
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were observed without intervention, a rate that dwarfs that for any other pituitary pathology.24,25,37,41 The possibility that increased tumor invasiveness predisposes to a higher risk of spontaneous CSFL is also encountered in non-pituitary lesions of the anterior skull base treated with GKRS, with reported cases including CSFL four months after GKRS monotherapy for a metastatic renal cell tumor, and four years after GKRS was used to treat residual tumor following two subtotal resections of a juvenile angiofibroma.16,26
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In both of our cases, the patients received high dose radiosurgery, since these were functioning tumors. The use of higher dose radiosurgery may predispose to the risk of radiation necrosis with breakdown of the adjacent skull base and delayed CSF leak. This may be even
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more applicable in our first case that also had previously undergone fractionated radiotherapy. Of course, it is also plausible that the very delayed leaks in our two cases had nothing to do with
other treatments for their pituitary adenomas years earlier.
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a history of GKRS, and would have occurred independently since both patients had received
Treatment recommendations for CSF leak are well established, and generally consist of
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operative repair for all surgical candidates—particularly in the setting of preceding TSR.2,4,8,9,12 Spontaneous leaks or those attributable to medical therapy may be amenable to nonoperative management with either a lumbar drain, or bed rest and withdrawal of causative agents; however, almost 90% of reported cases ultimately required an operative repair, and moving directly to
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surgical repair without attempting nonoperative modalities remains justified.20 Considerable technical variation in CSF leak repair has been described: traditional packing with autologous fat, fascia, or muscle; synthetic materials including Vicryl patches,
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polymer-based dural substitutes, or a combination of compressed gelatin sponge and collagen fleece; and pedicled nasoseptal flaps, among others.6-9,20,33 Both of the present cases—as well as
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17 of the 38 cases reported in association with medical therapy—required a second surgical revision for definitive treatment after recurrent CSF leak.20 Although the specific details regarding the extent of each patient’s leak, the size of the visible defect, and their operative histories must weigh in surgical decision making, this trend may argue in favor of a lower threshold for operative repair, particularly via incorporation of a vascularized nasoseptal flap.
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CONCLUSION Our two cases continue to expand the limited knowledge regarding delayed CSF leak— particularly beyond the first postoperative year. Although quite rare, the potential consequences
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of an untreated leak are severe, and a high index of suspicion is requisite in any patient
presenting with headaches, postnasal drip, or other related symptoms in the setting of a known pituitary tumor. A history of TSR, GKRS, medical therapy with a dopamine or somatostatin
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analogue, or prior radiographic evidence of invasion into the sellar floor or parasellar region increases the probability of a late leak. Perhaps most importantly, GH or prolactin-secreting
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tumors demand the highest level of scrutiny, as all the reported cases of CSF leak more than 18 months after treatment have belonged to those two pathologic subtypes. Patients that present with delayed CSF leak require urgent operative repair, preferably with a vascularized nasoseptal flap as these leaks seem particularly refractory. Adjuvants bolstering early healing such as
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lumbar drain and acetazolamide may also be helpful.
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FIGURE LEGENDS Figure 1: Planning MRI brain for GKRS in 1998, demonstrating left sellar mass (A). Routine surveillance MRI brain in 2013—one year prior to presentation—demonstrating significant
pneumocephalus (C-D) and bony sellar defect (D).
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reduction in tumor volume (B). Head CT at time of presentation, demonstrating significant
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Figure 2: Planning MRI brain for GKRS in 2002, demonstrating right sellar mass encasing the intracavernous carotid artery (A). Routine surveillance MRI brain prior to presentation in 2004
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demonstrating post-radiation changes including tumor necrosis (B). Maxillofacial CTs at time of initial CSF leak—identifying a bony sellar floor defect on one image (C)—and recurrence—
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demonstrating bony sellar floor defects on three contiguous images (D-F).
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Figure 1 A
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Figure 1. Planning MRI brain for GKRS in 1998, demonstrating left sellar mass (A). Routine surveillance MRI brain in 2013—one year prior to presentation—demonstrating significant reduction in tumor volume (B). Head CT at time of presentation, demonstrating significant pneumocephalus (C-D) and bony sellar defect (D).
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B
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Figure 2. Planning MRI brain for GKRS in 2002, demonstrating right sellar mass encasing the intracavernous carotid artery (A). Routine surveillance MRI brain prior to presentation in 2004 demonstrating post-radiation changes including tumor necrosis (B). Maxillofacial CTs at time of initial CSF leak—identifying a bony sellar floor defect on one image (C)—and recurrence—demonstrating bony sellar floor defects on three contiguous images (D-F).
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Figure 2 A
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1, Michael J Link MD1
HIGHLIGHTS:
1. Skull base CSF after gamma knife radiosurgery is a very rare complication
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2. We report two cases of delayed CSF leak; one occurred 16 years after treatment
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3. Mechanisms may include bony destruction, radiation necrosis, secondary empty sella
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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ABBREVIATIONS: Transsphenoidal hypophysectomy: TSSH Cerebrospinal fluid: CSF Gamma Knife radiosurgery: GKRS Growth hormone: GH Empty sella syndrome: ESS
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1, Michael J Link MD1
S1878-8750(17)30009-8
DOI:
10.1016/j.wneu.2017.01.001
Reference:
WNEU 5098
To appear in:
World Neurosurgery
Received Date: 30 July 2016 Revised Date:
31 December 2016
Accepted Date: 2 January 2017
Please cite this article as: Perry A, Graffeo CS, Copeland III WR, Van Abel KM, Carlson ML, Pollock BE, Link MJ, Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology, World Neurosurgery (2017), doi: 10.1016/ j.wneu.2017.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1,3, Michael J Link MD1,2 ORIGINATING INSTITUTION: Department of Neurologic Surgery1, Department of Otolaryngology-Head and Neck Surgery2 and Department of Radiation Oncology3, Mayo Clinic, Rochester MN Michael J. Link, MD Department of Neurologic Surgery – Mayo Clinic 200 First St SW Rochester, MN, USA 55905
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CORRESPONDING AUTHOR:
Telephone: 507-284-4871 Fax: 507-284-5206 Email: [email protected]
FINANCIAL MATERIAL & SUPPORT: None
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CONFLICT(S) OF INTEREST TO DECLARE: None KEYWORDS: Cerebrospinal fluid leak, gamma knife, transsphenoidal surgery, acromegaly, late outcomes
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RUNNING HEADER: Delayed CSF Rhinorrhea
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PREVIOUS PRESENTATION: Components of this research were presented at the North American Skull Base Society 2016 annual meeting WORD COUNT: 2,693
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ABSTRACT Background: Skull base cerebrospinal fluid (CSF) leak after gamma knife radiosurgery (GKRS) is a very rare complication. In patients who were treated with both GKRS and transsphenoidal resection (TSR) for pituitary lesions, early CSF leak occurs at a comparable rate to the general
therapy, is exceedingly rare.
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Methods: Retrospective chart review and review of the literature
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TSR population (4%). Delayed CSF leak occurring more than a year after TSR, GKRS, or dual
Results: We present two cases of delayed CSF leak following GKRS to treat pituitary adenoma.
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One patient developed CSF rhinorrhea 16 years following GKRS for growth hormone producing pituitary adenoma. She had previously undergone TSR surgery 7 years prior to GKRS without complication. Additionally, a 55-year-old man developed high flow CSF rhinorrhea 2 years following GKRS for a prolactinoma that failed dopamine agonist therapy. Both patients underwent a complicated clinical course following presentation, requiring multiple revisions for
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definitive CSF leak repair.
Conclusion: Delayed CSF leak is a rare but serious complication after GKRS independent of TSR status; urgent repair is the treatment of choice. Based on our experience, these leaks have the potential to be refractory, and we recommend aggressive reconstruction, preferably with a
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vascularized flap, and potentially supplemented by placement of a lumbar drain and acetazolamide. Current evidence is scant and provides little insight regarding an underlying
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mechanism, which may include bony destruction by the tumor, delayed radiation necrosis, or a secondary empty sella syndrome.
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INTRODUCTION Cerebrospinal fluid (CSF) leak is perhaps the most common and troublesome postoperative complication after pituitary surgery, with a widely quoted incidence of 3.9% following
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transsphenoidal resection (TSR)—although other reports have published rates ranging from 0.515%.5,8,10-12,29,33,34 A potential advantage of Gamma Knife radiosurgery (GKRS) treatment for pituitary tumors is very low risk of CSF leak.15,27,31
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CSF leak after GKRS without preceding TSR or dopamine agonist therapy is exceedingly rare, with preceding large series reporting zero cases, and one case report appearing in the
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literature.13 Although early CSF leak rates may occur after TSR for pituitary adenomas, delayed leaks—even following resection of large tumors—are uncommon, with <1% occurring in the 30to-90 day window, and exceedingly rare cases documenting CSF leaks beyond the six-month threshold after surgery.12,19,28,29,32,39
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We report two cases of delayed CSF leak occurring years after TSR and GKRS. Notably, ours is also only the second reported case of a leak occurring more than ten years after either
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TSR or GKRS for any pathology.13,29
CASE HISTORIES
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Case 1
A 74-year-old woman initially presented in 1984 to an outside institution with signs of acromegaly and imaging findings consistent with pituitary macroadenoma. She underwent sublabial transsphenoidal resection of the tumor; gross total resection was achieved, and her endocrinologic derangements resolved. Pathology confirmed pituitary adenoma.
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In 1991, the patient presented again to an outside institution with symptoms and imaging findings concerning for tumor recurrence. She was treated with external beam radiation therapy (dose/fractionation records not available), which halted tumor progression, but also precipitated
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pan-hypopituitarism requiring long-term supplementation with hydrocortisone and levothyroxine.
In 1998, the patient presented to our facility with new complaints of headache, and
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surveillance MRI revealed an enlargement of the known sellar mass (Figure 1A). She
subsequently underwent GKRS 14 years after initial TSR, receiving 30 Gy to the 50% isodose
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line covering a volume of 0.9 cc. Follow-up including annual MRI scans and serum IGF-1 levels, showed stable tumor regression and no biochemical evidence of recurrent acromegaly (Figure 1B).
In November 2014, the patient sneezed and experienced immediate, copious, drainage of
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clear fluid from her nose. Over the course of several hours, she developed headache, lethargy, and confusion, prompting presentation to an outside emergency department. Head CT revealed severe pneumocephalus, and the patient was transferred to our facility for further work-up and
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treatment (Figure 1C). Repeat head CT acquired preoperatively demonstrated a large bony defect of the sellar floor with clear communication between the clivus and intracranial space
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(Figure 1D).
The patient was taken emergently to the operating theater for exploration and repair of a
presumed CSF leak. A lumbar drain was placed in the L3-4 interspace, and 0.25mL of 10% fluorescein mixed in 20mL of sterile saline was injected into the thecal sac. A nasoseptal flap was raised, and the sphenoid sinus was then explored using endoscopic technique. An obvious defect of the sellar floor was noted with frank drainage of fluorescein-stained CSF. The bony
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margins of the defect were demucosalized and debrided, and further exploration revealed that the diaphragm sella had herniated into the sella turcica, and was overlying the defect intracranially. The sella was packed with abdominal fat wrapped in rectus fascia, followed by additional fat and
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fascial tissue within the bony tract. A Valsalva maneuver was performed, and no egress of CSF was observed. The nasoseptal flap was then positioned on top of the bony defect, covered with polymer sealant and secured with bioresorbable intranasal dressing.
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The patient returned to her neurologic baseline within 24 hours. Broad-spectrum
antibiotics were maintained throughout her admission, lumbar drainage was continued at a rate
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of 10mL every two hours for six days, and the patient underwent an unremarkable recovery, with no symptoms concerning for complications including meningitis or diabetes insipidus. She was discharged home on postoperative day seven in stable condition; head CT prior to hospital dismissal showed a marked improvement in pneumocephalus.
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On postoperative day 26, the patient presented again to our emergency department, complaining of clear, salty nasal drainage, and worsening headaches for three days. Head CT showed significant recurrent pneumocephalus, and a sample of nasal fluid tested positive for
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beta-2 transferrin. The patient was taken again to the operating theater, and a lumbar drain was placed for injection of fluorescein dye. Endoscopic exploration demonstrated minimal drainage
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of fluorescein from around the nasoseptal flap, which was carefully lifted and temporarily reflected into the choana. The face of the sella was further demucosalized, and the fascia and fat used to pack the initial defect were removed. A collagen matrix graft was placed within the sella, covering the site of the CSF leak along the posterior diaphragm. New abdominal fat and fascia lata were packed within the sella and the bony defect, and the nasoseptal flap was repositioned and covered with polymer sealant. No CSF leak was observed on Valsalva, and the repair was
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covered with layers of oxidized cellulose hemostat, compressed gelatin sponge, and petroleum gauze. Lumbar drainage, 10cc every 2 hours, was again used for three days, and acetazolamide (250mg BID by mouth) was also employed to decrease pressure exerted on the repair by the CSF
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compartment.
The patient again returned to her neurologically intact pre-leak baseline, and serial imaging studies demonstrated progressive decrease in pneumocephalus, which resolved
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completely by dismissal (Figure 1E). Five days following admission, the patient was discharged in stable condition, without evidence of on-going CSF leak, on a one-month course of
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acetazolamide. She was seen in follow-up at one, three, and twelve months, with no findings concerning for recurrent CSF leak; nasal endoscopy demonstrated a healthy nasoseptal flap and robust healing at the defect site, without evidence of dehiscence.
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Case 2
A 55-year-old man initially presented to an outside institution in 1999 with erectile dysfunction, loss of libido, gynecomastia with galactorrhea, and visual changes, leading to the diagnosis of
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pituitary prolactinoma. He was initiated on cabergoline, resulting in improvement but incomplete resolution of his symptoms. He presented to our institution in 2002, reporting significant
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dissatisfaction with his symptomatic control. MRI at that time demonstrated encasement of the right intracavernous carotid artery; correspondingly, the patient was treated with GKRS (25Gy to the 50% isodose line; volume: 3.4cc) and continued on cabergoline (Figure 2A). Following treatment, the patient noted marked, progressive improvement in all of his
symptoms, follow-up imaging demonstrated expected post-radiation changes, tumor necrosis, and regression, and laboratory studies showed a moderate decrease in serum prolactin from
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39ng/mL on cabergoline alone to 20ng/mL (Figure 2B). In 2004, the patent experienced an episode of unprovoked clear fluid drainage from the nose, prompting him to present for outpatient evaluation. Laboratory analysis was positive for beta-2 transferrin, and a bony defect
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of the right sphenoid sinus was demonstrated on maxillofacial CT (Figure 2C). An endoscopicassisted microscopic repair was carried out, and the bony defect was identified in the posterior sphenoid wall, with an underlying dural defect. The bony margins were demucosalized, and the
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repair was carried out in layers, using fat and muscle to pack the defect, followed by an
autologous fascia lata onlay graft secured with polymer sealant, bone graft, additional fat and
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muscle, compressed gelatin sponge, and reticulated polyvinyl alcohol sponge. The patient had an uneventful recovery and was dismissed home at his neurologic and endocrine baseline. Ten months later, he presented again, with intermittent clear nasal drainage over several weeks. Repeat maxillofacial CT showed a more prominent bony defect in the sellar
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floor (Figure 2D-F), and CSF leak was confirmed by nuclear cisternography, following which the patient underwent a second operative repair. Fluorescein dye was used to localize a pinpoint tear in the mucosal layer overlying a pulsatile pituitary mass bulging into the sphenoid sinus. The
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mucosa was elevated, and the defect was packed with abdominal fat, local mucosal graft, polymer sealant, and a right superior turbinate rotational flap, which was fixed in place with
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additional polymer sealant, abdominal fat, and reticulated polyvinyl alcohol sponge. The patient again recovered without issue, and close clinical follow up disclosed no additional signs or symptoms concerning for recurrent CSF leak over five years.
DISCUSSION
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Delayed CSF leak is an exceedingly rare complication after any neurosurgical intervention for pituitary pathology. CSF leak following TSR is relatively rare and almost always occurs in the early postoperative period, with almost no cases presenting beyond the six-month threshold. CSF
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leak after GKRS in neurosurgery-naïve patients is exquisitely rare outside the context of
dopamine agonist therapy. Ours is the second reported case of CSF leak more than ten years after multi-modality initial therapy in a patient who underwent both TSR and GKRS, with one
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additional case documenting a leak beyond the ten-year threshold after GKRS monotherapy.13,29 The overall CSF leak rate after TSR for pituitary pathology is frequently approximated at
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3.9%, although various reports have demonstrated incidences ranging from 0.5-15%.3,12,33 Some disagreement exists regarding risk factors, with prior evidence demonstrating associations with both micro- and macroadenomas, ACTH-producing tumors, prolactinomas, history of multiple transsphenoidal operations, history of radiotherapy of any modality, or an observed
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intraoperative leak—an occurrence that is thought to increase the risk of a postoperative leak by more than three-fold.2,12,21,28,32,39
Timing of CSF leak after TSR is heavily skewed towards the early postoperative period.
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In a large, contemporary series of 607 pituitary operations in 592 patients, the overall leak rate of 4.4% occurred a mean time of 23.1 days after initial surgery, with no presentations beyond six
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months.12 Another series of 152 cases demonstrated a 3.3% leak rate, with a mean presentation time of 43.6 days—which was skewed in part due to one case presenting at 90 days.39 The same study also observed an 8.1% leak rate after combined TSR and radiotherapy, as compared to 1.7% after TSR alone. Still another series of 168 consecutive pituitary adenoma operations documented a 3% overall leak rate; 80% of leaks occurred within one week of surgery, with one
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patient developing symptoms at 90 days after TSR for a nonfunctioning macroadenoma that had been previously treated with GKRS.28 Rare case reports have documented delayed leaks, including Kudo’s case report seven
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months after TSR for a growth hormone (GH)-secreting adenoma, and Ogawa’s report at ten years after combined TSR and GKRS for prolactinoma—notably, in a patient with a history of bromocriptine therapy.19,29 When our own cases are incorporated into this brief review, multi-
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modality therapy stands out as a significant component of most patient histories, potentially marking an important risk factor for this rare complication. GKRS without TSR precipitating a
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CSF leak is all but unheard of, with Hongmei reporting a lone case 11 years after GKRS for a GH-secreting tumor.13
Several preceding authors have posited a relationship between empty sella syndrome (ESS) and CSF leak after GKRS—including Hongmei, who documented radiographic
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development of ESS in the patient who ultimately went on to leak 11 years post-treatment.13 This possibility is supported by the rationale that both idiopathic and tumor-associated ESS can precipitate CSF leak, as well as the association between ESS and postoperative CSF leak after
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TSR.17,23,35,36,40 Notwithstanding, as Hongmei also points out, the association is far from universal, with parallel cases demonstrating similar development of frank ESS post-GKRS for
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pituitary adenoma, but without CSF leak over more than five years of follow-up.13,14,17 Taken together, these findings suggest that ESS likely bears a small increase in risk of CSF leak postGKRS; further study is required to confirm and characterize this potential association. Dopamine agonist therapy for prolactinoma is a significant exception to the general
paradigm of CSF leak being rare in the absence of recent TSR. Overall, 37 cases of dopamine agonist-induced CSF leak have been documented, with a mean onset time of 3.3 months
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following initiation of therapy, and isolated presentations at up to 18 months.20 In addition to a long history of cases and short series, two longer retrospective reviews of 114 and 41 macroprolactinoma patients documented non-neurosurgical rhinorrhea rates of 6.1% and 7%
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within the first year of medical treatment—more than double the typical rate observed after TSR.22,37 Mechanistically, the drug has been demonstrated to produce substantial tumor
shrinkage, which is thought to precipitate dehiscence of the sellar floor, or perhaps “unplug”
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bony defects formed by tumor invasion—resulting in open channels for CSF flow following tumor regression.1,18,20,30,37 A similar pattern was observed in the one reported case of CSF leak
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after somatostatin analog therapy—although interpretation of the drug effect in this case is complicated by a history of both TSR and GKRS.38
Spontaneous CSF leak presents a final etiology for CSF rhinorrhea in the setting of pituitary adenoma. An additional 14 tumors have been reported as presenting with spontaneous
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CSF rhinorrhea, without compelling evidence for a clear trend.20 One of these cases involved a GH-secreting adenoma, although the overwhelming majority were prolactinomas or nonfunctioning macroadenomas.20,41 The invasive nature of prolactinomas and GH-secreting
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adenomas is thought to underlie this propensity for spontaneous leakage—a theory that finds further support in the finding of a 2.6% incidence of spontaneous leak among prolactinomas that
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were observed without intervention, a rate that dwarfs that for any other pituitary pathology.24,25,37,41 The possibility that increased tumor invasiveness predisposes to a higher risk of spontaneous CSFL is also encountered in non-pituitary lesions of the anterior skull base treated with GKRS, with reported cases including CSFL four months after GKRS monotherapy for a metastatic renal cell tumor, and four years after GKRS was used to treat residual tumor following two subtotal resections of a juvenile angiofibroma.16,26
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In both of our cases, the patients received high dose radiosurgery, since these were functioning tumors. The use of higher dose radiosurgery may predispose to the risk of radiation necrosis with breakdown of the adjacent skull base and delayed CSF leak. This may be even
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more applicable in our first case that also had previously undergone fractionated radiotherapy. Of course, it is also plausible that the very delayed leaks in our two cases had nothing to do with
other treatments for their pituitary adenomas years earlier.
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a history of GKRS, and would have occurred independently since both patients had received
Treatment recommendations for CSF leak are well established, and generally consist of
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operative repair for all surgical candidates—particularly in the setting of preceding TSR.2,4,8,9,12 Spontaneous leaks or those attributable to medical therapy may be amenable to nonoperative management with either a lumbar drain, or bed rest and withdrawal of causative agents; however, almost 90% of reported cases ultimately required an operative repair, and moving directly to
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surgical repair without attempting nonoperative modalities remains justified.20 Considerable technical variation in CSF leak repair has been described: traditional packing with autologous fat, fascia, or muscle; synthetic materials including Vicryl patches,
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polymer-based dural substitutes, or a combination of compressed gelatin sponge and collagen fleece; and pedicled nasoseptal flaps, among others.6-9,20,33 Both of the present cases—as well as
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17 of the 38 cases reported in association with medical therapy—required a second surgical revision for definitive treatment after recurrent CSF leak.20 Although the specific details regarding the extent of each patient’s leak, the size of the visible defect, and their operative histories must weigh in surgical decision making, this trend may argue in favor of a lower threshold for operative repair, particularly via incorporation of a vascularized nasoseptal flap.
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CONCLUSION Our two cases continue to expand the limited knowledge regarding delayed CSF leak— particularly beyond the first postoperative year. Although quite rare, the potential consequences
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of an untreated leak are severe, and a high index of suspicion is requisite in any patient
presenting with headaches, postnasal drip, or other related symptoms in the setting of a known pituitary tumor. A history of TSR, GKRS, medical therapy with a dopamine or somatostatin
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analogue, or prior radiographic evidence of invasion into the sellar floor or parasellar region increases the probability of a late leak. Perhaps most importantly, GH or prolactin-secreting
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tumors demand the highest level of scrutiny, as all the reported cases of CSF leak more than 18 months after treatment have belonged to those two pathologic subtypes. Patients that present with delayed CSF leak require urgent operative repair, preferably with a vascularized nasoseptal flap as these leaks seem particularly refractory. Adjuvants bolstering early healing such as
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lumbar drain and acetazolamide may also be helpful.
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FIGURE LEGENDS Figure 1: Planning MRI brain for GKRS in 1998, demonstrating left sellar mass (A). Routine surveillance MRI brain in 2013—one year prior to presentation—demonstrating significant
pneumocephalus (C-D) and bony sellar defect (D).
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reduction in tumor volume (B). Head CT at time of presentation, demonstrating significant
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Figure 2: Planning MRI brain for GKRS in 2002, demonstrating right sellar mass encasing the intracavernous carotid artery (A). Routine surveillance MRI brain prior to presentation in 2004
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demonstrating post-radiation changes including tumor necrosis (B). Maxillofacial CTs at time of initial CSF leak—identifying a bony sellar floor defect on one image (C)—and recurrence—
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demonstrating bony sellar floor defects on three contiguous images (D-F).
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Figure 1 A
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Figure 1. Planning MRI brain for GKRS in 1998, demonstrating left sellar mass (A). Routine surveillance MRI brain in 2013—one year prior to presentation—demonstrating significant reduction in tumor volume (B). Head CT at time of presentation, demonstrating significant pneumocephalus (C-D) and bony sellar defect (D).
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Figure 2. Planning MRI brain for GKRS in 2002, demonstrating right sellar mass encasing the intracavernous carotid artery (A). Routine surveillance MRI brain prior to presentation in 2004 demonstrating post-radiation changes including tumor necrosis (B). Maxillofacial CTs at time of initial CSF leak—identifying a bony sellar floor defect on one image (C)—and recurrence—demonstrating bony sellar floor defects on three contiguous images (D-F).
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Figure 2 A
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1, Michael J Link MD1
HIGHLIGHTS:
1. Skull base CSF after gamma knife radiosurgery is a very rare complication
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2. We report two cases of delayed CSF leak; one occurred 16 years after treatment
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3. Mechanisms may include bony destruction, radiation necrosis, secondary empty sella
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TITLE: Delayed CSF Rhinorrhea after Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology
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ABBREVIATIONS: Transsphenoidal hypophysectomy: TSSH Cerebrospinal fluid: CSF Gamma Knife radiosurgery: GKRS Growth hormone: GH Empty sella syndrome: ESS
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AUTHORS: Avital Perry MD1, Christopher S Graffeo MD1, William R Copeland III MD1, Kathryn M Van Abel2, Matthew L Carlson MD2, Bruce E Pollock MD1, Michael J Link MD1