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Neurosurgical Management of Bipolaris-Specific Skull Base Allergic Fungal Sinusitis: Diagnostic Criteria and Outcome ver the past decade, the incidence † Jamie J. Van Gompel, MD Oof fungal infections has increased Scott D. Wait, MD dramatically. Fungal paranasal sinus dis- ‡ Stephen W. Coons, MD ease, a large component of fungal in- William L. White, MD fections, is common and is defined by the host and the host’s response to the Skull base allergic fungal sinusitis is a rare but important neurosurgical entity that fungus. Invasive fungal sinusitis occurs can be mistaken for a skull base tumor during preoperative assessment. Due to in immunocompromised hosts and can the significantly variable clinical presentation of and preoperative evaluation for manifest as acute, fulminant, and life- this disease, clinicians are often surprised when the diagnosis becomes appar- threatening or as a more manageable ent during surgery or thereafter. However, SBAFS must be differentiated from chronic/granulomatous indolent form. malignancy and invasive fungal disease because this allergic disease does not However, the hallmark of invasive dis- require aggressive, complete resection or potentially toxic antifungal medica- ease is the presence of large amounts of tions. We report six cases of SBAFS to illustrate the neurosurgical management the fungal element in the associated pa- of this rare disease. thology without immune containment. Key Words: allergic fungal sinusitis, Bipolaris, skull base In contrast, noninvasive fungal si- nusitis occurs in immunocompetent in- dividuals. It exists in two forms, both characterized by the host’s response to the fungal agent. With the first, myce- toma, the host’s immune response is in- adequate and the fungal agent proliferates as an encapsulated mass. The second, AFS, the subject of this report, occurs when the host provides an overly exu- berant immune response to the antigens of the fungus. Skull base allergic fungal sinusitis, a term first introduced by Kinsella et al., denotes the specific condition in which AFS extends intracranially.10 Ten to 20% of patients with AFS have an in- tracranial extension.13 Once SBAFS is encountered, neurosurgical interven- tion is required. Because of their variable presentation and rarity, these Abbreviations Used: AFS, allergic fungal sinusitis; CT, computed to- lesions are seldom expected preopera- 15 mography; GMS, Gomori methenamine silver; MR, magnetic resonance; tively. Consequently, SBAFS is often SBAFS, skull base allergic fungal sinusitis mistaken for a malignancy,11,12,18,27 and patients may receive overly aggressive Divisions of Neurological Surgery and ‡Neuropathology, Barrow Neurological Institute, St. therapy. Because SBAFS is noninva- Joseph’s Hospital and Medical Center, Phoenix, Arizona sive, surgical debulkment is standard Current Address: †Saint Marys Hospital at the Mayo Clinic, Rochester, Minnesota therapy; radical resection or toxic med-

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Table 1. Clinical Summary of Six Patients with Bipolaris SBAFS

Case Age/ Presenting Presenting Medical Surgery Bacterial Neurological Sex Symptoms† Signs History Isolate‡ F/U 1 31/M HA, OD vision loss, OD blindness/RAPD, NP, asthma, TNTS Staphylococcus resolved OS blurring Dysconjugate gaze chronic sinusitis

2 25/F OS vision loss OS vision loss NP, allergies, SLTS Staphylococcus resolved chronic sinusitis

3 20/F HA, N/V OD proptosis and NP, asthma TNTS Staphylococcus resolved vision loss

4 36/M Chronic nasal CN 6 paresis NP, allergies, SLTS§ Haemophilus resolved drainage chronic sinusitis

5 75/F Tremor, falling, HA, Head and upper NP, allergies TNTS Staphylococcus resolved decreasing memory extremity tremor

6 19/M OD proptosis and Diplopia on left NP, allergies, BCC Staphylococcus resolved blurring lateral upward gaze asthma †No patient had presenting symptoms consistent with pituitary malfunction. ‡All cases cultured Bipolaris heavily; bacterial isolate represents coincident culture. §Complicated by aseptic meningitis. F/U = follow-up, HA = headache, N/V = nausea and vomit- ing, OD = right eye, OS = left eye, RAPD = relative afferent pupil defect (nonreactive pupil), NP = nasal polyps, CN = cranial nerve, TNTS = transnasal transsphenoidal, SLTS = sublabial transsphenoidal, BCC = bicoronal craniotomy. ical regimens are unnecessary. We pre- quent sign was ocular defect. All pa- weighted MR images lacked lesional or sent six patients with Bipolaris-specific tients had a history of atopy, including perilesional hyperintensity, suggesting no SBAFS to highlight the neurosurgical polyps and at least one other indicator inflammation. All but one lesion was iso- management of this rare clinical entity. of atopy. intense to brain parenchyma; the excep- tion was hypointense (Table 2). Four cases showed intense uptake on gadolin- Bipolaris-Specific AFS ium-enhanced MR imaging, and an- Between January 1998 and August Clinical Materials and other lesion was considered ring en- 2004, 28 cases of culture-proven Bipo- Methods hancing. There was no gadolinium laris-specific AFS were treated at our in- enhancement in the remaining case. In Bipolaris-Specific SBAFS stitution. There were 20 men and 8 all cases CT showed increased attenua- The records of six patients (3 men, 3 women (mean age, 30 years; range, 13 to tion and bony destruction with expan- women; mean age, 34 years; age-range, 80 years). Three patients had an intra- sion of its associated sinus or sella without 19 to 75 years) who underwent resec- cranial extension consistent with SBAFS evidence of hyperostosis. The location of tion with pathologic verification of AFS (invasion rate, 10.7%). Of these 28 cases, the pituitary in relation to the tumor var- and culture-proven Bipolaris from Janu- only 1 had fungal elements identified ied across the cases. ary 1989 to August 2004 were analyzed on a KOH preparation. Eleven had retrospectively. The criteria for patho- concomitant positive cultures for bac- logic verification were allergic mucin- teria. Three patients who underwent Treatment containing eosinophils, Charcot-Ley- surgery were not included in the mi- Five cases consisted of a primary den crystals, cellular debris, and sparse crobiology database because they pre- sphenoidal extension and were treated hyphae. To evaluate the invasive nature dated its establishment. through a transsphenoidal approach of this disease, all cases of Bipolaris-spe- (Table 1). A tumor that originated from cific AFS were identified by querying the frontal sinus and extended into the our microbiology database from Janu- Results anterior cranial fossa was approached ary 1998 to August 2004. through a bicoronal craniotomy. In all Most patients became symptomat- Radiology cases a coincident positive culture of bac- ic with visual complaints or headache Bipolaris-specific SBAFS lesions were terial isolate (nasopharyngeal flora) was of gradually increasing intensity (Table isointense on T1-weighted MR images also treated (Table 1). Postoperatively, 1). On examination, the most fre- relative to brain tissue (Table 2). T2- one patient was diagnosed with aseptic

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Table 2. Bipolaris SBAFS Imaging Characteristics

Case MRI† Gadolinium Attenuation† CT Bone Pituitary T1 T2 Uptake Destruction Location‡ 1 Isointense Isointense Intense Increased + Posterior

2 Isointense Isointense Intense Increased + Elevated

3 Isointense Isointense Ring enhancing Increased + Posterior

4 Isointense Isointense Intense Increased + Anterior

5 Isointense Isointense No uptake Increased + Posterior

6 Isointense Hypointense Intense Increased + None †Relative to brain parenchyma. ‡Relative to mass and sella.

meningitis. The resulting transient re- atopy, nasal polyposis, chronic sinusitis Moreover, involvement of the optic nerve current sixth cranial nerve palsy resolved with eight previous sinus surgeries, and suggested chiasmopathy and involvement with treatment. Whether this complica- childhood asthma. of the perichiasmal segment (Fig. 3). tion was related to surgery is unclear. After surgical decompression neurologic Physical Examination Treatment symptoms resolved in all cases (range of On neurologic examination the pa- The patient began steroid therapy and follow-up, 2 months to 15 years). All pa- tient was alert and oriented. His right his vision subsequently improved. He tients received postoperative steroids from pupil was nonreactive to light; his left then underwent frameless stereotactic 2 weeks to 4 months. Three patients also pupil was miotic but briskly reactive. Vi- transnasal-transsphenoidal debulking of received 2 weeks of antifungal therapy. sion was full to confrontation in the left the lesion. A firm white mass intermin- There were no recurrences. eye. Extraocular movements were intact gled with fibrous tissue, which had erod- bilaterally; however, gaze was dyscon- ed the planum sphenoidale and anterior jugate. Evaluation of pituitary function and basal sellar floors, was encountered. was unremarkable. Its adherence to the sellar diaphragm and Illustrative Case frontal fossa dura made its removal diffi- Patient History Radiological Examination cult. An intraoperative frozen-section A 31-year-old African-American Noncontrast head CT showed a hy- biopsy was consistent with an inflamma- man was transferred from an outside perattenuating mass occupying the sphe- tory process. The lesion was debulked hospital with the radiographic diagno- noid sinus and sella (Fig. 1). The bony without complication. sis of a skull base tumor for further eval- confines were expanded, and multiple cal- uation. The patient reported an 8- cified foci were present within the lesion Histopathology month history of headache and pro- without evidence of hyperostosis or peri- Hematoxylin and eosin staining re- gressive loss of vision. The headache lesional edema. On T1- and T2-weight- vealed inflammatory infiltrate without consisted of constant throbbing frontal ed MR images, the lesion was isointense dysplasia. Sparse fungal elements with pain. It gradually progressed from low- relative to brain parenchyma (Fig. 2). Gad- the rare yeast were present on Fontana grade pain to an intensity of 10 on a 1 to olinium-enhanced MR images showed a and GMS stains. By Day 10, intraoper- 10 scale. Photophobia was present, but large, avidly enhancing lesion with its ative cultures were positive for Bipolaris. there was no evidence of nausea, vom- isocenter in the sphenoid sinus. It ex- iting, transient visual scotoma, or flash- tended to the planum sphenoidale inferi- Outcome ing lights. With the right eye, the pa- orly and abutted the clivus posteriorly. The patient recovered on steroid ther- tient could only see shadows. Vision in Furthermore, there was evidence of an apy without complications. At discharge his left eye was beginning to blur. His intracranial extension into the anterior his visual function had normalized, and history included evidence of significant cranial fossa beneath the frontal lobes. his headaches had improved significantly.

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A B Figure 1. Noncontrast head CT shows a Figure 2. (A) T1- and (B) T2-weighted MR images show an isointense lesion occupying hyperattenuating lesion occupying the the sphenoid sinus and sella. sphenoid sinus and sella, with evidence of expansion of these fossae and bony de- struction.

Discussion Natural History AFS accounts for 7% of all fungal sinus disease. Dematiaceous fungi, most prominently Bipolaris, account for 81% of AFS. The remaining cases are primarily caused by Aspergillus. Bipolaris is found in dust and soil and on plants. Many cases of Bipolaris occur in hot, arid climates with mild winters such as the southern Unit- A B ed States and Middle East.10,17,24,25 AFS caused by Aspergillus and fungal Figure 3. T1-weighted gadolinium-enhanced (A) coronal and (B) sagittal MR images agents of the dematiaceous family, Bipo- show chiasmopathy and impressive expansion of the sella. On the sagittal MR image (B), laris, represent different entities. Many an intracranial extension into the anterior cranial fossa resembles a dural tail. Aspergillus-associated cases of AFS have been associated with immunodeficiency tients, however, averaged 30 to 34 years treated had an intracranial extension, a such as chemotherapy for acute lym- old.4,14 There was no difference in the finding consistent with the literature.13 phoblastic leukemia, renal failure, or incidence of SBAFS patients by gen- In addition to those proposed by long-standing diabetes. Therefore, we der, but the 2:1 male-to-female ratio in Kinsella et al.,10 we support the follow- excluded such cases. However, all cases our AFS population is consistent with ing criteria for the diagnosis of Bipolaris reviewed and all cases reported as Bipo- published reports.14 All had nasal polyps SBAFS (Table 3). (1) Evidence of in- laris SBAFS fit the atopic pattern of with at least one other atopic finding, tracranial extension by radiographic, young, immunocompetent patients, which is also consistent with previous surgical, or pathologic means must be suggesting that this group is homoge- reports. None of our patients had stig- present. (2) Histopathologically, the le- neous. Patients with aspergillosis AFS mata of immunoincompetency. Many sion must be consistent with AFS. As- may have elements of invasive disease and patients with SBAFS have proptosis or pergillus should be excluded. (3) Final- should not be considered to have AFS.19 visual defects.5,22,28 Five of our six sur- ly, many reports suggest that species The mean age of patients with AFS gical patients had an ocular defect. Al- such as Drechslera and others are separate ranges between 21 to 26 years. Our pa- most 11% of the 28 AFS patients we microbial agents, but this is not the case.

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Curvularia, Brachycladium, Drechslera, and Helminthosporium are obsolete synonyms Table 3. Diagnostic Criteria for SBAFS of Bipolaris. Cochliobolus is also a teleo- morph. Therefore, all of these mi- Skull base involvement crobes should be reported as Bipolaris. Radiographic evidence of sellar or anterior cranial fossa invasion. Surgical evidence of intracranial spread Diagnostic Imaging Pathologic abutment of dura The most remarkable aspect of SBAFS is the consistency with which Pathology findings on preoperative imaging are Inflammatory reaction to fungus with “sporadic fungal elements” considered to be a malignancy, as oc- No fungus ball collection (i.e., mycetoma) curred in our patient. Preoperative ra- diographic diagnoses often include chordoma, meningioma, chondrosar- coma, and head-and-neck squamous tion, permanent section, and microbial therapy after surgery, it is most likely not cell carcinoma. Such misdiagnoses can culture), debulkment, and aeration of useful and may even be harmful due to result in an overly aggressive surgical sinuses. Several authors describe ag- the toxicity of systemic antifungal agents. and/or medical intervention. Howev- gressive approaches such as facial de- Moreover, postoperative corticosteroid er, reported imaging characteristics are gloving. Such radical approaches reflect therapy may be necessary for complete relatively uniform. In early case reports, preoperative uncertainty about malig- resolution.10 Definitive treatment for sinus expansion was uniformly noted on nancy. Aggressive surgical approaches SBAFS is surgical debridement with ad- CT.3,30 As in our patient, bony erosion can be associated with complications junctive steroid therapy. with residual bony spiculation without such as granulomatous encephalitis or The prognosis of SBAFS is good. hyperostosis has been reported in all cerebrospinal fluid leakage. No case of After adequate surgical debridement and cases of SBAFS.6 dural invasion in histiologically con- aeration of the sinuses, complete neuro- The finding of a hyperattenuating le- firmed SBAFS has been described. No logic resolution can be expected, as in sion (45-60 Hounsfield units) is also uni- postoperative complications were asso- our 6 cases. Close follow-up care is im- form. Sinus expansion and bony de- ciated with conservative treatment in portant. CT, MR imaging, or both are struction may be related to pressure our patients. adequate for following SBAFS. The atrophy, and hyperattenuation may be Whether postoperative antifungal long-term use of topical steroids controls related to the high residual content of therapy should be used is also uncertain. relapses, and systemic steroids may be metallic ions in the lesion. Moreover, No differences have been reported in re- warranted for a recurrence. these lesions appear as areas of dimin- currence rates between cases of SBAFS ished signal intensity on both T1- and treated with or without antifungal med- T2-weighted MR images. As in our ications.26,31 In most early cases of Conclusions patient, the lesions often enhance with SBAFS, culture of a fungus was followed Although Bipolaris SBAFS associated the administration of gadolinium.2,16,23 by treatment with systemic ampho- with a skull base extension is rare, this di- CT evidence of a lesion extending from tericin B, ketoconazole, or itraconazole. agnosis should be considered when a a paranasal sinus associated with bony These agents were initiated despite lim- paranasal sinus mass is present in a young expansion, erosion, and hyperattenua- ited in vitro or in vivo activity of these atopic patient. CT findings of a hyper- tion should prompt suspicion of an drugs against Bipolaris. If treatment for attenuating mass extending from the SBAFS. When this diagnosis is doubt- the fungal agent was warranted, systemic paranasal sinuses with bony erosion and ful, MR imaging can be useful. The le- corticosteroids, which are usually pre- isointense to hypointense lesions on T1- sion should appear iso- to hypointense scribed with the antifungal agent, would and T2-weighted MR images are con- on both T1- and T2-weighted MR im- be contraindicated. However, patients sistent with Bipolaris SBAFS. These find- aging. Transnasal sampling under CT usually respond to systemic steroid ther- ings should raise suspicions of this entity guidance is possible.20 apy rather than to antifungal medication. in patients living in hot, arid climates. Several cases of recurrent AFS after anti- Definitive treatment consists of conserv- Treatment fungal therapy alone have been report- ative surgical debulkment with aeration Because the pathophysiology of AFS ed.9,31 No cases of AFS appear to have of the sinuses and pre- and postoperative is of an allergic nature and the disease is recurred after appropriate corticosteroid use of corticosteroids. Postoperatively, noninvasive,14 complete removal is un- therapy. However, cases of recurrent antifungal medications are not required necessary. The goals of surgery should AFS treated with corticosteroids have re- and complete neurologic recovery can be to provide tissue for pathologic ver- solved.1,7,8,21,26,29 Although three of our be expected. ification (via intraoperative frozen sec- patients with SBAFS received antifungal

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