Journal of Neuro-Ophthalmology, March 1999, Volume 19, Issue 1

Endoscopic Sinus Surgery in the Management of the Mucormycosis

This is a report of the use of endoscopic sinus surgery in the management of three patients diagnosed with rhino-orbital or rhino-orbito-cerebral mucormycosis. A retrospective review was performed of the clinical examinations and imaging studies of three patients who underwent endoscopic sinus surgery as part of their therapy for mucormycosis. In addition to endoscopic surgery, all patients had aggressive control of underlying risk factors (diabetes mellitus, immunosuppression) and prolonged intravenous amphotericin B therapy. All three patients survived and avoided orbital exenteration. In selected patients with rhino-orbito-cerebral mucormycosis, endoscopic techniques can play a valuable role in diagnosis and management.

Journal of Ncuw- Ophlhalmology 19( 1): 56- 61, 1999. © 1999 Lippincolt Williams & Wilkins, Inc., Philadelphia Endoscopic Sinus Surgery in the Management of Mucormycosis Patrick P. Avet, M. D., Lanning B. Kline, M. D., and Michael J. Sillers, M. D. This is a report of the use of endoscopic sinus surgery in the management of three patients diagnosed with rhino- orbital or rhino- orbito- cerebral mucormycosis. A retrospective review was performed of the clinical examinations and imaging studies of three patients who underwent endoscopic sinus surgery as part of their therapy for mucormycosis. In addition to endo­scopic surgery, all patients had aggressive control of underlying risk factors ( diabetes mellitus, immunosuppression) and pro­longed intravenous amphotericin B therapy. All three patients survived and avoided orbital exenteration. In selected patients with rhino- orbito- cerebral mucormycosis, endoscopic tech­niques can play a valuable role in diagnosis and management. Key Words: Endoscopic sinus surgery- Rhino- orbital mucor­mycosis- Rhino- orbito- cerebral mucormycosis. Rhino- orbito- cerebral mucormycosis is a fungal infec­tion well known to ophthalmologists for its devastating ocular morbidity and high rate of patient mortality. The term " aggressive" best describes the clinical approach for diagnosis and treatment of this condition ( 1- 7). Traditional surgical therapy entails extensive debride­ment of all infected tissues, which often requires debride­ment of the affected paranasal sinuses, coupled with or­bital exenteration. The latter procedure has been recom­mended by some as primary therapy in the presence of even minimal orbital infection ( 4,7,8). However, several reports have documented patient survival without ex­enteration in the presence of clinical orbital involvement ( 3,5,9- 28). We report three patients with mucormycosis in whom endoscopic sinus surgery facilitated diagnosis and man­agement of the disease. All three patients survived with­out orbital exenteration. CASE REPORTS Case 1 A 21- year- old woman experienced left periorbital pain without chills or fever and noted a precipitous loss in Manuscript received June 26, 1998; accepted November 24, 1998. From the Departments of Ophthalmology ( P. P. A., L. B. K.) and Sur­gery ( M. J. S.), Division of Otolaryngology, University of Alabama School of Medicine, Birmingham, Alabama, U. S. A. Address correspondence and reprint requests to Lanning B. Kline, M. D., 1000 South 19th Street, Birmingham, AL 35205, U. S. A. vision in her left eye over 2 days. Her medical history was significant for poorly controlled insulin- dependent diabetes mellitus of 16 years' duration. Visual acuity was 20/ 25 right eye and no light perception left eye. The right pupil reacted briskly to light, the left was nonreac-tive, and there was a left afferent pupillary defect. There was left periorbital edema and 3 mm of left proptosis. Eye movements on the right were full, whereas on the left there was complete ophthalmoplegia associated with total ptosis. Slit lamp examination findings were normal bilaterally. The right fundus was unremarkable, whereas the left showed edema of the optic disc and peripapillary retina with venous engorgement. General physical and neurologic examinations were otherwise normal. Contrast- enhanced computed tomography and mag­netic resonance imaging ( MRI) ( Fig. 1) snowed left eth­moid sinusitis with orbital inflammation. The patient un­derwent transnasal endoscopic exploration of the left eth­moid and maxillary sinuses. The inferior turbinate and extensive portions of these sinuses were friable and ne­crotic in appearance. A left total ethmoidectomy, sphe-noidotomy, maxillary antrostomy, and inferior turbinec-tomy were performed by endoscopy. The lamina papy-racea was removed. The orbital fat was examined and found to be healthy. Biopsy specimens from the parana­sal sinuses showed invasive fungal elements consistent with mucormycosis. Complete blood count, serum chemistries, and cere­brospinal fluid analysis were normal. Serum glucose was 82 mg/ dl with no ketosis. Therapy consisted of 1 mg/ kg intravenous amphotericin B per day, supplemented with intranasal aerosolized amphotericin B and 10 g per day oral 5- flucytosine, later changed to 600 mg per day rifampin. During the next month, the patient's clinical course stabilized. Serial imaging studies showed persistent sinus and periorbital soft tissue changes but no progression of disease. She was taken back to the operating room on two more occasions for endoscopic evaluation of her sinuses and left orbit to be certain no active infection was present. None was found. After 1 month, the patient was discharged with intra­venous access to complete her course of amphotericin B ( total dose of 2 g). Over the ensuing 7 months the patient regained most of the function of the levator palpebrae 56 ENDOSCOPIC SINUS SURGERY IN MUCORMYCOSIS 57 FIG. 1. Case 1. Contrast- enhanced magnetic resonance imaging shows left paranasal sinusitis with left orbital extension on axial ( A) and coronal ( B) scans. and extraocular muscles on the left, although her vision improved only to light perception in the left eye. Case 2 A 46- year- old man reported the onset of diplopia as­sociated with left ptosis and left periorbital pain. The patient had a 20- year history of insulin- dependent diabe­tes mellitus and 11 years previously had undergone a right vitrectomy for treatment of a macular hole. Visual acuity on the right eye had stabilized to 20/ 200. Acuity of the left eye had been 20/ 40 after focal macular laser photocoagulation for diabetic macular edema. Visual acuity was 20/ 400 OU. Pupils measured 3 mm and were briskly reactive to light, with no relative affer­ent pupillary defect. Eye movements were normal on the right but on the left were consistent with a partial left oculomotor nerve palsy. Corneal sensation was intact. There was 6 mm of left ptosis and no proptosis. Both fundi showed diabetic retinopathy with laser photoco­agulation scars and a right macular hole. Over the next week the patient experienced worsening vision on the left associated with left facial pain. Acuity remained 20/ 400, right eye, but declined to hand motions on the left. Four millimeters of left proptosis was present with total left ptosis and ophthalmoplegia. The fundi were unchanged. The patient was immediately admitted to the hospital. Contrast- enhanced MRI showed bilateral ethmoid and sphenoid sinusitis with left orbital involvement ( Fig. 2) and enhancement of the basal meninges and falx cerebri ( Fig. 3). Endoscopic exploration of the ethmoid and sphenoid sinuses was performed. Gross necrosis was apparent, ne­cessitating left middle turbinectomy, right total eth-moidectomy, and bilateral sphenoid sinusotomies, all by way of endoscopy. An external left ethmoidectomy in­cluding removal of the lamina papyracea was performed. Inspection of the left orbit showed no signs of necrosis. Biopsy specimens from the paranasal sinuses were con­sistent with mucormycosis. Therapy consisting of intravenous amphotericin B and rifampin was begun, as well as aggressive control of the diabetes mellitus. Over the next 12 days, despite im­provement in periorbital edema and proptosis, vision de­teriorated to light perception. During this period the pa­tient underwent three bilateral endoscopic explorations of the medial orbit and maxillary and ethmoid sinuses. No evidence of necrosis was found, and each procedure was terminated with irrigation of the sinus cavities and amphotericin B solution. The patient received a total dose of 1.8 g amphotericin B and has been clinically unchanged during 12 months of follow- up. FIG. 2. Case 2. Contrast- enhanced axial magnetic resonance scanning reveals extensive bilateral ethmoid sinusitis with left orbital involvement. J Neum- Onhlhulmol. Vol. 19. No. I. 1999 58 P. P. AVETETAL. FIG. 3. Case 2. Coronal magnetic resonance image after intra­venous gadolinium shows enhancement of the basal meninges ( arrows). Case 3 A 49- year- old man who had undergone cardiac trans­plantation one month previously reported right jaw pain associated with nasal discharge. The patient had had in­sulin- dependent diabetes for 13 years. Medications in­cluded prednisone, cyclosporine, azathioprine, and insu­lin. Otolaryngologic examination revealed erythema and edema of the nasal turbinates on the right. Plain radio­graphs were consistent with right maxillary sinusitis, but transnasal culture of the sinus revealed no pathogenic organisms. Within 24 hours, right upper and lower lid edema and mild chemosis was noted, but after 3 days of intravenous antibiotics the symptoms had improved, and the patient was discharged with a course of azithromycin. Sixteen days later, right facial weakness developed associated with numbness in the distribution of the max­illary and mandibular divisions of the right trigeminal nerve. Facial edema of the right parotid region was present, but examination of a specimen obtained in fine-needle biopsy of the parotid gland was unremarkable. Eye examination showed acuity of 20/ 200 right eye, 20/ 30 left eye. Marked chemosis on the right was associated with proptosis and limited eye movements in all direc­tions. The optic discs were normal, and retinal examina­tion showed mild nonproliferative diabetic retinopathy. Contrast- enhanced MRI showed right maxillary, sphe­noid, and ethmoid sinusitis ( Fig. 4), with adjacent cere-britis of the right temporal lobe ( Fig. 5). Endoscopy of the paranasal sinuses was performed revealing extensive disease. Total ethmoidectomy, sphe-noidotomy, maxillary antrostomy, resection of turbi­nates, and removal of the lamina papyracea were effected by right nasal endoscopy. Orbital fat appeared healthy without signs of necrosis. Specimens obtained were con­sistent with and cultures were positive for Rhizopus spe­cies. The patient underwent excision of the right temporal lobe tip and underlying dura and bone. Histologic ex­amination revealed mucormycosis in the brain specimens ( Fig. 6). Treatment was begun with intravenous ampho­tericin B ( 1 mg/ kg/ day). The following day, the patient was noted to have left hemiplegia, and cranial MRI showed an infarct in the right motor cortex. Over the ensuing 6 weeks the neuro­logic deficits improved. Dosage of his immunosuppres­sive medication was carefully decreased. Periorbital FIG. 4. Case 3. Contrast- enhanced axial mag­netic resonance imaging shows right ethmoid and sphenoid sinusitis. ./ Neuro- Ophlhalmol, Vol. 19, No. I, 1999 ENDOSCOPIC SINUS SURGERY IN MUCORMYCOSIS 59 • > • 49 M llbbl 1 • r\ FIG. 5. Case 3. T2- weighted axial magnetic resonance image shows right orbital involvement and cerebritis of the adjacent temporal lobe ( arrows). edema and chemosis resolved, with restoration of full extraocular movements on the right. Visual acuity re­mained poor in the right eye. The patient received a total of 3.5 g amphotericin B intravenously. DISCUSSION Prompt diagnosis of rhino- orbito- cerebral mucormy­cosis requires a high index of clinical suspicion in any patient with diabetes and in debilitated or immunosup-pressed patients who report facial or orbital pain, diplo­pia, or diminished vision ( 2,4,5,7,28). Every effort should be made in such patients to perform a biopsy and to culture material from the nose, palate, paranasal si­nuses, or orbit ( 2- 4,7,28). With histopathologic evidence of the disease, certain aspects of management are es­sential. Multidisciplinary care should include aggres­sive control of underlying systemic disease ( 2,3,11- 14,16,17,19,20,28- 32); reduction in dosage or discon­tinuation of immunosuppressive drugs, if possible ( 2,8, 13,21,33,34); and administration of intravenous ampho­tericin B in therapeutic doses ( 2,3,10- 14,16,17,29- 21, 28- 31,33). Surgical removal of all necrotic tissue is essential in the treatment of rhino- orbito- cerebral mucormycosis ( 1,2,5- 7). However, there are no clear guidelines for achieving this goal. For example, there are reports of patients with rhino- orbito- cerebral mucormycosis sur­viving without undergoing orbital exenteration. They had orbital signs ( ophthalmoplegia, proptosis) and received intravenous amphotericin B. Surgical therapy included biopsy alone or was combined with selective excision of nonviable orbital tissue. None of these patients was found to have extensive necrosis within the orbit ( 3,5,9- 28). In a review of 179 patients with mucormycosis, Blitzer et al. ( 3), although showing a clear benefit with surgery, were unable to show a detrimental effect in delaying it. In fact, 35% of their survivors had surgery more than a week after initial diagnosis of mucormycosis. Similar findings were reported by Peterson et al. ( 28) in their study of 28 patients with mucormycosis. Thus, in se­lected cases, it appears that with close observation and serial imaging, orbital contents can be spared until clini­cal deterioration mandates exenteration. It should be emphasized that none of our patients showed necrosis of the orbital tissues. Necrosis was ab­sent despite clinical findings of amaurosis, proptosis, ophthalmoplegia, and imaging studies showing orbital inflammation. It is possible that these findings were the result of Mucor cellulitis ( 35) or spillover inflammation from the adjacent paranasal sinuses. If extensive necrosis had been found, most authorities would have performed orbital exenteration ( 2,5,18). Therefore, direct inspection FIG. 6. Case 3. Brain biopsy specimens. A: Marked perivascular inflammatory cellular infiltrate of neutrophils, lymphocytes, and mac­rophages. Fungal forms ( arrows) are present in the vessel wall ( hematoxylin- eosin, x400). B: Fungal elements are seen within a vessel causing thrombosis ( GMS stain, x400). 60 P. P. AVET ET AL. of orbital contents, looking carefully for signs of necro­sis, is critical in determining the need for paranasal sinus surgery alone or more aggressive surgical therapy, in­cluding exenteration. Endoscopy provides an effective surgical approach in the diagnosis and management of patients with rhino-orbito- cerebral mucormycosis. This procedure can often be performed in an outpatient setting with modified local anesthesia, and unlike traditional anterior rhinostomy, allows visualization of the posterior nasal cavity and si­nuses. It allows the surgeon to inspect infected tissues, selectively remove necrotic material, and spare healthy structures. It affords repeat examinations and debride­ment of the paranasal sinuses and orbital contents in monitoring response to therapy ( 36). Ophthalmic complications have been reported after endoscopic sinus surgery ( 37,38). Neuhaus classified these into four categories: nasolacrimal sac or duct in­jury, extraocular muscle injury, intracerebral hemor­rhage/ emphysema, and optic nerve injury ( 38). In addition, the endoscopic approach is limited in its access to the orbit. It primarily allows visualization of the medial and inferomedial orbit through the ethmoid si­nuses. Yet this is of great advantage in patients with mucormycosis, because the medial orbit appears to be the most common orbital entry site of the infectious pro­cess ( 13,39,40). In support of this, cases in series with orbital involvement almost universally have mucormy­cosis of the ethmoid sinuses ( 3,5,21). Factors contribut­ing to the ease of spread include the thinness of the lamina papyracea, the thinnest orbital bone, congenital dehiscences often present along the medial wall, and the perforation of the medial orbital wall by arteries and veins ( 41). A number of other methods hold promise in the treat­ment of rhino- orbito- cerebral mucormycosis. Local ap­plication of amphotericin B ( cases 1 and 2) allows in­creased concentration of the agent at the source of active infection ( 5,8,13,19,26,29,34,42,43). Hyperbaric oxygen may prove beneficial, because members of the family Mucoraceae are susceptible to increased oxygen tension ( 22,24,31,42). Liposomal preparations of amphotericin B may allow use of this antifungal agent with less systemic toxicity, theoretically raising its therapeutic index ( 24, 27,44), Endoscopic sinus surgery should be added to this list as an effective surgical approach in the diagnosis and follow- up care of patients with rhino- orbito- cerebral mu­cormycosis, reducing the need for orbital exenteration. REFERENCES 1. Gass DJM. Ocular manifestations of acute mucormycosis. Arch Ophthalmol 1961; 65: 226- 37. 2. Schwartz JN, Donclly EH, Klintworth GK. Ocular and orbital phy-coinycosis. Surv Ophthalmol 1977; 22: 2- 28. 3. Blitzer A, Lawson W, Meyers BR. Patient survival factors in para­nasal sinus mucormycosis. Laryngoscope 1980; 90: 635^ 18. 4. Ferry AP, Abedi S. Diagnosis and management of rhino- orbito-cerebral mucormycosis ( phycomycosis). Ophthalmology I983; 90: 1096- 104. 5. Kohn R, Hepler R. Management of limited rhino- orbital mucor­mycosis without exenteration. Ophthalmology 1985; 92: 1440- 1443. 6. Yohai RA, Bullock JD, Aziz AA, ct al. Survival factors in rhino-orbito- cerebral mucormycosis. Surv Ophthalmol 1994; 39: 3- 22. 7. Miller NR. Mucorales ( mucormycosis). In: Miller NR, ed. Walsh and Hoyt's clinical neuro- ophthalmology. 4th ed. Baltimore, MD: William & Wilkins, 1995; 5: 3193- 207. 8. Nussbaum ES, Hall WA. Rhinocerebral mucormycosis: Changing patterns of disease. Surg Neurol 1994; 41: 152- 6. 9. Harris JS. Mucormycosis: Report of a case. Pediatrics 1955; 16: 857- 67. 10. Burrow GN, Salmon RB, Nolan JP. Successful treatment of cere­bral mucormycosis with amphotericin B. JAMA 1963; 183: 370- 2. 11. DeWeese DD, Schleuning AJ, Robinson LB. Mucormycosis of the nose and paranasal sinuses. Laryngoscope 1965; 75: 1398- 407. 12. Abramson E, Wilson D, Arky RA. Rhinocerebral phycomycosis in association with diabetic ketoacidosis: Report of two cases and a review of clinical and experimental experience with amphotericin B therapy. Ann Intern Med 1967; 66: 735^ 12. 13. Bergstrom L, Hemenway WG, Barnhart RA. Rhinocerebral and otologic mucormycosis. Ann Otol Rhinol 1970; 79: 70- 81. 14. Zak SM, Katz B. Successfully treated spheno- orbital mucormyco­sis in an otherwise healthy adult. Ann Ophthalmol 1985; 17: 344- 6. 15. Gass JDM. Acute orbital mucormycosis: Report of two cases. Arch Ophthalmol 1961; 65: 214- 20. 16. Prockop LD, Silva- Hunter M. Cephalic mucormycosis ( phycomy­cosis): A case with survival. Arch Neurol 1967; 17: 379- 86. 17. Best M, Obstbaum SA, Friedman B, et al. Survival in orbital phycomycosis. Am J Ophthalmol 1970; 71: 1078- 80. 18. Bullock JD, Jampol LM, Fezza AJ. Two cases of orbital phyco­mycosis with recovery. Am J Ophthalmol 1974; 78: 811- 5. 19. Meyers BR, Wormser G, Hirschman SZ, et al. Rhinocerebral mu­cormycosis premortem diagnosis and therapy. Arch Intern Med 1979; 139: 557- 60. 20. Kasper LH, Bernat JL, Nordgrcn RE, et al. Bilateral rhinocerebral phycomycosis. Ann Neurol 1979; 6: 131- 3. 21. Parfrey NA. Improved diagnosis and prognosis of mucormycosis. Medicine 1986; 65: 113- 23. 22. Couch L, Theilen F, Mader JT. Rhinocerebral mucormycosis with cerebral extension successfully treated with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol Head Neck Surg 1988; 114: 791- 4. 23. Quingle L, Orcutt JC, Seifter LS. Orbital mucormycosis with reti­nal and ciliary artery occlusions. Br .1 Ophthalmol 1989; 73: 680- 3. 24. Tkatch LS, Kvsne S, Eibling D. Successful treatment of zygomy-cosis of the paranasal sinuses with surgical debridement and am­photericin B colloidal dispersion. Am J Otolaryngol 1993; 14: 249- 53. 25. Jurgens MA, Martinez VV, Peiro CG, ct al. Mucormycosis of paranasal sinuses: benign type; report of one case. Acta Otorhino-laryngol Esp 1994; 42: 117- 20. 26. Luna JD, Ponssa XS, Rodriguez SD et al. Intraconal amphotericin B for the treatment of rhino- orbital mucormycosis. Ophthalmic Surg Lasers 1996; 27: 706- 8. 27. Strasser MD, Kennedy RJ, Adam RD. Rhinocerebral mucormyco­sis: Therapy with amphotericin B lipid complex. Arch Intern Med 1996; 156: 337- 339. 28. Peterson KL, Wang M, Canalis RF, et al. Rhinocerebral mucor­mycosis: Evolution of the disease and treatment options. Laryngo­scope 1997; 107: 855- 62. 29. La Touche CJ, Sutherland TW, Telling M. Rhinocerebral mucor­mycosis. Lancet 1963; 2: 811- 3. 30. Hamill R, Oney LA, Crane LR. Successful therapy for rhinocer­ebral mucormycosis with associated bilateral brain abscesses. Arch Intern Med 1983; 143: 581- 3. 31. Ferguson BJ, Mitchell TG, Moon R, et. al. Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect Dis 1988; 10: 55. 32. Blazquez R, Pinedo A, Cosin J, et al. Nonsurgical cure of isolated cerebral mucormycosis in an intravenous drug user. Eur .1 Clin Microbiol Infect Dis 1996; 15: 598- 9. 33. Zwas ST, Czerniak P. Head and brain scan findings in rhinocer­ebral mucormycosis: case report. J Nucl Med 1975; 16: 925- 7. J Neuro- Ophlhalnml, Vol. 19, No. I, 1999 ENDOSCOPIC SINUS SURGERY IN MUCORMYCOSIS 61 34. Henriquez M, Levy R, Raja RM, et al. Mucormycosis in a renal transplant recipient with successful outcome. JAMA 1979; 242: 1397- 1399. 35. Ferry AP. Discussion of management of limited rhino- orbital mu­cormycosis without exenteration. Ophthalmology 1992; 92: 1443^-. 36. Sillers MJ, Kuhn FA, Owen RG. Surgery of the nose and paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg 1994; 2: 42- 7. 37. Buus DR, Tse DT, Farris BK. Ophthalmic complications of sinus surgery. Ophthalmology 1990; 97: 612- 9. 38. Newhaus RW. Orbital complications secondary to endoscopic si­nus surgery. Ophthalmology 1990; 97: 1512- 8. 39. Goodwin J. Orbital complications of ethmoiditis. Otolaryngol Clin N Am 1985; 18( 1): 139- 147. 40. Johnson EV, Kline LB, Julian BA, ct al. Bilateral cavernous sinus thrombosis due to mucormycosis. Arch Ophthalmol 1988; 106: 1089- 92. 41. Sheman DD, Lemke BN. Orbital anatomy and its clinical applica­tions. In: Tasman W, Jaeger EA, eds. Ditcme's Clinical Ophthal­mology. Philadelphia: Lippincott- Raven Publishers, 1992: 1- 26. Vol. 2, Chapter 21. 42. De La Paz MA, Patrinely JR, Marines HM, el al. Adjunctive hy­perbaric oxygen in the treatment of bilateral cerebro- rhino- orbital mucormycosis. Am J Ophthalmol 1992; 114: 208- 1 1. 43. Blaine DA, Frable MAS. Mucormycosis: Adjunctive therapy with hydrogen peroxide. Va Med Q 1996; 123: 30- 2. 44. Ericsson M, Anniko H, Gustalsson H, et al. A case of chronic progressive rhinocerebral mucormycosis treated with liposomal amphotericin B and surgery. Clin Infect Dis 1993; 16: 585- 7. [VBcerebritis]