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Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop This is an Open Access article licensed under the terms of the Creative Commons Attribution NonCommercial NoDerivs 3.0 License ( www.karger.com/OA license ), applicable to the online version of the article only. Distribution for non commercial purposes only. Derek H. Ohlstein, MD Neuro Ophthalmology Service, Department of Ophthalmol ogy University of Florida, 1600 SW Archer Road Gainesville, FL 32610 (USA) Tel. +1 352 273 8787, E Mail DHO @ ufl.edu 46 Orbital Aspergillosis: Voriconazole T he New Standard Treatment? Derek H. Ohlstein Claudia Hooten Javier Perez Charles L. Clark III Hazem Samy Neuro Ophthalmology Service Department of Ophthalmology University of Florida Gainesville, Fla. USA Key Words Orb ital a spergillosis Orbital apex syndrome Voriconazole Aspergillus fumigat u s Abstract Background/Aim: To descr ibe a case of invasive orbital a spergillosis and evaluate treatments and ou tcomes. Method s : A case report and review of orbital aspergillosis treatment with voriconazole in the English language literature. Conclusion : Amphotericin B with debridement is the current standard of care for orbital aspe rgillosis; however, its prognosis is unfavorable. When compared to amphotericin B voriconazole demonstrates a survival benefit, has less systemic toxicity, and is better tolerated by patients. While a prospective trial comparing amphotericin B to voriconazole in orbital aspergillosis is not feasible, there is evidence to support the use of voriconazole as primary therapy. Background Orbital aspergillosis is a rare and often fatal condition in healthy patients. Due to its vague initial symptomatology, it is often misdiagnosed and improperly treated which, in turn, facilitat es disease progression. Once proper treatment is initiated, the therapy is often poorly tolerated and the mortality rate remains high. In this case report, we will discuss a patient whose symptoms began in July 2010 and follow the historical, clinical, radiographic, and histological course until the diagnosis of invasive orbital aspergillosis was made in November 2010. We will then discuss treatment options presented to this patient and sum marize treatment options in the context of the available literature.
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 47 Case Report A 68 year old white man with a past medical history of glaucoma with remote bilateral trabeculectomies, hypertension, depression, and sinusitis present ed with a 1 month histor y of headaches and pain around his right eye. The patient described the pain as a constant ache behind his right eye which over the course of the month had intensified to become a sharp stabbing pain. During the third week, he began to have blurred visi on and ptosis of the right lid. He sought treatment at his local hospital where he was admitted and had a head CT, a head MRI, and bilateral temporal artery biopsies. No pathology was seen on imaging and the temporal artery biopsies were negative. As a re sult, the patient was presumptively diagnosed with giant cell arteritis (GCA) and treated with corticosteroids. He was subsequently discharged. The patient presented in our neuro ophthalmology clinic 4 weeks after the initial onset of his symptoms. At this Amlodipine, Valsartan, Paroxetine, Omeprazole, and Oxycodone. His best corrected visual acuity was 20/60 OD and 20/25 OS; his color vision tested with I shihara plates was 1/11 OD and 11/11 OS. On examination, h e had a trace right relative affe rent pupillary defect complete ptosis of the right lid, and a frozen right eye due to paralysis of cranial nerve s III, IV, and VI ( fig. 1 a). The combination of the visual and clinical findings led to the diagnosis of orbit al apex syndrome. His trabeculectomy blebs were moderately elevated and avascular bilaterally. F undus exam ination demonstrated pink optic nerves with a cup/disc ratio of 0.8 OD and 0.9 OS. The e xam ination was otherwise unremarkable. The patient was immedia tely admitted to the hospital for further workup. We held corticosteroids due to the suspicion of an infectious etiology. Laboratory testing revealed a C reactive protein level of 7.9 mg/ l erythrocyte sedimentation rate of 46 mm/h, and white blood cell co unt of 6 900/ l with 93% neutrophils. An MRI and CT of the head were ordered which demonstrated an infiltrative process centered in the right pterygopalatine fossa and involving the soft tissues of the nasal posterolateral recess, right orbital apex, right sphenoid sinus and dura adjacent to the clinoid process ( fig. 2 ). The infiltrative process was suggestive of a lymph omatous rather than fungal etiology. The Department of O tolaryngology was consulted, and a right trans sphenoid orbital biopsy was perform ed. Preliminary pathology from the biopsy demonstrated an infiltrate consisting of a mixture of granulocytes, giant cells, and small mature lymphocytes without evidence of infection. The slides were considered suggestive of a nonspecific inflammatory etiol ogy, such as Tolosa Hunt s yndrome, and were sent for further staining. The patient was discharged on prednisone 80 mg/day (1 mg/kg/ day). The following morning, a pathological examination revealed numerous septate hyphae branching at 45 angles consistent with Aspergillus This finding was later confirmed by a culture positive for Aspergillus fumigat u s The patient was immed iately notified and readmitted. corrected visual acuity had deteriorated to 20/100 OD and his right eye remained frozen. According to recommendations provided by the Division of Infectious Disease s h e was started on voriconazole 4 mg/kg i.v. impro ved dramatically within 72 h and after 6 days of therapy t OD. There was resolution of his relative affe rent pupillary defect and color vision deficits. He also showed a marked improvement in motility ( fig. 1 b ). He was discharged on voriconazole 350 mg p.o. b.i.d. with close f ollow up. After 6 weeks of treatment, the patient returned to our clinic with full extraocular movements, full color vision, and a visual acuity of 20/30 OD. An interval MRI of the orbits demonstrated an overall improvement. During this visit, the patient complained of a new rash on his trunk and upper extremities. The Divisions of Infectious Disease s and Dermatology were consulted, and it was found that the patient had developed a drug induced photosensitivity rash secondary to voriconazole. His therapy wa s changed to daily intravenous micafungin 150 mg, which he has tolerated well for the last month.
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 48 Discussion Orbital aspergillosis is a rare infection in healthy individuals. Aspergillus is a ubiquitous species that resides in the soil. Approximately 5.7 10 7 A spergillus spores are inhale d daily by the average American  The best established risk factor for orbital aspergillosis is sinusitis of a paraorbital sinus ; however, there is no consensus on which loci confer the greatest risk [1 3] Other risk factors include trauma, facial surgery, high exposure professions (demolition, yard work, or working in endemic areas of A spergillus flavus such as the Sudan), and immunocompromised states including AIDS, absolute neutrophil count < 1 000, l eukemia, and dia betes mellitus. The two most common pathogens in humans are A. flavus and A. fumigatus In the orbit, A. flavus causes an invasive granulomatous infection, whereas A. fumigatus may present as a noninvasive or an invasive necrotizing fulminate infection. No ninvasive orbital aspergillosis is typically found in diabetics, corticosteroid users, and immunocompetent individuals. There is typically a sparse immune response resulting in a slow indolent course. Patients often present with a chronic, dull retrobulbar pain present for months, headache, red eye s and proptosis. Over time, these symptoms may progress to include sharp pain, cranial nerve palsies, amaurosis, and orbital apex syndrome. These symptoms can be temporarily ameliorated with steroids. As the dise ase progresses, A spergillus may invade the vasculature resulting in necrotizing angiitis, mycotic aneurysms, dissemination, and thrombosis of the cavernous sinus leading to mortality within days [2, 4] As a result, aggressive early treatment of noninvasi ve infections is paramount. Invasive orbital aspergillosis presents similarly but with a more rapid progression and is uniformly fatal if untreated. Invasive aspergillosis typically manifests in immunocompromised individuals and is characterized by a granu lomatous or fulminate immune response with a centrifugal invasion of adjacent tissues, vasculature, and bone. Invasive orbital aspergillosis may result in orbital apex syndrome, necrotizing angiitis, mycotic aneurysms, thrombosis, systemic dissemination, e rosion of the orbit, and direct invasion of the central nervous system. When the disease is limited to the orbit, there is a 28% mortality rate for patients receiving sta ndard treatment with amphotericin B  However once orbital apex syndrome has manif ested, the mortality rate increases to 70 80% despite standard treatment and if the central nervous system is involve d the morta lity rate increases to 80 100% [4 7] The diagnosis of orbital aspergillosis is difficult to confirm and is often delayed 2 10 months from the i nitial presentation of symptoms  Orbital aspergillosis should be suspected whenever a patient presents with painful ophthalmalgia However, since its initial symptoms are vague, similar to more prevalent conditions, and respond to steroids aspergillosis is often misdiagnosed as orbital pseudotumor or GCA ( table 1 ) Many patients, including ours, are presumptively started on corticosteroids and demonstrate a subsequent improvement resulting in a premature conclusion to the workup. Steroids decrease the inflammation in the orbit and transiently improve symptoms but may hasten t he course of aspergillosis. When a diagnosis of orbital aspergillosis is suspected, an MRI of the orbit is indicated. MRI is useful for evaluating the optic ne rve, cerebral dura, paraorbital sinuses, and masses. Any sinusitis (>8 mm thickening of the sinus mucosa) with an
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 49 enhancement of the optic nerve or erosion of the orbital bones should prompt suspicion for orbital aspergillosis. A CT of the orbit without co ntrast may aid in the diagnosis by screening for bony erosion and examining for intraluminal calcification, which is pathognomonic. To confirm the diagnosis, a biopsy is required. Fungal cultures of the nares have been shown to be unreliable and s hould not be used for screening  If imaging reveals a paraorbital sinusitis, an anterior rhinoscopy as well as a biopsy may be performed. While anterior rhinoscopy is the least invasive approach, 50% of cases requir e a second biopsy [1, 8] Alternative approach es include orbital fine needle aspiration or trans sinus orbital biopsy ; these approaches have a higher yield but are more invasive than anterior rhinoscopy. The tissue should be sent for both frozen and permanent sections to look for fungi as well as othe r pathology. In addition, s lides should be sent for per i odic acid Schiff stain and Gomori methenamine silver stain to look for h a emotoxophilic organisms with 45 branching septate hyphae 2 4 m in wid th Cultures should be incubated for at least 30 days. If pathological testing is initially negative but a high suspicion of aspergillosis is maintained, corticosteroids should be held until cultures are known and empiric treatment for aspergillosis should be initiated. Treatment for orbital aspergillosis in t he literature is based upon previous case reports. There are no prospective studies evaluating the efficacy of treatments in orbital aspergillosis. The current mainstay of therapy for orbital aspergillosis is amphotericin B i.v. 0.5 mg/kg/day with debridem ent of focal abscesses [1, 2, 4] In total, 40 60% of patients show a response to amphotericin B i ncluding liposomal preparations  Despite treatment with amphotericin B once the infection has manifested as an orbital apex syndrome the mortality rat e remains 7 0 80% [1, 2, 4 6] Due to a high rate of relapse, prolonged treatment f or 2 years to life is suggested [1, 2] Amphotericin B has numerous side effects, including irreversible nephrotoxi ci ty, and as a result is often poorly tolerated. There is a case report of a patient who died as a direct result of amphotericin B therapy for invasive orbital aspergillos is  Alternative therapies in the literature include itraconazole 200 400 mg/day. Itraconazole is better tolerated than amphotericin B, bu t has similar response, relapse, and mortality rate s [1, 4] This drug should not be used if there is pulmonary involvement because a higher mortality has been demonstrated in these cases Concomitant induction of amphotericin B and itraconazole may increa se response, and maintenance with itraconazole alone is significantly bet ter tolerated than with amphoteri cin B  Fl uconazole 100 200 mg/kg/day and rifampin 600 mg/day have also been shown to be effective but there are too few reports to evaluate thei r role in th erapy [4, 9] Ketoconazole on the other hand has been shown to be ineffective in treating orbital aspergillo sis [4 ] Voriconazole is a second generation triazole antifungal that has become the usual treatment of extraorbital invasive aspergillo sis after demonstrating a 22% survival benefit over amphotericin B in a comparative evalu ation [10, 11] Voriconazole 6 mg/kg for 1 day then 4 mg/kg/day has less systemic side e ffects than amphotericin B favorable bone penetration, and is better to lerat ed for maintenance therapy [10 12] De spite its favorable profile, we could only find one case report in the English literature and two abstracts in the Japanese literature o n voriconazole treatment of invasive orbital aspergillosis [10, 13, 14] I n each of the se case reports, the patients demonstrated a dramatic improvement within several days of voriconazole therapy.
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 50 In the English literature, Sasindran et al.  presented a case of an 8 year old boy who developed an orbit al apex syndrome after a trau m a. He was initially treated with steroids ; however, his symptoms worsened. A biopsy was obtained revealing A. f lavus infection He was successfully treated with 150 mg voriconazole b i d for 12 months. The Japanese literature presented 2 cases of patients in their 70s being successfully treated for orbital aspergillosis, but the treatment protocols were not discussed in the abstracts [13, 14] Conclusion Despite being the current standard of treatment for invasive orbital aspergillosis, amphotericin B prep arations offer an unfavorable prognosis. With optimized amphotericin B therapy, the mortality rate in orbital apex syndrome patients remains 70 80%. Additionally only 40 60% of patients with orbital aspergillosis will respond to treatment with amphoteri cin B and patients poorly tolerate prolonged therapy. Most patients develop serious complications such as nephrotoxicity, and 1 patient is reported to have died as a direct result of the therapy  While the role of voriconazole as the mainstay of thera py for extraorbital invasive aspergillosis is well defined, its role in orbital aspergillosis has not yet been documented. The use of voriconazole seems intuitive for orbital aspergillosis since it confers a survival benefit, provides better bone penetr ati on and is better tolerated than amphotericin B preparations in extraorbital invasive aspergillosis. The efficacy of voriconazole has been demonstrated in our patient and the 3 above mentioned case reports found in the literature. Each patient reported a q uick response, dramatic symptom improvement, and no relapses. Out of the 4 patients, only our patient reported a side effect (photosensitive drug rash) due to voriconazole. d type 2 diabetes and a history of previous sinusitis. These risk factors are usually associated with noninvasive orbital aspergillosis rather than with the invasive disease as confirmed by MRI in our case Our patient may initially have had a noninvasive orbital aspergillosis t hat was exacerbated by the use of corticosteroids for the treatment of probable GCA. The reversible immunosup p ression conferred by the steroids may explain the rapid invasive progression and the favo rable response to voriconazole. While 4 patients do not d emonstrate a statistical benefit voriconazole can be considered an efficacious alternative to amphotericin B for the treatment of orbital aspergillosis that is better tolerated by patients Disclosure Statement All authors are affiliated with University o f Florida and have no other disclosures.
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 51 Table 1 Differential diagnosis Inflammatory Idiopathic orbital inflammation Tolosa Hunt s y n drome Sarcoidosis Infectious Extension of bacterial sinusitis Tuberculosis Histoplasmosis Coccidiomycosis Other fungi ( Mucor, F usarium ) Vasculitis Giant cell arteritis Weg ene Neoplastic B cell lymphoma Primary orbital t u mors Neuro ophthalmic Optic n euritis Fig. 1 a Extraocular movements prior to treatment, demonstr ating an orbital apex syndrome. b Eye movements after 2 weeks of voriconazole therapy
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 52 Fig. 2 MRI T 1 ( a ) and T 2 weighted ( b ) images from our patient demonstrating an infiltrative process centered in the right pterygopalatine fossa and involving the adjacent soft tissues of the nasal posterolateral recess, right orbital apex, right sphenoid sinus and dura of the clinoid process. References 1 Sivak Callcott JA, Livesley N, Nugent RA, R asmussen SL, Saeed P, Rootman J: Localized invasive sino orbital aspergi llosis: characteristic features. Br J Ophthalmol 20 04; 88 :681 68 7 2 Richard D, deShazo R, Chapin K, Swain RE: Fungal s inusitis. N Engl J Med 1 997;337:254 259 3 Bray WH, G iangiacomo J, Ide CH: Orbital apex syndrome. Surv Ophthalmol 19 87; 32 :136 140 4 Levin LA, Avery R, Shore JW, Woog JJ, Baker AS: The spectrum of orbital aspergillosi s: a clinicopathological review. Surv Ophthalmol 19 96; 41 :142 154 5 Heidegger S, Mattfeldt T, Rieber A, Wikstroem M, Kern P, Kern W, Schreiber H: Orbito s phenoidal Aspergillus i nfec tion m imicking c luster h eadache : a case report Cephalalgia 1997 ;17:676 679 6 Matsuo T, Notohara K, Yamadori I : Aspergillosis c ausing b ilateral o ptic n euritis and l ater o rbital a pex s yndrome. Jpn J Ophthalmol 20 05; 49:423 433 7 Tekin C, Gltekin B, Sakarya S: Invasive fungal granuloma of the brain caused by Aspergillus fumigatus: a case repo rt and review of the literature. Surg Neurol 200 8; 69:169 174 8 Fernandes YB, Ramina R, Bor ges G, Queir oz LS, Maldaun MV, Maciel JA Jr: Orbital a pe x s yndrome d ue to a spergillosis. Arq Neuro p siquiatr 2001; 59 :806 808 9 Rowed DW, Kassel EE, Lewis AJ: Transorbital intracavernous needle bi opsy in painful ophthalmoplegia. J Neurosurg 1985;62:776 780 10 Sasindran V, Ravikumar A, Senthil : O rbital apex syndrome in a child. Indian J Otolaryngol Head Neck Surg 200 8;60:62 65
Case Rep Ophthalmol 2012;3:46 53 DOI: 10.1159/000336276 Published online: February 4, 2012 2012 S. Karger AG, Basel ISSN 1663 2699 www.karger.com/cop 53 11 Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubi n RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group: Voriconazole versus amphotericin B for primary th erapy of invasive aspergillosis. N Engl J Med 2002; 347:408 4 15 12 Parize P, Chandesris MO, Lanternier F, Poire S, Viard JP, Bienvenu B, Mimoun M, Mchai F, Mamzer MF, Herman P, Boug noux ME, Lecuit M, Lortho lary O: Antifungal t herapy of Aspergillus i nvasive o titis e xterna: e ffi cacy of v oriconazole and r eview. Antimi crob Agents Chemother 2009 ;53:1048 1053 13 Sugai A, Oyak e M, Umeda M, Umeda Y, Fujita N: Case of orbital apex syndrome caused by invasive aspergill osis successfully treated during the diagnostic proce dure by the use of voriconazole (in Japanese) Rinsho Shinkeigaku 2008;48 :7 46 74 9 14 Kug a A, Oishi K, Ishida H, Kanda F: A case of orbital apex syndrome caused by localized invasive aspergillosis success f ully treated with voriconazole (in Japanese) Rinsho Shinkeigaku 2 007;47 :207 2 10