After a 75-year-old male, who pursued gardening as a hobby, noticed decreased vision in his left eye, he visited an ophthalmologist in September of 2015. He had a history of hypertension, colon cancer and metastatic hepatic tumor. As an ophthalmologic examination revealed macular edema in his left retina resulting from branch retinal vein occlusion (BRVO), he underwent a posterior STTA injection in his left eye to treat the macular edema. After routine disinfection of the lid margins and conjunctival sac with 10% and 0.625% (16-fold dilution) povidone iodine, respectively, the procedure was performed uneventfully. The patient once again visited his ophthalmologist in November due to complaints of ocular pain and hyperemia in his left eye. The symptoms did not improve even though he received oral and topical antibiotic treatment for 3 days. Computed tomography of the orbit was performed and revealed a peribulbar high density lesion of the left eyeball. Due to a suspected peribulbar infection, he was subsequently referred to our hospital in the middle of November.\nAt his first visit, best corrected visual acuity (BCVA) (decimal) was 1.2 in the right eye and 0.15 in the left eye. Intraocular pressures were normal. Although the upper and lower eyelids of his left eye were swollen, we observed no restrictions of his eye movement. Slit lamp examination of the left eye showed ciliary injection, cells in the anterior chamber and a subtenon abscess in the superotemporal quadrant, which corresponded to the site of the posterior STTA (Fig. ). While our fundus examination did not reveal any intravitreal involvement, it did find macular edema and BRVO, which had been reported by his previous doctor. The right eye exhibited no abnormal findings, including both the anterior and posterior segments. The patient had no fever. The orbital magnetic resonance imaging (MRI) revealed the presence of a peribulbar high intensity lesion that corresponded to the subtenon abscess (Fig. ). The MRI did not detect any paranasal sinus or intracranial invasion. The serologic test, which included white blood cells, C-reactive protein and beta-D-glucan, only revealed a slight elevation of C-reactive protein (1.11 mg/dL). To determine the causative pathogen, incision and drainage of the subtenon abscess were performed, with the obtained purulent fluid submitted for bacterial and fungal cultures. While the smears revealed polymorphonuclear leukocytes and a large number of round or oval conidia-like structures, a fungal filamentous appearance was not observed (Fig. ). Based on these results, we suspected fungal infectious scleritis induced by STTA. Therefore, the patient was initially started on 1% voriconazole (VRCZ) and 1.5% levofloxacin (LVFX) eye drops that were each administered six times per day in an outpatient department. Inflammation of the anterior chamber of the left eye worsened after 4 days, with choroidal detachment observed in the temporal region of the fundus. The fungal culture found an early colony of a filamentous fungus. Based on the definitive diagnosis of infectious scleritis by filamentous fungi, we then performed debridement of the infected sclera and Tenon’s capsule. The resected scleral tissue was submitted for further pathological examination. The conjunctival sac of the left eye was irrigated with 0.625% povidone iodine, followed by hospitalization for treatments with 1% natamycin ointment, 1% atropine eye drops and intravenous VRCZ. Ten days after the initial visit, we noted improvement in both his ocular pain and inflammation of the anterior chamber. As a result, we switched the voriconazole from an intravenous to an oral administration. Histopathological examination using Grocott staining revealed infiltration of branching hyphae into the sclera (Fig. ). Due to a novel subtenon abscess of the adjacent upper region of the left eyeball that developed at 18 days after the initial visit, we once again performed scleral debridement. The fungal species, Scedosporium apiospermum, was identified by DNA sequencing of the internal transcribed spacer (ITS) region of ribosomal DNA amplified by polymerase chain reaction (PCR) with ITS1F and ITS1R primers []. The strain was sent to Teikyo University for complete species identification. The susceptibility testing of the antifungal agents was performed using the broth microdilution method based on CLSI M38-A2 []. Results indicated low minimum inhibitory concentrations against micafungin, VRCZ and miconazole (Table ). Based on the antifungal susceptibility test findings, the natamycin ointment was discontinued. Topical and systemic voriconazole administrations were continued for 2 and 1 months, respectively, and then stopped once the ciliary injection subsided. However, 1 month after the discontinuation of topical VRCZ, the subtenon abscess recurred at the same place (superotemporal quadrant). Incision and drainage of the abscess was performed three times. Light microscopic examination of the smears of the subtenon abscess revealed that septate hyphae were still present. As a result, we resumed the 1% VRCZ and 1.5% LVFX eye drops for 2 weeks and then stopped the administration. No recurrence was observed after the final treatment. Due to the prolonged macular edema, however, the final BCVA (decimal) of the left eye was 0.2 as of April 2016 (Fig. ).\nCharacteristics of the colonies found on the potato dextrose agar incubated at 28 °C for 21 days included a grayish white and cottony appearance with an umbonate center on the surface, and a reverse side showing a brownish dark wrinkle appearance in the center and a yellow-white appearance on the margin (Fig. ). Microscopic features observed when using the slide culture technique on potato dextrose agar at 10 days included septate hyphae that were 2 μm in diameter and branching irregularly, along with the production of lateral and terminal conidia, which were round or oval (3 to 5 by 5 to 10 μm) (Fig. ). We also observed a Graphium synanamorph that produced a brush of cylindrical conidia (3 by 12 μm) (Fig. ).\nIn order to confirm the species identification using a molecular approach, the BUT locus of the β tubulin gene was also amplified by PCR using Bt1a/Bt1b primers [, ] and then applied to DNA sequencing [, ]. The obtained DNA sequencing was compared by using the Basic Local Alignment Search Tool. Both the ITS and the BUT exhibited 100% homology with that reported by Zouhair et al. for Scedosporium apiospermum (GenBank accession no. JQ690950 and JQ691056) []. Based on the current and previous results, we were finally able to identify the causative fungal strain as Scedosporium apiospermum sensu stricto.
A 59-year-old man with a 1-month history of headache was examined in an otolaryngological clinic of a general hospital. The patient’s anterior nasal septum was swollen, and he was diagnosed with nasal septal abscess and admitted to the hospital the same day. Enhanced computed tomography (CT) revealed a swollen, ring-enhanced lesion in the anterior nasal septum (Fig. ). He was treated with incisional drainage of the abscess and antibiotic drip for 1 month (fosfomycin, ampicillin/sulbactam, ceftriaxone, and meropenem). In addition, insulin-based therapy was started because the patient had uncontrolled diabetes and hemoglobin A1c of 13.3%. His symptoms persisted despite 1 month of antibiotic drip. Pus from the nasal septum was cultured three times. Culture tests detected low concentrations of Capnocytophaga spp. and Serratia marcescens, which were sensitive to the antibiotic drip. No fungi were detected. The septal lesion was biopsied twice and showed granulation-like tissue with infiltrated inflammatory cells (nothing indicating malignancy or fungus). Despite the antibiotic drip for >1 month, diplopia developed due to bilateral abducens nerve palsy, with subsequent impairment of right eye movement and eventual visual loss. The patient was then referred to our department.\nThe patient’s initial visit revealed a saddle nose. Nasal fiberscope revealed bulging of the nasal septum and granulation-like tissue on the right side of the nasal septum. The patient’s left eye fixed at the central position and the supraduction and adduction of the right eye were limited. His visual acuities were light perception in the right eye and “count fingers” in the left eye. The functions of the 5th, 7th, and 8–12th cranial nerves were intact.\nThe patient’s hemoglobin A1c was 9.2%. Plain CT showed a poorly marginated lesion with soft tissue density at the superior nasal septum, which was invading the anterior cranial fossa. Another mass with soft tissue density appeared in the left maxillary sinus (Fig. ). A spinal tap and cerebrospinal fluid culture were immediately performed, and the results revealed elevated glucose levels (130 mg/dL) and cell counts (mononucleosis 19/m3, polynucleosis 1/m3). No pathogen was detected by microscopic examination or culture methods. Owing to the possibility of a fungal and/or bacterial infection, we prescribed an antibiotic (ampicillin/sulbactam) and antifungal (amphotericin B) drip. Subsequently, we performed diagnostic endoscopic sinus surgery under general anesthesia. Histopathological examination revealed that the ball-like lesion in the left maxillary sinus harbored fungi, with filaments slightly thinner than those of Aspergillus spp. (Fig. ). A commercially available fungal DNA detection kit (Robust HotStart ReadyMix PCR Kit; KAPA biosystems, Inc., U.S.A.) was used to detect pathogens in tissues from the nasal septal lesion and ball-like fungal lesion in the left maxillary sinus. A broad-range polymerase chain reaction (PCR) was performed targeting the highly conserved sequence of the ribosomal RNA genes in fungal DNA shared by most fungi. Internal transcribed spacer (ITS) regions in ribosomal DNA were then amplified by PCR using primers ITS1F (5′-TCCGTAGGTGAACCTGCGG-3′) and ITS4R (5′-TCCTCCGCTTATTGATATGC-3′). PCR products of 150–500 bp were obtained and sequenced to match a known DNA sequence from a reference database (BLAST: Basic Local Alignment Search Tool). The organism detected by PCR and tissue cultures was S. apiospermum. Subsequent enhanced magnetic resonance imaging (MRI) revealed strongly enhanced lesions of the nasal septum, ethmoid sinuses, bilateral orbital apexes, and cavernous sinus. The dura along the anterior and bilateral middle cranial fossa was thickened and well-enhanced. (Fig. ). The diagnosis was orbital apex syndrome and hypertrophic pachymeningitis secondary to fungal nasal septal abscess caused by S. apiospermum.\nDrug susceptibility testing (Table ) led us to change the antifungal drip to voriconazole (500 mg/day). Since voriconazole had no apparent effect on the patient’s symptoms after four days, we surgically resected the lesion under general anesthesia.\nUsing endoscopy-assisted open skull base surgery, we removed the fungal ball-like lesion and the mucosa of the left maxillary sinus. We then incised the anterior border of the nasal septum and removed the mucosa of the bilateral ethmoid and sphenoid sinuses. After anterior craniotomy, we resected the anterior skull base between both sides of the ethmoid tegmen, from the frontal table anteriorly to the optic chiasm posteriorly. We avoided the extirpation of the eye ball or removal of the orbital content, because the medial bony wall of the orbit was intact.\nThe resected nasal septum was thickened and necrotic, strongly suggesting infectious inflammation and necrosis of the tissue. Mild mucosal edema was observed in the bilateral ethmoid and sphenoid sinuses. No fungal invasion or pus was observed. The dura was thinned just above the affected part of the cranial fossa, suggesting that the infection and inflammation had spread to the dura; however, there was no apparent dural deficit, and the dura was preserved. Following resection, we reconstructed the affected anterior cranial fossa with pericranium.\nThe patient’s headache decreased and almost disappeared 3 weeks postoperatively. His preoperative mild fever and inflammation normalized, and he was discharged on postoperative day 29. The patient continued oral voriconazole (400 mg/day) until 12 months post-surgery, when bilateral ocular movements completely improved; however, loss of visual acuity persisted. At 22 months post-surgery, a follow-up MRI demonstrated that the enhanced lesion in the orbital apex diminished. Thirty months has passed without any evidence of recurrence until now. The timeline of the patient’s illness is illustrated in Fig. .