Chapter 3

............................

Periocular Fungal Infections

3.1

Palpebral Involvement

Fungal infections of the eyelids have been described several times. The eyelids alone may be aVected, or their involvement may be part of a generalized dermatomycosis [1–4]. Table 3.1 lists fungi that have been implicated in palpebral disease. Both aspergilloma [5] and sporotrichosis [2] can simulate a chalazion, and coccidioidomycosis may be mistaken for an infected basal cell carcinoma. Aspergillomas respond well to direct injection of amphotericin B [5]. In North America, generalized blastomycosis aVects the eyelids in a quarter of the patients [6] and commonly causes a cicatricial ectropium [7–9].

As from the conjunctivae (see chapter 4, p. 68), it may be possible to isolate fungi from the lids in the absence of a manifest infection [10, 11]. A fungal infection of the lid margins may resemble a staphylococcal infection [12]. Nelson et al. [13] successfully treated Pityrosporum blepharitis with topical ketoconazole, but equally good results were obtained in the control group of this double-blind study, whose sole treatment consisted of cleansing with baby shampoo. It thus seems that mechanical cleansing of the lid margins may be the key aspect of the management of chronic blepharitis [14].

3.2

Infections of the Lacrimal Ducts

Since the time of von Graefe, who in 1854 was the first to describe actinomycosis of the canaliculi [15], there have been repeated reports in the literature of infections and stenoses of the tear ducts caused by this microorganism (table 3.2). The incidence in Central Europe is probably considerably less than 2% of the dacryostenoses, a figure quoted by Wissmann [16] for the population of Breslau, Silesia in 1913. The fact that actinomycetes (Streptothrix spp., Leptothrix spp., Nocardia spp.), despite their names, are not fungi but

52

Table 3.1. Reported fungal infections of the eyelids

bacteria was first emphasized in the ophthalmological literature by HoVmann [17] (see also p. 21–22).

As with the eyelids, several fungi can cause infections of the nasolacrimal duct, and these are listed in table 3.3. Dacryostenosis caused by true fungi is probably rare. C. albicans was isolated from only 2 of 236 patients (1.2%) with dacryocystitis [18]. Busse [19] found that only 2 cases of approximately 4,000 occlusions of the lacrimal caniculi were caused by infections with C. albicans, with 1 case of canaliculitis and 1 case of diverticulitis of the lacrimal sac [19]. Candida spp. have also been reported in 2 cases of dacryocystitis, without dacrolith formation [20].

Dacryoliths, or brittle, hard concretions in the lacrimal canaliculi however, are characteristic of the condition. They may occasionally fill the entire lumen. It is often possible to express these fungal concretions with the aid of two glass rods. Where this is not feasible, an incision has to be made in the canaliculus to remove the concretion (1-snip or 2-snip procedure). This should be followed by microsurgical apposition of the wound margins. It is always advisable to irrigate with an antifungal agent, e.g. amphotericin B 0.5%.

3.3

Fungal Infections of the Orbit

Various types of fungus have been described in infections of the orbit [21, 22]. The most commonly diagnosed conditions are mucormycosis and

Table 3.3. Fungal infections of the nasolacrimal duct

aspergillosis. Other pathogens are listed in table 3.4. After injury to an eyelid, a 4-year-old child developed an orbital and brain abscess caused by P. boydii . The child was successfully treated with surgical debridement and intravenous miconazole [23]. In a similar case, the organism was resistant to amphotericin B, but after surgical debridement responded to a 6-week course of intravenous

Table 3.4. Fungal infections of the orbits

miconazole [24]. A case of periorbital necrotizing fasciitis caused by Cryptococcus sp., also after an eyelid injury, healed after surgical debridement and treatment with fluconazole [25].

3.3.1

Mucormycosis

Mucormycosis (phycomycosis, zygomycosis) is usually caused by fungi of the genera Absidia, Rhizomucor or Rhizopus. Infection may be centered on one area, such as an orbit or paranasal sinus (orbital, rhinocerebral), stomach (gastrointestinal), lung (pulmonary) or skin (cutaneous), or it may be more widespread (disseminated) [26]. Most cases of mucormycosis are associated with an underlying disease, though it has been reported in healthy persons [27]. Diabetes mellitus is the most common underlying disorder, especially if complicated by metabolic acidosis [26, 28–30]. Other predisposing factors

Table 3.5. Initial symptoms and signs in 16 patients with mucormycosis1 [30]

1 Several signs or symptoms developed concurrently in some patients.

include cancer chemotherapy, organ transplantation with immunosuppressive therapy, treatment with corticosteroids, and leukemia and lymphoma [30, 31]. Treatment with deferoxamine represents an additional risk factor, as the fungi need iron for growth [32–40]. More than 100 cases of rhino-orbital-cerebral mucormycosis have been reported [28, 41, 42], and invasion of the optic nerve has also been described [43, 44].

The first clinical symptoms are often orbital pain associated with sinusitis or pharyngitis [30, 45], followed by rapidly increasing proptosis. One characteristic of mucormycosis is the invasion of blood vessels by fungal hyphae and subsequent infarction [28, 46–48], which not uncommonly leads to a sudden loss of vision due to occlusion of the central artery [39, 49, 50]. Later, black discoloration of the mucous membranes or skin appears as a characteristic sign [30]. The disease often takes a fulminating course, so that it is misdiagnosed as a bacterial infection [51]. The initial symptoms and signs of the disease in a series of 16 patients are listed in table 3.5 [30].

The prognosis is serious, particularly as the condition is often complicated by cerebral involvement. Preceding or concurrent bacterial infections are common [30].

Surgical excision of infected tissues in addition to antifungal chemotherapy has been life saving [29, 39]. Debridement must be radical to be beneficial; persistence of unsuspected areas of infection may lead to serious postoperative complications, e.g. hemorrhage [52]. In appropiate cases a frozen sectionguided surgical debridement may provide an alternative to traditional radical surgical excision [53]. Drug treatment consists of systemic administration of amphotericin B, possibly combined with flucytosine [26, 30, 39, 54]. Hyperbaric oxygen may also be useful [55]. A case resistant to amphotericin B (MIC, 64 mg/l in vitro) was successfully treated with oral ketoconazole, 600 mg/day

for 5 months [56]. Where appropriate, treatment may also be attempted with itraconazole or fluconazole [42]. This treatment may be supported by repeated intraconazole instillation of amphotericin B, 1 mg/ml, every 12 h via an Abbocath No. 18 catheter [50].

Mucormycosis has also been diagnosed in the eye [30, 57] and was once misdiagnosed as Coats’ disease [58]. It has also, though doubtfully, been reported in the cornea [59].

3.3.1.1

Case Report [39]

A woman aged 24 years was diagnosed in 1988 as having acute myeloid leukemia, FAB classification type M2. The initial treatment consisted of 2 cycles of daunorubicin, cytarabine and etoposide chemotherapy. After complete remission was achieved in August 1988, and in the absence of an allogeneic bone marrow donor, autologous marrow was removed and then transplanted after myeloablative conditioning therapy with busulphan and cyclophosphamide. Despite her continuing complete remission, the patient developed chronic pancytopenia as her bone marrow function did not recover. The essential regular transfusions of erythrocytes and thrombocytes (red cells every 14 days, platelets every 5 days) resulted in an accumulation of iron which from October 1990 onwards, with ferritin levels of 10,000 ng/ ml, required intermittent treatment with deferoxamine, 5 g, which was given by intravenous injection at the end of every infusion.

Although she had been treated throughout as an out-patient, the woman was admitted in mid-May 1991 because of violent mid-frontal headache that had increased within 1 week, with swelling of the left periorbital region that had developed during the previous 24 h and pyrexia (38.5 ºC axillary). Corrected visual acuity of both eyes was unimpaired. Pupillary reaction to both direct and indirect light was normal. The motility of both eyes was undiminished, but there was a slight pain on movement on the left side.

The suspected diagnosis based on the clinical findings was frontal and maxillary sinusitis on the left side, and on the day of admission the patient was commenced on antibiotic therapy with 2.2 g amoxycillin with clavulanic acid 3 times daily. Orbital phlegmons developed within 24 h of this treatment, which was therefore changed to rifampicin, 300 mg twice daily, and ciprofloxacin, 200 mg twice daily, but the infection advanced.

Within the next 2 days, the vision in the aVected eye deteriorated rapidly to blindness, due to occlusion of retinal arteries (fig. 3.1.).

Computed tomography (CT) revealed extensive tissue proliferation, isodense to soft tissue, which most nearly resembled an abscess or an orbital phlegmon. There was also a protrusion of the bulb on the left side, and infiltration of the medial and inferior rectus muscles and marginally also of the optic nerve.

As the condition failed to respond to antibiotics, and the CT findings indicated considerable deterioration, orbital decompression was carried out by a paranasal incision on the left. The orbital plate of the ethmoid bone was removed, and the orbit incised. Extensive mucosal biopsies were taken from the region of the paranasal sinuses, and R. rhizopodiformis was cultured from these.

On the basis of these findings, parenteral combination therapy with amphotericin B and flucytosine was initiated 7 days after the start of the clinical symptoms. Amphotericin

Fig. 3.1. Ischemic retinal edema in the region of the superior and inferior temporal arteries. Preretinal and subretinal bleeding with thrombocytopenia (6,000/ll) and hyperfibrinogenemia of 600 mg/dl (normal range, 180–450 mg/dl).

B was given as a single test dose of 1 mg and then immediately in a dose of 1 mg/kg/day. Flucytosine was infused in the standard dose of 150 mg/kg/day. This treatment was continued unchanged for 10 days and then for another 12 days at half the dose of amphotericin B. The total dose of amphotericin B was only 0.8 g. Apart from shivering, which was controlled by intravenous injection of pethidine, 50 mg, the treatment caused no serious adverse eVects. Figure 3.2 shows the clinical condition of the patient at the start of the antifungal treatment after orbital decompression.

The earlier progression of clinical symptoms stabilized within 24 h of the start of antifungal therapy, and then slowly subsided. However, blindness of the left eye due to occlusion of the central artery, which had occurred only 5 days after the clinical manifestation of the mucormycosis, remained irreversible.

3.3.2

Aspergillus and Other Fungal Organisms

Orbital aspergillosis usually arises from nasal and paranasal fungal sinusitis. The spectrum of Aspergillus infections is complex and may present in 4 fundamental patterns [60–63]: allergic, noninvasive, invasive and fulminant. Host immune defences are of crucial importance in determining susceptibility to aspergillosis. Table 3.6 lists the known risk factors for aspergillosis [63].

The first 2 modes (allergic, noninvasive), which are usually less aggressive, are typically found in nonimmunocompromised individuals. Allergic Asper-

Fig. 3.2. Proptosis immediately after orbital decompression and before the start of antifungal treatment.

Table 3.6. Risk factors for aspergillosis [63]

Total neutrophils less than 1000/mm3 T cell defects, e.g. AIDS [161] Defects of phagocytosis Haematological malignancy

Steroids or other immunosuppressive agents Diabetes mellitus

Prosthetic devices or trauma

Excessive environmental exposure, e.g. nearby demolition or restoration of buildings, outdoor work, compost heaps

Residence in an endemic area, e.g. Sudan Advanced age?

gillus sinusitis is a cause of chronic sinusitis in atopic but otherwise normal individuals [64, 65] and is thought to be a combination of type I and type III immunological reactions to Aspergillus antigens via granulomatous inflammation. This saprophytic condition may take a benign course, or may result in a progressive sinus wall erosion with rapid visual loss [66]. Noninvasive disease results in the formation of an aspergilloma (a fungus ball) and behaves like chronic sinusitis [63]. In some cases, the course of the disease may extend over several years [67]. Occasionally, chronic inflammation induced

by Aspergillus may cause tissue destruction without actual invasion by the organisms [68].

The other 2 forms (invasive, fulminant) are typically associated with immunocompromised patients. The invasive form behaves like a malignant neoplasm, presenting with granulomatous inflammation and fibrosis. Exceptionally, invasive aspergillosis may occur even in otherwise healthy individuals [69]. Fulminant aspergillosis is rapidly destructive with tissue necrosis and vascular invasion and is often fatal. Thus, there is a wide spectrum of disease [63, 68, 70–72]. Prolonged Aspergillus infections may also lead to the production of mycotoxins, such as aflatoxins and ochratoxins. These mycotoxins may produce optic neuritis and ophthalmoplegia in cases of noninvasive sinus mycoses [73].

The clinical symptoms include orbital inflammation and a red proptotic eye with or without associated pain [45, 59, 63, 67, 68, 70–77]. In addition, ophthalmoplegia may develop [71, 78]. Embolization of vessels of the optic nerve [79], or direct involvement of the nerve may occur [66, 80, 81]. Bilateral involvement has also been described [82].

The diVerential diagnosis includes infectious, neoplastic and noninfectious granulomatous processes. In particular, orbital pseudotumor and the early stages of Tolosa-Hunt syndrome may mimic orbital aspergillosis, leading to treatment with corticosteroids with a fatal outcome [78, 80, 83].

Both CT and magnetic resonance imaging (MRI) are useful in establishing the diagnosis. The presence of dense intraluminal calcifications on a CT scan is highly indicative of aspergillosis [84, 85], particularly if the density exceeds 2,000 Hounsfield units [86]; however, calcifications are present in only 50% of infected patients [73]. Fine-needle aspiration [87] or a biopsy may be performed.

Treatment consists of radical surgical debridement [63, 67, 75, 88, 89], if necessary with orbital exenteration [90]. Medical treatment may also be attempted with amphotericin B plus flucytosine or with itraconazole [63, 70, 91–93]. Itraconazole has fewer side-eVects than amphotericin B and has been used successfully [89, 94]. Direct injection of amphotericin B into the cavity of the abscess without surgical debridement has been reported to be an eVective palliative treatment of an orbital mass induced by A. fumigatus in a patient with AIDS [77].

Other fungi mimicking aspergillosis are Bipolaris spp., which include most Drechslera species. The infections particularly resemble allergic Aspergillus sinusitis [95–97]. Other pathogens described in this context, inducing slowly progressive exophthalmos, include Alternaria spp. [98], Curvularia spp. [99],

C. immitis [100], B. dermatitidis [101], Histoplasma spp. [102] and Penicillium spp. [103]. Fulminant invasive aspergillosis may be mimicked by rhino-orbital- cerebral mucormycosis.

References

1Faulkner, R.F., Ocular coccidioidomycosis. Am. J. Ophthal., 1962. 53: p. 822–827.

2Gordon, D.M., Ocular sporotrichosis. Arch. Ophthalmol., 1947. 37: p. 56–72.

3Irvine, A.R., Coccidioidal granuloma of Lid. Trans. Am. Acad. Ophthalmol., 1968. 72: p. 751–754.

4Wood, T.R., Ocular coccidioidomycosis. Am. J. Ophthal., 1967. 64: p. 587–591.

5Harrell, E.R., R. Wolter, R.F. Gutow and A. Arbor, Localized aspergilloma of the eyelid. Arch. Ophthalmol., 1966. 76: p. 322–324.

6Franc¸ois, J. and M. Rijsselaere, Factors which favor mycotic infections. 1972: Charles Thomas.

7Blodi, F.C. and W.C. HuVman, Cicatricial ectropion caused by cutaneous. Arch. Ophthalmol., 1958.

59:p. 459–462.

8Witorsch, P. and J.P. Utz, North American blastomycosis. A study of 40 patients. Medicine, 1968.

47:p. 169–200.

9Starr, M.B., Infections and hypersensitivity of the eyelids. 1986: Mosby.

10Fazakas, A., U¨ ber die von Bindehaut, Hornhaut, Lidrand und Tra¨nenwegen gezu¨chteten Pilze. Graefes Arch. Ophthal., 1935. 133: p. 461–466.

11Olson, C.L., Fungal contamination of conjunctiva and lid margin. Arch. Ophthal., 1969. 81: p. 351–355.

12Fazakas, S., Zusammenfassender Bericht u¨ber die sekunda¨ren Mykosen bei Erkrankungen des Augenlidrandes, der Bindehaut und der Hornhaut. Ophthalmologica (Basel), 1959. 138: p. 108–118.

13Nelson, M.E., G. Midgley and N.R. Blatchford, Ketoconazole in the treatment of blepharitis. Eye, 1990. 4: p. 151–159.

14Key, J.E., A comparative study of eyelid cleaning regimens in chronic blepharitis. CLAO J., 1996.

22:p. 209–212.

15Graefe, A.V., Mittheilungen von Krankheitsfa¨llen und Notizen vermischten Inhalts. Konkretionen im unteren Tra¨nenro¨hrchen. Arch. Ophthal., 1854. 1: p. 284–288.

16Wissmann, R., U¨ ber Pilzkonkremente im Tra¨nenkana¨lchen, zugleich ein Beitrag zur Frage der Streptotrichen. Klin. Mbl. Augenheilkd., 1913. 51: p. 287–333.

17HoVmann, D.H., Ein Beitrag zur Aktinomycose der Tra¨nenro¨hrchen. Klin. Mbl., 1962. 140: p. 834–845.

18Coden, D.J., Fungal dacryocystitis. Ophthalmology, 1993. 100: p. 150.

19Busse, H., Personal communication, 1990.

20Purgason, P.A., A. Hornblass and M. LoeZer, Atypical presentation of fungal dacryocystitis. Ophthalmol., 1992. 99: p. 1430–1432.

21Ferry, A.P., Current review. Cerebral mucormycosis (phycomycosis). Ocular findings and review of literature. Surv. Ophthal., 1961. 6: p. 1–24.

22Thomas, J.V., W.R. Green and A. Garner, Fungus infections of the eye and periocular tissue. 1982: New York.

23Anderson, R.L., T.F. Carroll, J.T. Harvey and M.G. Myers, Petriellidium (Allescheria) boydii orbital and brain abscess treated with intravenous miconazole. Am. J. Ophthalmol., 1984. 97: p. 771–775.

24Nunery, W.R., M.G. Welsh and R.L. Saylor, Pseudallescheria boydii (Petriellidium boydii ) infection of the orbit. Ophthalmic Surg., 1985. 16: p. 296–300.

25Doorenbos-Bot, A.C.C., J.M.M. Hooymans and L.J. Blanksma, Periorbital necrotising fasciitis due to Cryptococcus neoformans in a healthy young man. Doc. Ophthalmol., 1990. 75: p. 315–320.

26Lehrer, R.I., D.H. Howard, P.S. Sypherd, J.E. Edwards, G.P. Segal and D.J. Winston, Mucormycosis. Ann. Int. Med., 1980. 93: p. 93–108.

27Blodi, F.C., F.T. Hannah and J.A. Wadsworth, Lethal orbito-cerebral phycomycosis in otherwise healthy children. Am. J. Ophthal., 1969. 67: p. 698–705.

28Schwartz, J.N., E.H. Donnelly and G.K. Klintworth, Review: Ocular and orbital phycomycosis. Surv. Ophthal., 1977. 22: p. 3–28.

29Parfrey, N.A., Improved diagnosis and prognosis of mucormycosis. Medicine, 1986. 65: p. 113–123.

30Ferry, A.P. and S. Abedi, Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis). Ophthalmol., 1983. 90: p. 1096–1104.

31Das, T., A. Gupta, V. Sakhuja, K. Gupta, M. Minz and K. Chugh, Ocular complications in renal allograft recipients. Nephrol. Dial. Transplant., 1991. 6: p. 649–655.

32Boelaert, J., A. Fenves and J. Coburn, Deferoxamine therapy and mucormycosis in dialysis patients. Report of an international registry. Am. J. Kidney Dis., 1991. 18: p. 660–667.

33Boelaert, J., J.V. Cutsem, M.D. Locht, Y. Schneider and R. Crichton, Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no eVect. Kidney Int., 1994. 45: p. 667–671.

34Sane, A., S. Manzi, J. Perfect, A. Herzberg and J. Moore, Deferoxamine treatment as a risk factor for zygomycete infection. J. Infect. Dis., 1989. 159: p. 151–152.

35McNab, A.A. and P. McKelvie, Iron overload is a risk factor for zygomycosis. Arch. Ophthalmol., 1997. 115: p. 919–921.

36Veis, J., R. Contiguglia, M. Klein, J. Mishell, A. Alfrey and J. Shapiro, Mucormycosis in deferox- amine-treated patients on dialysis. Ann. Intern. Med., 1987. 107: p. 258.

37Slade, M. and A. McNab, Fatal mucormycosis therapy associated with deferoxamine. Am. J. Ophthalmol., 1991. 112: p. 594–595.

38Sugar, A.M., Mucormycosis. Clin. Infect. Dis., 1992. 14(suppl 1): p. 126–129.

39Ammon, A., K.W. Rumpf, C.P. Hommerich, W. Behrens-Baumann and R. Ru¨chel, Rhinozerebrale Mucor-Mykose unter Deferoxamin-Therapie. Dtch. Med. Wschr., 1992. 117: p. 1434–1438.

40Johnson, E.V., L. Kline, B. Julian and J. Garcia, Bilateral cavernous sinus thrombosis due to mucormycosis. Arch. Ophthalmol., 1988. 106: p. 1089–1092.

41Gass, J.D.M., Ocular manifestations of acute mucormycosis. Arch. Ophthal., 1961. 65: p. 226–237.

42Rasse, M., O. Male and E. Knosp, U¨ ber rhinozerebrale Mykosen durch Mucorazeen-Arten (Mucormykosen). Wien. Klin. Wochenschr., 1990. 102: p. 395–403.

43Lee, B.L., G.N. Holland and B.J. Glasgow, Chiasmal infarction and sudden blindness caused by mucormycosis in AIDS and diabetes mellitus. Am. J. Ophthalmol., 1996. 122: p. 895–896.

44Downie, J., I. Francis, J. Arnold, L. Bott and S. Kos, Sudden blindness and total ophthalmoplegia in mucormycosis. A clinicopathological correlation. J. Clin. Neuroophthalmol., 1993. 13:

p.27–34.

45Centeno, R.S., J.R. Bentson and A.A. Mancuso, CT scanning in rhinocerebral mucormycosis and aspergillosis. Neuroradiology, 1981. 140: p. 383–389.

46Stefani, F.H. and P. Mehraein, Acute rhino-orbito-cerebral mucormycosis. Ophthalmologica, 1976. 172: p. 38–44.

47Qingli, L., J. Orcutt and L. Seifter, Orbital mucormycosis with retinal and ciliary artery occlusions. Br. J. Ophthalmol., 1989. 73: p. 680–683.

48Friedenwald, J.S., H.C. Wilder, A.E. Maumenee, T.E. Sander, J.E.L. Keyes, M.J. Hogan, W.C. Owens and E.U. Owens, Fungus Infection. 1952: W. Saunders Company.

49OhrloV, C. and E. Weigelin, Pilzerkrankungen des Auges und seiner Umgebung. Diagnostik, 1979. 12: p. 137–140.

50Luna, J., X. Ponssa, S. Rodriguez, N. Luna and C. Juarez, Intraconal amphotericin B for the treatment of rhino-orbital mucormycosis. Ophthalmic Surg. Laser., 1996. 27: p. 706–708.

51Rosenberger, R.S., B.C. West and J.W. King, Case report. Survival from sino-orbital mucormycosis due to Rhizopus rhizopodiformis. Am. J. Med. Sci., 1983. 286: p. 25–30.

52Editorial, Mucormycosis. Lancet, 1986. 14 i: p. 1362–1363.

53Langford, J., D. Cartney and R. Wang, Frozen section-guided surgical debridement for management of rhino-orbital mucormycosis. Am. J. Ophthalmol., 1997. 124: p. 265–267.

54Hale, L.M., Orbital phycomycosis. South Med. J., 1970. 63: p. 886–890.

55Ferguson, B., T. Mitchell, R. Moon, E. Camporesi and J. Farmer, Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev. Infect. Dis., 1988. 10: p. 551–559.

56Barnert, J., W. Behr and H. Reich, An amphotericin B resistant case of rhinocerebral mucor mycosis. Infection, 1985. 13: p. 48–50.

57Wilder, H.C. and M.J.H. Bickerton, Scientific exhibits. Organism identified in inflammatory lesions of eyes in the registry of ophthalmic pathology. Arch. Ophthal., 1955. 53: p. 575–584.

58Wadsworth, J.A.C., Ocular mucormycosis. Report of a case. Am. J. Ophthal., 1951. 34: p. 405– 409.

59Veirs, E.R. and C.T. Davis, Fungus infections of the eye and the orbit. Arch. Ophthal., 1958. 59:

p.172–176.

60Young, R.C., J.E. Bennett, C.L. Vogel, P.P. Carbone and V.T. deVita, Aspergillosis. Medicine, 1970.

49:p. 147–173.

61Hartwick, R.W. and J.G. Batsakis, Sinus Aspergillus and allergic fungal sinusitis. Ann. Otol. Rhinol. Laryngol., 1991. 100: p. 427–432.

62Sarti, E.J. and F.E. Lucente, Aspergillosis of the paranasal sinuses. Ear, Nose, Throat J., 1988. 67: p. 824–831.

63Levin, L., R. Avery, J. Shore, J. Woog and A. Baker, The spectrum of orbital aspergillosis. A clinicopathologial review. Surv. Ophthalmol., 1996. 41: p. 142–154.

64Waxman, J.E., J.G. Spector, S.R. Sale and A.L.A. Katzenstein, Allergic aspergillus sinusitis. Concepts in diagnosis and treatment of a new clinical entity. Laryngoscope, 1987. 97: p. 261–266.

65Allphin, A.L., M. Strauss and F.W. Abdul-Karim, Allergic fungal sinusitis. Problems in Diagnosis and Treatment. Laryngoscope, 1991. 101: p. 815–820.

66Dunlop, I.S. and F.A. Billson, Visual failure in allergic Aspergillus sinusitis. Case report. Br. J. Ophthalmol., 1988. 72: p. 127–130.

67Green, W.R., R.L. Font and L.E. Zimmerman, Aspergillosis of the orbit. Report of ten cases and review of the literature. Arch. Ophthal., 1969. 82: p. 302–312.

68Rowe-Jones, J.M. and V. Moore-Gillon, Destructive noninvasive paranasal sinus aspergillosis. Component of a spectrum of disease. J. Otolaryngol., 1994. 23: p. 92–96.

69Breadmore, R., P. Desmond and K. Opeskin, Intracranial aspergillosis producing cavernous sinus syndrome and rupture of internal carotid artery. Aust. Radiol., 1994. 38: p. 72–75.

70Heier, J.S., T.A. Gardner, M.J. Hawes, K.A. McGuire, W.T. Walton and J. Stock, Proptosis as the initial presentation of fungal sinusitis in immunocompetent patients. Ophthalmol., 1995. 102: p. 713–717.

71Brown, P., P. Demaerel, A. McNaught, T. Revesz, E. Graham, B.E. Kendall and G. Plant, Neuroophthalmological presentation of non-invasive Aspergillus sinus disease in the non-immunocom- promised host. J. Neurol. Neurosurg. Psych., 1994. 57: p. 234–237.

72Bodey, G.F. and S. Vartivarian, Aspergillosis. Eur. J. Clin. Microbiol. Infect. Dis., 1989. 8: p. 413–437.

73Stammberger, H., Functional endoscopic sinus surgery. 1991: Philadelphia.

74Houle, T.V.J. and P.P. Ellis, Aspergillosis of the orbit with immunosuppressive therapy. Surv. Ophthal., 1975. 20: p. 35–42.

75Chhabra, A., K.K. Handa, A. Chakrabarti, S.B.S. Mann and N. Panda, Allergic fungal sinusitis. Clinicopathological characteristic. Mycoses, 1996. 39: p. 437–441.

76Mauriello, J.A., N. Yepez, R. Mostafavi, J. Barofsky, R. Kapila, S. Baredes and J. Norris, Invasive rhinosino-orbital aspergillosis with precipitous visual loss. Can. J. Ophthalmol., 1995. 30: p. 124–130.

77Cahill, K.V., C.D. Hogan, S.L. Koletar and M. Gersman, Intraorbital injection of amphotericin B for palliative treatment of Aspergillus orbital abscess. Ophthalmic Plast and Reconstr Surg, 1994.

10:p. 276–277.

`

78 Lemoine, J.J., J. Le Rebeller and M.B. DArc, Ophtalmoplegie amaurotique a` bascule associee´ a` une aspergillose du sinus spheno´idal. Bull. Soc. Ophtalmol. Fr., 1984. 84: p. 787–790.

79 Krause, A.C. and W.G. Hopkins, Ocular manifestation of histoplasmosis. Am. J. Ophthal., 1951. 34: p. 564–566.

80 Spoor, T., W. Hartel, S. Harding and G. Kocher, Aspergillosis presenting as a corticosteroidresponsive optic neuropathy. J. Clin. Neuro-Ophthalmol., 1982. 2: p. 103–107.

81 Fernando, S. and C. Lauer, Aspergillus fumigatus infection of the optic nerve with mycotic arteritis of cerebral vessels. Histopathology, 1982. 6: p. 227–234.

82 Chang, W.J., Bilateral orbital involvement with massive allergic fungal sinusitis. Arch. Ophthalmol., 1996. 114: p. 767–768.

83 Freilich, T., Aspergilloma producing painful ophthalmoplegia. N. Y. State J. Med., 1986. 86: p. 27–28. 84 Kopp, W., R. Fotter, H. Steiner, F. Beaufort and H. Stammberger, Aspergillosis of the paranasal

sinuses. Radiology, 1985. 156: p. 715–716.

85 Stammberger, H., Zur Entstehung ro¨ntgendichter Strukturen bei Aspergillus-Mykosen der Nasennebenho¨hlen. Hno, 1985. 33: p. 62–64.

86 Krennmair, G., F. Lenglinger and H. Muller-Schelken, Computed tomography (CT) in the diagnosis of sinus aspergillosis. J. Craniomaxillofac. Surg., 1994. 22: p. 120–125.

87Austin, P., A. Dekker and J. Kennerdell, Orbital aspergillosis. Report of a case diagnosis by fine needle aspiration biopsy. Acta Cytopathol., 1983. 27: p. 166–169.

88Maniglia, A.J., F.G. Kronberg and W. Culbertson, Visual loss associated with orbital and sinus diseases. Laryngoscope, 1984. 94: p. 1050–1062.

89Rowe-Jones, J.M. and A.R. Freedman, Adjuvant itraconazole in the treatment of destructive sphenoid aspergillosis. Rhinology, 1994. 32: p. 203–207.

90Yumoto, E., S. Kitani, H. Okamura and N. Yanagihara, Sino-orbital aspergillosis associated with total ophthalmoplegia. Laryngoscope, 1985. 95: p. 190–192.

91Harris, G.J and B.R. Will, Orbital aspergillosis, conservative debridement and local amphotericin irrigation. Ophthal. Plast. Reconstr. Surg., 1989. 5: p. 207–211.

92Dortzbach, R.K. and D.R. Segrest, Orbital aspergillosis. Ophthalmic Surg., 1983. 14: p. 240–244.

93Denning, D.W., Treatment of invasive aspergillosis. J. Infection, 1994. 28 Suppl. 1: p. 25–33.

94Massry, G.G., A. Hornblass and W. Harrison, Itraconazole in the treatment of orbital aspergillosis. Ophthalmol., 1996. 103: p. 1467–1470.

95Jacobson, M., S.L. Galetta, S.W. Atlas, M.T. Curtis and A.W. Wulc, Bipolaris induced orbital cellulitis. J. Clin. Neuro-Ophthalmol., 1992. 12: p. 250–256.

96Manning, S.C., S.D. Schaefer, G. Close and F. Vuitch, Culture-positive allergic fungal sinusitis. Arch. Otolaryngol. Head Neck Surg., 1991. 117: p. 174–178.

97Klapper, S., A. Lee, J. Patrinely, M. Stewart and E. Alford, Orbital involvement in allergic fungal sinusitis. Ophthalmol., 1997. 104: p. 2094–2100.

98Bartynski, J., T. McCaVrey and E. Frigas, Allergic fungal sinusitis secondary to dermatiaceous fungi – Curvularia lunata and alternaria. Otolaryngol. Head Neck Surg., 1990. 103: p. 32–39.

99Brummund, W., V.P. Kurup, G.J. Harris, J.A. Duncavage and J.A. Arkins, Allergic sino-orbital mycosis. JAMA, 1986. 256: p. 3249–3253.

100Rodenbiker, H.T. and J.P. Ganley, Review. Ocular coccidioidomyces. Surv. Ophthal., 1980. 24:

p.263–290.

101Vida, L. and S. Moel, Systemic North American blastomycosis with orbital involvement. Am. J. Ophthalmol., 1974. 77: p. 240–242.

102Olurin, O., A. Lucas and A. Oyediran, Orbital histoplasmosis due to Histoplasma duboisii . Am. J. Ophthalmol., 1969. 68: p. 14–18.

103Morriss, F.H. and A. Spock, Intracranial aneurysm secondary to mycotic orbital and sinus infection. Report of a case implicating Penicillium as an opportunistic fungus. Am. J. Dis. Child, 1970. 119:

p.357–362.

104Persaud, V. and J.B.M. Holroyd, Mycetoma of the palpebral conjunctiva. Br. J. Ophthal., 1968. 52:

p.857.

105Timm, G., Die Histologie der Lidaspergillose. Ophthalmologica, 1963. 146: p. 250–259.

106Harrell, E.R. and A.C. Curtis, North American blastomycosis. Am. J. Med., 1959. 27: p. 750–766.

107Noojin, R.O. and H.B. Praytor, Systemic blastomycosis complicated with pregnancy. Report of a case, with clinical immunologic reactions. J. Am. Med. Assoc., 1951. 147: p. 749–751.

108Kreibig, W., Beiderseitige metastatische Ophthalmie durch Blastomyzeten. Klin. Mbl. Augenheilk., 1940. 104: p. 64–77.

109Barr, C.C. and J.W. Gamel, Blastomycosis of the eyelid. Arch. Ophthalmol., 1986. 104: p. 96–97.

110Bongiorno, F.J., U.W. Leavell and J.D. Wirtschafter, The black dot sign and North American cutaneous blastomycosis. Am. J. Ophthalmol., 1974. 78: p. 145–147.

111Ostler, H.B. and M.W. Ostler, Diseases of the eyelid and lid margin. 1993: Williams & Wilkins.

112Roth, H.W., Pilzinfektionen der Lider bei Immundefekt eines Kontaktlinsentra¨gers. Augenspiegel, 1998. 6: p. 62.

113Belfort Jr, R., O. Fischmann, Z.P.D. Camargo and A. Almada, Paracoccidioidomycosis with palbreal and conjunctival involvement. Mycopathologia, 1975. 56: p. 21–24.

114de Moraes Silva, M.R.B., R.P. Mendes, J.C. Lastoria, B. Barraviera, S.A. Marques and A. Kamegasawa, Paracoccidiodioidomycosis. Study of six cases with ocular involvement. Mycopathologia, 1988. 102: p. 87–97.

115Romano, A., E. Segal and M. Blumenthal, Canaliculits with isolation of Pityrosporum pachydermatis. Br. J. Ophthalmol., 1978. 62: p. 732–734.

116Duggan, J.N., A case of Rhinosporidium kinealyi . Br. J. Ophthal., 1928. 12: p. 526–530.

117Kuriakose, E.T., Oculosporidiosis. Rhinosporidiosis of the eye. Br. J. Ophthal., 1963. 47: p. 346–349.

118Sharma, K.D., J.B. Shrivastav and S. Agarwal, Ocular rhinosporidiosis simulating a tumour. Br. J. Ophthal., 1958. 42: p. 572–574.

119Gupta, O.P., Unusual extranasal manifestations of rhinosporidiosis. Laryngoscope, 1966. 76: p. 1842– 1849.

120Hill, H.F., Sporothrix infection of the eye and adnexa. Trans. Am. Acad. Ophthalmol. Otolaryngol., 1930. 35: p. 128–139.

121GiVord, S.R., Ocular sporotrichosis. Arch. Ophthal., 1922. 51: p. 540–547.

122Wirtz, Ein Lidulkus durch Trichophytieerreger. Klin. Mbl. Augenheilkd., 1922. 68: p. 384–385.

123Ostler, H.B., M. Okumoto and C. Halde, Dermatophytosis aVecting the periorbital region. Am. J. Ophthalmol., 1971. 72: p. 935–938.

124BrinckerhoV, A.J., Actinomycosis of the inferior lacrimal canaliculus. Am. J. Ophthal., 1942. 25:

p.978–981.

125Fo¨rster, Pilzmassen im unteren Tra¨nencana¨lchen. Arch. Ophthal., 1869. 15: p. 318–323.

126Graefe, A.v., Ein Fall von Pilzbildung im unteren Thra¨nenro¨hrchen. Arch Ophthal., 1856. 2: p. 224– 227.

127Graefe, A.v., U¨ ber Leptothrix in den Thra¨nenro¨hrchen. Arch. Ophthal., 1869. 15: p. 324–344.

128Gru¨ter, W., Eine Pilzgeschwulst (Aktinomykose) im oberen Tra¨nenro¨hrchen (Actinomyces discofoliotus). Z. Augenheilkd, 1933. 79: p. 477–510.

129Kipp, C., A case of tearstone in the canaliculus of the lower eyelid. Med. Rec., 1883. 24: p. 289–290.

130Mu¨ller, F., Krankheiten der Tra¨nenorgane. 1960: Leipzig.

131Pine, L., W.A. Shearin and C.A. Gonzales, Mycotic flora of the lacrimal duct. Am. J. Ophthal., 1961. 52: p. 619–625.

132Pine, L. and H. Hardin, Actinomyces israelii , a cause of lacrimal canaliculitis in man. J. Bact., 1959. 78: p. 164–170.

133Richards, W.W., Actinomycotic lacrimal canaliculitis. Am. J. Ophthal., 1973. 75: p. 155–157.

134Savir, H., E. Henig and N. Lehrer, Exogenous mycotic infections of the eye adnexa. Ann. Ophthalmol., 1978. 10: p. 1013–1018.

135Thies, O., Aktinomyces des Sehorgans. Klin. Mbl. Augenheilkd., 1931. 86: p. 55–58.

136Donahue, H.C., Unusual mycotic infection of the lacrimal canaliculi and conjunctiva. Am. J. Ophthalmol., 1949. 32: p. 207–210.

137Rosenvolt, L.K., Dacryocystitis and blepharitis due to infection by Aspergillus niger. Report of a case. Am. J. Ophthal., 1942. 25: p. 588–589.

138Kristinsson, J. and H. Sigurdsson, Lacrimal sac plugging caused by Aspergillus fumigatus. Acta Ophthalmol. Scand., 1998. 76: p. 241–242.

139Salah, M.E.-D., Aspergillus niger infection of the eye. Am. J. Ophthal., 1966. 62: p. 204–205.

140Brightbill, F.S. and L.K. Fraser, Unilateral keratoconjunctivitis. Arch. Ophthalmol., 1974. 91:

p.421–422.

141Ostler, H.B. and M.W. Ostler, Fungal ocular infections diseases of the external eye and adnexa. 1993: Williams & Wilkins.

142Bosniak, S., Principles and practice of ophthalmic plastic and reconstructive surgery. 1996: Saunders.

143Brownlie, W.B., A case of infection of the lacrymal sacs, maxillary antra, pharynx, tonsils, mouth and parotid glands caused by Blastomyces albicans (thrush organism). Rhinol. Otol., 1919. 34: p. 425–431.

144Buesseler, J.A. and I.D. Godwin, Chronic dacryocystomycosis due to Candida parakrusei . Trans. Am. Acad. Ophthal., 1963. 67: p. 173–176.

145Hanssens, M., M. Rysselaere and F. Domen, Candida parapsilosis associated with dacryoliths in obstructive dacryocysitis. Bull. Soc. Belge Ophtalmol., 1982. 201: p. 71–81.

146Fine, M. and W.S. Waring, Mycotic obstruction of the nasolacrimal duct Candida albicans. Arch. Ophthalmol., 1947. 38: p. 39–42.

147Brook, I. and E. Frazier, Aerobic and anaerobic microbiology of dacryocystitis. Am. J. Ophthalmol., 1998. 125: p. 552–554.

148Newton, J.C. and C.B. Tulevech, Lacrimal canaliculitis due to Candida albicans. Am. J. Ophthalmol., 1962. 53: p. 933–936.

149Wolter, J.R., T. Stratford and E.R. Harrell, Cast-like fungus obstruction of the nasolacrimal duct. Report of a case. Arch. Ophthal., 1956. 55: p. 320–322.

150Wolter, J.R. and M.R. Deitz, Candidiasis of the lacrimal sac. Am. J. Ophthal., 1963. 55: p. 153–155.

151Buogo, A. and V. Renna, Un caso di micosa da cryptococcus neoformans di interesse oftalmologico. Boll. Oculist., 1963. 42: p. 620–629.

152Wolter, J.R., Pityrosporum species associated with dacryoliths in obstructive dacryocystitis. Am. J. Ophthal., 1977. 84: p. 806–809.

153Wright, R.E., Rhinosporidium kinealyi of the conjunctiva. Ind. Med. Gazette, 1922. 17: p. 6–7.

154Karunaratne, W.A.E., The pathology of rhinosporidiosis. J. Pathol. Bacteriol., 1936. 32: p. 193–202.

155Kirkpatrick, H., Rhinosporidium of the lacryma. Ophthalmoscope, 1916. 14: p. 477–479.

156Fazakas, A., Sporotrichose des unteren Tra¨nenkana¨lchens. Klin. Mbl. Augenheilkd., 1936. 96:

p.227–230.

157Bergaust, B., Obstruction of the lacrimal passage due to Trichophyton rubrum infection. Report of

acase. Acta Ophthal., 1965. 43: p. 708–713.

158Jou, J.R., S. Patel, C. Yo and A.A. Sadun, Orbital coccidioidomyosis presenting as a lacrimal gland fossa mass. Br. J. Ophthalmol., 1995. 79: p. 1145–1146.

159Berry, A.J., T.M. Kerkering, A.M. Giordano and J. Chiancone, Phaeohyphomycotic sinusitis. Ped. Infect. Dis., 1984. 3: p. 150–152.

160Morax, V., Fa¨lle von Mykosen des Augenapparates. Ber. Dtsch. Ophthal. Ges., 1910. 36: p. 330–333.

161Johnson, T., R. Casiano, J. Kronish, D. Tse, M. Meldrum and W. Chang, Sino-orbital aspergillosis in acquired immunodeficiency syndrome. Arch. Ophthalmol., 1999. 117: p. 57–64.