Mucormycosis is a multisystemic, aggressive and an opportunistic fatal fungal infection caused by the fungi
Mucormycetes and class
Mucorales. The common forms of mucormycosis are rhino-orbito-cerebral (ROC), pulmonary, cutaneous, gastrointestinal, disseminated, and isolated renal mucormycosis. Among these, the most common type is ROC mucormycosis (ROCM) accounting for almost 40% of the cases [
1-
3]. The most common route of infection is by invasion from the adjacent paranasal sinuses or direct traumatic inoculation into the orbit. After the fungal colonization in the sinonasal mucosa, it enters the orbit through the ethmoid and maxillary sinuses or via the nasolacrimal duct, and spread towards the brain occurs either through ophthalmic artery, superior orbital fissure, or via cribriform plate. The spread of the infection to the frontal lobes and to the cavernous sinus occurs via perivascular and perineural channels through the cribriform plate and the orbital apex [
4,
5].
Discussion
DM is the most common risk factor for mucormycosis accounting for 60% to 80% of the reported cases of mucormycosis worldwide. Other predisposing conditions include DKA, immunosuppressive therapy, chronic renal failure, cirrhosis, hematological malignancies, solid organ transplantation, and HIV infection [
11,
12]. In our study, DM was seen in 51 of 52 patients (98.1%), DKA in 15 of 52 patients (28.8%), renal involvement in 14 of 62 patients (26.9%), and hepatic failure in four of 52 patients (7.7%). However, none of the patients that were diagnosed and treated at our center as orbital mucormycosis during the current study period had hematological malignancy or organ transplantation as risk factors. This is unlike few other studies where these risk factors were noted as frequently as DM [
6,
13]. Similar to this study, Kashkouli et al. [
14] had reported type 1 DM, type 2 DM, and renal failure in 10 (15.9%), 33 (52.4%), and two of 63 cases (3.2%), respectively. In another study by Yohai et al. [
15] DM, DKA, and renal disease was present in 87 (60%), 43 (30%), and 21 of 145 cases (14%), respectively. Uncontrolled blood sugars at presentation, in fact, was a factor associated with poor treatment outcome on both univariate analysis and logistic regression analysis in this study. Control of blood sugar levels is, therefore, very essential for successful treatment of a case of orbital mucormycosis.
The signs and symptoms of ROCM depend upon the route of entry and the involved structures. Initial presentation may be in the form of loss of vision or nerve palsy causing restriction of extraocular movements and diplopia followed by ptosis, proptosis, internal ophthalmoplegia, and CRAO. Intracranial spread may cause severe headache, altered sensorium, and finally death [
11,
16-
18]. Ocular findings seen in this study were conjunctival chemosis (94.2%), proptosis (82.7%), ptosis (76.9%), restriction of extraocular movements (76.9%), RAPD (55.8%), exposure keratitis (48.1%), NPL vision at presentation (42.3%), neurotrophic keratitis (21.5%), CRAO (30.8%), proliferative DR (17.3%), and nonproliferative DR (23.1%). In the study by Bhansali et al. [
19], where 35 cases were studied, the ocular features noted were ophthalmoplegia (89%), proptosis (83%), loss of vision (80%), chemosis (74%), periorbital swelling (66%), CRAO (20%), etc. Kashkouli et al. [
14] studied 63 cases, and the reported ocular features include proptosis (39.2%), extraocular movement abnormality (83.5%), frozen eye (55.7%), loss of vision (24.1 %), etc. The duration of ocular symptoms at initial presentation also served as a predictor for poor treatment outcome on univariate analysis in our study. Delay in diagnosis and treatment was noted to be associated with poor patient survival in prior studies as well [
15,
19].
Presence of ptosis, RAPD, CRAO, NPL vision at presentation, and conjunctival chemosis were all significantly associated with poor treatment outcome on univariate analysis. On logistic regression analysis, NPL vision at presentation (aOR, 10.67), conjunctival chemosis (aOR, 7.11), and RAPD (aOR, 10.60) maintained significant association with poor treatment outcome. Presence of these ocular features at presentation may serve as predictors of poor treatment outcome. The current study, therefore, identifies these ocular features as predictors that may herald worsening of the systemic disease and, thereby, determine the need for more aggressive treatment in such cases. In the study by Kashkouli et al. [
14], frozen eye (OR, 4.6) was associated with poor outcome on multivariate analysis. In the study by Bhansali et al. [
19], presence of eyelid gangrene (
p < 0.05) was related to poor survival.
CECT and magnetic resonance imaging are both invaluable tools for diagnosing and assessing the disease progression in ROCM [
20]. Maxillary sinus (84.61%) followed by ethmoidal sinus (75%) were the two most affected sinuses in our study population—findings similar to the study by Abdollahi et al. [
21]. In the study by Kashkouli et al. [
14], ethmoidal sinus (74.6%) was most commonly affected followed by the maxillary sinus (68.3%). Two or more sinuses were involved in 63.3% of cases in their study but this was not associated with poor treatment outcome. In contrast, 39 patients (75%) in our study had two or more sinuses involved on radiological imaging and this was a significant factor for poor treatment outcome in both univariate analysis (OR, 4.22) and logistic regression analysis (aOR, 4.90). Radiological findings can, therefore, serve as predictors of severe disease and guide the treatment course.
Vision survival was noted in 38.5% of patients and globe survival in 52.0% of patients in our study. Vision loss in ROCM can result from either CRAO, exenteration, or cavernous sinus thrombosis [
3-
5]. In our study, 16 patients had CRAO, and seven patients had cavernous sinus thrombosis. CRAO was associated with poor treatment outcome on univariate analysis which, however, lost significance on logistic regression analysis. Indications of orbital exenteration include progressive disease with proptosis, cranial nerve involvement, CRAO, etc. [
5,
14,
22-
24]. Exenteration can improve patient survival in cases with intracranial extension and rapid progression. However, survival may not improve if the patients already have aggressive disease prior to exenteration [
25,
26]. In this study, five patients needed exenteration and globe survival was noted in 26 of total 31 patients that completed full course of medical treatment. We could not analyze the factors associated with globe survival or vision survival in our study. In the study by Kashkouli et al. [
14], higher white blood cell count was the only factor that was found to be associated with the need for exenteration. No other studies have evaluated the factors affecting vision and globe survival. Future prospective studies may, therefore, be planned to determine the factors that can affect the vision and globe survival in ROCM. Our current study showed a patient survival rate of 59.6%, which is comparable to the survival rates—73.3%, 70%, 57%—of the studies done by Abdollahi et al. [
21], Roden et al. [
6], and Kashkouli et al. [
14], respectively. However, one important aspect to be considered here is that the early stage I of the disease was not included in our study which has affected the survival rate in this study. More advanced diseases, stage II and stage III with poorer survival rates, were included in the study. Prompt diagnosis, early initiation of treatment with systemic antifungals and surgical debridement of the sinuses are the key steps to a higher survival rate in ROCM.
Strength of our study lies in its large sample size. Only few prior studies had equivalent or more sample size [
14,
15]. Also, the current study analyzed and identified ocular and radiological features as predictors of aggressive systemic disease and poor treatment outcome. One limitation of the study is the retrospective study design. However, ROCM being a rare and aggressive disease, patient recruitment and follow-up may be difficult for a prospective study design.
Patient survival, globe survival, and vision survival were 59.6%, 52.0%, and 38.5%, respectively in this study. DM was the most common underlying systemic disease. High blood sugar at presentation, NPL vision at presentation, ptosis, conjunctival chemosis, RAPD, bony erosion of orbital wall, and two or more sinus involvement were the major predictors for poor treatment outcome.