In our comprehensive study of ROCM, a striking pattern emerged regarding the underlying health conditions of the patients. Out of the 77 individuals diagnosed with ROCM, a predominant majority of 64 patients were suffering from DM, reinforcing the established link between uncontrolled DM and increased vulnerability to this fungal infection. Although patients with ROCM infection had higher random blood sugar (RBS) levels at presentation, Sharma.et al. did not find the correlation between higher RBS and poorer outcome in terms of mortality. But they found a statistically significant association between higher RBS levels at the time of presentation and higher staging of ROCM¹². COVID-19 has been shown to significantly disrupt immune cell functions and even increase glycemic level and cause uncontrolled DM¹³. In another study of mucormycosis in the Iranian population, the average time between COVID-19 infection and the diagnosis of CAM was found to be less than one month¹⁴. Specifically, COVID-19 can lead to an expansion of immature and dysfunctional neutrophil populations, characterized by altered surface marker expression and activation features. This phenomenon may contribute to the hyper inflammatory response observed in severe cases^15,16.

Orbital involvement may lead to destruction of the ophthalmic artery and optic nerves resulting in ptosis of the eyelid, proptosis, vision disturbances and blindness. In a large retrospective study from India (19%) patients presented with vision loss¹⁷. In our recent study on common symptoms and signs of ROCM, we found that 64.9% of cases exhibited complete ptosis, while 57% showed impaired extraocular muscle movement and a condition informally referred to as ‘frozen eye’. The degree of ocular motility impairment correlated with extensive orbital involvement and the likelihood of orbital exenteration. Interestingly, although the mortality rate was higher in cases with ‘frozen eye,’ this correlation did not reach statistical significance, possibly due to the limited number of cases.

ROCM initially manifests with facial pain, nasal congestion, local tenderness, fever, and discolored discharge (bloody/brown/black). Subsequently, patients may develop an eschar over the nasal mucosa or skin, chemosis (conjunctival swelling), proptosis, and palate perforation. The infection can spread transneuronally, affecting individual cranial nerves (such as the 2nd, 5 th, and 7 th cranial nerves). This progression can lead to orbital apex syndrome, thrombosis in cavernous sinus, and involvement of multiple cranial nerves. Additionally, central retinal artery occlusion or posterior ischemic optic neuropathy may contribute to optic nerve damage in ROCM¹⁸. In our follow up, we observed periorbital swelling in 74%, periorbital pain in 57%, conjunctival chemosis in 36%, and a notably high incidence of necrosis in the mouth and nasal mucosa at 76%. This high prevalence of necrosis differs from previous studies where it was less common and associated with late-stage disease and increased mortality¹⁹. Commonly, necrotic mucormycosis begins in the nasal lining, turbinate, or palate, and then extends to the paranasal sinuses. It can potentially reach the retro-orbital area by infiltrating through the ethmoid sinus. Initially originating in the nasal passages, the infection advances toward the paranasal sinuses and orbital region. If it invades the orbit, there is a risk of further progression into the CNS. It has been suggested that the fungi may initially invade the anterior ethmoidal sinus without causing noticeable symptoms until reaching the orbital region. Additionally, the disease can penetrate intracranially by breaching the thin cribriform plate or orbital roof. In our follow up, especially in the first 6 months, we observed a high incidence of neurologic signs such as headaches (78.6%) and loss of consciousness requiring ICU admission and intubation (17.1%). However, it’s important to note that these signs cannot be exclusively attributed to ROCM, as the majority of our cases were also infected with COVID-19. COVID-19 can cause systemic illness affecting various body parts, including pulmonary involvement that may necessitate ICU care.

Regarding the extension of intraorbital and intracranial disease in our patients, CT and MRI imaging contribute to diagnosis and determine disease extension. Radiological assessments have revealed several characteristic findings. These include signs of sinusitis, such as thickened mucosa and opacification of the paranasal sinuses, as well as the presence of air-fluid levels. Additionally, imaging has identified orbital invasion, cavernous sinus thrombosis, infiltration of the internal carotid artery, cerebritis, cerebral infarction, thrombosis of surface veins and dural venous sinuses, mycotic aneurysms, subarachnoid hemorrhage, and abscess formation¹⁸. Other radiologic features of ROCM was showed that the maxillary sinus was the most commonly affected PNS (96.2%).²⁰In our center, consistent paranasal inflammation was observed in all patients. The ethmoid sinuses were most frequently affected (97.9%). Among the extra sinus sites, retro antral soft tissue (89.6%) and the orbital cavity (87.5%) showed frequent involvement. Notably, dacryocystitis occurred in 50% of cases, while optic nerve inflammation was present in 43.2%. Globe involvement was noted in 18.9%, and trigeminal nerve participation occurred in 16% of patients. Remarkably, inflammation extended into the cavernous sinuses and alongside the internal carotid arteries in 24% of cases²¹. Other studies have also observed the intracranial extension of ROCM. While various routes exist for fungal invasion into the intracranial space, the pterygopalatine space frequently serves as the primary entry point. Subsequently, the infection can propagate to the orbital and facial soft tissues, eventually reaching the retro-globular area of the orbit via the inferior orbital fissure. This progression often manifests in ocular symptoms^{22,23,24,25,26}. This pattern of pterygopalatine involvement and also high prevalence of mucosal necrosis at the time of disease diagnosis may be linked to the high prevalence of COVID-19 infections among our cases.

Early signs of cavernous sinus involvement, such as double vision and ophthalmoplegia, may occur before visible changes on diagnostic imaging. The fungus enters posteriorly through the optic foramen, causing swelling, inflammation, and damage to the optic nerves and ophthalmic artery. As a result, orbital apex syndrome can manifest with chemosis, eyelid drooping, eye bulging, vision loss, and potential blindness^22,27,28.

Our follow up data demonstrated that, due to fungal extension to the orbital apex, there was a significant occurrence of NLP vision loss, positive RAPD, optic disc pallor and retinal vessel occlusion. Additionally, over half of our patients experienced restricted eye movement or ‘frozen eye’ due to orbital apex and cavernous sinus involvement. Trigeminal nerve involvement also indicated intracranial spread. Notably, our findings revealed that patients with an intact V1 nerve during the study period had a twofold higher chance of survival compared to those with impaired V1 nerve function. Additionally, patients with intact V2 nerve sensation had a fourfold higher survival chance therefore, the involvement of the V2 nerve had a statistically borderline association with mortality rates, with higher mortality observed in cases with impaired V2 function. Our study’s analysis of the impact of cranial nerve involvement on survival is unprecedented, as no previous studies have examined this aspect. This phenomenon could potentially be associated with the transneural spread of the disease, indicating more widespread involvement.

In previous report, 96.7% of patients exhibited gingival and palatal abscesses, while 63.3% had palatal ulceration²⁹. In our study, we observed a high incidence of nasal discharge and obstruction, present in nearly all cases, along with toothache reported by almost 70% of patients. Notably, the predominant presenting symptom in our cohort was prolonged, persistent toothache, often without any accompanying symptoms or signs.

Effective management of ROCM centers around several key strategies. The management of COVID-19-associated mucormycosis (CAM) presents significant challenges, compounded by the rapid mutations of the COVID-19 virus and the limited knowledge available for treating mucormycosis, traditionally considered a rare infection^{2,28,30,31,32}. Meticulous management of DM and its associated complications is paramount in mitigating the risk and impact of ROCM infections. In previous cases of ROCM, 80% of patients received medical treatment with Amphotricine B and other Azole drugs besides the surgical debridement and sinus surgery^18,20,33,34. The current recommendations consider that liposomal amphotericin B plus surgical debridement are the first options for the treatment of mucormycosism while isavuconazole and posaconazole are considered the second option therapy^{2,27,30,35,36}.

High mortality is often associated with initial CNS involvement, and delayed diagnosis and treatment in ROCM can result in facial necrosis, bilateral sinus affliction, and hemiparesis^22,25. Delaying the initiation of treatment by more than 6 days can lead to a twofold increase in mortality rates at 12 weeks. However, early, aggressive surgical management combined with high-dose systemic antifungal therapy has been associated with a 1.5-fold increase in survival rates¹⁸. Endoscopic sinus surgery is beneficial for patients with localized disease, offering low morbidity³⁶. COSMIC study showed Surgical debridement of the paranasal sinus and orbit led to a reduction in mortality rates from 52 to 39% in patients with advanced ROCM¹⁸.

We employed intravenous amphotericin B as the primary medical treatment for all cases and performed FESS as the surgical intervention in all patients. Notably, due to the extensive disease observed in our cases, particularly those who tested positive for COVID-19 by PCR, the utilization of additional oral antifungal therapy was remarkably high, reaching 90% of cases.

There are several previous studies which uses the transcutaneous retrobulbar amphotericin B for treatment of intraorbital extension of ROCM^23,24,37. These injections should be considered as an adjuvant therapy for ROCM to reduce disease progression as well as to preserve globe or sight. It has a promising role in preventing potential orbital and central nervous system exenterations³⁷.

We administered retrobulbar liposomal amphotericin B (1 mililiter from concentration of 3.5 mg/mL) as an adjunct therapy in 76.7% of cases over a 3-day period. Notably, there was a 26% improvement in V/A post-treatment and long term follow up. While this improvement aligns with our findings, it’s essential to consider the multifaceted treatment approach. Simultaneously combining medical amphotericin and azole therapy with FESS alongside retrobulbar injections makes it challenging to isolate the specific impact of retrobulbar injections on visual outcomes. However, early use of these injections, in conjunction with other therapeutic approaches, appears to enhance visual results. Unfortunately, patients with NLP vision at the study’s outset did not experience any improvement in vision.

In the line of previous study, our study, analysis revealed that glycemic levels and DM were not statistically associated with increased mortality rates. However, consistent with prior research, these factors were correlated with a greater extent of orbital disease and a higher incidence of orbital exenteration.

Among the 35 patients with NLP vision, seven underwent orbital exenteration within 2 months of study initiation due to the severity and progression of orbital involvement. Remarkably, there was a significant correlation between NLP vision and the rate of orbital exenteration. NLP vision often resulted from central retinal vessel and optic nerve involvement, which are indicative of orbital apex disease. Mortality was higher in patients presenting with initial V/A of NLP. Patients presenting with visual acuity greater than NLP at the time of diagnosis have a twofold increase in survival chances. However, NLP vision did not statistically correlate with mortality rates. Other factors, such as comorbidities like COVID-19, may have independently influenced mortality outcomes.

We observed that orbital exenteration as part of treatment protocols in some patients, played a crucial role in preventing mortality. All patients who underwent orbital exenteration survived during the 3-year follow-up period, even in cases of extensive orbital involvement. Research on ROCM patients in Peru demonstrated that survival analysis indicated a reduced likelihood of survival for those who did not undergo surgical intervention³⁸.

In our 3-year follow up, overall mortality rate was 44%, aligning with previous research about ROCM was done in Iran²⁵; Similar survival rates were reported a 40% survival rate in other studies on COVID-19 and ROCM^22,25. Mortality rates vary in the literature. The fatality rate of cases with ROCM are less than the other forms of mucormycosis systemic involvement³⁹. This is likely the result of the different forms of the disease, the challenging diagnosis, especially for pulmonary mucormycosis, and the association with either mild, moderate or severe COVID-19, which also affects mortality. In Europe, mortality ranges from 53.8 to 88%. But overall, the conclusive data on mucormycosis-related mortality are lacking in the literature and follow up periods are somehow short.[75] Delay in diagnosis may be an important prognostic factor related to the mortality.[75] Also, a shorter duration of antifungal therapy was linked to decreased patient survival. All patients who underwent orbital exenteration due to extensive orbital disease in our study survived during the 3-year follow-up period. Despite the aggressive nature of exenteration, these findings underscore the importance of timely and aggressive surgical intervention in patients with extensive orbital and intracranial involvement to enhance survival rates, particularly in developing countries. Our findings on the impact of orbital exenteration on survival diverged from a prior study conducted in India. The earlier study, using Kaplan-Meier survival analysis, indicated no survival advantage of exenteration at 3 and 6 months for CAM. This discrepancy might be attributed to a smaller sample size, a shorter follow-up period, or variations in postoperative care⁴⁰. The 10-year cohort study demonstrated that tailored surgical management of ROCM based on the impacted structures is crucial. This approach not only enhances patient survival but also takes into account aesthetic and functional outcomes⁴¹.

However, it is difficult to determine the exact mortality rate of the COVID-19-related ROCM because the death might be due to other complications of COVID-19 in certain patients.[77].

Our study stands out due to its comprehensive 3-year follow-up of patients during the outbreak of ROCM in the context of the COVID-19 pandemic. Obtaining data from patients’ medical records posed challenges due to the majority being in the red zone of COVID-19-related hospitals, receiving oxygen therapy, or intubated. Consequently, gathering a comprehensive history and conducting physical examinations proved difficult, leading to incomplete information in the patient case sheets and missed cases of ROCM.