Rhino-orbital-cerebral mucormycosis (ROCM) is an invasive fungal infection caused by fungi of the order Mucorales, particularly Rhizopus oryzae. It is a fatal disease that rapidly progresses from the paranasal sinuses to the orbit and brain, and was previously called orbital zygomycosis. It was first described by J.E. Gregory in 19431).
Rhizopus species account for approximately 85–90% of rhinocerebral cases. The estimated annual incidence is 1.7 per million people8), and in India, the incidence is reported to be 80 times higher than in developed countries9). In Europe, the incidence is reported as 0.2–3 per million4). The overall mortality rate exceeds 50%, reaching 79% without treatment and approximately 40.5% with treatment. Central nervous system involvement occurs in 33–49% of diabetic patients with poor glycemic control8).
Although rare, the mortality rate is high, with a reported mortality rate of 94% for the invasive form of fungal sinusitis. Since the COVID-19 pandemic, cases have increased rapidly, especially in India6).
The estimated annual incidence is 1.7 per million people8). In India, the incidence is reported to be 80 times higher than in developed countries, showing significant regional variation. The risk of developing the disease is markedly increased in patient populations with diabetes, hematologic malignancies, or immunodeficiency.
May worsen rapidly within 1–2 days.
Characteristic ocular and systemic findings appear as the disease progresses.
Sinus Stage (Early)
Black eschar: A characteristic finding observed on the sinus mucosa, nasal turbinates, and palatal mucosa.
Involvement of the maxillary and ethmoid sinuses: These are the most frequently involved sites.
Necrosis without hyperemia is characteristic, differing from typical infections.
Orbital Extension Stage
Proptosis: Reported in 64–83% of cases.
Extraocular muscle palsy to frozen globe: The most frequently reported ocular sign.
Ptosis, eyelid edema, eyelid gangrene: Reflect progression of inflammation and necrosis.
Cerebral Extension Stage
Orbital apex syndrome (OAS): Accompanied by frozen globe, suggesting extensive cranial nerve involvement. High mortality.
Cavernous sinus thrombosis: Due to impaired venous drainage.
Central retinal artery occlusion (CRAO): Cherry-red spot on the fundus.
In all cases of COVID-19-associated ROCM, CRAO, proptosis, and complete ophthalmoplegia were observed, and the prognosis was extremely poor (all cases died) 3).
Fungi of the order Mucorales, especially Rhizopus oryzae, are the main causative organisms. They are fast-growing, aseptate filamentous fungi, widely distributed in tropical and subtropical regions. They enter the body through inhalation of spores.
Cases of ROCM after COVID-19 infection have increased rapidly worldwide, with 2,826 cases reported in India in 2021 alone 6). The cytokine storm, immune abnormalities, steroid use, and hyperglycemia caused by COVID-19 are thought to synergistically promote fungal growth.
Biopsy and culture are the gold standard for definitive diagnosis. Histopathology uses H&E staining, PAS staining, and GMS staining, and characteristic findings include broad, ribbon-like, nonseptate hyphae branching at right angles (90 degrees), vascular invasion, thrombosis, and necrosis 2). Species identification by culture is also important for selecting treatment, but the culture positivity rate is low. Definitive diagnosis is made by demonstrating the organism through histopathological examination or culture.
DNA sequences of Rhizopus species can be detected in cerebrospinal fluid. Positivity was reported in all 7 cases (all cultures were negative), and it is particularly useful when conventional methods are negative.
The characteristics of the diagnostic methods are shown below.
| Test method | Features | Cautions |
|---|---|---|
| Biopsy + culture | Gold standard for definitive diagnosis | Low culture positivity rate |
| mNGS (cerebrospinal fluid) | Detectable even in culture-negative cases | Requires specialized facility |
| β-D-glucan and GM | Routine fungal markers | Low sensitivity to Mucorales, unsuitable for diagnosis |
The basic approach is a combination of antifungal drugs and surgical debridement, and treatment in an internal medicine department capable of systemic management is desirable. Since antifungal drug penetration into necrotic tissue is poor, combination with surgical treatment is essential.
First-line: Liposomal amphotericin B (L-AMB)2)
Posaconazole: Step-down or salvage therapy. Response rate 60–70%2).
Isavuconazole: Effective as alternative therapy with good tolerability7). 200 mg loading dose, then 200 mg/day (oral available).
Combination therapy: Amphotericin plus caspofungin has been reported to have better outcomes than monotherapy, but echinocandins have low in vitro activity against Mucorales, and strong evidence is lacking2).
Surgical debridement of necrotic tissue is essential. Resection should be performed until normal bleeding is obtained, and pathological confirmation of the resection margin is strongly recommended. Functional endoscopic sinus surgery (FESS) is the standard procedure, and multiple surgeries may be required 4). In cases with extensive orbital involvement, orbital exenteration with bone removal may be necessary.
The mortality rate for antifungal therapy combined with surgery is 18.5%, whereas it is significantly higher at 60% for antifungal therapy alone 2).
The duration of liposomal amphotericin B administration ranges widely from 3 to 36 months, and is individually adjusted based on clinical and imaging improvement 2). Severe cases or those with brain involvement often require longer administration. Surgical debridement may also need to be performed multiple times.
Inhalation of spores leads to proliferation within the paranasal sinuses, reaching the orbit via direct invasion or through the nasolacrimal duct. From the orbit, invasion into the brain occurs through the orbital apex, cavernous sinus, cribriform plate, and blood vessels.
The main mechanism of spread is angioinvasion, penetrating the endothelial cells of blood vessel walls and extracellular matrix proteins. GRP78 (glucose-regulated protein) is involved in this penetration process. It progresses through the pathway of angioinvasion → thrombosis → ischemia → avascular necrosis, resulting in necrosis without congestion.
Under acidic conditions, iron is released from transferrin, and Mucorales fungi utilize the free iron to proliferate rapidly. The same mechanism occurs in iron overload states (hemochromatosis, frequent blood transfusions, deferoxamine therapy).
Cytokine storm (elevation of IL-1, IL-2, IL-6, TNF-α, etc.), decreased IFN-γ expression in CD4+ T cells, use of steroids and immunomodulators, and the overlap of hypoxic environment + hyperglycemia + acidic environment + high iron levels provide an ideal environment for fungal spore germination7).
Yang et al. (2026) reported 7 cases of ROCM presenting with cerebral infarction as the initial symptom5). In all cases, Rhizopus species were detected by mNGS of cerebrospinal fluid, but cultures were negative in all cases. The median time to diagnosis was 5 days, and the only survivor was diagnosed within 2 days (mortality rate 85.7%). mNGS is a promising early diagnostic tool for ROCM, especially valuable when conventional cultures and serum markers are negative.
mNGS (metagenomic next-generation sequencing) is useful when β-D-glucan and galactomannan have poor sensitivity and cultures fail to identify the causative organism. In atypical ROCM presenting with cerebral infarction as the initial symptom, cerebrospinal fluid mNGS may be the only diagnostic method5).
In response to the global surge in ROCM associated with COVID-19, Ostovan et al. (2021) reported that all patients with a history of mechanical ventilation died 6). In India, Sen et al. (2021) reported 2,826 cases of COVID-19-associated ROCM, highlighting it as a significant new complication of the pandemic.
Al Reesi et al. (2023) reported a case of a child with acute chronic kidney disease and malnutrition who achieved cure with aggressive treatment including liposomal amphotericin B (5→9 mg/kg/day) plus posaconazole plus multiple surgeries 2). Early diagnosis within 24 hours and aggressive treatment are considered key to favorable outcomes.
