Rhino-Orbital-Cerebral Mucormycosis
Also known as: Rhinocerebral Mucormycosis, ROCM, Black Fungus, Rhino Orbital Cerebral Mucormycosis
Rhino-orbital-cerebral mucormycosis is the commonest form of mucormycosis in people with diabetes and in COVID-19 associated disease, and the second commonest form in haematological patients. Spores inhaled into the nose and sinuses germinate in mucosa, invade vessels, and spread to the orbit, brain, and face in days. It is a surgical and medical emergency in which time to treatment determines survival.
Diabetes mellitus (often newly diagnosed, with ketoacidosis) accounts for 60 to 80 percent of cases in India and a large part in other regions. Other hosts are haematological malignancy and neutropenia, transplant, corticosteroid treatment, and deferoxamine use, and cases follow COVID-19 with steroids, particularly in India. Rhizopus arrhizus is the commonest organism. Overall mortality is 25 to 60 percent, over 50 to 70 percent with intracranial spread, and below 30 percent in treated diabetic patients diagnosed early.
| Stage | Extent |
|---|---|
| I | Nasal mucosa and turbinates |
| II | Paranasal sinuses (ethmoid, maxillary, sphenoid, and frontal) |
| III | Orbit (extension through lamina papyracea or the inferior orbital fissure) |
| IV | Brain (cavernous sinus, internal carotid artery, frontal lobe), with palate and face |
Early features are non specific and easily mistaken for sinusitis or dental infection. Fever is absent in many patients.
- Unilateral facial or periorbital pain, headache, nasal stuffiness, and bloody or dark nasal discharge.
- Facial swelling, cheek numbness (maxillary branch of the trigeminal nerve), and tooth loosening.
- Black or necrotic eschar on the nasal turbinate, nasal septum, or hard palate (a late sign and not always present), and a palatal ulcer.
- Periorbital oedema and erythema, proptosis, chemosis, and ptosis.
- Ophthalmoplegia (cranial nerves III, IV, and VI), visual loss (orbital apex, optic nerve, or retinal artery occlusion), and the orbital apex syndrome.
- Cavernous sinus thrombosis with bilateral eye signs, internal carotid artery occlusion, and stroke.
- Cerebral abscess, infarction, mycotic aneurysm, seizures, altered consciousness, and coma.
- Facial skin necrosis in advanced disease.
- Hyperglycaemia, ketoacidosis, and metabolic acidosis in diabetic patients, and in neutropenic patients the signs may be minimal.
| Modality and finding | Meaning |
|---|---|
| Computed tomography of sinuses | Mucosal thickening and opacification, usually unilateral, with fat stranding around the sinus (periantral fat stranding) and orbital fat; bone erosion appears late because vascular invasion precedes bone destruction |
| Contrast magnetic resonance imaging | The preferred modality; shows sinus, orbital, cavernous sinus, perineural, and cerebral involvement; signal change and lack of enhancement of the turbinates (black turbinate sign) is an early sign of devitalised mucosa |
| Magnetic resonance angiography and venography | Carotid involvement, cavernous sinus thrombosis |
| Chest computed tomography | Looks for pulmonary disease |
Normal imaging does not exclude early disease, and endoscopy with biopsy is done in suspected cases.
| Condition | Points that separate it |
|---|---|
| Invasive aspergillosis of the sinuses | Septate hyphae with acute angle branching; galactomannan positive |
| Bacterial sinusitis and orbital cellulitis | Purulent discharge, response to antibacterials, no necrosis |
| Septic cavernous sinus thrombosis | Positive blood culture and imaging |
| Chronic granulomatous invasive fungal sinusitis | Slow growth, immunocompetent, granulomas |
| Allergic fungal sinusitis and fungus ball | Non invasive, no tissue invasion |
| Granulomatosis with polyangiitis | Autoantibodies and renal involvement |
| Sinonasal lymphoma (NK/T cell) and carcinoma | Biopsy |
| Diabetic orbital cellulitis, dental abscess, and herpes zoster ophthalmicus | History, examination, and imaging |
Diagnosis rests on tissue. Nasal endoscopy and biopsy of necrotic or pale mucosa (and of sinuses at surgery) for direct microscopy with calcofluor white, histology, and culture; frozen section can give a rapid answer. Blood and tissue Mucorales polymerase chain reaction are used where available. A diagnostic delay of 6 days or more has been linked to a doubling of mortality in some series, so treatment is started on clinical suspicion without waiting for confirmation.
Treatment rests on four elements, started together: early diagnosis, correction of the underlying cause, surgical debridement, and effective antifungal therapy.
1. Correct underlying risk factors
- Diabetic ketoacidosis and hyperglycaemia: intravenous fluids, insulin infusion, correction of acidosis and electrolytes, and tight glucose control.
- Corticosteroids and immunosuppressants: stop or reduce at once.
- Neutropenia: granulocyte colony stimulating factor, and granulocyte transfusion in selected patients.
- Deferoxamine: stop; iron chelation with deferasirox is not recommended, because a randomised trial showed no benefit and a signal of harm.
- Remove contaminated devices and sources.
2. Surgery
Early, aggressive, and repeated debridement of all necrotic tissue to bleeding margins is essential, because drugs do not reach necrotic, thrombosed tissue.
Endoscopic sinus surgery is the usual approach, with open approaches for extensive disease (maxillectomy, ethmoidectomy, and palatal resection).
Orbital exenteration is considered for progressive orbital disease with necrosis, loss of vision, and ophthalmoplegia, and its use is individualised because it is disfiguring and its benefit is not proven in every case.
Repeat endoscopy is done every few days, and imaging guides re-operation.
3. Antifungal therapy
| Agent | Dose | Notes |
|---|---|---|
| Liposomal amphotericin B | 5 mg per kg intravenously once daily, with up to 10 mg per kg once daily for central nervous system involvement | First line; 10 mg per kg gives higher exposure but more nephrotoxicity, with limited evidence of better outcomes; infusion reactions, nephrotoxicity, hypokalaemia, hypomagnesaemia |
| Amphotericin B lipid complex | 5 mg per kg intravenously once daily | Alternative lipid formulation |
| Amphotericin B deoxycholate | 1 to 1.5 mg per kg intravenously once daily | Only when lipid formulations are unavailable; high nephrotoxicity |
| Posaconazole | Delayed release tablets 300 mg every 12 hours on day 1, then 300 mg once daily; intravenous 300 mg every 12 hours on day 1, then 300 mg once daily; trough above 1 microgram per mL | Step down after initial control, salvage, and in intolerance of amphotericin; take tablets with food |
| Isavuconazonium sulphate | 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses, then 372 mg once daily | Step down or first line when amphotericin is contraindicated; in a single arm trial outcomes were similar to matched amphotericin controls |
| Combination | Liposomal amphotericin B with an echinocandin (caspofungin 70 mg then 50 mg daily) or with posaconazole | Retrospective data suggest possible benefit in rhino orbital disease in diabetic patients, and routine combination is not recommended |
4. Adjunctive and local therapy
- Local amphotericin B: irrigation of the sinuses and transcutaneous retrobulbar injection of amphotericin B (for example 1 mL of a 3.5 mg per mL solution) have been used for orbital disease, particularly in India, with limited evidence.
- Hyperbaric oxygen: reported benefit in diabetic patients, but evidence is limited and it is not routine.
- Adjunct to immune function: granulocyte colony stimulating factor and interferon gamma in selected patients.
- Early identification of other infections and prophylaxis against bacterial superinfection.
Duration and monitoring
Treatment is continued for at least 6 to 8 weeks and until clinical and radiological resolution, sterile culture, and reversal of immunosuppression, and long term suppression with posaconazole or isavuconazole is used when immunosuppression continues. Monitoring includes renal function, potassium, magnesium, and liver tests, drug levels for posaconazole, and repeat imaging. Isavuconazole shortens the QT interval and posaconazole prolongs it, so electrocardiograms and interactions are checked.
Survival is better after early debridement combined with amphotericin B and control of diabetes, with a 12 week mortality of about 25 to 45 percent in many series. Mortality exceeds 60 to 80 percent with cerebral involvement, persistent neutropenia, carotid or cavernous sinus disease, and delayed treatment. Survivors often have loss of an eye, facial deformity, and cranial nerve deficits, and reconstruction is needed.
Control of diabetes, rational use of corticosteroids (including in COVID-19), avoidance of deferoxamine in iron overloaded patients at risk, sterile water in humidifiers and oxygen equipment, hospital environmental control during construction, and early evaluation of diabetic patients with sinus or periorbital symptoms. Mould active prophylaxis with posaconazole is considered in high risk haematology patients, although voriconazole prophylaxis may favour Mucorales.
