Etiology

• Fungi of the phylum zygomycota, class phycomycetes, family mucoraceae called phycomycosis, also called mucormycosis or zygomycosis
• Genera most commonly responsible: rhizopus, mucor, and absidia
• These "bread molds" are present in decaying fruits and vegetables, seeds, soil, animal excreta, and other carbohydrate-rich substrates.
• The phylum thallophyte includes algae and fungus; the subphylum of fungi includes pseudomycetes (slime molds) and eumycetes (true fungi).
• Phycomycetes are aseptate hyphae and differentiated from other human fungal pathogens that are septate.
• The order mucorales includes the family mucoraceae, which includes genus (plural is genera) mucor, rhizopus, and absidia
• Fungi detected in 22% of air samples from 2 hospital wards compared to only 5% of samples from outside air
• Mucorthrombosis leads to ischemic necrosis in the nose, sinus, orbit, and brain.

Epidemiology

• A prospective survey of 25 US transplant centers found a 1‑year cumulative incidence rate of mucormycosis of 0.29% in allogeneic stem-cell transplant patients and 0.07% in solid-organ transplant patients (Clin Infect Dis 2010; 50:1091).
• A US population–based survey estimated that there are 500 new cases per year (Clin Infect Dis 1998; 27:1138).

History

• Pertinent general health including risk factors for immunosuppression
• Initial symptoms (Ophthalmology 1983; 90:1096)
• Sinus pressure and pain
• Pharyngitis
• Unilateral orbital pain or hypoesthesia
• Headache
• Fever
• Nasal discharge

Clinical features

• Blurred vision/visual loss with optic neuropathy
• Proptosis
• Lid edema
• Lacrimal sac inflammation (OPRS 2009; 25:494)
• Tissue necrosis
• Internal and external ophthalmoplegia
• Cornea and facial anesthesia
• Declining level of consciousness
• Extension to optic canal, orbital apex, cavernous sinus, and other neurovascular structures of skull base, optic nerve, and chiasm can occur.
• CNS infection occurs by direct extension of organisms.
• Acute retrobulbar optic neuropathy
• Endophthalmitis
• Orbital apex syndrome
• Cavernous sinus syndrome
• Vascular invasion produces cerebral infarction or hemorrhage.
• Meningitis, intracranial abscess, epidural and subdural abscesses, mycotic aneurysm, encephalitis, cavernous sinus thrombosis
• Rapid progression of signs and symptoms if left untreated

Testing

• Ophthalmologic and otolaryngologic exams
• Ocular and orbital findings as above
• Classic necrotic eschar visible in nasal cavity, roof of mouth
• Imaging studies of the brain or orbit as appropriate
• Careful detail of orbital apex, skull base, and adjacent sinus structures.
• Angiography can demonstrate vascular occlusion.
• Biopsy of affected tissue demonstrates tissue necrosis and vascular invasion.
• Culture and microscopic examination of affected tissue
• Thrombosing vasculitis caused by hyphal invasion
• Impairs host defenses
• Enhances fungal growth with regional acidosis and hypoxemia
• Tissue necrosis proceeds in advance of hyphal invasion.
• Large nonseptate branching hyphae that are demonstrated in periodic acid Schiff and hematoxylin-eosin stain and silver preparation — unusual for fungi
• Fungal culture is typically positive for rhizopus species (Ophthalmology 1983; 90:1096).
• The fungi grow readily under aerobic conditions on Sabouraud's glucose agar.

Tests for staging or fundamental impairment level

There is no staging for this disease.

• Patients with diabetes mellitus and elderly are susceptible.
• Immunosuppressed and debilitated patients, such as cancer patients
• HIV infection (Am J Ophthalmol 2001; 132:111)
• Iron overload
• Zygomycosis can occur after prolonged treatment of aspergillus infection with voriconazole.

• Aspergillus or other fungal infection
• Tumor
• Painful pseudotumor
• Bacterial infection
• Giant-cell arteritis
• Granulomatosis with polyangiitis (formerly Wegener's) with tissue necrosis

Natural history

• Survival rate without surgical debridement and medical treatment believed to be 25% (Arch Ophthalmol 2007; 125:848)
• Survival rate with current surgical and medical treatment is about 85% (Arch Ophthalmol 2007; 125:848).
• Survival depends on depth of disease penetration on presentation and clinical recognition.

Medical therapy

• Antifungal medications include the polyenes (amphotericin B deoxycholate), the triazoles (fluconazole, voriconazole), and the echinocandins (caspofungin, micafungin, anidulafungin).
• Liposomal form of amphotericin B lowers systemic toxicity.
• Catheter infusion into affected sinus or area of debridement
• Voriconazole might be preferred as first-line therapy (Mycoses 2012; 55:352).
• Voriconazole has the advantage of initiation with intravenous and conversion to oral therapy.
• In cases of primary treatment failure, alternative antifungal therapy (Am J Ophthalmol 2006; 142:187) includes oral posaconazole (Arch Ophthalmol 2007; 125:848).
• Posaconazole is a triazole antifungal agent used as adjuvant or salvage therapy for the treatment of zygomycosis (Pharmcotherapy J Hum Pharmacol Drug Ther 2013; 33:e1).
• Induction antifungal therapy may require three months of treatment (Muggeo, 2019).
• Maintenance antifungal therapy may be continued for more than 12 months.
• Oral posaconazole or isavuconazole may be appropriate for maintenance therapy.
• Hyperbaric oxygen can improve regional host defenses, preserve tissue, and decrease regional acidosis (Am J Ophthalmol 1992; 114:208).

Surgery

• Wide local excision and surgical debridement of all devitalized and necrotic tissue including mouth, nose, sinus, and orbit
• Frozen-section histopathology can guide debridement by defining affected and devitalized tissue (Am J Ophthalmol 1997; 124:265).
• Indications for exenteration in mucormycosis were evaluated by literature review of 113 articles (1943-2004) (OPRS 2006; 22:286).
• The authors failed to define an evidence-based standard on when patients would benefit from exenteration.

Other management considerations

• Correction of diabetic ketoacidosis and other metabolic abnormalities
• Wound care can include irrigation with antifungal agents via catheter.

Common treatment responses, follow-up strategies

Prolonged oral therapy, up to 6 months, might be indicated.

• Deformity
• Expected with aggressive debridement
• Must sometimes be accepted to preserve life
• Loss of vision
• Renal failure secondary to Amphotericin B

• Mortality is primarily related to intracranial extension
• Causes invasion and thrombosis of intracranial tissue (Mulki, 2016)
• Multiple cerebral infarctions and abscesses may be evident on imaging.
• Cavernous sinus thrombosis (Arch Ophthalmol 2007; 125:848)
• Can cause bilateral cavernous sinus thrombosis (Arch Ophthalmol 1988; 106:1089)
• Internal carotid thrombosis
• Visual loss with ischemia including central retinal artery occlusion
• Chiasmal infaction (Am J Ophthalmol 1996; 122:895)
• Orbital apex syndrome
• Mycotic aneurysms with vascular occlusion or rupture
• Necrosis of orbital, sinus, facial and CNS tissues
• The fungus can advance by direct perineural invasion (OPRS 2007; 23:326).
• Progression can be demonstrated by contrast enhanced magnetic resonance imaging (MRI).
• Morbidity is high with orbital phycomycosis, especially in immunocompromised patients.

• The syndrome of acute orbital mucormycosis characterized by uncontrolled diabetes, unilateral internal and external ophthalmoplegia, proptosis, meningoencephalitis, and rapid death was first described by Gregory in 1943 (Bull Johns Hopkins Hospital 1943; 73:405).
• The first recorded human infection by the phycomycetes was a case of pulmonary mucormycosis reported by Sluyter in 1847 (Arch Ophthalmol 1961; 65:226).
• Ocular mucormycosis in the form of keratomycosis following corneal trauma was first reported by Cavara in 1913 (Ann Otolaryngol 1913; 42:650).
• The term mucormycosis was first used by Paltauf in 1885 to describe a patient with widespread infection from nonseptate, broad, branching hyphae typical of bread molds comprising the family mucoraceae.
• The term phycomycosis was proposed in the general pathology literature by Joe et al in 1959 (Arch Ophthalmol 1961; 65:226) as a more inclusive term.

1. Ferry AP, Abedi S: Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis): a report of 16 personally observed cases. Ophthalmology. 1983; 90:1096-1104.
2. Gelston CD, Durairaj VD, Simoes EAF: Rhino-orbital mucormycosis causing cavernous sinus and internal carotid thrombosis treated with posoconazole. Arch Ophthalmol. 2007; 125:848-849.
3. Gregory JE, Golden A, Haymaker W: Mucormycosis of the central nervous system: report of 3 cases. Bull Johns Hopkins Hospital. 1943; 73:405.
4. Hargrove RN, Wesley RE, Klippinstein KA, et al: Indications for exenteration in mucormycosis. Ophthal Plast Reconstr Surg. 2006; 22:286.
5. Kohn R, Hepler R: Management of limited rhino-orbital mucormycosis without exenteration. Ophthalmology. 1985; 92:1440-1444.
6. Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Infect Dis. 2010; 50:1091.
7. Muggeo P, Calore E, Decembrino N, et al. nvasive mucormycosis in children with cancer: A retrospective study from the Infection Working Group of Italian Pediatric Hematology Oncology Association. Mycoses 2019; 62:165-170.
8. Mulki R, Masab M, Eiger G, Perloff S. Lethargy and vision loss: Successful management of rhinocerebral mucormycosis. BMJ Case Reports 2016; 2016, Jun2.