Rhino-Orbital-Cerebral Mucormycosis

From EyeWiki


Disease Entity

Disease

Rhino-orbital-cerebral-mucormycosis (ROCM), previously referred to as orbital zygomycosis, refers to the presentation of pathologic symptoms in the orbit as a result of fungal infections caused by fungi in the order Mucorales, most commonly by the species Rhizopus oryzae. ROCM usually occurs in an immunocompromised host and presents with initial symptoms such as vision loss, ptosis, diplopia, and external ophthalmoplegia. Left untreated, ROCM can progress to acute vision loss and death [1][2].

Etiology

The primary species responsible for the development of ROCM is the fungus Rhizopus oryzae. This fungus is a fast growing, aseptate filamentous fungus that is responsible for nearly 90% of all rhinocerebral cases and has an overall mortality rate of over 50%[3] [2]. Rhizopus oryzae is commonly found in tropical and subtropical regions, such as Australia, India, and the costal parts of Texas[4]. Like most diseases of fungal origin, mucormycosis is usually introduced to the body through inhalation of spores. The two characteristics most often responsible for the proliferation and development include its propensity for induction of angiogenesis and rapid growth rate.

Risk Factors

Risk Factors [5]:

  • Diabetes Mellitus II, particularly with diabetic ketoacidosis
  • Immunosuppressant therapy
  • Intravenous Drug Users
  • Human immunodeficiency virus (HIV) infection
  • Neutropenia
  • Hemochromatosis
  • Deferoxamine therapy

Pathophysiology

Ketoacidosis is a very common predisposing factor for invasion and spread by mucor. Under acidotic conditions, iron fails to bind to its sequestering proteins like transferrin and is now available to invading pathogens like mucor which depend on iron for survival. This makes ketoacidosis a very susceptible predisposing condition for development of ROCM[6]. This is also the mechanism for iron overload conditions to cause ROCM (e.g., hemochromatosis, multiple blood transfusions, desferroxamine). Mucormycosis commonly begins after the paranasal inhalation of spores and the formation of coenocytic hyphae that can spread. Once inhaled, they initially proliferate in the sinuses and can find their way to the orbit either through direct invasion or via the nasolacrimal duct. It can gain access to the brain either via spread from the orbital apex, cavernous sinus, through cribriform plate or through the blood vessels. The primary mechanism of spread is through angioinvasion of blood vessels. Following angioinvasion, mucormycosis causes injury through excessive vessel thrombosis and tissue necrosis. The angioinvasion also gives the fungus access to additional heme as a source of iron [6]. One critical step that allows for angioinvasion to occur is the penetration of and damage to the endothelial cells and extracellular matrix proteins lining the blood vessels. One receptor that is known to be involved in the penetration process is a protein known as glucose-regulated protein (GRP78)[6].

Once spread to the orbit, the disease is classified as ROCM. Initial ophthalmic problems presenting in ROCM are due to the tissue inflammation resulting from necrosis of the adjacent tissue to the orbit and reduced blood flow. Potentially serious ophthalmic problems associated with ROCM include occlusion of the central artery of the retina and infraction of the orbit including the optic nerve and can ultimately cause complete vision loss. From the orbit, ROCM can spread to the brain through the cribriform plate and orbital apex, causing potential complications such as internal carotid artery occlusion, cranial nerve palsy, chiasmal infarction, intracranial aneurysm, fungal meningitis, and even death [1][7][8].

Primary prevention

A chronic immunocompromised is the most common predisposing condition for ROCM (e.g. HIV, diabetes mellitus II, organ transplant recipients taking immunosuppressants, deferoxamine treatment).

Signs & Symptoms

The early clinical signs of Mucormycosis include sinusitis, nasal discharge, and epistaxis. The hallmark of spread beyond the sinuses involve a characteristic black eschar over the skin over the orbit, palate, and nasal mucosa[9] . The maxillary and ethmoid sinuses are more frequently involved as evidenced on CT/MRI studies [10]. Initial external ophthalmic signs of ROCM may include the following [1][7]with ophthalmoplegia and proptosis being the most common eye signs reported [8] [11].

  • Periorbital Edema
  • Cellulitis
  • External Ophthalmoplegia
  • Proptosis
  • Ptosis
  • Orbital apex syndrome
  • Eyelid gangrene
  • Cavernous sinus thrombosis

Systemic:

  • Malaise
  • Fever

There can be occlusion of the central artery of the retina, or the branch retinal arteries which on funduscopic exam typically reveals opacification of the superficial retinal layers and the characteristic cherry-red spot on the macula[12]. Rarely vision loss can also occur from infarction or direct fungal invasion of the optic nerve or chiasm [13][14].

Another manifestation of mucormycosis in the nasal-orbit area is a black eschar that may present in the nose mucosa or upper palate, therefore, careful examination of these areas are advised when ROCM is suspected.

Diagnostic procedures

It is important to notice that because the fungus stays predominately intravascular, a CT scan without contrast may not reveal any lesion if no mass is formed.

Imaging studies may include CT/MRI of orbit, brain and sinuses demonstrate involvement of maxillary and ethmoid sinus, orbit, cavernous sinus and less frequently involve the frontal and sphenoid sinus. In order to obtain a true diagnosis of mucormycosis, a fine needle aspiration biopsy of infected tissues must be obtained for histopathology and culture. Characteristic of this disease is aseptate hyphal elements that branch at right angles [15].

The most common areas to be involved are nasal cavity, maxillary sinus, ethmoid sinus and orbit. [16]

On MRI, it is common to see isointense lesions (when compared to brain) in T1-weighted images. Most of the patients show hypointense T2-weighted images.< ref name=":19"> Fahrenkopf MP, Nelson JJ, Eichhorn M, Conway J, Hassan A. Rhino-Orbital-Cerebral Mucormycosis and Orbital Exenteration. Eplasty. 2016;16:ic42. Published 2016 Nov 2.</ref> When cavernous sinus involvement, the cavernous sinus will show “lack of enhancement”.

Some of the signs noted on a study of 43 patients with mucormycosis in the midface and skull base included: [17] -No sinus wall destruction -Inflammatory changes -Cavernous sinus and the carotid artery involvement -Isolated hard palate only (one patient)

Finally, the Gold standard diagnostic procedure is biopsy and cultures. Histopathological confirmation included H+E(hematoxylin-eosin), PAS(periodic acid-Schiff) and GMS(Grocott-Gomori's methenamine silver stain), among others.


Differential diagnosis

Ruling out another species of fungi, Aspergillus, is essential for diagnosis of ROCM. Circulating antigen detection test and 1,3 beta-D-glucan detection test cannot confirm the distinction between the Aspergillus and Rhizopus Oryzae. In conditions when tissue biopsy cannot be obtained due to patient conditions, samples such as sputum sample or even bronchoalveolar lavage may allow for delineation between the two [18]. Biopsy of the specimen will identify a 45 degree branching dichotomous (two symmetric almost equal branches) septate fungus as Apergillus.

Management

General treatment

The standard treatment for the early stages of ROCM is antifungal therapy and debridement (e.g., liposomal amphotericin B)[19]. Combination therapy of amphotericin with capsofungin has shown to be associated with better outcomes and might be considered [2]. In the event of spread to the craniofacial tissues and the orbit, surgical treatment becomes essential. Because mucormycosis spreads through blood vessels and tissues, surgical debridement of infected sites is considered to avoid further complications. Once the infection is transformed to ROCM and has been demonstrating symptoms consistent with deep spread within the orbit, orbital exenteration may be considered to avoid the lethal spread to the vessels of the brain, such as the Circle of Willis. Liposomal amphotericin B can be continued throughout the surgical treatments [20].

Prognosis

The long-term outlook for patients with ROCM depends on the spread of the disease and the sites to which spreading has occurred. In terms of disease states, treating the mucormycosis disease and underlying immunosuppressive conditions are associated with better survival rates. In conducted studies in recent years, overall survival is 59.5% with treatment and only 21% without[21]. Factors associated with poor prognosis include: [8]. • Delay in diagnosis and initiation of treatment • Treatment with amphotericin alone • Eyelid/facial gangrene • Intracranial/cerebral invasion • Hemiplegia

References

  1. 1.0 1.1 1.2 Mukherjee, B., Raichura, N. D., & Alam, M. S. (2016). Fungal infections of the orbit. Indian journal of Ophthalmology, 64(5), 337-45
  2. 2.0 2.1 2.2 Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005 Sep 1;41(5):634-53
  3. Ma L-J, Ibrahim AS, Skory C, Grabherr MG, Burger G, Butler M, et al. (2009) Genomic Analysis of the Basal Lineage Fungus Rhizopus oryzae Reveals a Whole-Genome Duplication. PLoS Genet 5(7): e1000549. https://doi.org/10.1371/journal.pgen.1000549
  4. Prabhu, R.M., & Patel, R. (2004). Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis, and treatment. Clinical Microbiology and Infection, 10(1), 31-47
  5. Cox, G., Kauffman, C., & Thorner, A. (2019). Mucormycosis (zygomycosis). Uptodate
  6. 6.0 6.1 6.2 Ibrahim, A. S., Spellberg, B., Walsh, T. J., & Kontoyiannis, D. P. (2012). Pathogenesis of mucormycosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 54 Suppl 1(Suppl 1), S16-22
  7. 7.0 7.1 Bhansali A, Bhadada S, Sharma A, et al.Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgraduate Medical Journal 2004;80:670-674
  8. 8.0 8.1 8.2 Lee BL1, Holland GN, Glasgow BJ Chiasmal infarction and sudden blindness caused by mucormycosis in AIDS and diabetes mellitus. Am J Ophthalmol. 1996 Dec;122(6):895-6
  9. Prabhu, R.M., & Patel, R. (2004). Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis, and treatment. Clinical Microbiology and Infection, 10(1), 31-47
  10. Bhansali A, Bhadada S, Sharma A, et al. Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgraduate Medical Journal 2004;80:670-674
  11. Lam SC, Yuen HKL. Management of bilateral rhino-orbital cerebral mucormycosis. Hong Kong Med J. 2019;25(5):408-409. doi:10.12809/hkmj187588
  12. Qingli, L., Orcutt, J., Seifter, L. (1989). Orbital mucormycosis with retinal and ciliary artery occlusions. British Journal of Ophthalmology, 73, 680-683
  13. Reed C, Bryant R, Ibrahim AS, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47(3):364-7115,6
  14. Mukherjee, B., Raichura, N. D., & Alam, M. S. (2016). Fungal infections of the orbit. Indian journal of Ophthalmology, 64(5), 337-45
  15. Lam Choi, V. B., Yuen, H. K., Biswas, J., & Yanoff, M. (2011). Update in pathological diagnosis of orbital infections and inflammations. Middle East African journal of ophthalmology, 18(4), 268-76.
  16. Herrera DA, Dublin AB, Ormsby EL, Aminpour S, Howell LP. Imaging findings of rhinocerebral mucormycosis. Skull Base. 2009;19(2):117-125. doi:10.1055/s-0028-1096209
  17. Raab P, Sedlacek L, Buchholz S, Stolle S, Lanfermann H. Imaging Patterns of Rhino-Orbital-Cerebral Mucormycosis in Immunocompromised Patients: When to Suspect Complicated Mucormycosis. Clin Neuroradiol. 2017;27(4):469-475. doi:10.1007/s00062-017-0629-1
  18. Skiada, A., Lanternier, F., Groll, A. H., Pagano, L., Zimmerli, S., Herbrecht, R., Lortholary, O., Petrikkos, G. L.(2013). Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica, 98(4), 492-504
  19. Rogers, T. (2008). Treatment of zygomycosis: current and new options. Journal of Antimicrobial Chemotherapy, 61(1), i35-i40
  20. Rapidis, A.D. Orbitomaxillary mucormycosis (zygomycosis) and the surgical approach to treatment: Perspectives from a maxillofacial surgeon. Clinical Microbiology and Infection, 15(5), 98-102. DOI: https://doi.org/10.1111/j.1469-0691.2009.02989.x
  21. Vaughan, C., Bartolo, A., Vallabh, N., Leong, S.C. (2018). A meta-analysis of survival factors in rhino-orbital-cerebral mucormycosis-has anything changed in the past 20 years?. Clinical Otolaryngology, 43(6), 1454-1464