|Year : 2021 | Volume
| Issue : 1 | Page : 16-20
Rhino-orbital-cerebral mucormycosis: A clinical guide for ophthalmologists
Srujana Laghimsetty1, Y Sujatha2, Vivekananda Reddy Muddam1
1 Consultant Ophthalmologist, Dr. MV Reddy Eye Hospital, Narasaraopeta, Guntur, Andhra Pradesh, India
2 Consultant Ophthalmologist, Savitri Netralayam, Vijayawada, Andhra Pradesh, India
|Date of Submission||23-Jun-2021|
|Date of Decision||05-Sep-2021|
|Date of Acceptance||06-Sep-2021|
|Date of Web Publication||01-Nov-2021|
Dr. Srujana Laghimsetty
Consultant Ophthalmologist, Dr. MV Reddy Eye Hospital, Narasaraopeta, Guntur, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
This article aims to provide relevant clinical pearls to help in the diagnosis and treatment of Rhino-orbital-cerebral mucormycosis (ROCM). The main risk factors apart from SARS-CoV 19 infection for ROCM are uncontrolled diabetes mellitus, diabetic ketoacidosis, and steroid usage. The major clinical findings in the case of orbital involvement are loss or decrease of vision, ophthalmoplegia, proptosis, and panophthalmitis-like picture. Effective management of the disease lies in prompt diagnosis, adequate surgical debridement, and appropriate systemic antifungal therapy. With timely attention, we can save the vision, globe, and life of the patient.
Keywords: Amphotericin B, COVID-19, rhino-orbital cerebral mucormycosis, SARS-Cov 19
|How to cite this article:|
Laghimsetty S, Sujatha Y, Muddam VR. Rhino-orbital-cerebral mucormycosis: A clinical guide for ophthalmologists. J Ophthalmol Clin Res 2021;1:16-20
|How to cite this URL:|
Laghimsetty S, Sujatha Y, Muddam VR. Rhino-orbital-cerebral mucormycosis: A clinical guide for ophthalmologists. J Ophthalmol Clin Res [serial online] 2021 [cited 2022 Oct 1];1:16-20. Available from: http://www.jocr.in/text.asp?2021/1/1/16/329769
| Introduction|| |
In these pandemic times, we have all noticed a marked rise in the number of cases of mucormycosis in post-COVID patients. Mucormycosis is classified into six types based on the site of involvement.
Rhino-orbital cerebral when sinuses, eye, and brain are involved. The other variants being pulmonary (lung involvement), gastrointestinal (involvement of gastrointestinal system by the fungi), cutaneous (skin involvement), disseminated (multiple organ systems are involved), and mucormycosis of uncommon sites. This article aims to provide relevant clinical pearls to help in the diagnosis and treatment of rhino-orbital-cerebral mucormycosis (ROCM).
| Aetiology|| |
Mucormycosis is an invasive fungal infection caused by fungi belonging to the order mucorales. Rhizopus oryzae is the most commonly isolated organism from patients and is responsible for almost 70% of infections. Fungi belonging to the species of Lichtheimia, Cunninghamella, Saksenaea, and Rhizomucor are also isolated from patients. Species identification is a difficult procedure in cases of mucormycosis but this process becomes clinically relevant when mucormycosis is caused by non-Rhizopus species.
For example, it is noted that when mucormycosis is caused by Cunninghamella bertholletiae, it tends to be more severe. This phenomenon is explained by the increased ability of the fungi to extract iron from the host as well as its ability to suppress host immune reactions. Thus infection caused by C. bertholletiae has a poorer prognosis. On a more encouraging note, Rhizomucor pusillus is found to be less virulent than R. oryzae thus having a better prognosis.
| Pathogenesis|| |
The main pathological mechanism noted in mucormycosis is angioinvasion by fungal hyphae in turn causing thrombosis and tissue necrosis. Multiple factors contribute to this angioinvasion. In ROCM perineural spread of fungi is also noted.
| Pre-COVID Times and Theories|| |
The fungi causing mucormycosis have certain virulence factors which help them to overcome host defenses and establish themselves. Similarly, the host also has several defense mechanisms which will protect from such fungal invasion. When there is a breach in these defenses, the fungi will gain an upper hand and cause mucormycosis.
| Host Factors that Promote Mucormycosis|| |
The first one on the list is uncontrolled diabetes mellitus (DM) with associated diabetic ketoacidosis (DKA). The factors lead to an acidic internal milieu, thus facilitating the germination of fungal spores.
It is also known that hyperglycemia and acidosis negatively impact neutrophil chemotaxis and phagocytic activity, which leads to unchecked fungal spore germination in the host tissues.
Moreover, any systemic acidosis, not just DKA, leads to increased available iron in serum due to dissociation of iron from sequestering proteins. Thus causing hyperferritinemia which is a favourable factor for the growth of fungal hyphae.
Deferoxamine therapy is another known risk factor; here, deferoxamine acts as a Xeno siderophore and facilitates fungal growth. Other factors like chronic steroid usage and immune suppression in organ transplant patients also predispose patients to mucormycosis.
| Fungal Virulence Factors|| |
Rhizopus secretes an iron permease mediated by proteins secreted by the FTR1 gene. In vivo studies noted a decrease in the virulence of Rhizopus when FTR1 protein is neutralized by targeted antibodies, thus confirming its importance. The clinical significance here is if we can administer FTR1 protein neutralizing antibodies, it can protect from potential infection in susceptible patients.
Glucose-regulated protein 78 (GRP78) is a novel host receptor that selectively and specifically interacts with Mucorales during the invasion and subsequent damage of host tissues. Elevated glucose and iron levels upregulate GRP78 expression and promote endothelial cell invasion and damage by R. oryzae in a receptor-dependent manner. The fungal ligand which helps in binding the GRP78 during the early invasion of Mucor belongs to a spore coating protein family (CotH3), an upregulation of this protein is also noted in a hyperglycemic environment.
| COVID Times and Theories|| |
As previously acknowledged, uncontrolled DM and DKA promote mucormycosis. It is observed that SARS-Cov 19 promotes hyperglycemia. The theory put forward is that the virus affects the ACE2 receptors of the pancreas, thus causing insulin resistance and uncontrolled DM.
The other factor to consider is the upregulation of the GRP78 receptor on the endothelial cells in a setting of hyperglycemia. This upregulation, in turn, promotes invasive fungal disease.
Multiple clinical reports are stating that even postrecovery, patients tend to be immunosuppressed and continue to have insulin resistance for a prolonged period. This possibly explains the incidence of mucormycosis even after recovery from COVID-19 [Figure 1].
| Clinical Features of Rhino-Orbital Cerebral Mucormycosis|| |
The fungal spores find an entry into the nasal cavity through the air we breathe and germinate when the conditions are favorable.
The infection starts from the nasal cavity and spreads to the sinuses, then to orbits, and finally to the brain. The mucoralean fungi are angiotropic fungi and have an affinity for endothelial cells. When they infect the nasal mucosa, it appears to be reddish or grey, as the disease progresses, the mucosa turns necrotic, forming blackish eschars. These eschars can be noted on the nasal septum, hard palate, turbinates, orbital areas, and even on facial skin [Figure 2].
Once the infection spreads to orbit, it can present with ptosis, mild proptosis, total or incomplete ophthalmoplegia, orbital apex syndrome.
The major intraocular findings noted are uveitis, vitritis, endophthalmitis, or panophthalmitis [Figure 3]. The other notable features are central retinal artery occlusion secondary to angioinvasion of the target vessel by fungal hyphae
Further spread into the cranial cavity leads to cavernous sinus thrombosis.
Cavernous sinus thrombosis with loss of vision is considered to be a characteristic feature of mucormycosis, and CST without loss of vision is a feature of bacterial infection.
The route of the spread of fungi from paranasal sinuses to orbit. The most common and relevant one states that the disease spreads to the orbit and soft facial tissue from pterygopalatine space, and then through the inferior orbital fissure, extends to the retrobulbar area of the orbit, resulting in ophthalmic manifestations.
In addition, the cribriform plate and the roof of the orbit is very thin could be a portal of entry to the intracerebral area. All the clinical findings are summarized in [Table 1].
| Proposed Staging of Rhino-Orbital-Cerebral Mucormycosis|| |
When the infection is confined to the nasal cavity, it is defined as Stage 1. When there is a spread of infection to the paranasal sinus, it is defined as Stage 2. The disease when it spreads to orbit is defined as Stage 3. The involvement of central nervous system (CNS) is Stage 4. This is only a proposed staging based on anatomical involvement (both clinical signs and imaging signs are taken into consideration), further validation is needed.
Another attempt to stage the disease is made by Naik and Rath. They have categorized the disease and gave a severity score to each subclass. They have also proposed possible treatment options applicable to each category. The proposed staging has three categories each one assigned to an anatomical site, R for sino-nasal involvement, O for orbital involvement, and C for CNS involvement. And each category has severity grading from 0 to 3, higher numerical represents more severe disease. An attempt is made by the authors to validate this staging.
| Diagnosis|| |
ROCM can be categorized as possible, probable, and proven. A patient who has symptoms and signs of ROCM in the clinical setting of concurrent or recently (<6 weeks) treated COVID-19, uncontrolled DM, use of systemic corticosteroids and tocilizumab is considered as possible ROCM. When the clinical symptoms and signs are supported by diagnostic nasal endoscopy findings or contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) scan, the patient is considered probable ROCM. When there is microbiological confirmation, the patient can be categorized as a Proven case of ROCM.
Diagnostic nasal endoscopy to look for signs of ROCM in the nasal cavity should be the first step in confirming a diagnosis of ROCM. The ENT surgeon looks for the color of the nasal mucosa, presence of any purulent discharge or black eschars on the nasal mucosa, turbinates, and septum. They should also collect a swab or tissue for microbiological analysis from the edge of necrotic tissue.
| Imaging|| |
Contrast-enhanced MRI is considered the best imaging modality for identifying ROCM. As previously discussed mucormycosis is an angio invasive disease, failure of enhancement of anatomic sites that normally get enhanced is a sign of angioinvasion and can be considered a definitive sign of invasive fungal disease.
Sinus mucosa shows thickening with areas of nonenhancement. When there is non-enhancement of nasal mucosa in a contrast MRI, it is given the name “black turbinate.”
Sinus cavity contents may show variable signal characteristics with mixed areas of hypointensity (caused by paramagnetic compounds present in fungal hyphae) and hyperintensity (caused due to tissue necrosis).
When there is extra sinus extension the fat planes surrounding the maxillary antrum show oedema and enhancement. Similarly, orbital involvement is characterized by edema and enhancement of fat planes in the retro-orbital area. When there is orbital invasion through the medial wall, inflammatory tissue or abscess formation may be seen along the medial aspect of the orbit.
When there is an invasion of the optic nerve, an increase in its caliber may be noted along with associated signal intensity changes. Involvement of optic nerve alone signifies fungal invasion along the ophthalmic artery, and it needs aggressive management. In the case of orbital apex syndrome, soft tissue enhancement of apical tissues along with spread into the optic canal and superior orbital fissure can be noted.
Cavernous sinus involvement is characterized by filling defects and narrowing of vessel lumen in postcontrast images. Arterial wall involvement is characterized by areas of enhancement.
CT scan with contrast is useful in studying the sinus anatomy, the extent of disease, and in identifying bone involvement. It is a cheaper and quicker, and more easily available option. One can always get an initial CT scan done when logistics issues do not allow for an MRI.
| Laboratory Diagnosis|| |
Direct microscopy of freshly collected specimens using wet mounds of KOH and fluorescent brighteners such as blankophor and calcofluor white is the most inexpensive and rapid mode for establishing a diagnosis.
Fungal cultures, if obtained provide a definitive diagnosis. But the pitfalls here are cross-contamination and the need for strict and expensive procedures.
Molecular tests using polymerase chain reaction to identify specific molecular targets like 28S rDNA, the mitochondrial gene rnl, the cytochrome b gene, or the mucorales-specific CotH gene are the newer and emerging modalities useful for confirming the diagnosis of mucormycosis.
| Medical Management|| |
When a diagnosis of ROCM is made, either possible/probable or proven, it is recommended to start systemic antifungal treatment immediately. The best drug available now is liposomal amphotericin B; it should be administered in a dose of 5–10 mg/kg body weight with strict metabolic control under the care of a physician or intensivist.
In cases where amphotericin-B is contraindicated, intravenous Isavuconazole 200 mg thrice a day on days 1 and 2 followed by 200 mg once a day from day 3 or intravenous posaconazole 300 mg twice a day for 1 day, 300 mg once a day from day 2, can be administered.
This induction treatment should continue for a minimum of 4 weeks followed by step-down treatment with oral isavuconazole or oral posaconazole for 3–6 months.
| Role of Retrobulbar Amphotericin B|| |
Transcutaneous retrobulbar amphotericin B (TRAMB) has gained acceptance in recent years. This modality was introduced to treat moderate localized orbital disease without resorting to disfiguring surgeries like exenteration. In a recent retrospective comparative study published by Ashraf et al., they concluded that “TRAMB had a lower risk of disfiguring exenteration without an apparent increase in the risk of mortality” in cases of invasive fungal rhino-orbital sinusitis.
There are only a limited number of anecdotal reports and case series where TRAMB is discussed as an option.
The most common regimen followed is to inject 1 ml of Amphotericin deoxycholate or liposomal amphotericin in a concentration of 3.5 mg/ml into the retrobulbar space. If there is limited orbital involvement as per imaging, injecting into the affected quadrant can give a better resolution.
These injections tend to cause orbital inflammation leading to decreased vision, chemosis, and eyelid edema. The other reported complication is orbital compartment syndrome. Performing a lateral canthotomy and cantholysis can mitigate these complications to an extent.
It is mandatory to regularly assess the clinical condition of these patients. Repeated contrast-enhanced MRI scans can provide crucial information regarding disease status.
Till now, there are no guidelines to state the duration of treatment or the number of injections to be given. The treating ophthalmologist is left to decide the treatment regimen on a case-to-case basis. Further evaluation of this procedure is needed.
| Surgical Management|| |
The best possible outcome in the case of ROCM is obtained only by combining systemic anti-fungal treatment with surgical debridement of sinuses and orbit. As soon as a diagnosis of possible, probable, or proven ROCM is made, it is mandatory to start the patient on systemic antifungal treatment and plan for surgical sinus debridement. Extensive debridement of infected and necrotic tissue will reduce fungal load and better recovery.
MRI with contrast enhancement will provide an anatomic guide for surgical debridement. Non-contrast enhancing tissues are usually nonviable.
When there is a limited orbital spread of disease and contrast enhancement of tissues on MRI TRAMB will be a good option. In nonresponsive cases or when progression is noted, limited orbital debridement is another conservative option available.
In cases of severe or diffuse orbital disease, with nonenhancement on imaging and poor visual potential exenteration might be helpful. However, there is no standard of care to guide ophthalmologists on when exenteration will be useful for a patient with mucormycosis. Hence, the decision on orbital exenteration should be made after thorough consideration of various factors such as the extent of the disease and comorbidities of the patient. The decision should be based on a dialogue with specialists from other concerned departments as well as with the patient and family.
While performing exenteration, a lid sparing approach will give a better cosmetic result to the patient. Systemic antifungal treatment should continue until there is radiological and clinical evidence of resolution [Figure 4].
|Figure 4: (a) Type II: Palpebral skin is spared, and the globe and its appendages are removed with the conjunctiva (b) Type III: both eyelids are removed with orbital contents|
Click here to view
| Conclusion|| |
ROCM is a fatal disease. Its concurrent incidence along with SARS-Cov 19 is a challenging situation to handle. Moreover, lack of proper treatment guidelines is proving to be an additional hurdle. In these testing times, a united effort by a multidisciplinary team is the need of the hour. Researching newer and effective modes of medical and surgical treatment is quite essential.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis 2012;54 Suppl 1:S16-22.
Gomes MZ, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species. Clin Microbiol Rev 2011;24:411-45.
Spellberg B, Edwards J Jr., Ibrahim A. Novel perspectives on mucormycosis: Pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18:556-69.
Ibrahim AS, Kontoyiannis DP. Update on mucormycosis pathogenesis. Curr Opin Infect Dis 2013;26:508-15.
Jose A, Singh S, Roychoudhury A, Kholakiya Y, Arya S, Roychoudhury S. Current Understanding in the pathophysiology of SARS-CoV-2-associated rhino-orbito-cerebral mucormycosis: A comprehensive review. J Maxillofac Oral Surg 2021;20(3):1-8.
Abdollahi A, Shokohi T, Amirrajab N, Poormosa R, Kasiri AM, Motahari SJ, et al
. Clinical features, diagnosis, and outcomes of rhino-orbito-cerebral mucormycosis – A retrospective analysis. Curr Med Mycol 2016;2:15-23.
Honavar SG. Code mucor: Guidelines for the diagnosis, staging and management of rhino-orbito-cerebral mucormycosis in the setting of COVID-19. Indian J Ophthalmol 2021;69:1361-5. [Full text]
Naik MN, Rath S. The ROC Staging System for COVID-related Rhino-Orbital-Cerebral Mucormycosis. Semin Ophthalmol 2021 Jul 14:1-5. [doi: 10.1080/08820538.2021.1946094. Epub ahead of print. PMID: 34260342].
Singh VP, Bansal C, Kaintura M. Sinonasal mucormycosis: A to Z. Indian J Otolaryngol Head Neck Surg 2019;71:1962-71.
Sreshta K, Dave TV, Varma DR, Nair AG, Bothra N, Naik MN, et al
. Magnetic resonance imaging in rhino-orbital-cerebral mucormycosis. Indian J Ophthalmol 2021;69:1915-27.
] [Full text]
Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: An update. J Fungi (Basel) 2020;6:E265.
Ashraf DC, Idowu OO, Hirabayashi KE, Kalin-Hajdu E, Grob SR, Winn BJ, et al
. Outcomes of a modified treatment ladder algorithm using retrobulbar amphotericin B for invasive fungal rhino-orbital sinusitis. Am J Ophthalmol 2021. [doi: 10.1016/j.ajo.2021.05.025. Epub ahead of print. PMID: 34116011].
Hargrove RN, Wesley RE, Klippenstein KA, Fleming JC, Haik BG. Indications for orbital exnteration in mucormycosis. Ophthalmic Plast Reconstr Surg 2006;22:286-91.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]