Abstract
Rhino-orbito-cerebral mucormycosis is a potentially fatal disease requiring early magnetic resonance imaging (MRI) for disease evaluation and timely detection of intracranial complications. Angio-invasive nature leading to necrosis and infarction is the hallmark of mucormycosis. The disease follows a fulminant course extending from the paranasal sinuses to involve the orbit, deep neck spaces, skull base, facial bones, and intracranial compartment. Loss of vision either due to direct extension into the orbit or optic nerve infarction adds to disease morbidity. Prompt MRI using dedicated sequences can help in assessing the exact disease extent including early osseous and intracranial changes, which aid in precise disease management.
Keywords
Introduction
Mucormycosis is an ominous angio-invasive fungal infection affecting individuals with compromised immunity. Until recently, the disease was seen mainly in patients with poorly controlled diabetes mellitus and patients on immunosuppressive drugs. Increased usage of steroids and immune dysregulation caused by SARS-CoV-2 has resulted in a surge in cases of rhino-orbito-cerebral mucormycosis. It is caused by the fungi belonging to the class Phycomycetes of the order Mucorales (1). Mucor, Rhizopus, and Lichtheimia are the species most frequently identified. Human infection occurs after inhalation of spores by a susceptible individual followed by invasion of mucosa of nose and paranasal sinuses. Rhino-orbito-cerebral mucormycosis (ROCM) (incidence of 45%–74%) is the most common form of disease followed by cutaneous (10%–31%) and pulmonary (3%–22%) disease (2). Pathologically, invasion of the vascular lamina resulting in infarction and necrosis is characteristic of mucormycosis. It is potentially fatal; therefore, timely institution of appropriate antimicrobial therapy can be life saving, emphasizing the importance of early clinical suspicion and rapid diagnosis of ROCM. Imaging plays a vital role in the rapid diagnosis of clinically suspected patients and detailed evaluation of disease extent in already proven or even treated cases of ROCM. The aim of the present study was to describe the magnetic resonance imaging (MRI) features of ROCM, with wider availability and use of MRI for imaging of this disease entity.
Risk factors
Until recently, the most important risk factors were uncontrolled diabetes mellitus and patients on high-dose corticosteroids or immune suppressants/modulators (2). Patients with acute myeloid leukemia, myelodysplastic syndrome, hematopoietic stem cell transplant, and acute lymphoblastic leukemia are at greater risk of acquiring mucormycosis during the neutropenic phase. Solid-organ malignancies and solid organ transplant recipients (renal followed by liver, heart, and lung in frequency) are also susceptible to ROCM due to impaired macrophage and neutrophil function. Elevated levels of free serum iron and deferoxamine chelation therapy are also found to increase the risk of mucormycosis as iron helps in the growth of these fungi. Other risk factors associated with mucormycosis are HIV infection, intravenous drug use, low birth weight infants, malnutrition, chronic alcoholism, liver diseases, chemotherapy, and use of calcineurin inhibitors. In the last couple of years, the extensive use of glucocorticoids for patients with SARS-CoV-2 has induced a favorable environment due to steroid-induced hyperglycemia further assisted by hypoxia, metabolic acidosis, high ferritin, and decreased white blood cells. These conditions are thought to allow spores to germinate and lead to the catastrophic picture of ROCM co-infection with coronavirus disease.
Clinical presentation
Headache and facial pain are the most common complaints, found in 55% of the patients followed by cheek swelling in 20% of the patients (3). Being non-specific, these symptoms require a high index of suspicion and a low threshold for further evaluation in susceptible individuals. Nasal discharge/congestion/bleeding, facial numbness, orbital swelling/pain, ophthalmoplegia, proptosis, and diminution of vision are other commonly encountered complaints and, often, these symptoms are unilateral. Ophthalmoplegia and proptosis develop either secondary to orbital infiltration by soft tissue, edema of the extraocular muscles, or involvement of oculomotor and abducens nerves at the orbital apex. Partial loss of vision suggests infiltrative or compressive optic neuropathy, whereas complete loss of vision suggests either posterior ischemic optic neuropathy or central retinal artery occlusion. Intracranial infection may present as altered consciousness, cranial nerves palsy, unstable gait, and seizures.
Diagnosis
According to Honavar (4), ROCM can be categorized into possible, probable, and proven disease. Symptoms and signs of ROCM in the clinical setting of concurrent or recently (<6 weeks) treated COVID-19, diabetes mellitus, use of systemic corticosteroids and tocilizumab, and mechanical ventilation are categorized as possible ROCM. Patients with clinical symptoms and signs along with suggestive diagnostic nasal endoscopy findings or contrast-enhanced MRI or computed tomography (CT) are considered as having probable ROCM. Clinico-radiological features combined with microbiological confirmation on direct microscopy or culture, or histopathology or molecular diagnostics are considered proven cases of ROCM.
Direct microscopy of the infected tissue is done using a variety of methods including 20% potassium hydroxide, Gomori's methenamine silver staining, hematoxylin and eosin staining, and periodic acid-Schiff staining. Mucorales have broad ribbon-like aseptate or pauciseptate hyphae with the angle of hyphal branching in the range of 45°–90°. When grown in appropriate temperature and culture media, fluffy white, gray, or brown colonies are produced in 1–7 days. Molecular techniques, such as the sequencing of the internal transcribed spacer (ITS) region of fungal DNA, in involved tissue samples can be used to confirm the diagnosis (5).
Role of imaging
Imaging plays an important role in the diagnosis of clinically suspected patients at the start of empirical therapy and for the evaluation of the extent of the disease in already diagnosed patients. This is vital for the management of patients and can influence decisions such as orbital exenteration, based on the exact extent and aggressiveness of the disease. Imaging also has a prominent role in guiding the site of tissue to be sampled during biopsy for confirmation of diagnosis, prognostication, and assessment of residual and/or recurrent disease after an intervention. CT is the usual initial investigation and is mainly performed to see the degree of sinonasal involvement and extension into the adjoining tissues with or without bone erosion; however, MRI with its superior soft tissue resolution may be used for the exact estimation of extra sinus disease, especially for the intracranial component. MR examinations are being increasingly used for the diagnosis and evaluation of ROCM complications as often repeat examinations may be required where the absence of ionizing radiation becomes a particularly attractive feature though assessment of thin cortical bones may be challenging.
MRI protocol
Evaluation using MRI should include the paranasal sinuses and entire brain parenchyma in all cases of mucormycosis. Thin section (2–3 mm) T1-weighted (T1W) and T2-weighted (T2W) fast spin-echo sequences of the paranasal sinuses, in axial and coronal planes, acquired on at least 1.5 T, or preferably 3 T, scanners are ideal. Axial images should span from the cranial aspect of frontal sinuses to cover the hard palate inferiorly. Coronal sections should extend from the nasal cartilage anteriorly to the pons. STIR or fat-saturated T2 and fat-saturated post-contrast T1W imaging, being the most sensitive for detecting early disease should be routinely acquired. High-resolution diffusion-weighted imaging (DWI) of the involved sinuses may be done as well. Besides routine brain imaging, DWI should be performed to pick up infarction and MR angiogram to look for thrombosis/angio-invasion.
MRI features of ROCM
Paranasal sinuses, though not routinely imaged using MRI, are air-filled structures that appear hypointense on all sequences with thin smooth mucosal lining. Mucormycosis begins typically in the nasal mucosa with spread into the mucosa of paranasal sinuses. Fungal hyphae invade the adjacent blood vessels causing necrosis and infarction of the involved tissue. Diseased sinuses show soft tissue contents of varying T2 signal intensity. Necrotic tissue is hyperintense. Interspersed hypointensities are frequently seen due to paramagnetic elements such as manganese and iron in the fungal hyphae. Increased signal on DWI and corresponding decreased signal on ADC images in the involved sinonasal tissue have been reported in some cases (6). Three patterns are identified on post-contrast images, namely, intense enhancement of soft tissue, heterogeneous enhancement with variable enhancing and non-enhancing areas, and complete central non-enhancement of the lesion with or without a thin irregular rim of peripheral enhancement (7). The devitalized mucosa and turbinate appear as contiguous foci of non-enhancing tissue on contrast-enhanced MRI known as the “black turbinate (BT) sign” (Fig. 1).
Black turbinate sign. (a) T1W and (b) T2W images reveal T1 hypointense and T2 hyperintense mucosal thickening (short arrows) involving the right maxillary sinus and ethmoid air cells. Note the T2 hypointense areas in the ethmoid air cells (arrowhead). (c) Minimal heterogeneous enhancement of the mucosa is seen on post-contrast T1W FS image. Also note the right middle and inferior turbinates show reduced enhancement (long arrow) compared to the contralateral side. (d) T2W FS axial image shows hyperintensity in the retroantral fat and adjacent pterygoid muscles on the right side (double arrow) with areas of diffusion restriction on (e) DWI and (f) ADC maps (curved arrows) suggesting extra sinus disease extension. No intra-orbital extension is seen. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
The BT sign was initially reported as an early sign in a case of mucormycosis but was later also seen to be associated with other invasive fungal sinusitis. The BT sign has also been found in certain healthy individuals. This so-called “benign BT” has been linked to the cavernous tissues within the turbinates and is usually seen as a well-defined lesion involving the posterior part of inferior and middle turbinates with progressive enhancement on dynamic contrast-enhanced scans. Fungal BT, on the other hand, is seen as irregular, confluent, non-enhancing areas commonly involving the middle turbinate as it filters the majority of nasal airflow (8).
Extrasinus spread of mucormycosis
Erosion and invasion of the surrounding bones is a feature that has been reported as an important characteristic suggesting invasive fungal sinusitis on CT. Though CT is superior to MRI for osseous involvement, on MRI early bone involvement in the form of bone marrow edema can be best appreciated on T1W imaging as hypointensity replacing the normal hyperintense marrow. This appears hyperintense on STIR and shows heterogeneous post-contrast enhancement.
Involvement of the retroantral fat is an early indicator and hallmark of invasive fungal sinusitis (9). Involvement of preantral fat is also commonly encountered in mucormycosis (Fig. 2). In later stages, there is extensive enhancing soft tissue infiltration and abscess formation.
Preantral region involvement. (a) T2W and (b) post-contrast FS T1W axial images reveal marked T2 hyperintense mucosal thickening in the left maxillary sinus with focal T2 hypointense areas within (arrow). There is soft tissue thickening and stranding noted in the adjacent preantral fat (double arrow). The mucosal thickening and preantral soft tissue show minimal heterogeneous enhancement on the post contrast image. FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Destruction of the nasal septum and alar cartilages along with infiltration and destruction of the floor of maxillary sinus and hard palate resulting in oro-antral and oro-nasal fistula formation has been encountered in many cases of mucormycosis (Fig. 3). Involvement of the superior alveolar arch can lead to the loosening of teeth and the involvement of pterygoid processes can lead to their separation from the rest of sphenoid bone resulting in foreign body sensation while swallowing.
Hard palate involvement. (a) T1W coronal, (b) FS T2W axial, and (c, d) post-contrast FS T1W axial images in a case of mucormycosis after surgery show T1 hypointense and T2 hyperintense contents completely occupying the right maxillary sinus, together with some degree of mucosal thickening noted along the floor and medial wall of left maxillary sinus. Extension of the disease into the inferior orbital compartment is seen (arrowhead) along with extension inferiorly into the oral cavity with erosion of floor of maxillary sinus, superior alveolar arch and hard palate on the right side showing peripheral heterogeneous enhancement(arrow). FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Involvement of the skull base in mucormycosis can result in extensive soft tissue infarction and necrosis, which appears as large areas of non-enhancing profoundly low signal devitalized soft tissue in and around the bony central skull base and along the nasopharynx, which is not encountered in bacterial skull base osteomyelitis (Fig. 4). Thus, necrosis or tissue infarction is seen in fungal skull base osteomyelitis in contrast to suppuration seen in bacterial etiology. Necrosis of the facial bones and bones of the skull base is seen late in the disease process but was often seen at the time of initial presentation in coronavirus disease-associated mucormycosis (10).
Skull base osteomyelitis. (a) T2W FS axial and (b) T1W FS post-contrast axial images demonstrate abnormal hyperintensity involving the right greater wing of sphenoid, walls of the sphenoid sinus (asterisk), and the anterior portion of clivus showing heterogeneous post-contrast enhancement. Increased enhancement is also noted in the right pterygoid muscles. There is evidence of thickening, abnormal hyperintensity, and heterogeneity in the right preantral region extending into the nasal region with altered signal intensity within the right nasal bone and septum showing heterogeneous predominantly peripheral post-contrast enhancement(arrow). FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Often, the disease spreads far beyond the paranasal sinuses along the perivascular and perineural pathways into the orbit, face, deep spaces of the neck (especially pterygopalatine fossa and infratemporal fossa), and skull base and can involve intracranial and vascular structures. Among these, orbital involvement (76%) was found to be the most common followed by involvement of the face (57%), orbital apex (50%), and pterygopalatine fossa (48%) (7).
Orbital involvement is seen as altered signal intensity and soft tissue stranding of orbital fat and extraocular muscles. Extension into the orbit can occur through the lamina papyracea via the anterior and posterior ethmoidal foramen, nasolacrimal duct, infraorbital foramen, inferior orbital fissure, and numerous perivascular channels even before the destruction of bones. In some cases, it may be predominant to occur even without involvement of paranasal sinuses, extending through the nasolacrimal duct and pterygopalatine fossa (Fig. 5). Infiltration of the orbital fat by soft tissue contents is the initial sign and is best seen on T2W fat-suppressed images.
Early orbital involvement. (a) T2W axial, (b) T1W coronal, and (c) post-contrast T1W FS coronal images show early involvement of the left orbit in a case of mucormycosis. There is minimal mucosal thickening in the bilateral maxillary sinuses along with widening and soft tissue contents within the left pterygopalatine fossa (arrowhead) and retroantral fat (arrow). Increased bulk and heterogeneity in the left inferior oblique muscle with surrounding fat stranding is seen (double arrows). Note the non-enhancing middle and inferior turbinates on the left side. FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Extension from the ethmoid sinuses via the lamina papyracea results in soft tissue infiltration of the medial extraconal compartment, increased bulk, altered signal intensity, and heterogeneous or even complete non-enhancement of the medial rectus muscle may occur due to necrosis (Fig. 6). Extension from the maxillary sinus can initially result in predominant involvement along the orbital floor with involvement of the inferior rectus and inferior oblique (Fig. 5).
Extensive right orbital involvement with optic nerve infarction. (a) FS T2W axial and (b) post-contrast FS T1W axial images show hyperenhancing mucosal thickening in the right ethmoidal air cells with involvement of the right orbit. The extraocular muscles appear bulky; extra- and intraconal fat stranding is noted with proptosis and mild deformation of the right ocular globe. T2 hyperintensity is noted along the medial orbital wall with complete lack of enhancement (compared to the contralateral side) of the right medial rectus while the lateral rectus shows peripheral heterogeneous post-contrast enhancement and central non-enhancing areas. Enhancement of the optic nerve sheath adjacent to the optic nerve head (short arrow) is also seen along with heterogeneous enhancement of the thickened preseptal soft tissue (arrowhead). Increased bulk and diffusion restriction on (c) DWI and (d) ADC maps is seen in the right optic nerve (long arrow). Extension of the disease via the orbital apex to the cavernous sinus is seen, which is bulky with thrombosis of the right internal carotid artery. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Optic nerve involvement by direct infiltration results in partial or complete loss of vision. Thickening, tortuosity, and altered signal intensity of the nerve indicate nerve infiltration, emphasizing an early MR examination for the detection of intraorbital spread. Another abnormality to be vigilant for is optic nerve infarction, which is seen as restricted diffusion (Fig. 6). Isolated optic nerve involvement can be seen in the spread of infection along branches of the ophthalmic artery, which should be treated aggressively. Non-enhancing soft tissue contents can also extend into the orbital apex. Often the disease is extensive and almost the entire intra- and extraconal compartments are involved with proptosis, distortion and tenting of the ocular globe, altered signal intensity, and enhancement of ocular coats (Fig. 7).
Extensive orbital involvement with abscesses in soft tissue. (a) T2W FS coronal and (b, c) FS T2W axial images show mucosal thickening in the bilateral maxillary and ethmoidal air cells. There is diffuse involvement of bilateral orbits in the form of increased bulk and heterogeneity in bilateral extraocular muscles, T2 hypointensity replacing intraconal fat, and distortion of bilateral (left > right) ocular globes. T2 hyperintensity is noted in the bilateral temporalis, medial pterygoids, and left masseter muscles (arrowheads). (d) Well-defined hyperintense lesions with hypointense areas within showing diffusion restriction on DWI are seen in left parapharyngeal and bilateral masticator spaces (arrows) suggestive of fungal abscesses. DWI, diffusion-weighted imaging; FS, fat saturation; T2W, T2-weighted.
From the orbital apex, the disease can spread to the cavernous sinus leading to its increased bulk, convex contour of its lateral wall, and filling defect within suggestive of thrombosis (Fig. 8). Narrowing of the cavernous segment of the internal carotid artery can result from its encasement by the soft tissue or thrombus in the cavernous sinus. Sometimes, the fungus can invade the arterial wall, causing luminal occlusion leading to cerebral infarcts.
Cavernous sinus involvement. FS T2W (a) axial and (c) coronal images and FS T1W post-contrast (b) axial and (d) coronal images show mucosal thickening in the bilateral ethmoidal air cells and sphenoid sinus with involvement of the right orbital apex. The right cavernous sinus appears bulky with the convex lateral wall and loss of normal flow void of the right internal carotid artery suggestive of thrombosis. Abnormal T2 hyperintensity and post-contrast enhancement is seen in the adjacent right greater wing of sphenoid, right temporalis, and lateral pterygoid muscles. Note the subtle meningeal enhancement along the anterior part of the right temporal lobe. Non-enhancing areas are noted within the right middle and inferior turbinates. FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
In addition to the involvement of the cavernous sinus, intracranial extension can occur to any of the three: anterior, middle, and posterior cranial fossae. Invasion across the cribriform plate and the wall of ethmoidal and frontal sinuses leads to involvement of the anterior cranial fossa while the perineural route along the trigeminal nerve is followed for the posterior cranial fossa structures. Involvement of the middle cranial fossa occurs after the extension of disease from pterygopalatine fossa. Meningeal thickening and enhancement are the earliest signs of intracranial disease extension, which are best appreciated on post-contrast T1W imaging (Fig. 8). Later, there can be infarction (Fig. 9), abscess formation (Fig. 10), or direct extension of the fungal hyphae into the brain parenchyma.
ICA thrombosis with cerebral infarct. (a) DWI and (b) ADC maps reveal areas of diffusion restriction in the right corona radiata region appearing hypointense on T1 with no post-contrast enhancement on (c) T1W post-contrast axial image suggestive of infarcts. (d) Post-contrast T1W FS axial and (e) MR angiography reveal non-visualization of the right internal cerebral artery in its entire course with post-contrast enhancement of its wall. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FS, fat saturation; ICA, internal carotid artery; MR, magnetic resonance; T1W, T1-weighted.
Intracerebral abscess. (a) T2W coronal image demonstrates hyperintense mucosal thickening in the right maxillary and ethmoid air cells with heterogeneous mucosal thickening in the right middle and inferior turbinates. (b) T1W post-contrast axial image shows peripherally enhancing lesion in the right posterolateral thalamic region with perilesional hypointensity. The lesion shows areas of diffusion restriction on (c) DWI and (d) ADC maps suggestive of intracerebral abscess formation. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FS, fat saturation; T1W, T1-weighted; T2W, T2-weighted.
Ill-defined areas not pertaining to any vascular distribution showing altered signal intensity, usually T2 hyperintensity with minimal perilesional edema and variable peripheral enhancement, point towards fungal extension into the brain parenchyma. A well-defined lesion with central T2 hyperintensity and diffusion restriction may indicate abscess formation. Because of a poor immunogenic response, abscesses in ROCM may not show the characteristic well-defined rim enhancement differentiating them from a bacterial cause.
Disease staging and management (4)
ROCM has been classified based on the extent of disease spread from the nasal mucosa to the surrounding structures progressively (Table 1) (4). Imaging coupled with nasal endoscopy can help in determining the exact extent of disease, which guides further management. Early management decision about resection of the amount of tissue based on disease staging can be extremely beneficial and life-saving in some cases.
Staging of rhino-orbito-cerebral mucormycosis.
Management of ROCM includes antifungal drugs and debridement of the infected tissues that are avascular. Until contraindicated, liposomal amphotericin B with strict metabolic control is considered for every case of mucormycosis. Imaging provides information about the extent of necrosis and avascularity, even for the areas such as the sphenopalatine foramen, pterygopalatine fossa, and retroantral space, which are not visualized by nasal endoscopy. Lack of enhancement on contrast-enhanced imaging in the involved tissue is a sign of necrosis and is used to guide the anatomical extent of resection. Follow-up imaging shows the amount of residual disease and serves as a guide for further line of management. In possible cases of ROCM where initial imaging is non-contributory, a repeat scan should be performed after 72 h to look for any changes from the previous scan.
In conclusion, imaging plays an essential part in planning the precise management of patients diagnosed or suspected of having rhino-orbito-cerebral mucormycosis. The perivascular and perineural route of spread along with the angio-invasive nature of this life-threatening disease makes dissemination possible even before osseous destruction and leads to serious consequences. Better delineation of soft tissue involvement using dedicated MR sequences allows the early detection of disease extent with no risk of radiation exposure on repeat examinations. Even early bone changes and intracranial extension are easily characterized on MRI to allow early administration of appropriate management, rendering MRI as the preferred modality for evaluation of the disease.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
