Rhino-Orbito-Cerebral Mucormycosis: An Audit

Abstract

This study aims at identifying the predisposing factors, clinical and radiological features that dictated the treatment outcome of Rhino-orbito-cerebral mucormycosis (ROCM). This is a retrospective observational study. Medical records of 39 patients with ROCM proven by fungal smear or histopathology (HPE), admitted in Sri Ramachandra Institute of Higher Education and Research from Jan 2015 to Dec 2019 were reviewed and audited. The mean age of the patients was 52.6 years and they were predominantly men (76.9%). There is a statistically significant association between uncontrolled diabetes and increasing severity of the disease in this study and an important cause of mortality. Fungal smear and HPE plays a crucial role in diagnosis. Radiological evaluation helps in identifying the extent of spread and in this study 31% of patients had intraorbital and 20% had intracranial extension. In-hospital mortality was 13%. Our results showed better outcome when combined medical and surgical intervention was undertaken. Rhino-orbito-cerebral Mucormycosis is a rapidly spreading invasive fungal infection with significant mortality and morbidity. Early diagnosis and proactive surgical and medical intervention is crucial for better outcome. Hence the clinician should be highly alert to certain subtle clinical signs and radiological features in a diabetic patients for improving the treatment outcomes and avoiding potentially fatal complications.

Introduction

Fungus is a ubiquitous organism that is most often found in the Sino nasal tract. Based on the clinical manifestation, various form of fungal rhinosinusitis depends on the immunocompetency of the host. Broadly, fungal infections of the nose and paranasal sinus can be classified into non-invasive and invasive fungal rhinosinusitis [1, 2]. There has been an increasing trend in the incidence of acute invasive fungal rhinosinusitis (AIFRS) and this has been recognised to be due to increase in the number of immunocompromised host [1–3]. Aspergillus and Mucor remains the most common organism causing AIFRS [2, 3].

Rhino-Orbito-Cerebral Mucormycosis (ROCM) is the most common, rapidly progressive, highly fatal, invasive, opportunistic infection of the nose and paranasal sinus usually occurring in immunocompromised hosts [1, 2, 4]. This fulminant infection spreads by angioinvasion and fungal thrombi that extends intracranially either by direct spread or through blood vessels [1–5]. Thus it is highly imperative that the treating physicians recognise this entity early and institute treatment to reduce the morbidity and mortality associated with it.

Surgeons and physicians who are managing this infection need to audit their treatment outcomes from time to time as to recognise the trends and lacunae so that their past experiences can be put to better use. With this in mind, a retrospective audit of all histopathologically confirmed cases of ROCM managed in our hospital for the past 5 years is analysed and discussed.

Materials and Methods

This is a retrospective observational study. Medical records and data sheets of histopathologically proven cases of ROCM over a period of 5 years (January 2015 to December 2019) in our hospital were reviewed. Patient who did not complete the treatment at our hospital where excluded from the study.

Initial diagnosis of ROCM was made based on the clinical symptoms and signs at presentation. At initial suspicion, nasal endoscopy was done in all patients and tissue taken for fungal smear (FS), histopathological examination (HPE) and for fungal culture. Computed tomography of the nose and paranasal sinus had been done for all and contrast enhanced CT scan was done if required. Magnetic Resonance imaging was done if there was suspicion of intracranial involvement. The initial clinical presentation, co-morbidities, evaluation, progress in the hospital and treatment outcomes where collated and analysed.

Observations and Results

A total of 39 patient’s data met the requisite inclusion and exclusion criteria. The mean age at presentation was 52.6 years with SD of ± 11.6. The age distribution ranged from 24 to 76 years. Most patients where male (76.9%). The mean time between the onset of symptoms to hospitalization was 18 days (range of 5–120 days).

Diabetes mellitus (DM) was seen in 34 (87.17%) patients, 27 (69.23%) of these patients had elevated blood sugars more that 400 mg/dl and 7 patients were diagnosed as diabetic ketoacidosis at the time of admission (Fig. 1). 5 of these 7 patients succumbed to the disease, despite all efforts. There is a statistically significant association between uncontrolled DM and increasing severity of the disease with Odd’s ratio of 14.2 and a P value of 0.021 for 95% CI.

Fig. 1.

Pie chart showing the status of DM in the study population

12 (30%) patients in this study had a documented history of undergoing dental procedure on the upper jaw just before the onset of symptoms. 2 of these 12 patients presented with rapid progress of disease and at presentation had evidence of intraorbital and intracranial involvement. All 12 who suffered from ROCM following dental procedure also had a co-existing DM. Other less frequent precipitating factors identified in the study group were in Table 1.

Table 1.

Frequency of various predisposing factors in the study population

Predisposing/precipitating factors	Number of cases (%)
Diabetes	34 (87%)
Tooth extraction	12 (30%)
Asthma	2 (5%)
Rheumatoid arthritis	1 (2.5%)
Chemotherapy for Lupus	1 (2.5%)
Chronic kidney disease	4 (10%)

The most common presentation were foul-smelling nasal discharge and crusting (49%) and facial swelling involving the premaxilla and periorbita (74%). Oral manifestation was in the form of palatal swelling/ulceration (28%) and loose tooth (Fig. 2). Ophthalmic signs were ophthalmoplegia (51%), Ptosis (28%) and Endophthalmitis (2.5%). Signs of intracranial involvement were loss of vision (17%), delirium, signs of meningeal irritation (20%), signs of CVA etc. Ophthalmic and non-ophthalmic features of all our patients are summarised in Figs. 3 and 4 respectively.

Fig. 2.

Diagnostic nasal endoscopy showing maxillary sinus ulceration and necrosis

Fig. 3.

Bar chart showing frequency of ophthalmic signs

Fig. 4.

Bar chart showing frequency of non-ophthalmic signs

Endoscopic nasal tissues sent in all patients were examined in 10% KOH smear. 28 (71.7%) smears were positive for aseptate hyphae with right angled branching. All patients had histopathological evidence of tissue invasion and many with evidence of angioinvasion (Fig. 5a, b). Fungal Culture was sent for 22 patients and fungal species isolated in 10 (45.5%) of these.

Fig. 5.

a Under light microscope showing broad aseptate hyphae, b Histopathology shows broad based branching hyphae invading the tissue

The following findings were noted on radiological evaluation with CT scan and MRI. All patients had evidence of paranasal sinuses involvement. The most common sinus involved at the time of presentation was ethmoid in 20 (51%), the maxillary sinuses in 16 (41%) followed by the sphenoid and frontal sinus in 4 (10%) each. Diffuse pansinus involvement was noted in 2 (5%) patients. Extension of infection beyond the sinuses with sinus wall erosion was noted in 28 (71%) patients. Orbital involvement (Fig. 6a, b) was observed in 12 (31%) and intracranial extension with cerebral lobe involvement presenting as hypodense/hypointense area with or without rim enhancement was observed in 8 (20%) patients.

Fig. 6.

a MRI showing post-operative changes in left orbit with absence of medial wall of left orbit. Left globe is distorted. Extensive edema is seen in the left side of the face. b CT showing palatal necrosis with erosion and intra orbital extension

All these patients received medical therapy with either conventional or liposomal amphotericin B depending on their renal status and affordability, with total doses varying from 1.9 to 3.5 g. Most of these patients had dyselectrolytemia at least once during their course of treatment. Serum electrolytes, blood glucose and renal functions were monitored, and timely correction given. Oral Posaconazole was given for 18 patients following intravenous antifungal therapy. This was continued till the patients had no evidence of tissue necrosis and FSs were negative.

Medical therapy combined with limited or extensive surgical debridement was done in most cases. 29 (74.3%) patients required extensive surgical debridement that consisting of multiple endoscopic debridement, orbital decompression, subtotal/total maxillectomy and orbital exenteration (Table 2). 2 patients who had presented with intracranial involvement succumbed to the disease even before surgical debridement could be done.

Table 2.

Types of surgical procedures done in the study population

Surgical procedure	Number of patients (%)
Limited endoscopic surgical debridement	27 (69%)
Extensive Endoscopic surgical debridement	21 (54%)
External maxillectomy (partial/total/extended)	11 (28%)
Extensive endoscopic surgical debridement with orbital decompression	9 (23%)
External maxillectomy with orbital exenteration	1 (2.5%)

Non-survivors were more than 60 years of age (P value < 0.05), mostly male and had DM. 5 (13%) out of 39 patients died. 4 of these patients had intracranial involvement in the form of cerebritis, extensive intracranial involvement and cavernous sinus thrombosis. 1 patient died due to systemic septicaemia with bronchopleural fistula following a massive haemoptysis.

The mean duration of hospitalisation was 25 days (range of 7–120 days). The duration of hospitalization was found to be associated with the severity of disease at presentation and the time taken to treat the associated co-morbidities.

Discussion

Chakrabarti A has observed that there has been an increasing trend in the incidence of Mucormycosis in Asia and has termed it as ‘Fungal Emergency’. He concluded that the epidemiology of this form of invasive fungal infection (IFI) is different in the Western and Asian countries [6]. ROCM is the most common form of Mucor mycosis. DM has been implicated as the most common predisposing factor in Asian countries as compared to haematogenous malignancy and chemotherapy that has been associated with ROCM in western literature [6–8]. Uncontrolled DM provides an optimal milieu of acidotic micro-environment for growth of this invasive fungus. It also impairs polymorphonucleocyte chemotaxis and thus the host’s ability to defend the infection [8]. The high prevalence of DM and poor compliance to therapy are the most important challenges that need to be addressed in this part of the world.

Dental procedures should be done judiciously and only when DM is under control. 12 (30.1%) patients in this study had history of dental procedure and coexisting DM. 2 of these patients had a rapid progress of disease with intraorbital and intracranial involvement. Wali et al. have observed that most patients gave history of tooth extraction prior to the onset of ROCM [8]. Association of rapid progress of the disease and fatal outcome of ROCM following dental extraction is not uncommon [9, 10]. Incidences of extensive ROCM in immunocompetent individuals following dental extraction have also been reported [11, 12].

Mignogna et al. have identified the major risk factors that are associated with the occurrence of Mucormycosis. Out of 212 cases, majority of the patients (44.3%) where from India and of these 84 patients had ROCM. The authors have attributed this high incidence of Mucormycosis in India to the prevailing socioeconomic and climatic conditions in this part of the world [13].

Awareness of the clinical presentation and high index of suspicion will help in early diagnosis and treatment. Symptoms and signs depend on the extent and localisation of ROCM lesion. Initial symptoms are nonspecific and may be like chronic rhinosinusitis. Suspicion should arise if there is persistent deep-seated facial pain that is out of proportion to the initial clinical presentation especially in uncontrolled diabetic or after dental extraction. The presence of dark brown or black eschar or necrotic soggy turbinate on endoscopy should raise an alarm [14]. Oral manifestations are palatal ulceration, crusting, necrosis or a black eschar and loose tooth [15].

Unilateral Ocular symptoms such as lid oedema, ptosis, ophthalmoplegia, blurring/double vision and loss of vision are common [16]. Delirium, irritability, decreased mental function, neck rigidity and hemiplegia are indicators of intracranial spread of disease [8, 17]. Intracranial extension in ROCM occurs through haematogenous spread through the anastomoses between the external and internal carotid artery system, or by direct extension through the superior orbital fissure, superior orbital vein, or the cribriform plate. The patient and the attenders need to be counselled regarding the prognosis, the morbidity and mortality associated with intracranial extension before surgery is attempted [18].

As per the updated definition of IFI as laid down by the a consensus group of the European Organization for Research and Treatment of Cancer/IFIs Cooperative Group (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG), this study includes only histopathologically proven cases of ROCM [19]. Tissue from the suspected lesion either from the Nose or the oral cavity was taken in three parts and sent in separate container to the central lab for processing. One sample for FS examination (10% KOH mount) was sent in a sterile container, one sample for fungal culture and sensitivity was sent in isotonic saline and another sample sent in 10% formalin solution for histopathological examination (HPE). It was observed in this study that 71.7% of the samples sent were positive for aseptate hyphae. FS is a simple, rapid and economical test that can be done to ascertain the diagnosis of ROCM in suspected IFI and early treatment can be instituted [20, 21]. In this study of the 22 samples that were processed for culture, only 10 (45.5%) grew fungi. Successful tissue culture was reported to be 33% and 50% by Kontoyiannis et al. and Spellberg et al. respectively [22, 23]. Fungi is difficult to recover on culture, moreover the time taken for the report is longer [20, 21]. It is recommended that HPE, FS and culture to be used as an integral part of all suspected cases of ROCM [20, 21]. Molecular diagnostic methods enhance the likelihood of diagnosis of probable and possible IFI [19, 24].

Radiological evaluation is important for assessing the extent of disease and also aids in predicting the prognosis and response to treatment. The first radiological description was by Green et al. in 1987, they described the characteristic finding that was (a) nodular thickening of soft issue lining the paranasal sinus (b) absence of fluid levels in erect Roentgenograph (c) spotty bone destruction [25]. The CT scan is useful for evaluation of the extent of sinus involvement, extent of bone destruction and peri-sinus spread. The ethmoid sinus (50%) were the most frequently involved sinus followed by the maxillary sinus (41%) in this study and similar observation has been made by Jacob et al. [26]. Orbital involvement was observed as an orbital mass or thickening of the recti and optic nerve, as was seen in 12 (31%) of our patients. Intracranial extension with cerebral lobe involvement was observed in 20% in this study. Infiltrations of the periantral/perisinus fat planes are the earliest imaging findings suggestive of ROCM. Heterogeneous soft tissue shadows with areas of hyperintensity and Obliteration of fat planes in the peri-sinus region are characteristic findings on CT scan. MRI is useful in cases of skull base, orbital, orbital apex, perineural and intracranial extension [26–28].

The mainstay of treatment is aggressive surgical debridement to reduce the fungal load and enable better penetration of antifungal drug. Endoscopic endonasal surgical debridement is preferred. Surgical debridement varies from limited debridement or extensive debridement in the form of removal of all bone and soft tissue from the anterior and middle skull base to the upper jaw and palate. Sometimes, endoscopic endonasal orbital decompression will be required if limited intraorbital involvement is suspected. External maxillectomy combined with endoscopic debridement of involved sinus with or without orbital exenteration is sometimes required. Neurological and neurosurgical intervention will be required in case of intracranial spread. Surgical debridement played a crucial role in improving the treatment outcome [14]. In our experience, most often multiple debridement was necessary. Endoscopic endonasal surgical debridement, Pansinusectomy, orbital decompression, orbital exenteration and sometimes intracranial surgery were performed depending upon the extent of the disease. 8 (20%) of our patients underwent debridement more than once, 21 (54%) patients underwent pansinusectomy. Extensive orbital involvement by Mucorales required orbital exenteration in 1 (2%).

Antifungal therapy should also be commenced at the earliest. Liposomal Amphotericin B formulations are preferred over conventional forms as they can be given in larger doses with minimal side effect and better tolerance. For most patients, affordability is an issue, hence they opt for the conventional form. Oral Posaconazole is used as a switch-over drug and for maintenance therapy following the initial intravenous Amphotericin B. The DM status, renal functions and electrolyte balance needs to be frequently monitored. Hypokalaemia and acute kidney injury are the two main problems that are frequently observed during intravenous Amphotericin B therapy and needs to be addressed on day to day basis.

In this study it was observed that 12% of our patients succumbed to the disease despite vigorous multidisciplinary management. The poor prognosis was due to their late presentation, uncontrolled diabetes and intracerebral or pulmonary extension.

Vaughan et al. had conducted a meta-analysis on ROCM from 1994 to 2015. They searched the available literature to assess the survival outcomes and compare it with the review done in 1993 by Yohai et al. [29, 30]. It has been observed that the survival outcomes have not changed over the last two decades. However, those with renal disease had better outcome with the use of liposomal amphotericin B [29, 30]. All the non-survivors were older (> 60 years) and mostly male. DM remained an important comorbidity that dictated the outcome. Intracranial extension and pulmonary involvement were associated with high mortality [14, 29, 30].

Conclusion

• ROCM is IFI which has a rapid progress causing widespread tissue necrosis of nose, orbit and intracranial involvement in immunocompromised host causing significant morbidity and mortality.

• DM is the major comorbidity that dictates the outcome.

• High index of suspicion based on clinical presentation, fungal smear and histopathology examination is vital for early diagnosis and treatment.

• Early diagnosis of ROCM allows for aggressive control of the underlying medical illness and timely initiation of intravenous antifungal therapy and aggressive surgical debridement that is necessary in achieving adequate cure, reduce morbidity and mortality.

Authors’ Contributions

Prasanna Kumar Saravanam: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Experimental studies, Data acquisition, Data analysis, Statistical analysis, Manuscript preparation, Manuscript editing, Manuscript review, Guarantor. Vinay Raj Thattarakkal: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript editing, Manuscript review. Arthi Arun: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript preparation, Manuscript editing, Manuscript review.

Funding

Nil.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics Approval

Not applicable.