Pterygopalatine Fossa- A Keystone Area in Disease Progression and Management in Rhino-Oculo-Cerebral Mucormycosis

Abstract

To analyze the involvement of disease in pterygopalatine fossa (PPF), its relation to regional extension of disease and the treatment outcome in rhino-oculo-cerebral mucormycosis (ROCM). A prospective study was done including 50 patients diagnosed with ROCM. All patients were examined and evaluated with high resolution CT and MRI imaging. Intravenous liposomal Amphotericin B was started, and endoscopic debridement was done based on the disease extension. Liposomal Amphotericin B is given until complete response for atleast a total dose of 3–4 g. T. Posaconasole 300 mg is given for 3–4 months in case of orbital or intracranial disease. 58% (29) patients showed involvement of disease in PPF. In MRI T1 contrast images, 21 of these patients showed hypo-intense lesion in the PPF and had necrotic tissue in PPF during surgery. Whereas, hyper-intense lesion that depicts inflammatory tissue was seen in the 8 patients. The tissue from these lesions showed aseptate fungal hyphae elements in histopathology in all these patients. 96% of patients with orbital mucormycosis (25 patients), 92% of patients with palatal mucormycosis (24 patients) and all patients with intracranial (15 patients) involvement had correlating PPF involvement in the disease process. The pterygopalatine fossa is the nidus for spread of disease and an important prognostic factor for extent of spread. Radiological imaging with CT and MRI are useful to assess the involvement of disease in PPF, and it is important to remove this disease during endoscopic debridement.

Introduction

Mucormycosis is an acute, rapidly progressive, angio-invasive infection caused by fungus of the order mucorales. It affects mostly immunocompromised individuals and has a mortality rate of around 30–60% [1]. In India, the prevalence of mucormycosis during the COVID-19 pandemic was around 0.14 per 1000 population, which is almost 80 times higher than the prevalence in developed countries [2]. The most common contributing factor for this is the increased prevalence of uncontrolled diabetes mellitus in India [3]. The excessive use of steroids during the COVID-19 pandemic, also contributed to a dramatic spike in mucormycosis cases. The disease can present in different forms, namely, rhino-oculo-cerebral, pulmonary, gastrointestinal, cutaneous and disseminated. The rhino-oculo-cerebral form of disease is the most common disease presentation.

Mucorales enter the human host through inhalation, percutaneous inoculation or ingestion [4]. The fungal spores adhere to the nasal mucosa through receptors and invade into the blood vessel. Hematogenous spread (Angio-invasive property) is the mode of invasion leading to rapidly disseminating disease. The fungus proliferates rapidly in acidic medium and spreads by attachment to the free iron in the blood stream. Hence, the disease is more common in uncontrolled diabetes patients in acidotic state.

The pterygopalatine fossa is considered as the main harbor for fungus proliferation. The pterygopalatine fossa communicates with various regions around it leading to spread of infection. It can spread superiorly through the inferior orbital fissure into the orbit and orbital apex, inferiorly through greater palatine vessel to the hard palate, laterally into the infratemporal fossa, and through Vidian canal and Foramen Rotundum to the intracranial cavity. The disease can spread to the cavernous sinus and intracranial cavity through the orbital apex. It is important to understand the extension of disease, as endoscopic debridement of all the infected dead tissue is an essential part of disease cure.

In this study, we have assessed the involvement of PPF in the disease process in patients of ROCM and its corresponding disease spread to adjoining areas of infratemporal fossa, orbit, palate and intracranial space.

Methods

This prospective study included 50 patients of ROCM in our tertiary care center over a period of 2 years during 2021–2023. The study included patients with clinical features suggestive of mucormycosis and proven on histopathological examination and KOH mount for aseptate fungus elements from nasal tissue.

Patients presenting to the ENT outpatient and emergency department with features of mucormycosis were assessed. The clinical features were recorded in a proforma. Diagnostic nasal endoscopy was done and suspicious tissues were sent for KOH mount and histopathological examination to confirm mucormycosis. CT and MRI imaging of paranasal sinus, orbit and brain were done to assess the disease extension. A multidisciplinary approach is necessary in treatment involving ophthalmologist, radiologist and medical physician. Medical treatment for mucormycosis was started with Injection liposomal Amphotericin B, along with electrolyte and renal parameter monitoring and blood sugar control.

Surgical debridement of paranasal sinus was planned based on the extent of disease in the imaging. The pterygopalatine fossa was opened in all cases, and the tissue was sent for histopathology examination of fungus. Orbital mucormycosis with limited disease was treated with orbit preserving procedures like medial orbital debridement and transcutaneous retrobulbar injection of Amphotericin B (1 cc given once a day for 3 consecutive days). Orbital exentration was performed in severe cases with absent vision. Palatal debridement was done in patients with palatal mucosal involvement. The hard palate was excised in patients with necrotic palatine bone and an obturator was fixed.

The study population was categorized into 2 groups - Group I with disease in pterygopalatine fossa and Group II with no disease in pterygopalatine fossa. The extensive spread of disease into orbit, intracranial spread, palate, infratemporal fossa and skull base osteomyelitis were compared between the groups.

Injection liposomal Amphotericin B 250 mg daily (preferably), or deoxycholate Amphotericin B 50 mg daily until a total dose of 3–4 g. This is continued further until complete resolution of clinical, histopathological and radiological features of infection. Tablet Posaconazole 300 mg was given for a further period of 3–4 months in patients with involvement of orbit, intracranial extension and osteomyelitis. The patients were kept on regular follow-up for 6 months. Nasal endoscopy was done every month for 3 months and then at 6 months. MRI imaging was done in suspicious cases to look for recurrence.

Results

The study included 50 patients with most common age group between 40 and 60 years. More males were affected than females in the study population. 48 patients had a prior history of, or were newly diagnosed with diabetes mellitus. 32 patients in the study had history of COVID-19 infection in the recent past. These characteristics of the study population are summarized in chart 1.

Chart 1.

Study population

Endoscopic debridement was done addressing all tissues involved with disease and were correlated with the imaging findings also. The regions involved are as summarized in chart 2.

Chart 2.

Regions involved by mucormycosis in the study population

Tissue from pterygopalatine fossa was sent separately for histopathological examination to look for fungal elements. The Pterygopalatine fossa was involved in 29 patients (58% of study population). 21 of these patients had white necrotic tissue and in the remaining 8 patients, inflammatory tissue was seen (Figure 1). All 29 patients had presence of broad aseptate fungus elements on histopathology.

Fig. 1.

Intraoperative finding with disease in pterygopalatine fossa (a) White necrotic tissue in PPF (b) Inflammatory tissue in PPF

The presence of fungus in pterygopalatine fossa were retrospectively correlated with the CT and MRI findings and the sensitivity of the imaging modalities were assessed. Figure 2 depicts disease involvement in PPF as seen in CT and MRI imaging. The CT scan findings had a sensitivity of 68.96% and specificity of 85.71% to diagnose disease in pterygopalatine fossa. The MRI scan findings had a sensitivity of 100% and specificity of 90.5% in our study (Chart 3).

Fig. 2.

Imaging findings showing disease in pterygopalatine fossa. (a) CT finding- soft tissue opacification in pterygopalatine fossa and retromaxillary area. (b) MRI finding- hypodense lesion in pterygopalatine fossa with surrounding hyper dense lesion in retro maxillary area in T1 post-contrast image

Chart 3.

Predictive analysis of imaging to diagnose disease in pterygopalatine fossa

The study population was categorized into 2 groups - Group I with presence of disease in pterygopalatine fossa and Group II with no disease in pterygopalatine fossa. Group I had 29 and group II had 21 patients. The extensive spread of disease into orbit, intracranial spread, palate, infratemporal fossa and skull base osteomyelitis were compared between the groups.

Orbital involvement- Out of the 26 patients with disease in orbit, 25 patients had disease in pterygopalatine fossa (96%). Orbital management was done based on the extent of disease in orbital tissue in MRI imaging and fundoscopy findings [5]. Orbital exenteration was required in 10 patients. All these patients had disease involvement in the orbital apex and pterygopalatine fossa. Medial orbital debridement with decompression was done when only the medial compartment in orbit was involved by disease (6 patients). Transcutaneous retrobulbar Amphotericin B injection was given along with orbital decompression for all patients with orbital mucormycosis managed conservatively (16 patients).

Intracranial spread- 15 patients had intracranial spread of disease. Cavernous sinus thrombosis was the common finding seen in 12 of these patients. 5 patients had meningitis, 3 patients had ICA thrombosis, and 1 patient had an intracranial abscess. All these 15 patients had disease in pterygopalatine fossa (100%).

Palate involvement- 26 patients had disease involving the hard palate. 24 of these patients had disease in pterygopalatine fossa (92%).

Infratemporal fossa involvement- 29 patients had ITF involvement in all patients with disease in pterygopalatine fossa (100%).

Skull base osteomyelitis- 3 patients had features of osteomyelitis involving skull base. All these patients had disease in pterygopalatine fossa (100%).

In our study, mortality was seen in 5 (10%) patients. All these patients had intracranial spread of disease. 45 patients (90%) had complete cure from disease after antifungal therapy. No loco regional recurrence of disease was seen in these patients. MRI scan was done in case of intracranial or orbital disease to look for disease control. CT scan was repeated to look for control of osteomyelitis.

Discussion

Mucorales are ubiquitous saprophytic fungus found on soil and decaying organic matter. Mucormycosis was first described by Paltauf in 1885 [6]. It is also called as zygomycosis or phycomycosis. Mucor, rhizopus, rhizomucor and cunninghamella are commonly reported genera in Mucorales [7]. The route of entry is commonly by inhalation of the fungal spores. The disease manifests only in patients with an underlying immunocompromised state. The main mechanism of spread is by angio-invasion of the blood vessels. Following spread, there is vascular thrombosis and tissue necrosis leading to disease manifestation [8].

Many studies support that diabetes mellitus and ketoacidotic state as major risk factor for mucormycosis [9]. COVID associated mucormycosis is more common in developing countries [10, 11]. In India, the drastic increase in incidence of mucormycosis was seen after diabetes mellitus patients contracted COVID infection [12]. Acute pancreatitis caused by COVID infection can be the possible cause for new onset of diabetes mellitus. Excessive use of steroids during treatment lead to high rates of uncontrolled diabetes.

In our study, 50 patients diagnosed with rhino-oculo-cerebral mucormycosis were involved. Almost all patients (48 patients) had uncontrolled diabetes mellitus as the underlying cause. Chronic renal disease and hypertension was the underlying disease in the other 2 patients. Out of the total 50 patients, 32 patients had history of prior/co-existent COVID-19 infection and treatment with steroids. All these 32 patients had uncontrolled blood sugar levels with either pre-existing or newly diagnosed diabetes mellitus. This is in concordance with the rapid rise in mucormycosis cases in India during the COVID-19 pandemic [13].

The pterygopalatine fossa is the main reservoir of infection for mucor that serves as a conduit for infection to move to the other sites [14]. The mucor can spread from the pterygopalatine fossa to the infratemporal fossa, palate, inferior orbital fissure, orbital apex, cavernous sinus, and intracranial structures. In a study by Hosseini et al. [15], all patients who had disease involvement in pterygopalatine fossa and disease spreading to adjoining areas were seen.

In our study, the pterygopalatine fossa was assessed in all patients. 29 patients had positive fungal elements in histopathology. 21 of these patients had necrotic tissue in the PPF with necrosed sphenopalatine artery. 8 patients had thick gritty inflammed tissue which was positive for fungus. CT and MRI findings were correlated with the intraoperative finding. The CT scan findings had a sensitivity of 68.96% and specificity of 85.71% to diagnose disease involvement in pterygopalatine fossa. The MRI scan findings had a sensitivity of 100% and specificity of 90.5%. The common finding in CT scan was of fat stranding in the retromaxillary area with enhancement in contrast images. MRI scan was a better modality to assess disease in PPF. T1 post contrast hypo intense lesion in PPF is a diagnostic sign corresponding to necrotic tissue. Likewise, hyperintense lesions suggested ongoing inflammatory disease in PPF. MRI scan is more sensitive and specific tool than CT scan to assess the extent of disease. CT scan is preferred only to assess bony involvement of the disease. The principle of debridement followed is that all dead necrosed are to be removed. The extent of surgical debridement is done based on the findings in the imaging to ensure removal of all diseases dead tissue.

Almost all patients with regional spread of disease had disease involvement in pterygopalatine fossa in our study (Chart 4). This implies that in most cases, the PPF serves as the pathway for disease spread to adjoining regions. Thus, it is important to address the disease in PPF during treatment. Surgical debridement of disease in PPF is always recommended along with sinonasal debridement. In a study of 39 patients of ROCM by Darla et al. [16], it was found that 74.3% of patients had disease involvement in pterygopalatine fossa.

Chart 4.

Regional spread of disease Vs Disease in pterygopalatine fossa

Liposomal Amphotericin B is the systemic antifungal agent of choice to treat mucormycosis. A recent study by Brunet et al. [17] stated that liposomal Amphotericin B is the anti-fungal drug of choice for treating mucormycosis. Surgical debridement of all diseased tissue is necessary prior to giving medical therapy [18]. Dosage of 5-10 mg/kg of liposomal Amphotericin B up to a total dose of 250 mg/day in 5% dextrose was given daily to all patients. The total duration is individualized to each patient based on the disease extension. Injection Amphotericin B is given for a total dose of atleast 3–4 g and is continued until a complete response is obtained in the form of resolution of clinical features, no radiological features of residual disease and absence of fungal growth from nasal tissue biopsy [19]. MRI imaging was done to evaluate intracranial and orbital disease to look of control of disease. In patients with orbit or intracranial extension, T. Posaconasole was given as 300 mg BD as loading dose and continued with 300 mg OD for 3–4 months. After discharge, the patients were followed up weekly for clinical evaluation for the first month. Thereafter, a monthly follow-up for atleast 6 months.

Conclusion

Multidisciplinary management involving various specialties like otorhinolaryngologist-physician-endoscrinologist-neurophysician-ophthalmologist-radiologist-orthodontist form a vital role in complete management of mucormycosis. Pterygopalatine fossa is the hive for the fungus to harbor and proliferate to spread to its surrounding areas. The pterygopalatine fossa has to be addressed during endoscopic surgery. Debridement in mucormycosis is not just a sinus surgery but also of surrounding areas and skull base. Thus, the pterygopalatine fossa and the surrounding regions involved must be evaluated in CT/MRI scan and disease extent correlated clinically.

Author Contributions

Dr. Gopishankar S had contributed with the review of literature, analysis and interpretation of the data. Dr. Renuka Bradoo and Dr. Anagha Joshi had peer reviewed our article and helped in guiding and proof-reading. Dr. Sakshi gavendra contributed in collecting data and patient management.

Funding

The author(s) received no financial support for the research, Authorship, and/or publication of this article.

Declarations

Conflict of Interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.