Rhino Orbital Mucormycosis Presenting as Palatal Ulcers-A Report of Two Cases : Case Report

Mucormycosis is a life threatening fungal infection caused by fungi of the order Mucorales and is one of the fulminant and fatal opportunistic infections, characterized by very acute onset, with a high mortality rate. Rhinocerebralmucormycosis is the most common type and its extension to the orbit and brain is quite usual. It is commonly reported in immunocompromised patients such as poorly controlled diabetics, immunosuppression with corticosteroids, hematological malignancy, solid malignancy, iron overload and burns. Mucormycosis is on the rise with an increase in incidence of Diabetes mellitus and HIV infection leading to immunocompromised status of the patient. Here in, reporting two cases of rhinocerebralmucormycosis in two diabetic patients with palatal perforation in both cases and this is a rare and late occurrence. One was in a known systemic lupus erythematosus (SLE) patient, which is a very rare incidence. Both the patients were successfully treated with a combination of surgical debridement and systemic amphotericin B administration. By presenting these two case reports we would like to point out that mucormycosis should be included in the differential diagnosis of hard palate ulcers and cellulitis, especially in diabetic patients.


Mucormycosis
(also known as zygomycosis or phycomycosis), is a rare lifethreatening infection caused primarily by fungi from the order Mucorales 9 .It was first described by Paulltauf in 1885 14 .Typically developed by poorly controlled diabetic patients, this opportunistic infection is characterized by a very acute onset.It produces vascular thrombosis and tissue necrosis and the most frequent form is the rhino-orbitocerebral 6 .The sites of pre-dilection for this infection are the nose and paranasal sinuses from where it involves the orbital structures and at times intracranial structures such as the cavernous sinus and the cerebral hemispheres 11 .Poorly controlled diabetics, immunosuppression with corticosteroids, hematological malignancy, solid malignancy, iron overload and burns are some of the conditions which predispose patients to the development of this disease 13 .Six clinical variants of mucormycosis such as "rhinocerebral, pulmonary, cutaneous, gastrointestinal, central nervous system, disseminated type" have been recognized so far 16 .The prognosis is poor, with severe sequelae and high mortality even in patients with a prompt diagnosis and correct treatment.
Here, we present two clinically and histopathologically proven cases of rhinomaxillarymucormycosis , clinically presented as deep palatal ulcers in diabetic patients.One case was in a known Systemic systemic lupus erythematosus (SLE) patient, which is a very rare occurrence.

Case report 1
A 30 year old female patient reported to the Department of Oral Medicine and Radiology, Tamilnadu Government Dental College and Hospital, Chennai -3, with a complaint of nasal regurgitation of food associated with a purulent discharge from the nasal cavityfor the past 30 days.Patient gave a history of spontaneous exfoliation of maxillary anterior teeth since two months (Fig 1 Biopsy was taken from nasal eschar, and it revealed non-septate hyphae with branches at right angles which confirmed the diagnosis of rhinocerebral mucormycosis.An antifungal regimen of amphotericin B 1mg/Kg/day was initiated.A sub total maxillectomy was done and the same antifungal regimen continued.The patient was on review for about a month, after which she failed to turn up for review.

Case report 2
A 29 year old female, reported to the Department of Oral Medicine and Radiology, Tamilnadu Government Dental College and Hospital, Chennai -3, with a chief complaint of pain and swelling on the right side of upper face for one month duration.The patient gave history of fever, before one month.The patient gave a history of diabetes mellitus for 2 years duration and diagnosed to have Systemic lupus erythematosus, nephroticsyndrome , along with lupus nephritis.The patient is moderately built and moderately nourished.
On extraoralexamination , there was diffuse swelling in relation to periorbital region of the right eye, with evidence of surgical scar in relation to right upper cheek region, 4 cm inferior to

DISCUSSION
Mucomycosis is a rare, invasive, fungal infection caused by fungi of the class phycomycetes 2 .It usually acts as an opportunistic pathogen 14 .There are six clinical forms of mucormycosis : rhinoorbito-cerebral, respiratory, gastrointestinal, cutaneouswidespread and mixed.The most frequent one is the rhino-orbitocerebral, with or without CNS involvement, but almost always with ocular damage 14 .Pterygopalatine fossa is considered to be the main reservoir for rhinocerebralmucormycosis, and extension into the orbit and facial soft tissues usually follows this route.After proliferation in the nasal cavity, the mucor reaches the pterygo-palatine fossa, inferior orbital fissure and finally the retroglobal space of the orbit, resulting in ocular signs 11 .
The sites of pre-dilection for this fungal infection are the nose and the paranasal sinuses from where it progresses to involve the orbit and at times intracranial structures such as the cavernous sinus and the cerebral hemispheres 11 .
Rhinocerebralmucormycosis begins with colonization of the nasal mucosa by air borne spores.Mucorales hyphae have a predilection for the growth into the artery and lymphatic systems.The fungi invade the nerves, fatty tissue and bone but muscles are usually spared.Angioinvation by the hyphae produces a fibrin reaction and the development of "mucor thrombi" which occludes the artery and lead to ischemia and infarction andconsequence formation of black necrotic eschar of the skin and mucous which is characteristic of rhinocerebralmucormycosis, is observed only in 20-40% of patients, and is a bad prognostic sign 12,

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. The infection spreads rapidly to adjacent sinuses and orbit and continue into the cranium via the ethmoid bone or orbital vessels 12 .
Rhino-cerebral mucomycosis mainly occurs in immunocompromised patients 13 .Poorly controlled diabetics, immunosuppression with corticosteroids, hematological malignancy, solid malignancy, organ transplant, chemotherapy, chronic renal insufficiency, iron overload and burns are some of the conditions which predispose patients to the development of this disease 13,14 It has been established that high glucose concentrations enhance fungus growth.In 1943 Gregory et al, reported 3 patients of RCM with fatal diabetic ketoacidosis 1 .About 70% of rhinocerebral cases (occasionally referred to as craniofacial) are found in diabetic patients in ketoacidosis 4 .Rhinocerebralmucormycosis continues to be the most common form of the disease, accounting for between one-third and one-half of all cases of mucormycosis 3 .Ulceration of the palate, is the commonest oral sign in mucormycosis , which results from necrosis due to invasion of a palatal vessel .Extension of the infection from the paranasal sinuses into oral cavity causes painful, black necrotic ulcerations in the hard palate .The palatal lesion is characteristically large and deep, causing denudation of the underlying bone .Differential diagnosis of a lesion presenting as palatal perforation should include mechanical trauma , tertiary syphilis , leprosy, cancrumoris, , intranasal cocaine abuse , malignancies such as nasal T cell lymphomas, Wegener's granulumatosis and midline non-healing granuloma .But, evidence of diabetes or immunosuppression in a patient presenting with necrotic lesions of the palate and nasal cavity strongly favours the diagnosis of a deep fungal infection 12 .
One of our patients presented with facial palsy on the right side.According to AlirezaMohebi et al , no obvious pathophysiology for facial nerve paralysis has been proposed yet.Some researchers believe that infection can reach from the pterygopalatine fossa to inferior orbital fissure, orbital apex, and infratemporalfossa .Whether or not the facial nerve is involved at stylomastoid foramen via mentioned pathway is not completely obvious 17 .
Both of our patients presented with oral and nasal symptoms with some orbital symptoms and CT scan revealed paranasal sinuses involvement without any evidence of CNS involvement .Erosion of bone is only the later manifestation of the disease.It has been suggested that any diabetic patient in a ketoacidotic state who presents with clinical and radiographic findings of rhino sinusitis should be suspected as having mucormycosis until proven otherwise 7 .
Computed tomography or magnetic resonance imaging are useful modalities to assess the extent of the disease.Paranasal sinuses were involved in both of our patients, as seen in computed tomography images.Radiographically, rhinocerebralmucormycosis has been associated with nodular thickening of sinus mucosa, sinusopacification without fluid levels, spotty destruction of the bony walls of paranasal sinuses 15 .
All these radiological findings were present in both of our patients.Radiological finding are helpful in assessing the stages of disease rather than making a definite diagnosis as because early lesions of rhinoorbitocerebralmucormycosis may mimic simple rhino sinusitis .Early diagnosis and treatment are of extreme importance for successful eradication of this invasive fungal infection and for patient survival.For a definitive diagnosis of mucormycosis, the histopathological specimen need not be of the isolated fungus, but may be a sample of the necrotic tissue from the site in question.The Grocott-Gomorimethenamine silver stain is the most effective for identifying fungi.However, haemotoxylin and eosin, periodic acid schiff or calcofluor white stains may also be used 15 .The detection of aseptate hyphae with right angled branching is pathognomonic 5 .Because initial cultures of diseased tissue may be negative, histopathological examination is essential for early diagnosis 15 .Mok CC et al 10 , reviewed the literature from 1970 till 2002 , reported that only eight cases of mucormycosis in Systemic lupus erythematosus patients were reported , worldwide .Even in this, Mok et al observed that disseminated form of mucormycosis was the most common presentation compared to rhino orbito cerebral, which lists one among the two of our cases to be a very rare case.Amphotericin B is usually administered for the management of mucormycosis, and isadministered intravenously, usually at a dose of 1mg/kg/day to a total dose of 3-3.5 gms, confers proven survival benefits in patients with mucomycosis 8 .Nowadays, we use liposomal amphotericin B, that although more expensive has less renal toxicity, fewer adverse effects, and a better solubility in the CNS.Hence the dose can be safely increased.Renal function as well as potassium and magnesium must be rigorously monitored during the treatment, that usually lasts for 3 to 7 months 14 .
The use of other drugs has been reported, such as the combination of rifampicin and amphotericin.In the US, posaconazole is employed in amphotericin resistance or intolerance, with good results.It can be administered orally, and is well tolerated with a high response rate.We can also find promising results with the use of granulocytemonocyte colony stimulating factor in patients with hematologic diseases 14 .Amphotericin B is partially effective therefore surgical debridement becomes essential.Antral wash, lateral rhinotomy, pansinusectomy, orbital exenteration, and sometimes intracranial surgery are performed depending upon the extent of the disease.Extensive orbital involvement by mucorales required orbital exenteration 11 .

CONCLUSION
Rhino orbito cerebral mucormycosis is an acute opportunistic mycosis that predominantly occurs in the patients with diabetes mellitus and in immunocompromised conditions.The dental surgeon may see patients with this deadly fungal infection in its earliest stages , presenting as palatal ulceration with other nasal and orbital symptoms.Early diagnosis, prompt controlling of predisposing factors like blood sugar control in diabetic patients, aggressive surgical debridment and, high dose amphotericin B are the most important factors to decrease the morbidity and mortality from this fungal disease .
) .Patient is a known type 2 diabetic since 4 years and hypertensive since 2 years.Patient was moderately built and debilitated.Examination of the nasal cavity revealed eschar of the right and left nasal septum.Intra oral examination revealed, denudation of gingiva in relation to maxillary teeth, extending from mesial of tooth #16 to mesial of tooth #26, with necrosis of underlying alveolar bone.There were empty tooth sockets in relation to # 13,12,11,21,22,23.A 3 x 1.5 cm sized oval perforation was noticed in the anterior region of the hard palate , exposing the bone of the hard palate (Fig 2).A through and through opening was formed due to perforation in the palate creating an oronasal fistula.Based on the history and clinical findings, a provisional diagnosis of mucormycosis was made.Random blood sugar was 368mg/dl .Paranasal sinus view radiograph was taken which revealed, destruction of nasal septum, floor of right nasal cavity and roof of right maxillary sinus.There was evidence of destruction of floor of right orbit also (Fig 3).Orthopantomograph revealed destruction of floors of right nasal cavity, right orbit and roof of right maxillary sinus.CT revealed destruction of nasal septum, and right nasal bone with soft tissue density lesion occupying the roof and posterior wall of right maxillary sinus.There was destruction of floor of right orbit.The lesion was seen to displace the nasal septum to the left (Fig 4).