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Rhinoorbito-cerebral mucormycosis is an uncommon and acute fungal infection which runs a fulminant course. Uncontrolled diabetes mellitus is the most common predisposing factor.
To assess the outcome of a poorly controlled diabetic with Rhinoorbito-cerebral mucormycosis using a multi-modality management.
We report a case of a 57-year old male who presented to us with proptosis and total external ophthalmoplegia diagnosed with rhino-orbito-cerebral mucormycosis. Patient was started on conventional intravenous amphotericin B to which he developed systemic toxicity. As an alternative, a combination therapy of oral posacanazole along with peribulbar amphotericin B injections for a more localised effect was initiated.
He had a favourable outcome with dramatic improvement in vision and marginal recovery of extra ocular movements within 20 days of initiation of combination therapy.
Rhinoorbito-cerebral mucormycosis is a major diagnostic dilemma with quick progression and a high mortality. Prompt medical management with a multi-modality approach can save the patient from orbital exenteration
Mucormycosis is a group of invasive infections caused by filamentous fungi of the order mucorales of the mucoracease family. Rhinoorbito-cerebral mucormycosis is a rare opportunistic infection affecting the nasal passages, sinuses, orbit, oral cavity and the brain. It is also known to occur in immunocompromised states like hematological malignancies, desferroxime therapy and renal transplant patients 1,2. The most common ocular manifestations include lid edema, proptosis, restriction of extraocular muscle movement , orbital fullness, decreased visual acuity and deep seated orbital pain. Successful management requires early diagnosis, prompt treatment of the underlying predisposing factors where possible, antifungal therapy and surgical debridement in selected cases.
We report a 57-year old with poorly controlled diabetic who presented with complaints of pain, diminution of vision for both distant and near vision, limitation of ocular movements with double vision and complete drooping of the right eye lid of one week duration. He had had similar complaints in the same eye 4 months prior to this episode for which he had been diagnosed with right rhinoorbital mucormycosis with cavernous sinus thrombosis and orbital apex syndrome. This had been confirmed with histopathology of the right maxillary sinus discharge at another centre. He was treated with intravenous liposomal amphotericin B for 3 months up to a total of 6gm. He had made marginal improvement.
On arrival at St Johns Medical College Hospital, Bangalore, India, his best corrected visual acuity in the right eye was counting fingers at half meter. He also had periorbital edema with complete ptosis, 3 mm of axial proptosis in comparison to the other eye, pale chemosed conjunctiva and clear cornea. The pupils were 4 mm and poorly reacting, with a total external ophthalmoplegia. Fundus examination was within normal limits. Examination of the nose showed crusting. MRI showed a hypointense mass extending from the right maxillary sinus into the intraorbital region and the orbital apex (Fig. 1). Endoscopic debridement of the sinuses was performed and the histopathology of the specimen from the sinuses showed predominantly aseptate wide ribbon like hyphae and the presence of tissue necrosis without angioinvasion suggestive of mucor species .
Intravenous liposomal amphotercin B was started with a dose of 1mg/kg/day with close electrolytes monitoring. This was gradually increased to 5mg/kg/day. However, the patient did not show any improvement for the first week, during which both his ocular and systemic condition started deteriorating. During this period his vision worsened to hand movements close to face and the proptosis increased by 2 mm. He also developed amphotercin B induced hypokalemia with mild renal failure. As a result of which intravenous Amphotericn B was discontinued. In view of the continued worsening condition of the patient and to avoid exenteration, oral posacanoazole was commenced in a dosage of 400mg BD along with alternate day peribulbar amphotericin B injections 6 ml of 0.5mg/ml after informed consent. Oral posaconazole was well tolerated by the patient and the injections were given for 14 days on alternate day basis. Regular nasal amphotercin B douching was done along with endoscopic debridement of sinuses when required. Over a period of 20 days visual acuity improved to 20/60; ptosis and proptosis reduced significantly. Extraocular muscle movements improved by 1 step but did not return to normal. The patient’s general condition improved and was discharged on oral posaconazole. It was discontinued after 60 days and the patient was followed up for 1 year and continued to be asymptomatic with no evidence of active disease. His best corrected visual acuity continues to be maintained at 20/60.
Mucormycosis is an opportunistic, fulminant, fungal infection caused by a member of the class zygomycetes. It is commonly found in soils, decaying organic matter and manure. These fungi are primitive fast growing, saprophytic aerobic fungi3. Earliest report of Rhinoorbito-cerebral mucormycosis was by Paltauf1 in 1885 and subsequently by Gregory et al3 in 1943 who reported three such cases in patients with uncontrolled diabetes with unilateral orbital cellulitis, complete ophthalmoplegia, cerebral tissue invasion, and death.
Mucormycosis is on the rise in the present day clinical scenario partly due to increased knowledge of the infection and thus a better diagnostic yield and also prolonged use of new antifungal drugs ineffective against zygomycetes as prophylactic or emperical treatment in bone marrow transplant recipients or other immunocompromised patients 1,12. In a French study by Bitar et al1,they demonstrated an increased incidence of disseminated mucormycosis cases from 0.7/million in 1997 to 1.2/million in 2006. Uncontrolled diabetes mellitus was the most common predisposing factor in 60 – 80% of cases1.This is moreso as the acidic environment created by the ketoacidosis provides an ideal environment for the growth of these organisms1. Diabetic patients with RCOM also have the best chance of survival, as the underlying metabolic derangement is most amenable to treatment1. For a good outcome, it is important to diagnose the disease early and treat aggressively as venous thrombosis impairs the drug delivery. There is also the difficulty in aggressive surgical management because of poor access to the location of the infections1.
Mucormycosis is confirmed by histopathological examination and potassium hydroxide staining preparation of biopsy specimens obtained from the nasal cavity. Imaging should be done to evaluate the extent and progression of the disease.
To date, the antifungal of choice has been amphotericin B at the highest tolerable dose. Other alternate promising options include hyperbaric oxygen, echinocandins, iron chelation therapy, posacanazole, pro-inflammatory cytokine and GM-CSF.1
Imbernon et al10 demonstrated in their study the benefit of oral posacanazole in combination with echinocandins and amphotericin B.
Posacanazole as a salvage therapy for zygomycosis was demonstrated by Greenberg et al11 who reported a cure in 17 of 19 (89%) patients on monotherapy, all of whom had developed toxicity to systemic amphotericin B. This usually can be given for several months without development of toxicity or resistance. It is given as a sequential therapy following liposomal amphotericin B due to the delay in plasma concentration achieved by it1,11. However long term effects of this drug is still unknown.
Therefore as a second line of management and a salvage therapy our patient was started on oral posacanazole 800 mg daily dose with periorbital amphotericin injections to achieve higher concentration in the orbit and to avoid thrombosis of vessels. The combination of the two modalities proved effective with visual acuity improvement and reduction of proptosis.
Though there has been a report by Joos et al in which they tried an intra-orbital irrigation with Ampotercin B1 , a combination of oral posacanazole with peribulbar amphotericin B injections is uncommon.
Mucormycosis has high mortality and morbidity despite treatment with permanent neurological deficits being common. Early diagnosis, prompt and effective combination therapy give a good outcome. However, there is a need to further test this treatment regime on a larger group of patients.
Competing Interests: The authors have declared that no competing interests exist.
Grant support: None