Reconstruction in Rhino-Orbito-Cerebral Mucormycosis Survivors

Abstract

Background

The COVID-19 pandemic has affected the entire world tremendously. Particularly during the second wave in India, a dangerous complication followed in the form of COVID-19–associated mucormycosis. On June 7th, 2021, the Indian Union Health Minister stated that 28,252 cases of mucormycosis were reported from 28 states/Union territories in the country.

Methods

A PubMed search was conducted for English-language studies published from 1988 through May 22, 2021 using the terms “reconstruction AND mucormycosis.”

Results

The search yielded 102 results. After excluding the articles not describing reconstruction in mucormycosis, 53 abstracts were screened. Then 34 articles dealing with reconstruction in non-ROC regions were excluded. The full text of 16 articles was reviewed. Additionally, 3 articles were identified from the reference search. Due to the aggressive debridements, rhino-orbito-cerebral mucormycosis survivors may be left with complex tissue defects with significant functional and aesthetic impairments. It is essential to offer reconstructive solutions that improve their quality of life. As far as the timing of reconstruction is concerned, the consensus is in favor of delayed reconstruction after ensuring that the infection has been eliminated/controlled and that there are no recurrences. The most common defects encountered were the ones that resulted from orbital exenteration and excision of a varying extent of the involved contiguous bony and soft tissue structures. Reconstruction with pedicled flaps was preferred rather than free flaps, especially in the cases where the infection was not eliminated completely. Adjuvant antifungal therapy was used in most of the cases. Long-term follow-up was considered essential to detect and treat recurrences.

Conclusions

A multitude of options are available for reconstruction in rhino-orbito-cerebral mucormycosis including skin grafts, pedicled flaps, free flaps and in some cases implants and prosthetics. These can be utilized to give as much as functional and aesthetic restoration as possible to the patient.

Introduction

The COVID-19 pandemic has affected the entire world tremendously. In India, the impact of the second wave was huge, with 19.29 million confirmed cases and 242,211 confirmed deaths reported between March 1 and June 30, 2021.¹ Particularly during the second wave, a dangerous complication followed in the form of COVID-19–associated mucormycosis (CoAM).² Widely reported in the popular media as the “black fungus,” CoAM had been declared by many states in India as an epidemic and a disease notifiable to the national health authorities.³ A systematic review of CoAM identified 101 cases, of which 82 were from India and 19 from the rest of the world, with a 31% mortality rate among the patients. It was also found that approximately 59.4% of these cases occurred during an active COVID-19 infection and 40.6% occurred in the survivors of COVID-19.⁴ On June 7, 2021, the Indian Union Health Minister stated that 28,252 cases of mucormycosis were reported from 28 states/union territories in the country, of which 86% cases had a history of COVID-19 and 62.3% had a history of diabetes.⁵

John et al found out that the clinical presentation of CoAM was similar to the clinical picture of mucormycosis in diabetic individuals where rhino-orbital or rhino-cerebral disease predominates.⁶ Rhino-orbito-cerebral mucormycosis (ROCM) refers to the entire spectrum ranging from limited sinonasal disease, limited rhino-orbital disease, to rhino-orbital-cerebral disease with central nervous system involvement.⁴ Patients with ROCM usually require multiple radical debridements for controlling the infection along with antifungal agents. A recent review of 41 cases of CoAM by John et al found that 33 (80%) of these patients underwent adjunct surgery (sinus and thoracic cavity debridement, orbital exenteration, decortication, and lung resection).⁶ In ROCM, this results in a variety of composite tissue defects of the facial region. In India, it is expected that over the course of next few months, many survivors of CoAM will present for reconstructive needs. The purpose of this review is to summarize the evidence regarding reconstruction in ROCM from the available literature to provide directions for the reconstructive efforts in CoAM survivors.

Methods

A PubMed search was conducted for English-language studies published from 1988 through May 22, 2021, using the terms “mucormycosis AND reconstruction.” Studies that dealt with reconstruction in rhino-orbito-cerebral mucormycosis were included. Studies that dealt with reconstruction in non-ROC mucormycosis and those that did not describe reconstruction were excluded. A manual search was also performed of the references of the selected articles. The final list of the selected articles was mutually agreed upon by the authors.

Results

The search yielded 102 results. After excluding the articles not describing reconstruction in mucormycosis, 53 abstracts were screened. Then 34 articles dealing with reconstruction in non-ROC regions were excluded. The full text of 16 articles was reviewed. Additionally, 3 articles were identified from the reference search. The selection process of the articles included is shown in Figure 1. There is a paucity of literature regarding reconstruction in ROCM, as it was a relatively uncommon disease before the COVID-19 pandemic. The available literature is in the form of isolated case reports or as a part of case series describing orbital exenteration. The available literature is summarized here. Some of the pertinent etiopathological, clinical, and therapeutic issues to be considered during reconstruction are also discussed.

FIGURE 1.

PRISMA flowchart, showing the selection process of the articles included in this review. ROC indicates rhino-orbito-cerebral.

Discussion

Etiology

Mucormycosis is a clinical syndrome caused by some genera of fungi belonging to the order Mucorales, which is a member of the class Zygomycetes.⁷ These are ubiquitous saprophytic fungi but become pathogenic in an immunocompromised host.^7,9 They grow rapidly and release large numbers of spores that become airborne and are inhaled by humans, hence they are frequently found in the upper airway mucosa. Mucormycosis is classified into 6 categories (Table 1).

Table 1.

Etiopathology of Mucormycosis

1. Causative agents10

Most common genera: Rhizopus spp., Mucor spp., and Lichtheimia (formerly absidia and Mycocladus) spp.

Less common: Rhizomucor, Sakseanea, Cunninghamell, and Apophysomyces spp.

2. Categories of mucormycosis

rhino-orbito-cerebral

pulmonary

cutaneous

gastrointestinal

disseminated

other unusual presentations

3. Possible predisposing factors in COVID-194

• hypoxia

• elevated blood glucose (diabetes, new-onset hyperglycemia, steroid-induced hyperglycemia)

• acidic medium (metabolic acidosis, diabetic ketoacidosis)

• high serum iron levels (raised ferritin)

• reduced phagocytic activity of the white blood cells due to immunosuppression (SARS-CoV-2 mediated, steroid mediated, or due to comorbidities)

• prolonged hospitalization with or without mechanical ventilation

ROCM is the most common form of presentation, seen in nearly 40% of cases.^9,10 Rhizopus oryzae is responsible for nearly 60% of mucormycosis cases in humans and accounts for 90% of the cases of ROCM.⁴ Once considered a fatal disease, the prognosis of ROCM remains poor with mortality rates of 15 to 34%.^7,11 Intracranial extension is very dangerous and must be prevented with early treatment.¹²

Pathophysiology

There are several possible factors that could be responsible for the germination of Mucorale spores in COVID-19 patients (Table 1).

Mucormycosis is an angioinvasive disease. Vascular invasion by the fungal hyphae produces a fibrin reaction and the development of mucor thrombi or dissecting aneurysms, which can lead to tissue ischemia and infarction.⁷ The infarction produces the black necrotic eschars in the nasal and oral cavities and face that are characteristic of ROCM. Vascular occlusion also impairs the penetration of the antifungal agents. The infection can spread rapidly to the sinuses and orbit and then into the cranium by direct extension through the ethmoid bone or orbital vessels. Mucorales can also cause cavernous sinus or carotid artery thrombosis.¹³ This results in a high risk of lethal outcomes or hematological spread and dissemination into other organs, such as the brain or lung.¹⁴

Clinical Presentation

Patients usually present when the infection extends to the orbital region. Clinical features may include fever, palpebral edema, ptosis, proptosis, decreased visual acuity, acute sinusitis, erythema over the sinuses, headache, and dark nasal and/or palatine mucosal eschar.^9,10,15 In patients with altered consciousness, imaging can be used to confirm clinical suspicion.⁸

Assessment and Diagnosis

Imaging should be used for initial evaluation. Computed tomography findings include mucosal thickening and occupation of paranasal sinuses, with the ethmoid and maxillary sinuses being most frequently involved; cavernous sinus thrombosis and cranial base involvement may be found in some cases. Magnetic resonance imaging may show hypointense areas in both T1- and T2-weighted images. The gold standard for diagnosis is biopsy and histopathology.⁸ Tissue biopsies can be obtained from endoscopy or during surgical debridement.⁹ These fungi are characterized by nonseptate, wide ribbon-shaped hyphae, branching at angles ranging from 45 to 90°.⁸ The laboratory culture of Mucorales is very difficult and often unsuccessful.¹⁴

Management

Overview of the Management of ROCM

Early diagnosis and treatment are vital for a successful outcome in ROCM.¹⁰ Treatment consists of the correction of the underlying predisposing factor(s) wherever possible, antifungal medications, improvement of the general health status, and radical surgical debridement of the necrotic and infected tissues.

The vascular invasion by the fungi may prevent adequate delivery and penetration of the antifungal agents into the affected areas; hence, adjunct surgical intervention may be needed. Surgical debridement reduces the microbial load and aids in diagnosis by enabling identification of the organisms. It also changes the anaerobic and microaerophilic tissue environment, which favors fungal growth. Debridement should continue to well-perfused bleeding tissues, taking into consideration the vaso-occlusive effects of mucormycosis. Sometimes a multidisciplinary approach involving various surgical specialties may be needed during the debridement.⁸ Very often multiple debridements may be required.¹⁶ It should be remembered that the cosmesis and possible loss of function should not take precedence over satisfactory surgical excision.¹⁵ According to a study published by Tedder et al, debridement of all infected tissues reduces the mortality by 49%.¹⁷

Where possible correction of the underlying predisposing factor, such as reversal of immunosuppression, leads to improved outcomes.¹⁰ Other adjunctive measures include aggressive management of acidosis and hyperbaric oxygen therapy.⁷

Aims of Reconstruction in ROCM

Owing to the aggressive debridements needed for clearance of the infection, ROCM survivors may be left with complex tissue defects, which may be associated with significant functional and aesthetic impairment. It is fundamental to offer reconstructive solutions that improve their quality of life once the infection has been brought under control.¹⁰ The aims of reconstruction may differ in individual cases according to the tissue and functional deficits present. These may include providing wound coverage, obliteration of the dead spaces, closure of fistulae, and restoration of the skeletal structure. It is important to try to restore as much function as possible and try to get a socially acceptable appearance for the patient. Functional goals include restoration of nasal breathing, oral nutrition, and comprehensible speech. Aesthetic goals are to restore cover, form, and volume, and in cases where orbital exenteration has been performed, to enable usage of an eye prosthesis that will look as natural as possible.¹⁶

Prerequisites for Reconstruction

The most important prerequisite is to achieve clearance of the infection. Metzen et al recommended delaying the reconstructive surgery until it is known that the patient is going to survive, infection has been cleared, and the remaining tissue is healthy.¹⁴ As and when required, serial imaging can be used to monitor the disease process and to guide further debridements. Biopsies play an important role in ensuring that the residual tissues are free from infection. Reinbold et al advocated controlling the infection with long-term antifungal therapy to ensure the success of free tissue transfers because the angioinvasive nature of the fungus can lead to thrombosis and vascular dissections.¹⁸ The vascular obstructions can also impede the penetration of antifungals into the tissues invaded by the fungus. To promote faster clearance of the infection, Navarro-Perea et al combined local treatment of the wound with liposomal amphotericin B along with the systemic treatment and achieved clearance of the infection within 1 month in 2 cases permitting subsequent reconstruction.¹⁰ Frozen section analysis of the margins can be performed to ensure clearance, especially when debridement and reconstruction are being performed simultaneously.

Timing of Reconstruction

The timing of reconstruction in the studies reviewed is given in Table 2. Based on the available literature, the consensus is in favor of delayed rather than immediate reconstruction after ensuring that the infection has been eliminated/controlled and that there are no recurrences. In the reports that described immediate reconstruction after debridement, patients had already been treated sufficiently with antifungals before the surgical intervention.

Table 2.

Summary of Studies Reviewed

No.	Source, Year	Study design	No. of patients reconstructed for post-ROCM defects	Diagnosis and Patient details (age, sex, predisposing factor/s)	Timing of reconstruction	Tissues resected/Tissue defect	Tissue defect	Reconstruction performed	Adjuvant antifungal treatment	Complications related to reconstruction	Last follow-up	Remarks
1	Alfano et al,13 2006	Case report	1	Combined mucormycosis and aspergillosis of rhinocerebral region (50 y, F, latent diabetes mellitus)	Immediate (patient was treated with combination of antifungals for 6 weeks prior to the surgery along with daily dressings)	Right maxilla and sinus, orbital floor with orbital exenteration, nasal bones, lateral side of the vomer, right hard palate, alveolar process, ethmoid bone, anterior wall of sphenoid bone	A large complex cavitary defect in place of orbit, maxilla, nose, palate, and alveolus on the right side	Pedicled pectoralis major myocutaneous flap + skin graft (skin paddle was used to reconstruct the palate, muscle obliterated the defect cavity, and a skin graft covered the deep surface of the muscle)	IV combined therapy of Voriconazole (6mg/kg for 2 doses followed by 4 mg/kg twice a day) + Caspofungin (70 mg on day 1 followed by 50 mg/day once a day) + liposomal Amphotericin B (1.5 mg/kg/day once a day was used for 6 weeks before surgery and continued for 6 weeks after the surgery	relapse of fungal infection, fungal attachment to the flap, and partial necrosis of the flap. It was managed with dressings and continued antifungal treatment	17 months after surgery, patient was left with a mucosalized cavity from the oropharynx and the posterior sphenoid wall to the right orbit, with no evidence of active disease.	This was a case of combined Mucormycosis and Aspergillosis. The authors mention their preference for pedicled flaps over free flaps considering fungal affinity for blood vessels.
2	Alleyne Jr et al,7 1999	Case report	1	ROCM (24 y, M, diabetic)	Immediate (after the second session of radical debridement performed by a multidisciplinary team. Orbital exenteration and debridement of right maxillary sinus were already performed earlier at a different center, where antifungal agent was already started)	Right orbital exenteration, right maxillary sinus, exenteration of ethmoid and sphenoid sinuses, right palate and alveolus	A complex defect in place of orbit, maxilla, palate, and alveolus on the right side and skin defect over right maxillary sinus	Temporalis muscle flap (anterior two-thirds of the muscle transposed across the defect in orbit and anterior cranial fossa to obliterate the communication between intracranial and transfacial dissections)	Amphotericin B was already being used at presentation. After reconstruction, IV and intrathecal administration of amphotericin B and intravenous rifampin were used for 35 days in a health care setting followed by intrathecal administration of amphotericin B (0.2 mm and 2 ml sterile water) twice a week for 4 weeks in an outpatient setting	deterioration of some skin in the eye socket at 6 month follow-up	12 months after surgery, no evidence of disease	In this case, multimodal therapy that included intravenous and intrathecal medical therapy, interventional neuroradiology, and aggressive resection was used.
3	Augustine et al,15 2017	Case series	2	Case 1: ROCM (2 y, M, chemotherapy for acute lymphoblastic leukemia)	Immediate (after diagnosis of ROCM, patient was treated with liposomal amphotericin B 3.8 mg/kg /day for 1 year without surgical intervention due to the presumed poor prognosis of the patient. Also, debridement was done with frozen section analysis of margins to ensure clearance)	Left medial maxilla, hard palate, alveolus, nasal septum, exenteration of left ethmoid sinuses	Defect spanning from root of the nose to palate and entire alveolus	Free fibula osteocutaneous flap (osteotomy to recreate the curve in the anterior palate, skin paddle inset into the soft palate and alveolus, dorsal nasal strut reconstructed with a bone graft plated to the frontal bone)	Liposmal amphotericin B 50 mg in 50 cc D5W over 2 hours everyday (duration not mentioned, but repeat biopsies taken during revision were negative for mucormycosis and the patient was discharged 2 weeks after surgical revision)	Reexploration of vascular anastomosis, partial dehisence of the flap needing surgical revision	6 months after surgery, no signs of recurrent infection, flap settled well and mucosalized fully	Patient died due to an intracerebral bleed during reinduction chemotherapy for recurrence of leukemia.
				Case 2: ROCM (4.5y, M, chemotherapy for acute myeloblastic leukemia)	Immediate (temporary reconstruction was done after 4th session of debridement, systemic antifungal therapy was started at 1st debridement)	Enucleation of the left eye, dorsal aspect of nose, left periorbita, left cheek, forehead, maxillary sinsus	Defect extending from above root of the nose to dorsal aspect and lateral wall of nose, left orbit and left cheek	Cheek rotation flap (to cover exposed orbital apex) and STSG (on the nose)	IV amphotericin and fluconazole (dose and duration not mentioned)	No	2 weeks after discharge to home, flap was healing well, no signs of infection
					8 months after temporary reconstruction (no signs of active mucormycosis infection)	Palate, left maxilla, frontal bone	Palatal fistula, enucleation defect, nasal dorsal defect	Osteomusculocutaneous iliac crest flap (for alveolus and zygoma reconstruction, was osteotomized and hinged for reconstructing the nasal dorsum. Two skin paddles were fashioned for reconstruction of the enucleation defect and palate)	No	small palatal fistula	2 years
					2 years after definitive recontruction		Nasal defect	forehead flap (for nasal reconstruction, some portion of the iliac skin paddle was used for lining of the nose as a turndown flap and some part was excised)	No	No	Not mentioned	Patient resumed a good quality of life with a functional reconstruction, but expired due to a complication of leukemia after few years (exact time not mentioned)
4	Davies et al,19 2015	Case series	1	ROCM (42 y, M, poorly controlled diabetes mellitus)	Delayed (1 month after second debridement, during which antifungals were used)	Left orbital exenteration, left maxillary and ethmoid sinuses, necrotic soft tissues over the face	A large complex cavitary defect in place of orbit, maxilla, root and lateral wall of the nose on left side	Free anterolateral thigh flap (for facial reconstruction)	After 1st debridement, amphotericin B 5 mg/kg IV every 24 hours and posaconazole 200 mg orally every 8 hours were started. After 2nd debridement intrathecal amphotericin B was added. Use after reonstruction is not mentioned.	No	Not mentioned	This was a case series of 4 cases of ROCM, who presented to the authors’ institution over a 1 month-period, after widespread flooding in the Denver-Boulder metropolitan area in September 2013. In this series, only one patient underwent reconstruction.
5	Herford et al,20 2013	Case report	1	Maxillary mucormycosis (13 y, M, acute lymphoblastic leukemia)	Not mentioned	Anterior maxilla	Malocclusion and paltal defect	Le Fort I advancement (to achieve occlusion) + tongue flap (to close the palatal defect)	Not mentioned	No	1 month	The authors' main emphasis is on the utility of the tongue flap for closure of large palatal defects.
					1 month after first surgery			division and inset of tongue flap	No	No	Not mentioned
6	Honeybul and Morrison,11 2012	Case report	1	ROCM with unusual involvement of cranial vault (52 y, M, controlled type 2 diabetes mellitus)	Delayed (6 months after bone debridement, during which antifungals were used)	Affected portions of the frontal, temporal, and parietal bones	135 mm transverse by 165 mm anterior posterior cranial vault defect involving the frontal, temporal and parietal regions	Cranioplasty with a 3d-printed titanium plate (for reconstruction of the calvarial defect)	At the first diagnosis of ROCM, IV liposomal Amphotericin B was given for 6 weeks at a dose of 5 mg/kg/d. It was then changed to oral Amphotericin B at a dose of 1 mg/kg/ d, which had to be stopped after 3 weeks due to acute renal failure. Then, oral Posaconazole 400 mg twice daily was given for 6 months before bony debridement and for 6 months afterwards till cranioplasty. After the reconstruction, Posaconazole was continued at the same dose for 6 months.	No	9 months after cranioplasty, patient was well, no clinical or radiologic evidence of recurrence	This is a report of an unusual case of ROCM where the fungal infection invaded and destroyed the skull vault and required aggressive surgical intervention to control the disease process.
7	Lari et al,21 2002	Case report	1	ROM (35 y, F, healthy, non-diabetic, no immune compromise)	Delayed (10 and 1/2 weeks following the 4th surgical debridement that included orbital exenteration, systemic and local antifungals were used during this time)	Left ethmoids, orbital exenteration including radical debridement of the involved adjacent structures	Left orbital exenteration defect and naso-orbital fistula	Anteriorly based galea-frontalis-pericranial flap (for the reconstruction of orbital exenteration defect and closure of fistula)	Amphotericin B 60 mg/day IV was started 3 days after the first debridement. When serum cretinine began to rise, it was discontinued. The exposed orbital cavity was irrigated with a solution of 1 mg amphotericin B in 100ml normal saline twice daily till reconstruction.	No	2 years, no recurrence, closure of fistula	This patient did not have any immune compromise. Due to the location of the defect, in lower medial orbit, an anteriorly based galea-frontalis-pericranial flap was preferred over the temporalis muscle flap in this case.
8	Metzen et al,14 2012	Case series	1	Rhino-sinusal and maxillary mucormycosis (63 y, F, Chemotherapy for non-Hodgkin's lymphoma)	Immediate (after bone debridement, antifungals and antibiotics were started at the same time)	Right hemi-maxilla	Right hemi maxillectomy defect, defect in vestibule mucosa	Free osseocutaneous scapula flap (maxillary complex reconstructed with bone, defect in the vestibular mucosa with skin paddle)	At the diagnosis of mucormycosis, a 3-fold anti infective regimen was started: liposomal amphotericin B (slowly increasing doses with maintenance dose of 35g/day), flu cloxacillin (3 g, 3 times/day) and meropenem (1 g, 3 times/day). It is mentioned that under continuous antibiotic and antifungal therapy, patient recovered and was discharged. Duration of anti infectives not specified.	No	9 months	Patient underwent oral rehabilitation with dental implants
					9 months after free scapula flap		Bone gaps in the scapula flap	autologous bone graft from the iliac crest (to fill gaps in the scapula and to thin out the soft-tissue flap)	Not specified	No	Not mentioned
9	Bhatnagar and Agarwal,22 2017	Case report	1	ROM (35 y, M, not mentioned)	Delayed (6 months after orbital exenteration, patient presented late)	Orbital exenteration, medial wall of orbit	Right orbital exenteration defect with a naso-orbital fistula	Free radial artery forearm flap (skin paddle used to create a matching eye patch, peripheral adipofascial component used for filling of the orbital defect)	No	No	6 months, flap settled well, fistula corrected	Patient settled for an external spectacle mounted prosthesis.
10	Navarro-Perea et al,10 2019	Case series	1	ROCM (50 y, F, immuno supressive therapy post-renal transplant)	Delayed (1 month after orbital exenteration, during this time antifungals were used, wound was treated with liposomal amphotericin B impregnated gauzes and immunosupression was reversed)	Right total orbital exenteration including skin of the eyelids, medial wall and floor of orbit	Right orbital exenteration defect, defect of medial wall and floor of orbit	Temporalis muscle flap and a pedicled skin island flap (for orbital exenteration defect), and a titanium mesh implant (in medial and lower region of the orbit)	At the diagnosis of ROCM, liposomal amphotericin B at 5 mg/kg, anidulafungin and meropenem at 1g 8th hourly were started. After orbital exenteration wound was treated with liposomal amphotericin B impregnated gauzes changed 12 hourly initially followed by 24 hourly after one week. Use of antifungals after reconstruction surgery is not mentioned.	No	2 years, no signs of infection or necrosis, flaps well settled
11	Odessey et al,9 2008	Case report	1	Rhino-cerebral and maxillary mucormycosis (64 y, M, diabetes mellitus and long term infliximab for rheumatoid arthritis)	Delayed (3 and 1/2 months after bone debridement, antifungals were used during this period)	Right maxilla, necrotic lateral nasal wall, hard palate, necrotic tissue within the maxillary sinus	Right lowerlid paralytic ectropion, right-sided brow ptosis.	Tarsal strip procedure for right lower lid, insertion of gold weight in right upper lid, endoscopic brow lift, scar revision in upper lip	“After diagnosis of ROCM, IV amphotericin B was started and debridement was done. It is mentioned that the patient was discharged on post-operative day 48 on long term Amphotericin B. The total doses mentioned are 240 mg of amphotericin B and 7,700 mg of liposomal amphotericin B, which was started because of renal failure. The duration till which this was continued is not specified.”	No	4 months, improvement in facial symmetry and ocular symptoms, persistent contour deformity of right cheek	Pathologic specimens obtained during each of the debulking procedures showed continued presence of Mucor spp. But, there was no evidence of active disease for 5 years despite colonization, presumably due to the reversal of immunosuppression.
					Timing not specified		Contour depression of right cheek, defect of hard palate, oro-pharyngeal fistula	Free vertical rectus abdominis myocutaneous flap (to improve cheek contour and obliterate the oro-phrayngeal fistula, skin paddle was used to reconstruct the hard palate)	Not specified	No	5 years, patient required 3 debulking procedures; cheek and oral commissure suspension
12	Rashid et al,23 2021	Case series	1	Rhino-sinusal and maxillary mucormycosis (young lady: age not specified, predisposing factor not mentioned)	Delayed (Timing not mentioned exactly, but it is said that she underwent multiple debridements)	Medial maxilla, cheek, lateral wall of nose	Large composite defect of cheek, maxilla, and lateral nasal wall	A combination of local flaps was used; forehead flap (for side of the nose), cheek rotation advancement flap (for the cheek defect) and temporalis muscle flap (to reconstruct palate and fill the dead space)	No	No	6 months, good healing, temporalis flap mucosalized by 4th week; flap division, advancement and scar revision were performed at around 6 months	It is a case series in which the authors share their experience of head and neck reconstruction during the covid-19 pandemic, using pedicled flaps.
13	Schmidt et al,24 2004	Case series	1	Maxillary mucormycosis (47 y, M, predisposing factor not mentioned)	Delayed (9.6 months after resection surgery)	Near total maxilla including piriform rims and buttress regions	Extensive maxillary defect, denture could not be supported	Reconstruction with 4 zygomaticus implants and 2 standard implants, the implants were supported with cross arch stabilization	No	No implant failure	2 years, prosthesis functioning, patient was able to use an obturator and denture, and with these in place had adequate upper lip support, and normal speech and swallowing	This is a retrospective review of 9 patients reconstructed with zygomaticus and standard endosseous implants after extensive maxillary ablation.
14	Murphy et al,25 2012	Case report	1	ROCM (68 y, M, Myelodysplastic syndrome)	Reconstruction was performed 2 weeks after the debridement surgery. During this time patient received combination antifungal therapy and his hemoglobin and platelet levels were optimized with transfusions	Right orbital exenteration; frontal, maxillary and ethmoidal sinuses, inferior and middle turbinates	Extensive hemifacial defect	Free anterolateral thigh flap incorporating a segment of vastus lateralis, anastomosis was performed to the facial vessels on the right side	After the diagnosis of ROCM, IV Posaconazole was started. Amphotericin B was added to Posaconazole after the debridement surgery. Patient received Posaconazole and Amphotericin B for 2 weeks before the reconstructive surgery, but it is not mentioned till when this was continued.	No	Not mentioned	This is a case report that demonstrates the feasibility of performing successful microvascular surgery in patients with thrombocytopenia by using thromboelastography for targetted clotting correction.
15	Sham et al,26 2010	Case series	1	Rhino-sinusal and maxillary mucormycosis (22 y, M, predisposing factor not mentioned)	Timing not mentioned	Maxillectomy	Maxillectomy defect	“Mid-face reconstruction with free serratus anterior flap including the 7th rib”	Not mentioned	Not specified	Flap survived, no donor site morbidity, no winging of scapula, upper limb function not affected	This is a case series of 26 cases wherein the authors describe their experience of using the serratus anterior free flap as a versatile reconstructive option.
16	Shand et al,27 2004	Case report	1	Invasive infection of the midfacial and orbital complex due to Scedosporium apiospermum and Mucormycosis (27 y, M, High speed motor vehicle trauma with multiple facial fractures, ICU stay, septic shock, acute renal failure, hyperglycemia, and steroid therapy)	Delayed (52 days after the 3rd debridement that included orbital exenteration, multiple further debridements were done during this period, twice daily irrigation and packing of the defect was done, antifungal agents were used, clearance of infection was ensured with multiple biopsies taken 17, 19, and 26 days after exenteration)	Exenteration of left orbit, medial maxilla, midfacial tissue, lateral orbital wall and orbital floor, zygomatic complex, soft tissues of left midfacial-temporal region and left nasal region, panendoscopic debridement of the sinuses	Midfacial orbital defect	Free radial forearm flap (for coverage of the midfacial orbital defect)	Patient was treated with fluconazole followed by itraconazole 300 mg once daily before orbital exenteration. After exenteration, liposomal amphotericin B 365mg IV once daily was added to the regimen. Due to the risk of potential spread to CNS, itraconazole was stopped, and Voriconazole 300mg IV twice daily was started. Voriconazole was continued for a total of 40 days, and amphotericin B for 42 days before reconstruction surgery.	No	2 months, flap well settled, planned for prosthetic reconstruction of the left orbit	This is a case report of a patient who survived the invasive necrotizing fungal infection due to Scedosporium apiospermum and mucormycosis, which was managed with aggressive surgical treatment and combination antifungal therapy.
17	Silberstein et al,16 2014	Case report	1	ROCM (24 y, F, Systemic lupus erythematosus, Diabetes mellitus, High-dose steroid treatment)	Delayed (2 months after second debridement which included orbital exenteration and subtotal maxillectomy, antifungal was used during this time)	“Orbital exenteration, left subtotal maxilla, bilateral ethmoids and sphenoids, part of nose”	Large complex cavity including left orbit, maxillary sinus, nose and oral cavity with exposed meningeal tissue	Free rectus abdominis myocutaneous flap (for filling of orbital and maxillary cavities), anastomosed to the branches of facial artery and vein. Due to the thick abdominal wall, the skin island of the flap was removed, flap thinning done and the skin used as a FTSG	Intravenous Amphotericin B was started when a clinical diagnosis of ROCM was made, before second debridement. After reconstruction surgery, it was continued (exact duration not mentioned).	No	4 months, flap settled well, no evidence of recurrence of fungal infection	This is a case report of a patient of ROCM who was successfully treated with intravenous antifungal therapy and radical debridement followed by reconstruction with a combination of methods including a free vertical rectus abdominis myocutaneous flap, tissue expansion, and STSG, Eye prosthesis could be used.
					4 months after initial reconstruction		Large oronasal fistula	Closure of the fistula and creation of ophthalmic socket in the muscle flap using STSG. An acrylic, nonintegrated oval eye prosthesis was used. Tissue expansion of the remaining cheek skin for reconstruction of lower eyelid, medial canthus and nasal skin. STSG was done over the remaining exposed surfaces of palate, nasal cavity, and external surface of orbit.	Amphotericin B was continued (exact duration not mentioned)	No	4 years, patient regained normal understandable speech and oral nutrition
18	Wali et al,12 2001	Case report	1	Rhino-sinusal mucormycosis (6 y, M, Chemotherapy for relapsed acute lymphoblastic leukaemia)	Delayed (nearly 100 days after the initial clinical signs of mucormycosis, antifungals were used for 57 days during this period, granulocyte colony stimulating factor (G-CSF) was used, debridement and scraping of the nasal defect carried out repeatedly with povidone iodine irrigation)	Repeated scrapings of the nasal defect	Skin defect near the right medial canthus region	Local cutaneous flap (to cover the defect), other details not mentioned	Patient was initially started on Amphotericin B when the initial signs of mucormycosis were noted, increasing the dose to 1mg/kg/day. Since the renal function started to deteriorate, this was stopped and Liposomal Amphotericin B was started, increasing the dosage upto 6mg/kg/day. Antifungals were given for a total of 57 days, which included 40 days of liposomal amphotericin B, before reconstruction surgery.	No	10 months, patient doing well, flap settled, no relapse of fungal infection	This is a case report of a life-threatening nasal sinus mucormycosis that developed during the remission induction therapy for a relapsed acute lymphoblastic leukaemia. The patient was successfully treated with liposomal amphotericin B and granulocyte-colony stimulating factor followed by surgical reconstruction of the resultant cutaneous defect.
19	Croce et al,28 2008	Case series	1	ROCM (76 y, M, long term diabetic)	Immediate	Left orbital exenteration, left subtotal maxilla, nasal fossa, ethmoid bone	Orbito maxillary defect	FTSG from abdomen (for eye socket reconstruction)	Fluconazole 300 mg/day + Liposomal Amphotericin B 150 mg/day (pre-operative usage and post-operative duration not mentioned)	No	12 months after surgery, patient died due to traumatic rupture of spleen; ocular prosthesis was offered but not accepted by the patient	This one case of ROCM was part of eight case series of orbital exenteration in elderly patients by the authors.

Tissue Defects in ROCM

A list of post-ROCM tissue defects that were encountered in the studies reviewed is given in Table 2. The most common defects were the ones that resulted from orbital exenteration and excision of a varying extent of the involved contiguous bony and soft tissue structures. Defects created by varying degrees of maxillectomy, defects of the palate, alveolus, nasal septum and side walls, skin and soft tissue defects over the cheek, and naso-orbital fistulae were the other defects reconstructed.^10,22 Honeybul et al reported an extensive calvarial defect following an unusual invasion and destruction of skull vault.¹¹ In some cases there were large composite defects, which were reconstructed with a combination of flaps or involved multiple stages of reconstruction. For instance, Rashid et al reconstructed a large composite defect of cheek, maxilla, palate, and nasal wall with a combination of 3 local flaps.²³ Augustine et al described a case wherein reconstruction involved multiple surgical interventions over more than 2 years.¹⁵

Technique of Reconstruction

The various reconstructions that were described are summarized in Table 2. The basic requirement in the majority of the cases was to obliterate the orbital cavity and achieve continuity of the epithelial lining. The consensus opinion favors reconstruction with pedicled flaps rather than free flaps in cases where the infection is not eliminated completely. The reason for this recommendation is the angioinvasive nature of mucormycosis, which can lead to vascular thrombosis and failure of the free flaps.¹³ Another very important consideration while contemplating reconstruction in ROCM, especially in postorbital exenteration cases, is to ensure that the reconstructive option chosen considers the planned ocular prosthetic rehabilitation.

Alfano et al performed a pedicled pectoralis major myocutaneous flap for reconstruction in their patient. A pedicled flap was preferred for reconstruction in this condition because of the patient's excellent blood perfusion, which enables antifungal agents and self-defense molecules to be transported to the site of infection after debridement. It was also suggest that free flaps may play a role in delayed reconstruction.¹³ Navarro-Perea et al used a combination of a pedicled temporalis muscle flap, a pedicled skin island flap, and a titanium mesh implant for reconstruction in their case with successful results. They believe that temporalis muscle flap allows acceptable reconstruction in a single stage without the need of microvascular surgery and provides adequate vascularization in combination with a shorter healing time than other techniques.¹⁰ Alleyne Jr et al transposed the anterior two-thirds of the temporalis muscle across a defect in the orbit and anterior cranial fossa and obliterated the communication between the intracranial and transfacial dissections.⁷ Lari et al reconstructed an exenterated orbital cavity with a concomitant naso-orbital fistula with an anteriorly based galea-frontalis pericranial flap; the flap filled the cavity completely and was folded to close the fistula.²¹

Rashid et al reconstructed a large composite defect with a combination of local flaps; a forehead flap was used to reconstruct the lateral wall of the nose, a cheek rotation advancement flap was used to cover the cheek defect, and the temporalis muscle flap was used to reconstruct the palate and obliterate the dead space. The flaps healed well with a good mucosalization of the temporalis flap seen by the fourth week. This patient underwent a second procedure consisting of flap division, advancement, and scar revision at around 6 months with good healing.²³

Herford et al performed a combination of Le Fort I advancement and a tongue flap with an anterior maxillectomy defect.²⁰

Bhatnagar and Agarwal used a free radial artery forearm flap for the reconstruction of an orbital exenteration defect with a concomitant naso-orbital fistula. The pedicle was anastomosed to the facial artery and vein in the neck. The adipo-fascial component was placed into the defect; the central skin paddle was sutured to the skin margins. Radial forearm flap was preferred because it offers a thin, soft, and easily foldable tissue in comparison to other free flaps. Also, the flexible pedicle length and pliable tissue offer a suitable contour restoration of the exenterated orbit.²² Sham et al described a case of a post-maxillectomy defect in which reconstruction of the mid-face was performed with a free serratus anterior flap including the seventh rib.²⁶

Augustine et al reported 2 cases of ROCM. In one case with a defect spanning from root of the nose to palate and entire alveolus, they performed a free fibula osteo-cutaneous flap and reconstructed the dorsal nasal strut with a bone graft. In another case, an initial temporary reconstruction was performed to cover the exposed orbital apex in the form of a cheek rotation flap and a skin graft was used for nasal defect. Definitive reconstruction was performed after 8 months with an osteo-musculo-cutaneous iliac crest flap after ensuring clearance of the infection. Skin paddles were fashioned for both the reconstruction of the enucleation defect and for the palate. Bone was used for alveolus and zygoma reconstruction and was osteotomized and hinged for the reconstruction of the nasal dorsum. Further, a forehead flap was also performed for the nasal reconstruction 2 years later, with the lining provided by a turndown flap from the skin paddle of the iliac crest flap.¹⁵ Davies et al performed a free anterolateral thigh flap for facial reconstruction.¹⁹ Metzen et al performed a free osteocutaneous scapula flap after hemi maxillectomy. Bone gaps in the flap were supplemented with autologous iliac crest bone graft after 9 months, and ultimately the patient could undergo oral rehabilitation with dental implants.¹⁴

Murphy et al reconstructed an extensive hemifacial defect with a free anterolateral thigh flap that incorporated a segment of vastus lateralis to obliterate the dead space left by debridement of the sinuses. The flap was anastomosed with the facial vessels.²⁵

Shand et al performed a free radial artery forearm flap for the reconstruction of a midfacial orbital defect due to an invasive infection of the midfacial-orbital complex with Scedosporium apiospermum and Mucormycosis. The flap settled well enough to permit prosthetic reconstruction of the orbit.²⁷

Odessey et al performed a tarsal strip procedure for paralytic ectropion of the lower eyelid, gold weight placement in the upper eyelid, endoscopic brow lift, and scar revision in the upper lip in their patient in the first stage. In the second stage they performed a free vertical rectus abdominis myocutaneous flap to improve the cheek contour and obliterate an orophrayngeal fistula, and the skin paddle was used to reconstruct the hard palate. Further debulking and cheek and oral commissure suspension were also performed at a later stage in this case.⁹

Silberstein et al used a free rectus abdominis myocutaneous flap for reconstruction of a large complex defect including orbit, maxillary sinus, nose, and oral cavity. The vascular anastomosis was performed on the branches of facial artery and vein. After 4 months further secondary reconstructive procedures were performed. These included closure of the oronasal fistula and creation of an ophthalmic socket in the muscle flap using split-thickness skin graft (STSG). Tissue expansion of the remaining cheek skin was performed for reconstruction of lower eyelid, medial canthus, and nasal skin. The remaining exposed surfaces of palate, nasal cavity, and external surface of orbit were skin grafted. An acrylic, nonintegrated oval ocular prosthesis could be used satisfactorily.¹⁶

Honeybul et al used a 3D-printed titanium implant for reconstructing a calvarial defect.¹¹

Schmidt et al performed reconstruction with a combination of 4 zygomaticus implants and 2 standard endosseous implants in their patient, who had undergone near total maxillectomy for maxillary mucormycosis; the patient was later able to use an obturator and denture. With the obturator and the denture in place, the patient had an adequate lip support, normal speech, and normal swallowing.²⁴

Croce et al performed eye socket reconstruction with a full-thickness skin graft (FTSG). They observed that for the reconstruction following orbital exenteration, a FTSG or a pedicled myocutaneous flap are the simplest options for the elderly population with significant comorbidities. In their experience the final outcome is comparable with that of more complex flap reconstructions, with less donor site morbidity and shorter operation times. Though with FTSG they note that some time is needed for it to take completely in the eye-socket, during which scabs and granulations need to be removed repeatedly.²⁸

A treatment algorithm for reconstruction of tissue defects in ROCM is proposed based on this literature review in Figure 2.

FIGURE 2.

Proposed algorithm for the reconstruction of tissue defects in ROCM. a: Split-thickness skin graft; b: Pectoralis major myo-cutaneous flap; c: Radial artery forearm flap; d: Anterolateral thigh flap; e: Rectus abdominis myo-cutaneous flap; f: Vertical rectus abdominis myo-cutaneous flap; g: Serratus anterior flap

Adjunctive Antifungal Treatment

The adjunctive antifungal treatments used in the studies reviewed are summarized in Table 2. Amphotericin B was the agent used most frequently.^{7,15,16,19,21,25} The use of liposomal amphotericin B was recommended in some studies because it was found to be more effective in ROCM than conventional amphotericin B; it could also be used when conventional amphotericin B failed.^{10,13,15,27,28} It was also found to be less nephrotoxic and hence was used in cases where the renal function started to deteriorate on conventional amphotericin B treatment.^9,11,12 Amphotericin B was given intravenously; it was also given intrathecally in some cases.^7,19 The use of amphotericin B for intraoperative irrigation and for daily dressings of the wound was also associated with favorable results.^10,21

Oral posaconazole (800 mg per day, in 2 or 4 doses) was used as an alternative in patients who could not tolerate amphotericin B; it is particularly useful for treatment in an outpatient setting.^14,25 Voriconazole was also used successfully in some cases.^13,27

Complications

The complications related to the reconstruction in the studies reviewed are summarized in Table 2. Complications were usually minor. Alfano et al had a relapse of fungal infection and partial necrosis of the pedicled pectoralis major myocutaneous flap in the immediate postoperative period.¹³ Augustine et al had to perform reexploration of vascular anastomosis for suspected arterial compromise in their free fibula osteocutaneous flap. Because the anastomosis was found to be patent, all the tension on the skin paddle was released and reinsetting was done without any tension. The flap survived but required minimal revision for partial dehiscence.¹⁵ Total loss of flaps was not reported in any of the cases.

Follow-up

Survivors of mucormycosis are high-risk patients. They are susceptible to recurrences and are also at a higher risk for other conventional bacterial infections and sepsis, which may be further aggravated in the setting of tissue ischemia. A close follow-up is required to detect and treat any possible recurrence of infection.¹⁶ The length of the follow-up in the studies reviewed is summarized in Table 2.

Conclusions

Patients and survivors of ROCM with tissue defects in the maxillofacial region can be satisfactorily reconstructed using a multitude of options. These include skin grafts, pedicled flaps, free flaps, and in some cases implants and prosthetics. Some patients with large complex defects may require a combination of techniques or multi-staged reconstruction. Ensuring eradication/control of mucormycosis infection with appropriate antifungal therapy prior to reconstruction is an essential prerequisite. Sometimes antifungals need to be continued after reconstruction to prevent recurrence of the infection. The ultimate aim of reconstruction should be to achieve as much functional restoration as possible and a socially acceptable appearance. In orbital exenteration defects, reconstruction should consider the possibility of prosthetic rehabilitation. More experiences with reconstruction of this condition are anticipated over the coming few months, which will lead to the publication of larger case series describing further treatment options.