Rhinocerebral Mucormycosis: A Diagnostic Challenge and Therapeutic Dilemma in Immunocompetent Host

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J Oral Maxillofac Surg70:1369-1375, 2012

Rhinocerebral Mucormycosis:A Diagnostic Challenge and Therapeutic

Dilemma in Immunocompetent HostVirendra Singh, MDS,* Bindu Sharma, MDS,† Rajeev Sen, MD,‡

Shalini Agrawal, MD,§ Amrish Bhagol, MDS,� and Rishi Bali, MDS¶

0

Rhinocerebral mucormycosis, also known as zygo-mycosis or phycomycosis, is an acute fungal diseasecharacterized by agonizing complications and avery high mortality rate. The causative fungal spe-cies is from the order Mucorales, with the mostcommon genera being Mucor, Rhizopus, Absidia,or Apophysomyces. The fungi are ubiquitous, foundin soil, manure, plants, and decaying materials.1

The organisms colonize the oral mucosa, nose,paranasal sinuses, and pharynx. Inhalation is thenatural source of infection, which begins in thenose and progresses through the paranasal sinuses,invading the orbit and eventually involving the in-tracranial structures either by direct extension orthrough blood vessels.2 A necrotic ulcer with a

lack eschar affecting the hard palate is one of theajor oral signs.3 In addition to the palate, the

isease also affects other areas such as the alveolarargin, lips, cheeks, tongue, and mandible.4 Histor-

ically, although these infections have occurred inpatients with immunocompromised medical status,they have also recently been found in otherwisehealthy individuals. A thorough knowledge ofchanges in trends of epidemiology and behavior ofthis invasive fungal infection is particularly impor-tant while devising effective diagnostic and thera-peutic strategies.5 We present a case series of 3mmunocompetent patients to share the diagnosticnd therapeutic challenges encountered by us inanaging this potentially fatal disease.

*Professor and Head, Department of Oral and Maxillofacial Sur-

gery, Government Dental College, Pt. B.D. Sharma University of

Health Sciences, Rohtak, India.

†Junior Resident, Department of Oral and Maxillofacial Surgery,

Government Dental College, Pt. B.D. Sharma University of Health

Sciences, Rohtak, India.

‡Professor and Head, Department of Pathology, Pt. B.D. Sharma

University of Health Sciences, Rohtak, India.

§Assistant Professor, Department of Radiology, Pt. B.D. Sharma

University of Health Sciences, Rohtak, India.

�Senior Resident, Department of Oral and Maxillofacial Surgery, d

1369

Case 1

A 48-year-old immunocompetent man was referredto our department with the chief complaint of painand swelling in the right maxillary region. Pain wasmild to moderate, radiating toward the right eye, andwas associated with blurring of vision in the same eyethe previous few days. The patient’s medical historywas not significant for any underlying medical ail-ment. His social history showed a village backgroundand association with farming and cattle rearing. Ongeneral physical examination, he was normally builtand was afebrile. On local examination, a firm andtender swelling with indefinite margins was palpated,occupying all of the right cheek region (Fig 1). Hypo-esthesia was observed in the distribution of the in-fraorbital nerve. Intraorally, the swelling involved theentire right palate and vestibule. The overlying mu-cosa was normal in color, with no evidence of necro-sis. The maxilla was intact, and no mobility was ob-served. The nasal mucosal lining was found to beintact and normal. His laboratory findings on admis-sion were within normal range. No documented evi-dence of compromised immunity was observed.

Conventional radiographs showed opacification ofthe maxillary sinus. The computed tomography (CT)scan showed a diffuse soft tissue mass with patchyhyperdensity involving the right maxillary sinus ex-tending into the inferomedial aspect of the orbit andthe ethmoid sinus. The right inferior rectus and infe-rior oblique muscles were involved. An incisionalbiopsy specimen showed ribbon-like aseptate hy-

Government Dental College, Pt. B.D. Sharma University of Health

Sciences, Rohtak, India.

¶Professor, Department of Oral and Maxillofacial Surgery, D.A.V.

Dental College, Yamunanagar, Haryana, India.

Address correspondence and reprint requests to Dr Singh: De-

partment of Oral and Maxillofacial Surgery, Government Dental

College, Pt. B.D. Sharma University of Health Sciences, Rohtak-

124001, Haryana, India; e-mail: [email protected]

© 2012 American Association of Oral and Maxillofacial Surgeons

278-2391/12/7006-0$36.00/0

oi:10.1016/j.joms.2011.06.209

mailto:[email protected]

1370 RHINOCEREBRAL MUCORMYCOSIS

phae, a characteristic feature of mucormycosis. Thesehyphae were surrounded by necrotic tissue, alongwith reactive giant cells. The same finding was alsoconfirmed on a section specially stained with periodicacid Schiff (PAS). The fungus cultures, obtained toidentify the specific species, were negative.

Intravenous amphotericin B, at 0.5 mg/kg bodyweight, was started, followed by aggressive surgicalintervention in the form of hemimaxillectomy alongwith orbital floor reconstruction. Orbital floor recon-struction was done with titanium mesh. The intrave-nous amphotericin B, at 0.5 mg/kg body weight, wascontinued for 2 months in a regional hospital in closeproximity to the patient’s home. Three months later,the patient came back with diminishing vision in theright eye associated with increased intensity of pain.This was associated with persistent headache andoccasional dizziness. Other clinical manifestations in-cluded proptosis, ophthalmoplegia, and restriction ofmovements of the eye in all gazes, along with signs ofcompressive ophthalmopathy. The patient’s visionwas 20/200 in the right eye and 20/20 in the left eye.He again underwent CT scan, which showed propto-sis of the right eye caused by a diffuse enlarged masswith ill-defined borders involving the retromolar fat,optic nerve, and medial and lateral recti. It extendedintracranially to involve the right temporal lobe andwas eroding the greater wing of the sphenoid.

The patient was rehospitalized, and intravenous

FIGURE 1. Preoperative clinical presentation of patient showingswelling in right cheek region and orbital involvement.

Singh et al. Rhinocerebral Mucormycosis. J Oral Maxillofac Surg2012.

amphotericin B, at 0.5 mg/kg body weight, was

started again for a period of 15 days. The symptomspersisted, and there was no improvement in his con-dition. He was switched to the oral antifungal agentvoriconazole. He was given a loading dose of 400 mgtwice a day for the first day, followed by a mainte-nance dose of 200 mg twice a day for 6 months.Within 1 month, there was marked improvement inclinical as well as radiologic features. Then, after 2months, the residual defect was reconstructed withtemporalis myofascial flap. The patient was regularlyfollowed up for 12 months and showed no significantalteration in clinical or radiographic findings (Fig 2).

Case 2

A 40-year-old otherwise healthy woman presentedto our department with a history of pain in the max-illary posterior teeth, followed by swelling in the leftmaxillary and periorbital region (Fig 3). Findings of aconventional radiologic examination were inconclu-sive. A CT scan showed a soft tissue mass involvingthe left maxillary sinus, temporal fossa, and orbitextending to involve the ethmoid air cells with ero-sion of the medial wall of orbit. The mass also invadedthe soft tissues involving the subcutaneous plane ofthe left cheek and upper lip. There were no signs ofintracranial extension. There was involvement of thelateral rectus, inferior oblique, and medial rectus mus-

FIGURE 2. Postoperative clinical presentation of patient showingreduced proptosis in right eye.

Singh et al. Rhinocerebral Mucormycosis. J Oral Maxillofac Surg
2012.

SINGH ET AL 1371

cles, but the optic nerve sheath was intact (Figs 4, 5).An incisional biopsy was performed, which con-firmed the lesion as mucormycosis. The most conspic-uous features on histopathologic examination werelarge areas of nondescript necrosis exhibiting colo-

FIGURE 3. Preoperative clinical presentation of patient showingswelling on left side of face and orbital involvement.


FIGURE 4. Axial CT scan shows proptosis of the left eye caused bya diffusely enhancing mass involving the temporal fossa and orbit,which also extended to involve the ethmoid air cells with erosion(arrows) of the medial wall of orbit.

2012.
nies of numerous large, branching, nonseptate hyphalforms (Figs 6, 7). PAS staining for fungal organismsshowed colonization by aseptate fungal organisms,with the hyphae branching haphazardly at 90° angu-lation. A diagnosis of fungal organisms compatiblewith mucormycosis was rendered. The findings of thefungal culture report were negative. Intravenous am-photericin B was given for 10 days initially at a dose of0.5 mg/kg body weight. Considering the locally inva-sive nature of the lesion, an access osteotomy wasplanned and pathologic tissue was removed aggres-

FIGURE 5. Axial CT scan shows a diffusely enhancing mass(arrow) involving the left maxillary sinus and the subcutaneousplane of the left cheek and upper lip.


FIGURE 6. Negatively stained hyphae (arrow) (hematoxylin-eosinstain, original magnification �400).

2012.


sively from the left maxillary region. Amphotericin Bwas continued for 2 months, because a continuousdull pain persisted on the left side of the face. After 8to 9 months, the patient awoke 1 morning with com-plete loss of vision in the left eye. On examination,there was complete loss of vision in the left eyeassociated with exophthalmos. The ipsilateral infraor-bital margin, maxilla, and buccal vestibule were moder-ately tender. The ophthalmologic opinion suggestedproptosis with restriction of eyeball movements in

FIGURE 7. PAS-positive wall of a negatively stained section show-ing hyphae (original magnification �400).


FIGURE 8. Follow-up photograph of patient showing reducedproptosis in left eye.

2012.
the left upward and downward gazes. An afferentpapillary defect with no light reaction was observedin the left eye, and fundus examination showed opticatrophy with poor visual prognosis.

The patient refused any surgical intervention. Intra-venous amphotericin B was again started; however,there was no improvement this time. She wasswitched to the oral antifungal agent voriconazolewith a loading dose of 400 mg twice a day on the firstday, and positive results followed. The patient’s com-pliance was good because she was motivated regard-ing the advantages of regular medicine intake, whichcontinued for 6 months at a maintenance dose of 200mg twice daily. The vision loss could not be reversed,but the patient has been clinically free of pain andother residual symptoms for 1 year (Fig 8).

Case 3

A 35-year-old housewife presented to our depart-ment with a chief complaint of swelling on the leftside of the cheek of 2 months’ duration. Her historyshowed that at 1.5 years previously, she fell from aroof, followed by swelling on the left side of the face.She subsequently underwent surgery for chronic sup-purative sinusitis at a private hospital. Three monthsafter surgery, she again noticed swelling at the samesite, which did not resolve after medications, and shewas referred to our institute. She was from a rural

FIGURE 9. Preoperative clinical presentation of patient showingswelling on left side of cheek region.


background and engaged in household work, farm-

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SINGH ET AL 1373

ing, and cattle rearing. There was no history of anysignificant medically compromised status.

On examination, a firm, fixed, and slightly tenderswelling measuring 2 � 2 cm was palpated on the leftide of the cheek region. The overlying skin waslightly erythematous (Fig 9). Intraorally, the mucosalining was healthy with intact upper and lower den-ition. No abnormality was detected in the adjacentasal mucosa. A small amount of pus was aspiratedxtraorally, and antibiotics were given initially. Radio-raphs and CT scans were obtained, and a biopsy waslanned. The CT scan showed a soft tissue mass in theegion of the left maxillary sinus involving the subcu-aneous tissues of the left cheek and upper lip.

A biopsy specimen from the soft tissue mass overhe maxillary sinus region showed extremely scleroticranulomas predominantly comprising foreign bodyiant cells. Occasional broad and thick hypha-liketructures that stained positively with methenamineilver stain were seen. A diagnosis of fungal granulo-as with possible mucormycosis was made. The pus

ulture yielded negative findings for fungus.The management included intravenous administra-

ion of amphotericin B and surgical debridement. Thebrosed and necrotic tissue was dissected out throughn intraoral approach, and amphotericin B was givenntravenously at a dose of 0.5 mg/kg body weight for 2

onths. The patient had been symptom free at the latest

FIGURE 10. Postoperative clinical presentation of patient showingresidual scar on left cheek.


ollow-up, except for a residual scar on the left cheek

due to perforation of overlying thin skin during surgery(Fig 10).

Discussion

Rhinocerebral mucormycosis is a rare fungal infec-tion that is potentially fatal. It generally involves thesinuses and can spread to the brain. Although it com-monly affects individuals with diabetes and those inan immunocompromised state, it can also cause in-fections in a healthy individuals.6-8 An increasing num-ber of cases are being recognized in immunocompe-tent individuals, predominantly those living in dustyand humid conditions. The main risk factors for thisaggressive infection are hematologic malignant dis-ease, poorly controlled diabetes mellitus, renal insuf-ficiency, organ transplantation, and chronic use ofiron-chelating agents.9 The causative fungus is ubiq-uitous in nature, grows rapidly, and releases a largenumber of airborne spores. The fungus belongs to theclass Phycomycetes, and Rhizopus is the predomi-nant genus isolated as a pathogen, accounting for 90%of the cases of rhinocerebral mucormycosis.10 In mostases the route of transmission is aerogenic and fungiain entry through the nose via inhalation of airbornepores. It is frequently found colonizing the nose, oralucosa, paranasal sinuses, and pharynx.The hallmark of mucormycosis infection is the

resence of extensive angio-invasion with resultantessel thrombosis leading to tissue necrosis.11 Inost cases the prognosis of mucormycosis is poor,

nd the mortality rates vary depending on its form andeverity. In the rhinocerebral form, the mortality rates between 30% and 70%, whereas disseminated mu-ormycosis presents with a mortality rate of up to0%. Rhinocerebral mucormycosis is the most com-on form of disease, accounting for between one-

hird and one-half of all cases of mucormycosis.12

Seventy percent of cases have been found in diabeticpatients.13 A survey published by the US Centers forDisease Control and Prevention showed an overallrise in mortality due to invasive mycoses over the past2 decades.14 The absence of reliable markers for earlyidentification of patients at risk of the development ofinvasive fungal disease is a challenge that needs to beexplored. There is a need for a review of the changingepidemiology of invasive mycoses, devising new diagnosticmethods and therapeutic options for this pathosis.14

All 3 cases reported in this study were otherwisehealthy individuals with laboratory findings withinnormal range. All of them were from a rural settingand were associated with farming and cattle rearing.Zygomycetes is a ubiquitous fungus in the environ-ment that is commonly found in decaying organicsubstrates, including bread, fruits, vegetable matter,
soil, compost piles, and animal excreta.15 It occurs

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sporadically in many animal species, such as domesticand wild mammals. The primary mode of transmis-sion is inhalation of spores from environmentalsources. Acquisition of Zygomycetes through the cu-taneous or percutaneous route also occurs with trau-matic disruption of skin barriers or burns or throughdirect injection or catheters.11,16 All of our patientsived a rural village life in close contact with animals.

e believe that the responsible factor for mucormy-osis in these patients might be the inhalation ofpores from environmental sources near animal hab-tats or through a cutaneous/percutaneous route withraumatically disrupted skin in close contact withnimal excreta or soil while performing animal care.lthough we do not have any strong evidence torove this hypothesis, we believe that future studieshould try to explore this association between theccurrence of mucormycosis in humans and theirlose contact with animals. Of the 3 patients, 2 wereomen and both were in their fourth decade of life.Combined sinus and orbital involvement can also

e seen in various other conditions. The differentialiagnosis includes sinusitis, cavernous sinus thrombo-is, orbital cellulitis, malignancy, Wegener granuloma-osis, and aspergillosis. In our series the site of originn all cases was the maxilla, causing unilateral swell-ng and pain in the facial region. The duration ofymptoms ranged from 15 days to 3 months, perhapsepresenting the individuals’ immune systems’ efforto fight against the invasion. The reactionary softissue fibrosis was the main finding, and the necroticony tissue or black eschar was conspicuous by itsbsence in these immunocompetent patients. Orbitalanifestations are the result of ischemic necrosis of

he intraorbital contents and cranial nerves. Thereforet is important for the ophthalmologist to consider theossibility of rhinocerebral mucormycosis, irrespec-ive of immune status, in all the following clinicalituations: orbital cellulitis (especially if not respond-ng to antimicrobials), mixed cranial nerve palsies,nd retinal or orbital infarction.17

The diagnosis of rhinocerebral mucormycosis is achallenge. With readily available samples, the diagno-sis so far is dependent on positive identification of thefungus on the biopsy specimen and its positive cul-ture on special media. The fungus can be in the formof colonies or can be sparsely distributed, evoking avariable tissue response ranging from suppurativegranulomas to a dense sclerotic host tissue responsewith scattering of foreign body giant cells. The dem-onstration in the biopsy specimen may not be easy ifthe hyphae are sparse and have evoked a dense scle-rotic host tissue response. Hence multiple biopsyspecimens may have to be submitted, particularly ifmalignancy is suspected on clinical and radiologic
examination. Because pus-like material is seldom ob-
tained, obtaining positive identification on culturemay not be possible in most of the cases. Althoughthe biopsy findings were suggestive of fungal pathol-ogy, cultures were negative in all of our cases. Thebiopsy specimen showed ribbon-like aseptate hy-phae, a characteristic feature of mucormycosis. Thesehyphae were surrounded by necrotic tissue alongwith reactive giant cells. The same finding was alsoconfirmed on a section specially stained with PAS.Detection of fungal antigens by molecular methodsappears to be promising, but the significance in vari-ous clinical settings is still under evaluation. Unfortu-nately, there are no serologic or polymerase chainreaction–based tests readily available to allow rapiddiagnosis. In most cases the diagnosis depends on acombination of clinical, radiologic, microbiologic,and histologic findings.18 The conventional radio-graphs showed opacification of the sinus and werenoncontributory toward confirmation of the diagno-sis. The CT scan showed a diffuse soft tissue masswith patchy hyperdensity involving the maxillary andethmoid sinuses, with extension into the orbit infero-medially. In 2 cases there was also involvement of theright extraocular muscles. Imaging findings, includinghypointense signal on T2-weighted images and hyper-dense areas on noncontrast CT scans, were suggestiveof fungal infection.

With the advent of new therapeutic regimens, thetreatment strategy now involves rapid diagnosis, re-versal and stabilization of underlying medical condi-tions if any, systemic antifungals, and appropriatesurgical debridement.

Aggressive surgical debridement and intravenousamphotericin B comprised the first line of treatmentin our cases. Amphotericin B (Fungizone; NicholasPiramal, Mumbai, India) is a polyene antimicrobialthat acts by binding to sterols (primarily ergosterol) inthe fungal cell membrane, with a resultant change inmembrane permeability. Initially, a test dose of 1 mgin 20 mL of 5% dextrose is infused intravenously overa period of 20 to 30 minutes, with careful monitoringfor side effects (ie, chills, fever, phlebitis, renal dam-age, and anaphylaxis) every 30 minutes for 2 to 4hours. If this dose is well tolerated, an initial dose of0.25 to 0.3 mg/kg per day is then prepared as a0.1-mg/mL infusion and delivered slowly over a pe-riod of 2 to 6 hours. Depending on the patient’scardiac and renal status, the dose may be graduallyincreased by 5 to 10 mg/d, up to a total dose of 0.5 to0.7 mg/kg per day. If minor side effects occur, themaintenance dose can be doubled and given on alter-nate days, but a single dose should not exceed 1.5mg/kg; overdoses can result in cardiorespiratory arrest.

In the first patient, aggressive surgical interventionwas required and hemimaxillectomy was performed,
followed by intravenous administration of amphoter-

SINGH ET AL 1375

icin B at a dose of 0.5 mg/kg body weight, but thepatient did not respond to the treatment. He had toswitch to oral administration of the antifungal agentvoriconazole. The results were dramatically positive,and successful reconstruction was subsequently per-formed with temporalis myofascial flap. In the secondpatient the surgical debridement was done aggres-sively through access osteotomy, and she also re-sponded well to voriconazole after failed therapy withamphotericin B. In the third patient the necrotic tis-sue was resected and thorough debridement was per-formed, followed by intravenous amphotericin B.

Amphotericin B is well-known for its severe and po-tentially lethal side effects. Often, a serious acute reac-tion after the infusion (1-3 hours later) is noted, consist-ing of high fever, chills, hypotension, anorexia, nausea,vomiting, headache, dyspnea, tachypnea, drowsiness,and generalized weakness. Intravenously administeredamphotericin B has also been associated with multi-ple-organ damage in therapeutic doses. Nephrotoxic-ity (kidney damage) is a frequently reported side ef-fect and can be severe and/or irreversible. Routineinvestigations (creatinine clearance, blood urea nitro-gen) were carried out regularly during the course oftherapy to assess our patients for side effects. Nosignificant side effects were observed in any of them.

Voriconazole is a new triazole derivative with invitro and in vivo activity against a wide range of fungalpathogens. Its superiority over amphotericin B hasbeen proven, as has its ability to penetrate into thecentral nervous system.3 The most common side ef-fects associated with voriconazole include transient vi-sual disturbances, fever, rash, vomiting, nausea, diar-rhea, headache, sepsis, peripheral edema, abdominalpain, and respiratory disorder. The emergence of zygo-mycosis in association with voriconazole therapy hasbeen the focus of particular interest. However, the con-nection between voriconazole therapy and break-through Zygomycetes infections has yet to be proven inprospective studies. The limited data available supportthe use of voriconazole for the treatment of invasivefungal infections in children, in those with rare fungalinfections caused by Fusarium spp or Scedosporiumspp, and in patients refractory to or intolerant of otherstandard antifungal therapies. The availability of both par-enteral and oral formulations and the almost completeabsorption of the drug after oral administration provideease of use and potential cost savings, and ensure thattherapeutic plasma concentrations are maintained whenswitching from intravenous to oral therapy.19

The etiopathogenesis of mucormycosis is still notvery clear. In addition, the clinicoradiologic presenta-tion is diverse, especially in immunocompetent hosts;thus further studies are definitely needed to deter-mine the predisposing factors and distinct clinicora-
diologic behavior of mucormycosis in immunocom-
petent hosts. The clinician must be vigilant to includeinvasive fungal infection in the differential diagnosisof an immunocompetent host with sino-orbital pre-sentation. An immunocompetent host poses a greatdiagnostic and therapeutic challenge for the clinician.Is aggressive and extensive surgery the only answer?Although aggressive surgical intervention remains themainstay of treatment, it definitely needs to be sup-ported by appropriate antifungal regimens. Further clin-ical experience will help to more fully determine theposition of voriconazole in relation to other licensedantifungal agents. A protocol for treatment cannot beestablished with such a small series of cases; however,this case series should contribute to the existing body ofknowledge on management of this pathology.

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Rhinocerebral Mucormycosis: A Diagnostic Challenge and Therapeutic Dilemma in Immunocompetent Host

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