Survival factors in rhino-orbital-cerebral mucormycosis

SURVEY OF O P H T H A L M O L O G Y VOLUME 39. NUMBER 1 • JULY-AUGUST 1994

MAJOR REVIEW Survival Factors in Rhino-Orbital-Cerebral Mucormycosis R O B E R T A. Y O H A I , MD, 1'2 J O H N D. B U L L O C K , MD, l A N D Y A. AZIZ, MD, l A N D R O N A L D j . M A R K E R T , PHD t

q,Vright State University School of Medicine, Dayton, Ohio, and 2Santa Rosa, Odifornia Abstract. Mucormycosis is a highly aggressive ff, ngal infection affecting diabetic, immunocompromised, and, occasionally, heahhy patients. This infection is associated with significant mortality. We have reviewed 208 cases in the literature since 1970, 139 of which were presented in sufficient detail to assess prognostic factors, and added data from six of our patients. The histories of these 145 patients were analyzed for the following variables: 1) underlying conditions associated with mucormycotic infections; 2) incidence of ocular and orbital signs and symptoms; 3) incidence of nonocular signs and symptoms; 4) interval fi-om symptom onset to treatment; ancl 5) the pattern of sinus involvement seen on inmging studies and noted at the time of surgery. Factors related to a lower survival rate include: 1) delayed diagnosis and treatment; 2) hemiparesis or hemiplegia; 3) bilateral sinus involvement; 4) leukemia; 5) renal disease; anti 6) treatment with deferoxamine. The association of facial necrosis with a poor prognosis fell just short of statistical significance, but appears clinically important. This is the first review that documents the heretofore intuitive claim that early diagnosis is necessary to cure this disease. Standard treatment with amphotericin B and aggressive surgery are reviewed and adjunctive therapeutic modalities are discussed, including local anaphotericin B irrigation, hyperbaric oxygen, and optimizing the imnannosuppressive regimen in transplant patients. Hyperbaric oxygen was found to have a favorable effect on prognosis. In addition, possible treatment options for patients with declining renal ftmction are reviewed. (Surv Opbthalmol 39:3-22, 1994)

Key words, amphotericill B • diabetes • fungal infection • hyperbaric oxygen • immunodeficiency • mucormycosis • orbital disease

Mucormycosis is the most acutely fatal fungal infection in h u m a n s . T h e first h u m a n case of diss e m i n a t e d m u c o r m y c o s i s with central n e r v o u s system i n v o l v e m e n t was described by Paltauf "r' in 1885. In 1943, G r e g o r y et a164 r e p o r t e d three cases with the now classic s y n d r o m e of uncontrolled diabetes, unilateral orbital cellulitis with total o p h t h a l m o p l e g i a , cerebral invasion, a n d rapid death. T h e first cure was r e p o r t e d by Hart'is~;'~in 1955. Mucormycosis is caused by fungi of the o r d e r Mucorales. "-'6'46'~v'TsE n t o m o p h t h o r a l e s , the o t h e r o r d e r p a t h o g e n i c to m a n u n d e r the class Phycomycetes, has not been d o c u m e n t e d to cause infections which invade blood vessels. Instead, m e m b e r s of this o r d e r cause e n t o m o p h t h o r a m y -

cosis, a localized, indolent, eosinophilic granulom a t o u s disease in the sinuses and subcutaneous tissues. 10,11,20,27A5,46.67,89,93 T o o u r knowledge, there have been no r e p o r t e d , c u l t u r e - p r o v e n cases of invasive, vaso-occlusive disease caused by organisms of the o r d e r E n t o m o p h t h o r a l e s . '~:~ T h e o r d e r Mucorales includes the family Mucoraceae, which encompasses the three g e n e r a most c o m m o n l y responsible for mucormycosis: Rhizopus, Mucor, and Absidia, as well as less comm o n causative agents u n d e r the families of Mortierellaceae, C u n n i n g h a m e l l a c e a e , Saksenaeaceae and S y n c e p h a l a s t r a c e a e ? 6''~:~'~ T h e Mucorales are ubiquitous s a p r o p h y t e s in nature, v_,'-,H u l n a n infection is felt to be caused by asexual spore f o r m a t i o n Y T h e tiny spores then

4

Surv Ophtlmlnlol 39 (1)July-August 1994

Fig. 1. Patient 1, initial exam, 11 clays after symptom onset. Note right lhcial edema, erythema, ptosis and facial paralysis.

become airborne, and land in the oral and nasal nmcosa of m a n f l ;'ss In the vast majority of immunologically c o m p e t e n t hosts, these spores will be contained by a phagocytic response, ss If this l~lils, germination will ensue and hypllae will develop. 4'~ Since p o l y m o r p h o n u c l e a r leukocytes (PMN's) are less effective in removing hyphae, the infection can then become established. 4'~ "Fhe rhino-orbital-cerebral infection typically begins in the nasal or oral mucosa. From there, the infection typically spreads to the paranasal sinuses and can enter the orbit easily via the ethmoid and maxillary sinuses. :~'ssOrbital extension may also occur via the nasolacrimal duct. ~s:"' Spread to tile brain may occur via the orbital apex, orbital vessels, or via the cribriform plate. :~'q~ Ahhougla it has o c c u r r e d in patients without underlying disease, tiffs infection most c o m m o n ly affects patients with pre-existing diabetes mellitus, leukemia, lymphoma, renal disease or other c a u s e O[ i l l l n l n n o s t l p p r e s s i o l l . "°'5'-''64'1°6'1:~6Several clinical tbrms are recognized: 1) Rhino-orbitalcerebral; 2) pulmonary; ,'4) disseminated; 4) cutaneous; and 5) gastrointestinal. ~~.ss.w..,.~:~ Rhinoorbital-cerebral mucormycosis (ROCM) is tile most c o m m o n and is of special interest to tile ophthahnologist, otolaryngologist ancl oculoplastic/orbital surgeon. ROCM is highly aggressive and despite many advances in diagnosis and treatment, still carries a high mortality. Prior to 1960, mucormycosis was ahnost unifi)rndy fatal. Ferry r e p o r t e d an 88c~ fatality,:"-' and Parfi'ey d e m o n s t r a t e d an 86e~ [~tality rate, 78c~ without a n t e m o r t e m diagnosis. "'~ T h e purification of amphotericin B in

YOHAI ET AL 1958, :~s'""~ and its first efficacious use in 1961, '~t coupled with an increased awareness of the diagnostic features of this disease, decreased mortality to 509~ :c-'" in the 1960s. As this trend toward accurate diagnosis and more aggressive treatment c o n t i n u e d in the 1970s, tile mortality rate further declined to 27-30%,'-'"'""; and has been r e p o r t e d as low as 15%. ""~ In this review we will present two cases in detail, and sununarize o u r e x p e r i e n c e with four additional cases o f R O C M . I n a d d i t i o n , 139 cases were collected fi'om case reports and series after 1970, and analyzed for prognostic factors. Cases prior to 1970 were excluded tbr two reasons: First and fbremost, the high mortality and lack of effective diagnosis and treatment prior to 1970 make these data i n a p p r o p r i a t e for an analysis of c u r r e n t prognostic factors. Second, many excellent reviews o f these cases already exist, and their inclusion here would be r e d u n d a n t . :~':''-''v-''-''~:~It is o u r hope that by sumnlarizing the clinical features o f both the early and late manifestations of ROCM, identifying factors that are associated with lower survival rates, and by summarizing treatment options, we will aid physicians in the p r o m p t and effective treatment o f this potentially fatal disease.

I. Case Reports CASE 1

A 75-year-old male with diabetes mellitus for twenty years p r e s e n t e d to his local physician with symptonas of right-sided nasal congestion, mild t:acial pain, and a n o n p r o d u c t i v e cough on 7/15/91. He was treated with ceFaclor 250 milligrams orally fi)ur times per day. On 7/21/91, he noted increased pain and swelling a r o u n d his right eye, fbl[owed a day later by blurry vision, increased swelling and proptosis. T h e tbllowing day, he presented to his local e m e r g e n c y room. Examination at that time revealed right-sided periorbital e r y t h e m a and e d e m a as well as right proptosis. Oral amoxicillin/clavulanate was given fbr a diagnosis ofpreseptal cellulitis and sinusitis. On 7/26/91 he r e t u r n e d with increased pain and a right orbital apex syndrome. A C T scan revealed right orbital cellulitis and right pansinusitis. His blood chemistries were significant tbr: bicarbonate 14 retool/L, glucose 562 mg/dl, BUN-50 mg/dl, creatinine 1.9 mg/dl, platelets 462, and white blood cell count 32,000. Naf?:iilin, gentamicin and insulin were given intravenously and tile patient was t r a n s f e r r e d to o u r emergency room at 0300 hours on 7/27/91. Upon arrival, he was alert and oriented but somewhat lethar-

SURVIVAL

FACTORS IN MUCORMYCOSIS

5

Fig. 2. Orbital and thcial CT scan at the time of initial examination, 11 clays after symptom onset. Left: Subtie areas of naucosal thickening are present in the left ethmoid sinus. The orbital fat on the right is slightly lighter than on the left, suggesting infiltration of orbital |ht. Right: Areas ofmucosal thickening are present in right sphenoid and left ntaxillary and nasal sinuses.

gic, with a t e m p e r a t u r e of 100 ° F. He had tense right periorbital and right premaxillary swelling (Fig. 1). T h e right eye was proptotic, chemotic and clemonstrated internal and external ophthahnoplegia. Vision was light perception OD and 20/80 OS, without correction. A 4 + relative at: ferent pt, pillary defect and clecreased corneal sensitivity were present OD. Dilated ophthalmoscopy clemonstrated normal fundi in both eyes. T h e r e m a i n d e r of the physical examination was significant for oral candidiasis, and a grayish discoloration of the nasal mucosa. Arterial blood gas analysis showed a pH of 7.41 and a bicarbonate of 22 mg/dl. His glucose had d r o p p e d to 260 mg/cll. O u r review of the C T scala confirmecl maxillary and etlamoid sinusitis on tim right. T h e r e was a slight thickening of tim mucosa in the right sphenoid sinus, and also in the left ethmoid and maxillary sinuses, which were felt to be reactive thickening (Fig. 2). A taint infiltrate was also present in the right orbit. He was treated with broad spectrum antibiotics and taken emergently to the operating room for p r e s u m e d mucormycosis. He u n d e r w e n t a right external ethmoidectomy and a Caldwell-Luc maxillectomy, turbinectomy and naso-antral window. During the p r o c e d u r e , a distinct lack o f bleeding was noted. Mucormycosis was diagnosed with a potassium h y d r o x i d e preparation offi'esh ethmoid sinus tissue (Fig. 3). Rhizopus species ultimately grew on culture. Amphotericin B was started immediately after surgery, and advanced to 40 milligrams per day (0.6 milligrams per kilogram per clay) over the course of three days. T h e dose was not advanced beyond 40 milligrams per day due to fluctuating renal status. Antibacterial medications were discontinued. T h e patient's blood sugar was very difficult to control, requiring periodic intravenous insulin administration. On 8/2/91, the patient developed a temperatnre of 101.2 ° F, and a p u l m o n a r y infiltrate on

chest X-ray in the left lower lobe. Broad spectrum antibiotics were restarted to treat his pneumonia. On 8/4/91 he became ,nuch more somnolent, with evidence of a mild left u p p e r extremity weakness. A C T scala revealed a right temporal lobe inthrction. On 8/10/91, he developed left hemiplegia. An MRI scala revealed a massive right middle cerebral artery stroke with marked cerebral e d e m a (Fig. 4). His sinusitis had spread to the left sphenoid sinus. At the same time his p n e u m o n i a spread to the right lower lobe. His condition progressively deteriorated. He expired on 8/14/91. An autopsy confirmed that the etiology of the internal carotid artery occlusion was m u c o r - t h r o m b n s (Fig. 5). H y p h a e were not i d e n t i f e d in the lungs. CASE 2

A 56-year-old female who had not visited a

Fig. 3. Patient 1. Large nonseptate hypha with rightangle branchi,lg. Potassium hydroxide preparation of fresh ethmoid sinus tissue. (Original magnification: 1000 x )

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Surv Ophthalnaol 39 (1) July-August 1994

Y O H A I ET AL

Fig. 4. MRI of head obtained after Patient 1 developed left hemiplegia (26 days after symptom onset). Left: T-2 weighted axial MRI demonstrates massive right cerebral infarct. Right: T-I weighted axial MRI shows normal internal carotid flow void on the left. The internal carotid flow w)id is absent on the right, confirming internal carotid artery occlusion as the cause of the stroke seen in the left figure.

physician in thirty years p r e s e n t e d to the e m e r gency r o o m u n r e s p o n s i v e to any stimuli on 8/13/74. H e r family noted that the patient lost sight in the left eye one day before b e c o m i n g comatose. She began having respiratory difficulty and confusion two days p r i o r to this admission. On examination she was a cachectic, unresponsive, white female. H e r breath had a distinct acetone odor, a n d she d e m o n s t r a t e d Kussmaul respirations. Vital signs were significant for a t e m p e r a t u r e of 94.8 ° F and a blood p r e s s u r e of 70/56 m m H g . T h e r e was ulceration of the skin

overlying the left medial canthus, a n d mild left eyelid swelling (Fig. 6). T h e r e was a left afferent pupillary defect and the left eye was immobile on doll's head m a n e u v e r . T h e c o r n e a a p p e a r e d cloudy a n d the conjunctiva was chemotic. T h e r e was black crusting and "dried blood" within the nose, bilaterally. Plain film X-ray d e m o n s t r a t e d a left maxillary sinusitis, with equivocal thickening o f the maxillary mucosa on the right. Lungs were clear. T h e initial laboratory data were significant for blood glucose o f 925 mg/di, p H 6.82, BUN 52 mg/dl, sodium 127 mmol/L, potassium 7.0 retool/L, chloride 97 mmol/L, bicarbonate 3

Fig. 5. Patient I. Autopsy specimen of right internal carotid artery. In the upper left portion of both photomicrographs is the vessel wall. Rhizopu.~ hyphae are seen invading intima (center of both photomicrographs). To the right of the hyphae is thrombus. Left: Hematoxylin/Eosin (original magnification, 250 x ). Right: Gomori methenamine silver (original magnification: 400 x ).

SURVIVAL FACTORS IN MUCORMYCOSIS ,,; ~ - ~ . ~

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7

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Fig. 6. Patient 2. Initial examination two days after symptom onset. Ulceration of medical canthal skin, chemosls and corneal clouding are prominent.

mmol/L, o x y g e n saturation o f 94%. T h e patient's diabetic ketoacidosis was aggressively treated with IV fluids, bicarbonate, and insulin. H e r electrolytes n o r m a l i z e d after 24 h o u r s and she b e c a m e responsive, but again b e c a m e u n r e s p o n sive 48 h o u r s after admission. T h e skin over the left medial canthus b e c a m e frankly necrotic two days after admission (Fig. 7). On 8/15/74 the patient u n d e r w e n t d e b r i d e m e n t of both nostrils. Rhizopus was cultured fi'om the nasal tissue bilaterally,. T h r o a t cultures were positive for Rhizopus and Candida albicans. A m p h o t e r i c i n B was started, but the patient e x p i r e d after four days of t h e r a p y d u e to r e s p i r a t o r y a n d cardiac arrest. Autopsy was refused. Cases 3, 4, 5 a n d 6 are s u m m a r i z e d along with the p r e s e n t cases in T a b l e 1. Cases 5 and 6 have been previously r e p o r t e d . '-'7

II. R e v i e w o f t h e L i t e r a t u r e An extensive literature search was p e r f o r m e d , and 208 case r e p o r t s published after 1970 were reviewed. O f these, 139 cases were found that p r e s e n t e d e n o u g h clinical data to allow analysis. References containing cases included in this review are indicated with an asterisk. T h e s e were a d d e d to the p r e s e n t series for a total o f 145 cases a n d then evaluated for the frequency o f conditions associated with mucormycosis. A t t e n d a n t survival rates were calculated. Next, for cases in which an a d e q u a t e c h r o n o l o g y was p r e s e n t e d , the relative frequency of signs and s y m p t o m s p r e s e n t at onset were cataloged. (Onset was defined as within 72 h o u r s of the first s y m p t o m . ) T h e case histories were then analyzed for the following variables: 1) incidence of ocular and orbital signs and s y m p t o m s ; 2) incidence of nonocular signs and s y m p t o m s ; 3) interval from onset of s y m p t o m s to t r e a t m e n t ; 4) the p a t t e r n of

Fig. 7. Patient 2, four days after symptom onset. Region of ulceration seen in Figure 6 is now fi-ankly necrotic. The patient expired four days later, despite treatment with amphotericin B.

sinus i n v o l v e m e n t seen on imaging studies and noted at the time of surgery. Survival rates were c o m p u t e d for each variable. I f a given variable was not a d d r e s s e d in a particular case report, then that case was not included in the analysis for that variable. Hence, the d e n o m i n a t o r varies for each analysis. W h e r e possible, survival rates were analyzed with the chi square test with Yates' correction for continuity when necessary. This m e t h o d was chosen because it allowed for a direct c o m p a r i s o n between the survival rates with and without a given associated condition. T h u s , the p value r e p o r t e d is the probability that a difference in survival rate as large or larger than the observed difference would occur by chance. Inferences were m a d e at the .05 level of significance. Although the study required m a n y statistical tests, Bonferroni's correction for multiple testing was not used so as to not seriously comp r o m i s e statistical power. Instead, survival percentages are r e p o r t e d in the text adjacent to p values to allow the r e a d e r to j u d g e the practical significance of differences.

A. UNDERLYING CONDITIONS I. Diabetes Mellitus T h e u n d e r l y i n g conditions associated with mucormycosis are found in Table 2. Diabetes

YOHAI ET AL

Surv Ophtlaahnol 39 (1) July-August 1994 "FABLE I

Summa U of Clinical Cases

Underlying Disease Case 1: Diabetes mellitns witltout DKA

Signs & Symptoms Nasal congestion, facial pain, periorbital swelling, orbital apex syndrome, loss of vision, clternosis, fever, elevated WBC, decreased mental status, bemiplegia.

Interval (days) front Onset of Symptoms to: Ampho B Therapeutic Diagnosis Therapy Surgery 12 12 12

Outcome Died

Unilateral by initial plain fihtts, bilateral by biopsy

Died

Rhizopus speties

No

Survived

Hyphae o n snlear

No

Survived

Hypltae on smear

I/2

No

Survived

R. arrhizn.~

6 & 16

No

Survived

Mucor ramom-

Diagnostic surgery only

Case 2: Diabetic ketoacidosis

Decreased ntental status (after normalization of electrolytes). Facial necrosis, periorbital edenta, loss of vision, oplttltalmoplegia, nasal crusting, APD, cltemosis, corneal clouding.

4

(;ase 3: Diabetes

Malaise, periorbital swelling, decreased vision, dacryocystitis, cbentosis, nasal crusting, v¢orsening ntental status despite norntalization of electrolytes.

12

12

Case 4: Diabetes, SIP renal transplant cyclospm'in,t prednisone3" previous sinusitis

Nasal discltarge, fever, decreased nlenta] status, t]tcial swelling, decreased vision. ,,phthalm,,plegia, chentosis, nasal crusting.

3

3

Case 5*: Diabetes ntcllit us, postoi)erative vndophtltalntitis, svstentic antibi~,tics and prednisone, metabolic acid,,sis cattsed by acetazolamide

Decreased vision (unoperated eye), orbital apex syndronte, proptosis. nasal crusting.

1/2

I/2

Case 6": Hyperosmolar Ityperglycemic conm, pH 7.:1

Fever, cltemosis, periorbital edema, proptosis. ophtbahnoplegia (internal and external). Decreased mental status.

ntellitus witltout ketoacidosis

Bilateral Sinus I nvoh,ement Equivocal at first, witb subsequent progression bilaterally

I

'22

Organism Rhizopus species

*Previously publisbed. See reference 28. tStopped prior to onset of ROCM.

mellitus accounted [br 60c~ of ROCM in this study, and 70-819~ in o t h e r series. '-'"':':u'-''''cmT h e survival rate [br all patients was 60c~, with the rate tbv diabetics being 77¢){ and for nondiabetics 34~ (P < .0001). (Survival rates may be skewed by a bias toward reporting survivals r a t h e r than deaths.) Diabetes mellitus, especially with acidosis, appears to weaken the initial containment of the infection by PMN's :<''ss'"~s'p-''and increases the p r o p o r t i o n of u n b o u n d iron," which aids ft, ngal growth. T h e sera of diabetics appears to lack a dialy'zable inhibitory [actor -'s's'~ ancl the glucoserich, acidic milieu facilitates fimgal growth. :u"' T h e higher survival rate in diabetics has been previously noted anti is f;elt to be due to the ability to reverse the t, nderlying hyperglycemia in diabetes mellitus.'":"-' Normalization of pH and

glucose may not stem the progression of disease, as poor perfttsion can cause localized acidosis. "m This is one reason why complete excision of necrotic and poorly perfused sites of infection is recommended. 2. Renal Disease

T h e frequency of renal disease in o u r study was 14c~, with patients kfirly evenly split between renal transplant and renal failure (Table 2). T h e survival rate fin" the 21 patients with renal disease was 19~ versus 67% ff)r patients without renal disease (p < .0001). Thirty percent of the ten renal transplant patients survived versus 629{ of the remaining patients (p = .0944). T h e median time of onset of ROCM is two months after transplant surgery,

SURVIVAL FACTORS IN MUCORMYCOSIS TABLE 2

Conditions Associated with Rhino-Orbital-Cerebral Mucormycosis

Condition All patients MI nondiabetics MI diabetics Ketoacidosis (DKA) Diabetes without ketoacidosis (DM) Pancreatitis + DM Pancreatitis + DM + cirrhosis DKA + cocaine use Dental extraction + DM Steroid-induced DM/DKA Steroid without hyperglycemia For cerebral edema For viral myocarditis Renal disease s/p renal transplant AZA + steroid Cyclo + steroid High dose steroid Dialysis + deferoxamine Chronic renal insufficiency Renal tubular acidosis Deferoxamine For Al overload For hemochromatosis Leukemia (all neutropenic) Other malignancies: Ovarian (cured)' Rectal adenocarcinoma Carcinoid 1,2 Sarcoidosis 1'2 Giant cell arteritis 1'2 Polyarteritis nodosa Hematologic disorders Fanconi's anemia 3 Idiopathic bone marrow aplasia ~y-,3 Myelofibrosis Myeloproliferative disorder lyThalassemia 2 No underlying disease Dental extraction (previously healthy) Chronic sinusitis (only) Healthy + ATB's prior to Mucor infection Healthy + ATB + steroid prior to Mucor infection Dehydration/acidosis Dehydration/malnutrition

Number of Patients

Frequency

Number Surviving (%)

145 58 87 43 38 2 1 1 2 4 2 1 1 21 10 7 2 1 8 1 2 9 8 1 8 3 1 1 1 1 1 1 5 1 1 1 1 1 3 2 1 1 2 1 1

100% 40% 60% 30% 26% 1.4% 0.7% 0.7% 1.4% 2.8% 1.4% 0.7% 0.7% 14% 7% 4.8% 1.4% 0.7% 5.5% 0.7% 1.4% 6.2% (see above) 0.7% 5.5% 2.1% O.7% 0.7% 0.7% 0.7% 0.7% 0.7% 3.4% 0.7% O.7% 0.7% 0.7% 0.7% 2% 1.4% O.7% 0.7% 1.4% 0.7% 0.7%

87 (60%) 20 (34%) 67 (77%) 33 (77%) 29 (76%) 2(-) 1(-) 1(-) 1(-) 3 (75%) l(-) 1(-) 0(-) 4 (19%) 3 (30%) 1 (14%) 2(-) 0(-) 0 (O%) 1 (-) 0(-) 0 (0%) 0 (O%) 0(-) 1 (12.5%) 3(-) 1(-) 1(-) l (-) 0(-) 1(-) 1(-) 0 (0%) 0(-) 0(-) 0(-) 0(-) 0(-) 2 (67%) I(-) 1(-) 0(-) 0(-) l (-) 1(-)

DKA = diabetic ketoacidosis; DM = diabetes mellitus without DKA; AZA = azathioprine; Cyclo = cyclosporin; ATB's = systemic antibiotics. i Receiving glucocorticoids. '-'Diabetes mellitus. 3Neutropenic. 4Felt to be completely healthy at time of infection. with a r a n g e f r o m two days to f o u r years. :)s B o t h diabetic a n d n o n d i a b e t i c t r a n s p l a n t recipients are p r o n e to R O C M . :~q''~s T h e diabetic patients h a d a survival o f 50% c o m p a r e d to 31c~ overall. In o u r series, only 3 o f 10 patients with renal t r a n s p l a n t had diabetes. T h e i m m u n o s u p p r e s s i v e agents used to pre-

vent rejection o f the t r a n s p l a n t e d kidney, also w e a k e n the r e s p o n s e to Mucorales. It has b e e n s u g g e s t e d that cyclosporin has less effect on P M N ' s than d o p r e d n i s o n e o r azathioprine, s° Kaplan et al assert that the T-cell specificity o f cyclosporin A, in c o m p a r i s o n to the b r o a d e r imm u n o s u p p r e s s i o n o f o t h e r regimens, " u n d o u b t -

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edly contributed to" their patient's successful outcome, s° More data will be needed to determine whether cyclosporin truly offers a higher survival rate than does azathioprine, and/or prednisone. All of the eight patients on hemodialysis were also receiving deferoxamine. None of them survived. (They are listed u n d e r both deferoxamine and hemodialysis in Table 2.) The metabolic acidosis, iron and a l u m i n u m overload, and extensive antibiotic therapy associated with uremia have been postulated to promote mucormycosis. '':~:°s'v-'9 Boelaert et al ''1 reported 59 mucormycosis patients from an international registry of dialysis patients. Of these, only 13 were not receiving deferoxamine and seven of these had other underlying conditions besides dialysis. Thus, of all 59 reported patients with any form ofmucormycosis, only six had dialysis as the sole risk factor, and only three of these patients had ROCM. The frequency of mucormycosis for patients in whom dialysis is the sole risk factor seems lower than previously recognized.

b o u n d by transferrin cannot, j'2~ Deferoxamine is a naturally occurring hydroxamate siderophore obtained from Streptomyces pilos us. ~:~ Similar siderophores are secreted and utilized by Rhizopus.l'2]'~8 Thus, deferoxamine, in the iron-chelate form, feroxamine, provides iron to Mucorales. Deferoxamine has been shown to promote pathogenicity in vitro, 21 as well as in v i v o . TM As deferoxamine is eliminated via renal clearance, its circulation time is prolonged in renal failure, making iron even more available to fungi in these patients. Iron overload states (eg., hemochromatosis) may also be risk factors. 21 Deferoxamine, however, has been shown to promote mucormycosis without iron overload. I In addition, DFO may also act by altering granulocyte and lymphocyte functions, vv:4~ Ironcatalyzed peroxidase production of free radicals, which is important for killing fungi, may be inhibited by DFO. 14j'14:~

3. Deferoxamine Therapy A total of nine patients with ROCM receiving deferoxamine for iron or aluminum chelation were found in the literature. ~6'~'~:~°'~'~¢''~:~ None survived. In comparison, 64% of remaining patients survived (p = .0006). Reports associating deferoxamine (DFO) with ROCM began surfacing in the mid-1980s. -'z':~''-'6"77'~q'-'H:~Boelaert et a129noted that mucormycosis developed in two of 132 dialysis patients treated with DFO, but in none of the 1371 dialysis patients not treated with DFO. In a recent report of 59 cases of mucormycosis in dialysis patients, Boelaert et ai '-'~ listed 21 cases of ROCM. Twelve of these had no risk factors other than DFO and dialysis. Only two of these patients survived. Thus, deferoxamine treatment accounts for the majority of infections and fatalities in ROCM in dialysis patients. The low survival rate associated with deferoxamine reached statistical significance in this review. Recently, multiple articles have clarified the ways in which deferoxamine may promote infection with mucormycosis, u~7''-'~:4~ Iron appears to be an important growth factor for Mucorales. ~''~ Transferrin, which binds serum iron, deprives fungi and other pathogens of this nutrient. L9.77A41 In order to obtain iron, micro-organisms secrete iron binding compounds known as siderophores. The iron bound to these siderophores can be utilized by fungi, whereas iron

4, Leukemia Mucormycosis in leukemia is u n c o m m o n . When it occurs, the p u l m o n a r y and disseminated forms of the disease are the most common.Jg:0q: ~5.~~o The dissemination of mucormycosis in leukemia most likely stems from the diminished function of the immature white blood cells in the leukemic state and the inability to fight off any infections in the neutropenic state.2S: ~9 Of the eight patients with leukemia in our review, all had neutropenia, and only one (I 3%) survived compared to 63% of the non-leukemic patients (p = .0143). This patient received alpha-interferon in an attempt to stimulate his bone marrow to recover from chemotherapy. ~v His white blood cell count increased from 500 to 4000 after one m o n t h of alpha-2 interferon. The extent to which this contributed to his survival is unclear. T h e poor prognosis in leukemia is attributed to the inability to reverse the underlying condition.'-'°'~s 5. Miseellaneous Conditions An extensive list of other conditions have been associated with mucormycosis. 4:~'52'ss:°4::~ Any form of metabolic acidosis may lead to ROCM. 4"~'97"jh:~ Dehydration and diarrhea, especially with acidosis, have been implicated as risk factors. :~:a''°7'~ Malignancies, ~°~ tuberculosis, "~6 cirrhosis, :~4.~°.~°~ ~1 106 aplasticanemia:-' Fanconi , sanemia, I ~ systemic lupus erythematosus, 1°6 multiple myeloma, ~°~ cholesteatoma, 106 polyarteritis nodosa, "~6 sarcoidosis, ~°'l°G viral myocarditis, '-'4'"~ severe burns, j°6 trauma, 14:~kwashiorkor, t:~6amebic dysentery, ~:~6typhoid fever, ~:~hepatitis ~v_,and hepatic failure ~:~ have all been reported associations,

SURVIVAL FACTORS IN MUCORMYCOSIS especially with the p u l m o n a r y , gastrointestinal, cutaneous and disseminated forms o f mucormycosis. T h r e e cases o f mucormycosis with AIDS were recently r e p o r t e d J ~'124 All three patients were IV d r u g abusers and had isolated cerebral mucormycosis without sinus or orbital involvement. N o n e survived. We are not aware o f any published reports of rhino-orbital-cerebral mucormycosis in AIDS patients, but are aware o f n o n p u b l i s h e d cases (personal communications with H o w a r d Wunderlich, M.D. and Diane Kraus, M.D.). Rarely, ROCM has o c c u r r e d in previously healthy patients.35..qg.107.113.1:~6.15~- TO rule out u n d e r l y i n g immunodeficiency, a complete immunologic work-up should be considered. :~5'~°v'm~:~ Four patients included in this review were healthy at the time of infection? 5'99' ~:~.~5~.T h r e e o f these are listed as "no u n d e r l y i n g disease" and the fourth had " c u r e d ovarian cancer" in Table 2. T h r e e o f four survived. O f the patients included in this series, n o n e of the five patients with n o n m a l i g n a n t hematologic diseases survived c o m p a r e d to 62% o f o t h e r patients (p = .0129). T w o of these patients were neutropenic.

B. PRESENTING SIGNS AND SYMPTOMS A knowledge of the early findings, r a t h e r than the full-blown syndrome, can aid in making an early diagnosis. T o d e t e r m i n e which signs and symptoms o c c u r r e d early in the disease, the 114 case reports of the 145 which provided a clear chronology were identified. T o provide an estimate o f the relative frequency of r e p o r t e d presenting signs and symptoms in mucormycosis, all cases that specified which findings o c c u r r e d within 72 hours of the first symptom were tabulated. Absence o f p e r t i n e n t negatives was not g r o u n d s for exclusion. Fever (44%), nasal mucosal ulceration/necrosis (38%), periorbital and facial swelling (34%), decreased vision (30%), ophthaimoplegia (29%), sinusitis (26%), headache (25%), facial pain (22%), and change in mental status were the most c o m m o n early findings (Table 3). T h e changes in mental status consisted o f somnolence, disorientation, coma, and, rarely, emotional lability. Ferry et al 5:~ noted that a black eschar of skin, nasal mucosa or palate was present in only 19% o f his 16 patients. T h e y stressed that although mucosal or facial necrosis is c o m m o n later in the course o f disease, it cannot be relied u p o n to aid in diagnosis initially. We agree with this assessment, and feel that o u r estimate o f these findings is higher because we included ulcerated lesions which ultimately became necrotic. Sinusitis was initially present in 69% of Ferry's 16 patients,

11 TABLE 3 Signs and Symptoms Present Within 72 Hours of Onset Total Patients = 114"

Sign or Symptom Fever Nasal ulceration, or necrosis Periorbital or facial swelling Decreased vision Ophthalmoplegia Sinusitis Headache Facial pain Decrease in mental status Increased WBC Nasal discharge Nasal stuffiness Corneal anesthesia Orbital cellulitis Proptosis Palatal or gingival necrosis Afferent pupillary defect CN VII palsy Periorbital pain Chemosis (without orbital cellulitis) Epistaxis Facial numbness Diplopia Facial necrosis Hemiplegia/stroke Malaise Ptosis (without ophthalmoplegia) Decreased hearing Toothache Earache

Number

Frequency (Percent)

50 43 39 34 33 30 29 25 25 22 20 19 19 18 18 16 15 13 13

44% 38% 34% 30% 29% 26% 25% 22% 22% 19% 18% 17% 17% 16% 16% 14% 13% 11% 11%

10 10 8 6 5 5 5

9% 9% 7% 5% 4% 4% 4%

4 4 4 4

3.5% 3.5% 3.5% 3.5%

Note: The total number exceeds 114 because patients presented with more than one sign or symptom.

c o m p a r e d with 26% in o u r review at 72 hours. We feel that sinusitis is u n d e r - r e p r e s e n t e d in o u r data because physical and radiographic examination often did not take place until at least the fourth day after symptom onset. T h e r e f o r e , there was no way to confirm the presence of sinusitis within 72 hours of symptom onset in many patients. As seen in Table 5, the frequency for sinusitis, at any time in the course of disease, was 79%, which corresponds well with the 69% r e p o r t e d by Ferry and Abedi. 5:~

1. Ophthalmic Signs and Symptoms T h e incidence o f ophthalmic and nonophthalmic signs and symptoms occurring at any time in the course o f disease were d e t e r m i n e d by reviewing case reports for the findings listed in Tables 4 and 5. If pertinent negatives were not specified, the case was excluded. T h e incidence and associ-

12

Surv Ophthalmol 39 (1)July-August 1994

Y O H A I ET AL

TABLE 4 Frequency and Survival Rates for Ophthalmic Signs and Symptoms - 80 Patients (S = 43, D = 37)

Sign or Symptom External ophthalmoplegia Total Partial Decreased vision Proptosis Periorbital edema Internal ophthalmoplegia Afferent pupillary defect Trigeminal anesthesia (V1) Conjunctival chemosis Orbital cellulitis CRAO Corneal anesthesia Cavernous sinus thrombosis Periorbital necrosis Periorbital/orbitai pain Eye pain Corneal edema/clouding Orbital abscess Optic disk edema Diplopia Periorbital discoloration (erythema or ecchymosis without necrosis) Ptosis (with partial or no ophthalmoplegia) Optic disk pallor Fungal eyelid abscess Fungal vitritis/endophthalmitis

Total Number 54 49 5 52 51 34 32 30 21 19 16 13 11 10 9 9 6 5 5 4 3 3 2 2 1 1

(52) (48) (50) (50) (33) (27) (18) (15) (10) (8)

(4)

Percent with Finding

Number Surviving

67% 61% 6% 65% 64% 43% 40% 38% 26% 24% 20% 16% 14% 13% 11% 11% 8% 6% 6% 5% 4%

29 26 3 30 22 19 15 19 12 11 7 9 6 4 3 4 3 2 3 3 1

4% 3% 3% 1% 1%

0 1 1 I 1

(27) (25) (28) (22) (18) (16) (10) (7) (6) (4)

(2)

Percent Surviving 54% 53% 60% 58% 43% 56% 47% 63% 57% 58% 44% 69% 55% 40% 33% 44% 50% 40% 60%

(52%) (52%) (56%) (44%) (55%) (59%) (56%) (47%) (60%) (50%)

(50%) * * * * * * *

S = survivors; D = deaths. 0 Indicates totals when the seven patients who received hyperbaric 02 were excluded. *No inferences drawn from sample sizes less than 5.

ated survival rates for o p h t h a l m i c signs and s y m p t o m s in 80 patients are listed in T a b l e 4. C o m p l e t e external o p h t h a l m o p l e g i a , decreased vision, proptosis, periorbital e d e m a and internal o p h t h a l m o p l e g i a were the most c o m m o n findings. O f the five patients with partial o p h t h a l m o plegia, three had cranial nerve VI paresis and two had cranial nerve I I I paresis with ptosis. Isolated cranial nerve IV paresis was not r e p o r t e d . T h e lowest survival rates were associated with periorbital necrosis (33%, p = .3425) and cave r n o u s sinus thrombosis (40%, p = .553). T h e s e were not statistically significant.

2. Nonophthalmic Signs and Symptoms T h e frequency and associated survival rates for n o n o c u l a r signs and s y m p t o m s for 80 patients are listed in Table 5. T h e most c o m m o n finding was a necrotic lesion on either the nasal or oral mucosa, seen in 80% of patients. Nasal mucosal necrosis was seen in 48%, and oral necrosis was seen in 32% of patients. Palatal lesions accounted for the majority of lesions within the

m o u t h . T h e s e lesions are typically d a r k red to black, and bleed little when biopsied. Less commonly, gray necrotic lesions have been r e p o r t ed?:' Sinusitis was p r e s e n t in 79% of patients. O t h e r c o m m o n findings were fever (36%), mental status changes (34%), facial swelling (30%), facial pain (23%), elevated white blood cell c o u n t (23%) and ipsilateral facial n u m b n e s s (20%). A low survival rate was seen with h e m i p l e g i a (28%, p = .011), facial necrosis (31%, p = .0622), mental status changes (32%, p = .002), and fever (41%, p = .047). As will be seen later, adjunctive t r e a t m e n t with h y p e r b a r i c oxygen appears to have a favorable effect on outcome. I f the two patients with strokes who received hyperbaric oxygen t r e a t m e n t s are excluded, then the survival rate decreases to three of 16, or 19% (p = .003). I f all cases with hemiparesis who also had o t h e r conditions f o u n d to affect prognosis (such as bilateral disease [see below], facial necrosis or h y p e r b a r i c oxygen treatments) are excluded, then the survival becomes two of 11, oi" 18%, (p = .002).

SURVIVAL FACTORS IN MUCORMYCOSIS

13 TABLE 5

Frequency and Survival Rates for Nonophthalmic Signs and Symptoms - 88 Patients (S = 48, D = 40)

Sign or Symptom Mucosal necrosis (nasal & oral) Oral mucosa (palatal, gingival, buccal) Nasal mucosa Sinusitis Fever Mental status changes Facial swelling Facial pain Leukocytosis Facial nerve paresis Facial numbness (V2,Vs) Hemiplegia/stroke Headache Facial necrosis (includes all facial skin) Nasal discharge Malaise Epistaxis Int. carotid occlusion Brain abscess Toothache Nasal stuffiness Increased ESR Decreased hearing Nausea, vomiting Seizures Previous facial fracture Otitis media

Total Number 70 28 42 69 32 31 26 20 20 19 18 18 15 13 11 10 9 8 7 6 5 3 3

(64) (26) (38) (65) (23) (19) (15) (17) (16) (14) (12) (8) (7) (5) (4)

2 1 1

Percent with Finding

Number Surviving

80% 32% 48% 79% 36% 34% 30% 23% 23% 22% 20% 20% 17% 15% 13% 11% 10% 9% 8% 7% 6% 3% 3%

40 14 26 39 13 10 13 11 12 8 13 5 9 4 5 4 6 4 5 3 4 0 1

2% 1% 1%

0 1 1

(35) (12) (23) (35) (11) (10) (8) (12) (3) (8) (3) (5) (3) (3) (3)

Percent Surviving 57% 50% 62% 62% 41%* 32%* 50% 55% 60% 42% 72% 28% 60% 31% 45% 40% 67% 50% 71% 50% 80%

(55%) (46%) (61%) (54%) (48%) (53%) (53%) (71%) (19%) (57%) (25%) (63%) (43%) (60%) (75%) --

S = survivors; D = deaths. *See Results Section. 0 Indicates numbers when the seven patients who received hyperbaric 02 are excluded. - No inferences from sample size less than five.

A similar analysis for facial necrosis reveals that if cases who received h y p e r b a r i c oxygen are excluded, the survival decreases to three of 12, or 25% (p = .0394). I f cases with facial necrosis who also had hemiparesis, bilateral disease or received t r e a t m e n t with h y p e r b a r i c oxygen are excluded, then the survival rate becomes three of eight, or 38% (p = . 102). T h u s , the association of facial necrosis with a lower survival rate retains only marginal statistical significance when viewed in isolation. Mental status changes and fever, however, both lose clinical significance when isolated from o t h e r factors. In o u r study, mental status changes were associated with strokes in 15 of 31 cases a n d with s u b d u r a l h e m a t o m a f r o m pres u m e d naucormycotic a n e u r y s m in one of 31 cases. I f these 16 cases are excluded, the survival becomes eight of 15, or 53%. I f all patients with bilateral infection, hemiplegia, facial necrosis o1" t r e a t m e n t With h y p e r b a r i c o x y g e n are excluded, then the survival becomes six of 11 (55%) for

patients with mental status changes (p = . 144). This p-value makes it unlikely that mental status changes are truly associated with a p o o r p r o g n o sis. As for fever, if patients with hemiparesis or hemiplegia, facial necrosis, bilateral disease or those treated with h y p e r b a r i c oxygen were excluded, then the survival rate b e c a m e eight o f 12, or 67% (p = .777). T h u s , hemiparesis or hemiplegia a p p e a r s to reach statistical significance as an i n d e p e n d e n t factor associated with a worse prognosis in rhinoorbital-cerebral mucormycosis. T h e association of facial necrosis with a p o o r prognosis d e m o n strates m a r g i n a l statistical significance. When fever a n d mental status changes are isolated fi'om o t h e r factors associated with a p o o r prognosis, they lose statistical significance. This lends statistical s u p p o r t to the findings of Blitzer. "-'° C. I N T E R V A L F R O M S Y M P T O M O N S E T T O TREATMENT: EFFECT ON SURVIVAL

T o assess the effect of delay of treatnaent on

14

Y O H A I ET AL

Surv Ophthalmoi 39 (1) July-August 1994 TABLE 6

TABLE 7

Interval From Symptom Onset to Amphotericin B

Interval From Symptom Onset to Surgery

Group All Diabetic Nondiabetic All Diabetic Nondiabetic All Diabetic Nondiabetic

Interval (Days)

Total Number

1-6 1--6 1-6 7-12 7-12 7-12 13-30 13-30 13-30

34 27 7 41 24 7 11 9 2

Number Surviving (%) 26 24 2 15 15 0 4 4 0

(76) (89) (29) (36) (63) (0) (36) (44) (0)

survival the case histories were carefully reviewed to d e t e r m i n e the intervals between the first s y m p t o m referable to mucormycosis, a n d t r e a t m e n t with a m p h o t e r i c i n B or surgery. I f the case r e p o r t s did not clearly address the sequence of events, the cases were excluded f r o m this analysis. For the first interval, s y m p t o m onset to amphotericin B, 76 patients with suitably clear histories were found. T h e data for these patients are seen in T a b l e 6, and are subdivided into "All Patients," "Diabetics" and "Nondiabetics." Because of the small s a m p l e size available with this r a r e disease, there were a n u m b e r of days w h e r e the p e r c e n t survival was either 0 or 100%, which is obviously artifactual. T o p r o v i d e m o r e m e a n ingful results, the survival rates are a v e r a g e d for three discrete intervals: days 1-6, 7-12, and 13-30. T h e y are p r e s e n t e d in bar g r a p h f o r m in Figure 8. T h e data for the second interval, " S y m p t o m Onset to T h e r a p e u t i c Surgery," is treated in a similar fashion (Table 7). It represents 70 patients. A graphic r e p r e s e n t a t i o n o f p e r c e n t survival as a function of the interval to t h e r a p e u t i c surgery is seen in Figure 9. T h e n u m b e r s of patients included for these two intervals (onset to a m p h o t e r i c i n B, a n d onset to surgery) varies because m a n y patients did not survive long e n o u g h for surgery. T h e survival rate begins to decline w h e n the interval to t r e a t m e n t is longer than six days. In diabetics, this curve assumes a very g r a d u a l slope, whereas in nondiabetics there are no survivors after 12 days of disease. T h r e e patients (not in g r a p h s or tables) were diagnosed and treated at 32, 34, and 90 days after s y m p t o m onset, and survived. All three received a m p h o tericin B a n d aggressive surgery. T h e first two were diabetic. '-'5''j5T h e third patient '~2 was without c o n c o m i t a n t illness, but did have a history of ovarian cancer, surgically c u r e d five years pre-

Group All Diabetic Non-diabetic All Diabetic Non-diabetic All Diabetic Non-diabetic

Interval (Days)

Total Number

1-6 1-6 1-6 7-12 7-12 7-12 13-30 13-30 13-30

31 24 7 27 21 6 12 9 3

Number Surviving (%) 25 21 4 14 13 1 5 5 0

(81) (87) (57) (52) (62) (17) (42) (56) (0)

viously. D. S U R V I V A L RATE AS R E L A T E D T O ORGANISM GROWN ON CULTURE

O f the 145 cases analyzed, 43 p r o v i d e d culture identification of the organism. T h e survival rate for infections caused by the genus Rhizopus was 47%, whereas, with Mucor it was 58%. This does not suggest a difference in virulence between the various o r g a n i s m s causing mucormycosis. Rhizopus a c c o u n t e d for 70% of culture positive cases (Table 8). E. S U R V I V A L RATE AS R E L A T E D T O E X T E N T OF P A R A N A S A L S I N U S I N F E C T I O N

T h e extent of nasal a n d paranasal sinus disease could well be e x p e c t e d to affect the p r o g n o sis. In this r e g a r d , we sought to answer two questions: 1) ls t h e r e an association between survival a n d the total n u m b e r o f sinuses involved? 2) Does bilateral i n v o l v e m e n t of the sinuses p o r t e n d a worse prognosis? 1. N u m b e r o f S i n u s e s I n f e c t e d

T o study these questions we first evaluated the relationship between the total n u m b e r of involved sinuses a n d survival. T h e involved sinuses were identified by i m a g i n g techniques (radiographs, C T scans, a n d MRI). In three cases, (reference 44, Case II; reference 147, patient 3; a n d Case 2 in the p r e s e n t series) sinuses that app e a r e d uninfected by imaging studies were subsequently shown to contain fungal h y p h a e on biopsy. T h e s e sinuses were c o n s i d e r e d positive in this tally. A total o f 94 cases with a d e q u a t e r a d i o g r a p h i c data were f o u n d in the literature. 7. [2. 13. [7.2o.24.25.2~i.3..~.34.35.3~.4D.44.49.56. fi7.60. 66. 70. 74,75, 76, 78,80.81,82,M7.t|2,95,96,9;'4,105, IU6, I 1 I. 112, 113, 114. 117. 119.120,

123.130,131,132.135,137,140.141.145.147,149,151,152 O u r six cases

SURVIVAL FACTORS IN MUCORMYCOSIS

15

Survival in Mucormycosis

Survival in Mucormycosis

(N-76 patients) lOO

%

(N • 70 patients)

Survival 100

80

80

60

60

40

40

20

20

0

(days) 1-6 7-12 13-30 Interval from symptom onset to Ampho B =11 petlenta

~

dlebetlee ~

% Survival

0

non'-dlebetlee

I! II

(days) 1-6 7-12 13-30 Interval from symptom onset to Surgery Bill all patients ~ ] diabetics

I---] non-diabetics

Fig. 8. Bar graph of percent survival as a function of the

Fig. 9. Bar graph of percent survival as a function of

interval between the first symptom referable to mucormycosis and treatment with amphotericin B. The data for this graph is listed in Table 6. Note that the decrease in survival for diabetics is gradual, whereas the survival for nondiabetics falls abruptly as the interval to treatment is prolonged.

interval from symptom onset to therapeutic surgery. The data for this graph is listed in Table 7. The curve mirrors the pattern seen in Fig. 8.

were also included for a total of 100 patients. Cases were divided into groups with involvem e n t of one, two, three and four or m o r e sinuses, with survival rates of 80%, 47%, 72% and 58%, respectively. Thus, there is no significant decrease in survival as patients have an increased n u m b e r of sinuses involved. This analysis is in a g r e e m e n t with Blitzer. 2° It is noteworthy that by removing cases with bilateral involvement, the survival rate increases uniformly to 86%, 55%, 88% and 90%, respectively. 2. Bilateral Sinus I n f e c t i o n

O f the 100 cases with imaging data, 28 were found to have bilateral involvement. T h e survival rate for the 72 patients with unilateral disease was 74%. T h e survival rate for patients with bilateral disease was 32% (Table 9). This difference was significant (p = .0001). When the patients receiving hyperbaric oxygen are excluded, the difference between the survival in the unilateral g r o u p (72%) and the bilateral g r o u p (18%) was also significant (p < .0001).

leukocytosis. T h e most characteristic nonocular findings (Table 5) are sinusitis and ulceration or necrosis of nasal or oral mucosa. Necrosis of facial skin, including eyelids and peripheral facial nerve palsies, typically occur later. H e a d a c h e or facial pain is often out of p r o p o r t i o n to radiographic findings. Diabetic control may be good, but more often, is not adequate. Mental status changes often occur when the disease spreads to the orbit, but may occur either earlier or later. 6'-'79'1-~2 Another classic presentation is the unresponsive patient in diabetic ketoacidosis whose mental status does not improve with normalization of electrolytes. Mucormycosis should be ruled out in these patients, w-'-' Orbital findings are due to ischemic necrosis of the intraorbital cranial nerves. This is caused by fungai invasion of the orbital blood vessels, and subsequent thrombosis. Thus, any array o f ipsilateral cranial nerve abnormalities can occur, but the orbital apex s y n d r o m e (OAS) and superior

TABLE 8 Organisms Grown in Culture #

F. DIAGNOSIS

Genus Species

1. S u m m a r y o f Clinical Features T h e typical presentation is that of a patient with diabetes (or o t h e r u n d e r l y i n g condition as described above) who presents with unilateral headache, facial pain, nasal stuffiness, facial a n d / o r eyelid swelling, epistaxis, r h i n o r r h e a with a granular or p u r u l e n t discharge, 4~ fever and

Rhizopus

(All) R. Oryzae* R. rhizopodiformis Mucor (All) M. Ramosissimus M. circinelloides CuninghameUa berthoUetiae

%

Total Survived Survived 30 8

14 4

47% 50%

1

1

-

12

7

58%

1 1 1

1 1 1

*Synonymous with R. arrhizus, ss

-

16

Surv Ophthalmol 39 (1)July-August 1994 TABLE 9

Comparison of Survival in Bilateral and Unilateral ROCM

All Unilateral Bilateral Patients Involvement Involvement Total number 100 Number survived 62 Number died 38 Survival rate 62%

72 53 19 74%

(69)* 28 (22) (50) 9 (4) (19) 19 (18) (72%) 32% (18%)

0 Indicates values when those who received adjunctive treatment with hyperbaric oxygen were excluded. Five of the six patients with bilateral disease who were treated with hyperbaric oxygen survived.

orbital fissure syndromes are the most characteristic. Thrombosis of the superior ophthahnic vein may occur, although Mucorales, as opposed to bacteria, have a greater propensity to invade arteries than veins) v-' Ocular invasion occurs rarely, most likely via intra-arterial spread. TM From the orbit the infection can spread into the cavernous sinus, causing a cavernous sinus thrombosis (CST). CST with visual loss is typical of mucormycosis, whereas CST without visual loss is more characteristic of a bacterial etiology. :*'77 Diagnosing cavernous sinus thrombosis in the presence of orbital mucormycosis can be difficult, given that ophthahnoplegia, proptosis, chemosis and lid edema may ah'eady be present. CT and MRI may be of limited use in confirming C S T . 4s'51~'77 From the cavernous sinus the fungus will often spread to the internal carotid artery. This then leads to internal carotid artery occlusion and a massive stroke, ultimately resulting in coma and death (see Case I). lntracranial spread can also occur via the cribriform plate into the region of the olfactory grooves and frontal lobe. 2. Imaging Studies hnaging studies with computed tomography or magnetic resonance should be obtained to determine the presence of sinus disease or orbital infiltrate. CT scans will typically demonstrate mucosal thickening without air fluid levels (Fig. 2). Evidence of bone destruction on CT scans is a late finding. Bone necrosis can lead to spread of infection into the pterygoid and infi'atemporal fossae, as well as into the parapharyngeal space) ~° Thrombosis of the superior ophthahnic vein may be seen as a faihn'e of the vein to enhance with intravenous contrast) ~" Imaging of the brain by CT scan, demonstrated that intracerebral fungi appeared as low density masses with variable peripheral e n h a n c e m e n t ) ~° Tile peripheral enhancement Cring abscess") may be absen( ~" or p l - o n a i n e n t . ~i°,4t~,l°l~

YOHAI ET AL Magnetic resonance imaging of sinuses infected with mucormycosis demonstrate a hyperintense signal from the thickened mucosa on proton density weighted and T-2 weighted images (Fig. 10). Subtle infiltration of orbital fat is best seen with proton density weighted images. TM Clinically evident areas ofcellulitis on the eyelid and face will appear hyperintense on proton density weighted MRI scans t~ (Fig. 10). Areas of cerebral ischemia and inflammation will appear hyperintense on T-2 weighted images. TM Post-gadolinium and gradient recalled acquisitions in the steady state (GRASS) images may help to define blood flow in the intraorbital and intracerebral vasculature r'2 (Fig. 4A). 3. Biopsy If radiographic and clinical features are suggestive of mucormycosis, then biopsy of any nasal, oral or sinus lesions must be obtained promptly. Biopsy specimens should be sent tbr fi'esh tissue preparations, fi'ozen sections, and p e r m a n e n t sections. In order to diagnose mucormycosis, one must identify large, sparsely septate fungal hyphae with right angle branching in tissue specimens: '~ Positive cultures alone are not sufficient to make the diagnosis, because Mucorales can be grown fi'om specimens taken fi'om uninfected mucosal and skin s l . n ' f a c e s . 53"~17''s8'1'-''-''1:~6 If initial biopsy specimens are negative for layphae, and clinical suspicion remains high, additional specimens which include arteries should be obtained. 77 Increasing the size of the biopsy specimen to include the junction of well and poorly perfilsed tissues may also serve to increase tile chances of finding hyphae. Preparations usefnl for identifying mucormycosis include hematoxylin-eosin (Fig. 6A), ';'5:~:v-''l:~'~ Gomori m e t h e n a m i n e silver, and periodic acid Schiff. 'r':~'' Fresh tissue preparations utilize 1020% potassium hydroxide :':~'v-''-' (Fig. 3). Touch preparations for cytologic analysis have also been reported to allow diagnosis. '~:~ G. TREATMENT Proper treatment of mucormycosis requires early definitive diagnosis, reversal of the underlying condition (where possible), systemic antifungal therapy, wide local excision of all necrotic tissue and establishment of adequate sinus and orbital drainage. '-'7.:':~:~:''~s'"''T h e benefits of Sl.lrgery and Amphotericin B have been clearly demonstrated by Blitzer et al.'-'" 1. Amphotericin B Amphotericin B is the treatment of choice [or

SURVIVAL FACTORS IN MUCORMYCOSIS mucormycosis. Tim dosage should be rapidly advanced to allow the highest possible tissue levels. T h e fi)llowing is the most c o m m o n l y accepted treatment schedule.SS'l" A 1 mg test close is given over several hours. If this is well tolerated, it is followed immediately by a 20 nag therapeutic close. This is increased in 10-15 milligram increments every twelve hours until 0.7-1.0 milligrams per kilograln as a single daily dose is reached. Patients may be p r e m e d i c a t e d with acetaminophen, diphenlaydramine hydrochloride, and 25-50 nag hydrocortisone sodium succinate (IV) to control f~ver and chills. Reversible nephrotoxicity is likely to occur. :~':u'ss T h e BUN and creatinine can be allowed to rise to 50 mgMI and 3.0 mg/dl, respectively. If these limits are exceeded, then the 0.7-1.0 mg/kg dose shotdd be given on alternate d a y s ) 'ss If the BUN and creatinine remain elevated beyond 50 and 3.0 mg/dl, the amphotericin-B dosage or fl'equency must be f u r t h e r r e d u c e d until renal thnction recovers. A cumt, lative dose of 2.0-4.0 grams shot, id be given. :~''~'~ Upon cessation of amphotericin B therapy, patients must be closely observed ibr signs of persistent infection. :~

17

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f,

~k~

~ i

'

,

"W

t

'

',,,,

I I

! J),

'l

I

~>

)F ,~

"

)H )

(

,.

I ;

,

ii.

Fig. I0. Post (;adoli,fit, m l)roton Density Weighted Axial MRI. Note hypcrintc,asc signal tiom left maxillary mucosa. This is abnc)rmal and suggests either ischcmia or i,fllammation. Postsurgical changes and sphc,mid sinusitis arc visible (m right. In this patient with proven mucormycosis on the ,ight, a bi()psy of the left maxillary ,nuc()sa would bc indicated to rt, lcot, t bilateral inti:cti(m.

2. Liposomal Amphotericin B T h e toxicities o f amphotericin B (AMP-B), including electrolyte abnormalities, phlebitis, anemia, fever, nausea and vomiting, are well known. :~'ls':u'ss'l'-'' It has been shown that administration of amphotericin B encapsulated in lip()somes (L-AMP-B) significantly decreases toxicity, while retaining and perhaps increasing efficacy. :'(i'!)°'t4'sReports have shown clinical response to L-AMP-B in patients with Aspergillus and Candida infections who had worsened on AMPB. "°'Hs 'i,Ve are aware of one patient who survived ROCM after treatment with L-AMP-B and surgery.:"; Tiffs patient tolerated a 1 ing/kg dose daily R)r 28 days with no alteration of electrolytes. renal function, or hepatic function. Once the patient stabilized, AMP-B was substituted tot the LAMP-B tor the r e m a i n d e r of a 2-gram course. Liposomal encapsulation of AMP-B appears to e n h a n c e its delivery to fungi, intiected organs and to phagocytes, thus accounting tbr increased elticacy. Conversely, renal delivery is decreased. This combination serves to markedly increase the therapeutic index of L-AMP-B c o m p a r e d to regular AM P- B.-";:'"'Hs

3. Surgery All necrotic tissue should be removecl when possible. Infected tissue typically bleeds little due to the vaso-occlusion caused by Mucorales. Ideal-

ly, tissue should be r e m o v e d until nornml bleeding is e n c o u n t e r e d . Unfortunately, this is not always possible with extensive infections, which can e x t e n d to the duva or beyond. T h e need tot repetitive surgery in these patients has been suggested by many autlmrs. '-'°':'". .,,_,.1.~,.1:~=,T o evaluate the need tbr further surgery, serial imaging studies are indicated to identiI!¢ any extension of disease after tim initial procedure. Re-operation to debride areas of progressive disease should be planned if the morbidity of the ofteu mutilating surgery does not outweigh its potential benetits. -':~ Many authors agree that in the presence of active ft, ngal invasion of the orbit, exenteration may be life-saving. :':~'a4 In general, exenteration should be considered tot an actively intlamed orbit with a blind, immobile eye. Exenteration is probably not indicated if a seeing eye is present unless extensive fungal invasion can lye demonstratecl. :u':~''s4'ss'w'2 By decreasing the total ft, ngal burden, exenteration of an invoh'ed orbit may still be laelpful even after intracranial spread has ( ) c c t . t r t ' e d . -'9

4. Treatment Effect of Hyperbaric Oxygen T o cletmmine whether hyperbaric oxygen of-

18

Surv Ophthalmol 39 (1) July-August 1994 TABLE 10

Survival Rates for Bilateral Mucormycosis as Related to Therapy Received

Treatment None Amphotericin B (Amp-B) Surgery Amp-B + surgery s Amp-B + surgery + local irrigation with Amp-B A 4 + S 5 + hyperbaric oxygen A4 + S 5 + hyperbaric 02 + local irrigation A4 + S5 + hyperbaric 02 + adjunctive antifungal 2 All bilateral cases receiving hyperbaric 02 All bilateral cases Bilateral cases receiving treatment with Amp-B, surgery or both

Number Number Survived I

Survival Rate I

4

0

0

3 2

0 0

0 0

12

3

25%

1

1

-

3

2

67%

1

1

-

2

2

-

6 28

5 9

83% 32%

18

4

22%

IIncludes 2 survivors with neurologic impairment. 2Ketoconozole 400 mg/d. 3One survivor also underwent daily debridements. 4Amphotericin B. 5Surgery - Too small a sample to make calculation meaningful.

fers a statistically significant treatment effect, bilateral cases treated with only AMP-B, surgery or both (standard treatment), were c o m p a r e d to those who received standard treatment plus adjunctive hyperbaric oxygen (Table 10). O f the 18 patients who received standard therapy, foul" survived (22%). Five of the six patients who received hyperbaric oxygen survived (83%). This appears statistically significant, despite the small n u m b e r s (p = .0285). By evaluating the effect of hyperbaric oxygen in patients with a low survival rate (i.e., those with bilateral infection), we have shown, for the first time, a statistically significant treatment effect. Close inspection of Table 9 also shows that all three patients with unilateral disease who received hyperbaric oxygen survived. Experimental studies have d e m o n s t r a t e d that 100% hyperbaric oxygen at one to three atmospheres exerts

YOHAI ET AL a fungistatic effectP ~ H y p e r b a r i c oxygen may also decrease tissue hypoxia, e n h a n c e oxygend e p e n d e n t cidal mechanisms and decrease tissue acidosis. 4°'5~ T r e a t m e n t s have consisted o f exposure to 100% oxygen at 2 to 2V2 atmospheres for 90 to 120 minutes. T h e s e were given every 12 to 24 hours. 4°''~1'59'6° Adverse effects of hyperbaric oxygen include spontaneous p n e u m o t h o r a x (typically small and transient) seizures from oxygen toxicity, and difficulty equalizing middle ear pressure (especially in the comatose patient). Should spontaneous p n e u m o t h o r a x occur, hyperbaric oxygen must be discontinued. At 2 atmospheres of pressure, the frequency of oxygen induced seizures was r e p o r t e d to be less than one in 6000 treatmentsP ~ Patients with a prior seizure history should have therapeutic anticonvulsant blood levels prior to hyperbaric oxygen therapy. 5~ T h e exact role for this therapeutic modality is uncertain. Based on the therapeutic response d o c u m e n t e d in this review, we propose that hyperbaric oxygen be considered as part of the initial t h e r a p y and c o n t i n u e d until evidence of disease regression is observed. W h e t h e r this should be instituted in all infected patients or just those with p o o r prognostic factors (renal disease, leukemia, d e f e r o x a m i n e , hemiplegia, bilateral infection, etc.) remains to be d e t e r m i n e d . Ideally, a prospective controlled study should be performed, but this may not be feasible with this rare, aggressive disease.

5. Local Irrigation and Packing with Amphotericin B Kohn and H e p l e r 84 p r e s e n t e d excellent results by adding daily AMP-B (1 mg/ml) irrigation and packing o f the involved orbit and paranasal sinuses. This modality poses little risk and likely aids in the delivery o f AMP-B to poorly perfused, infected tissues. O t h e r authors have also reported success with this therapy. 38'Sl'u4'96`~s2C o h e n et a138 placed a nasal-sinus catheter for irrigation, which greatly facilitated this treatment.

6. Adjunctive Antifungal Agents Although reports of survival with the adjunctive use o f ketoconazole and five-fluorocytosine (5-flucytosine, 5-FC), rifampin and tetracycline exist in the literature, 4°'s8'~°3'~~s.~~4.~~7no consistent in vitro or in vivo activity against m u c o r a c e a e has been demonstratedY 8 T h e s e agents should not be used alone in t r e a t m e n t of mucormycosis, ss T w o newer triazole antimycotics, fluconazole and itraconazole have been shown to have broad spectrum activity with good central nervous sys-

SURVIVAL FACTORS IN MUCORMYCOSIS tem penetration, v.,7T h e in vitro sensitivity o f zygomycetes to these agents was limited, v~6but given that Meyers et al "q6d e m o n s t r a t e d resistance of fungal isolates to AMP-B in vitro, with response to AMP-B, clinically, ~27'146we feel that f u r t h e r in vivo studies with fluconazole and itraconazole are indicated.

7. New Antifungal Agents A new class ofantifungal agents, the allylamine derivatives, has recently been developed. T h e s e agents work by binding squalene epoxidase, thus inhibiting ergosterol p r o d u c t i o n and causing squalene accumulation. ~-~c~26Agents of this class include SF86-327 (Exoderil [R]), naftitine and terbinafine. T h e s e agents d e m o n s t r a t e minimal toxicity: In one recent case in the literature o f a mucormycotic w o u n d infection, cultures of biopsy material grew Rhizopus rhizopodiformis with high invitro resistance to AMP-B, 5-fluorocytosine, fluconazole, ketaconazole and itraconazole. It was sensitive to SF86-327, which was a d d e d to AMP-B with good clinical response, t°t O t h e r in vitro studies have not shown sensitivity o f Mucorales to allylamine derivatives, v-'6 T h e role of these new agents in mucormycosis needs to be clarified with f u r t h e r in vitro and in vivo studies.

III. C o n c l u s i o n By cataloging the conditions associated with mucormycosis in this retrospective analysis, we h o p e to u n d e r s c o r e that rhino-orbital-cerebral mucormycosis should be in the differential diagnosis o f sinus and orbital infections for both diabetic and nondiabetic patients. Because time is o f the essence, (especially in nondiabetics) a high index of suspicion should p r o m p t an early biopsy. T h e therapeutic decisions in mucormycosis can be difficult. T h e surgery is often mutilating and medical treatments are toxic. By identifying factors associated with a significantly lower survival rate, it may be possible to decide which patients merit the most aggressive treatment. We found that hemiparesis or hemiplegia (p = .011), bilateral infections (p = .0001), renal disease (p < .0001), leukemia (p = .0143), nonmalignant hematologic disease (p = .0129), deferoxamine therapy (p = .0006), and possibly facial necrosis (p = 0.0622) d e m o n s t r a t e d such an association. We s u p p o r t AMP-B and surgery as the mainstay of therapy, but also expect that the statistically significant t r e a t m e n t effect which we found with hyperbaric oxygen will continue as m o r e patients are treated with this exciting

19 adjunct. Finally, we feel that L-AMP-B should play a larger role in the therapy of mucormycosis because of its higher therapeutic index. This agent should be especially useful in the setting of severe renal impairment. T h e allylamine derivatives and triazole antifungal agents may also prove useful, especially in patients with decreased renal function.

References 1. Abe F, Inaha H, Katoh T, Hotchi M: Effects of iron and desferrioxamine on Rhizopus infection. Mycopathologia 110:87-91, 1990 2. Abedi E, Sismanis A, Choi K, Pastore P: Twenty-five years' experience treating cerebro-rhino-orbital mucormycosls./~'t~yngosc0pe 94:1060-1062, 1984* 3. Abramson E, Wilson D, Arky RA: Rhinocerebral phycomycosis in association with diabetic ketoacidosis. Ann lnlern Med 66:735-742, 1967 4. Abruzzo GK, Fromtling RA, Turnbull TA, et al: Effects ofbifonazole, fluconazole, itraconazole, and terbinafine on the chemiluminescence response of im,nune cells.J Antimicrobial Chemother 20:61-68, 1987 5. AggerWA, Capla,~ RH, Maki DG: Ocular sporotrichosis

mimicking mucormycosis in a diabetic. Amt Ophthalmol 10:767-771, 1978 6. Albert DM, Lesser RL, Cykiert RC, ZakovZN: Orbitofacial mucormycosis with unusual pathological features. Br J Ophthalmol 63:699-703, 1979" 7. Anaisste EJ, Shikhani AH: Rhinocerebral mucormycosis with internal carotid occlusion: report of two cases and review of the literature. Lm3,ngoscope 95:11071113, 1985" 8. Anderson NE, Ali MR, Simpson IJ: Rhinocerebral mucormycosis complicating poorly coqtrolled diabetes mellitus: case report. NZ MedJ 96:521-522, 1983" 9. Artis WM, Fountain JA, Delcher HK, et al: A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes 31:109-114, 1982 10. Baker RD: Mucormycosis -- a new disease? JAMA 163:805-861, 1956 11. Baker RD: The Phycomycoses. Ann NY Acad $ci 174: 592-605, 1970 12. Babadur S, Ghosh P, Chopra P, Rai G: Rhinocerebral phycomycosis. J Lao, ngol Otol 97:267-270, 1983" 13. BarenfangerJ, Klug C, Von Behren LA: Rhinocerebral mucormycosis. Microbiolog), 34:1-7, 1991 * 14. Bauer H, FlanaganjF, Sheldon WH: Experimental cerebral mucormycosis in rabbits with alloxan diabetes. Yale J Biol Med 28:29-36, 1955 15. Bauer H, Flanagan JF, Sheldon WH: The effects of metabolic alterations on experimental rhizopus oryzae (mucormycosis) infection. }'ale J Biol Med 29:23-32, 1956 16. Bauer H, Wallace J r GL, Sheldon WH: The effects of cortisone and chemical inflammation on experimental mucormycosis (rhizopus oryzae infection). Yale J Biol Med 29:839-395, 1957 17. Benqett CL, Westbrook CA, Gruber B, Golomb HM: Hairy cell leukemia and mucortnycosis. Am J Med 81:1065-1067, 1986" 18. Bergstrom LV, Hemenway WG, Barnhart RA: Rhinocerebral and otologic mucormycosis. Ann Otol Rhinol Latyngol 79:70-81, 1970 19. Bhaduri S, Kurrle E, Vanek E, Spanel R: Mucormycosis in the immunocompromised host. htfi'ction 11:170172, 1983 20. Blitzer A, Lawson W, Meyers BR, Biller HF: Patient survival factors in paranasal sinus mucormycosis. La~yngoscope 90:635-648, 1980" 21. Boelaert JR, Fenves AZ, Coburn JW: Deferoxamine

20

YOHAI

S u r v O p l a t h a l m o l 39 (1) J u l y - A u g u s t 1994

therapy and mucormycosis in dialysis patients: report ofan international registry. ,4mJ Kidm,y Dis 18:660-667, 1991 22. Boelaert JR, Van Roost GF. Vergauwe PL, et ale The role of desferrioxamine in dialysis-associated mucornlycosis: report of three eases and review of tile literature. CIm Nephrol 29:261-266, 1988 23. Boelacrt J R, Vergauwe PL. Vandepitte .1M: Mucormycosis infection in dialysis patients..-I,, I,lern Med 107: 782-783, 1987 24. Bray WH, Giangiacomo J, Ide CH: Orbital apex syndrome. Sum, Ophthahmd 32:136-140, 1987* 25. Breiman A. Sadowsky D, Friedman J: Mucormyc,,sis discussion and report of a case involving the maxillary sinus. Oral Surg 52:375-378, 198 I* 26. Brennan RO. Crain B.], Proctor AM, Durack DT: ('unninghamella: a newly recognized cause of rhinocerebral m ucormycosis. Am J c l i , Pathol 811.'98-102. 1983* 27. Bullock J D, Jampol LM, Fezza AJ : Two cases of orbital phycomycosis with recovery. Am J Ophthahmd 78.'811815, 1974 28. Bullock J D: Orbital infections in tile imnmnoconlproraised patient. Ophthahnic Plastic Reco,structive Sm~tg 2:189-196, 1986 29. Bullock J D: Mucornlycosis fifllowing cataract exu'aclion, ill Emery JM, Paton D (eds): C, rre,I Co,cepts i, Calarael Sut~'e13'. St Louis CV Mosbv, 1976, pp 349-355 30. Burns RP: Mucormycosis of the sinuses, orbit and central nel'VOtlS system. Trans Pacific Coast OIo-Ophlh Soe 40.'83-101, 1959 3 I. Butler WT, Bennett J E, Ailing DW. et ale Nephrotoxicity of Aml~hotericin B. Early and late elti:cts in 81 patients. ,,1,, I,ler, Med 61.'175-187. 1964 32. Bybee.I D, Rogers DE: The phagocytic activity of polymorphonuclear leukocytes obtained li't,m patients with diabetcs mellitus..] l~'tb (:fin Med 64.' 1-13, 1964 33. Caner H, Erkul I, Tinaztepe B: Successful treatment of rhinocerebral mucornlycosis: report on a pediatric patient. Turk J Pediate 23.'203-209, 1981 * 34. Carbone KlVi, Pennington LR, Gimenez LF, el ill: Mucornlycosis ill renal transplant patients - - a t'eporl o1" two cases and review of the literature. QJ Med 57:825831, 1985' 35. Castelli IB, PallinJL: Lethal ,-hinocercbral phycomycosis in a healtlay aduh: a ease report and review of the literature. OlolaQ',golo©, 86.'696-703, 1978" 36. (;hick EW, EvansJ, Baker RA: The inhibitory effect of amphotericin B on localized Rhizopus oryzae inti:ction (mucornlycosis) utilizing the pneunloderma pouch of the rat. ,'l,tibi0t ('hemolher 8:506-510, 1958 37. Clill" ]L, Mha,ldo P: Cerebral mucormycosis: a case report. East ..IJi" MedJ 59.'76-80. 1982" 38. Cohe,I St;. (.;reenberg MS: Rhinomaxilhn'y inuft)l'mvcosis in a kidney transplant patient. Oral Surg Oral Med Oral Palhol 50:33-:~8, 19811" 39. Cook BA White CB, Blanev SM, Bass IW: Survival after isolated cerebral nlucormycosis...Ira J Pediatr llematol Om'ol 1/.':*,30-333. 1989 40. Couch L, Theilen F, Mader JT: Rhinocerebral IlltlCOl-mycosis with cerebral extension successfully treated with adjunctive hyperbaric oxygen therapy...Itch Otoh,y,gol Head Neck Surg 114.'791-794, 1988" 41. ('uach'ado LM. GUelTel'O A. :~senjo JAL(;, et al: Cerebral InllcOl'lllycosis ill tWOcases o['acquil'ed inlllltlllodeliciency syndrome. Arch Neur0/45." 109-11 I, 1988 42. Deshpande DH. Desai APe Cerebral muctwmycosis in cases of renal failure. Ne,rologq, Italia 24:20-23, 1t)76* 43. De\Veese DD, Schleuning 11 A I. Robinson LB: MucorIIlVCt)SiSof the nose a n d pal'allilsal sinuses, l.xtQ,ngo.wope 75:1398-14117, 1965 44. Dhir SP, Munjal VP, Gupta A, Jain IS: Rhino-orbitocerebral, mucornlycosis. Iodian J Ophthohool 31:425427, 198:t* 45. Dworzack I)L. Pollock AS, Hodges GR, et ale Zvgoluyct)-

ET AL

sis of the maxillary sinus and palme caused by basidiobolus haptosporus. Arch Inter, Med 138:1274-1276, 1978 46. Edwards J E: Zygomycosis, ill Hoeprich PD (ed): I,fi, c-

lious Diseases: ,.I Moder, Treatise of h!fi'cliou.~ Processes. Philadelphia, Harper & Row, 1983. ed 3, pp 1125-1132 47. Eilderton TEe Fatal postextraction cerebral mucormycosis in an unknown diabetic. J Oral Surge~3, 32:2973110, 1974" 48. Erdman WA, Weinreb .]C, Cohen JM, et ale Venous 0u'ombosis: clinical and experimental MR imaging. Radiology 161:233-238. 1986 49. Esakowitz L, Cook SD. Adams J. et ale Rhino-orbitalcerebral mucormycosis - a clinico-pathological report of two cases. Scott Med J 32:180-182, 1987* 50. Estrem SA, Tully R, Davis WE: Rhinocerebral mucormycosis: computed tonlographic imaging of cavernous sinus thrombosis. A , , OIol Rhi,ol Lao,,gol 99:16{)-161, 1990 51. Ferguson BJ. Mitchell TG, Moon R, et ale Adjunctive hyperbaric oxygen tot treatment of rhinocerebral mucormvcosis. Rev I,fi,ct Dis 10:551-559, 1988 52. Ferry AP: Cerebral mucornlycosis (phycomycosis). Ocular tindings and review of tile literature. S,rv Ophlhahnol 6:1-24, 196 I 53. Ferry AP, Abedi S: Diagnosis and managelnent of rlaino-orbitocerebral mucormycosis (playco,uycosis): a report of 16 personally observed cases. Ophlhahnologq., 90:1096-1104, 1983 54. Finn D(;, Fal'lncl'J(]: Chronic mucor,llycosis. 1~,3',goscope 92:761-763. 1982 55. Finn DG: Mttcormycosis of the paranasal sinuses. Ear Nose Throat J 67:813-822, 1988 56. Fisher EW, Toma A. Fisher PH, Cheesman AD: Rhinocerebral IlltlCOl'lllycosis: u s e of liposomal amphotericin B.J Lmy,gol 01ol 105:575-577, 1991" 57. Forteza G, Burgeno M, Martorell V, Sierra I: Rhinocerebral nmcormycosis..] Cmniomaxilh![ac Sueg 16:80-84, 1988*

58. Gale GR, Welch AM: Studies of opportunistic fungi. 1. Inhibition of Rhizipus oryzae by human sertnn. Am.] Med Sci 241:6{14-612, 1961 59. Galetta SL, Wulc AE, Goldberg H 1, et ale Rhinocerebral IlltlCOl'lllycosis: nlanagement and survival a['ter carotid occlusion...Ira,' Neurol 28:103-107, 1990* 60. Gamba .]L, Woodruff WW, Djang WT, Yeates AE: Craniofacial mucormycosis: assessment with CT I . Radiolo~' 160:207-212, 1986* 61. Gass JDM: Acute orbital mucornlycosis: report of two cases. Arch Ophthahool 65:214-220, 1961 62. Gass J DM: Ocular nmnifestations of acute nlucormycosis. Arch Ophthahmd 65:226-237, 1961 63. (;teen WR, Font RL, Zilnmerman LEe Aspergilh)sis of the orbit: report of tell eases and review of tile literature. ,-Itch Ophthahmd 82:302-313, 1969 64. Gregory.] L. Golden A, Haymaher W: Mucormycosis of the central nel'VOlAS systelll: a report of three cases. Bull .]oh. Hopkins Hosp 73:4115-419, 1943 65. (;rewal RK, (;rcwal SS, Zacharich RM: Orbital mllCOl'mycosis (phycomycosis) ( a survival with alnphotericinB and potassium iodide), l,dm,.] Ophthalmol 33:239241, 1985" 66. Groote CA: Rhinocerebral phyconlycosis...Dwh Otolmy,gol Head Neck Surg 92:288-292, 1970" 67. Hammer (;S, Bottone EJ, Hirschman SZ: Mucormycosis in a transplant recipient..'hn.] CIm Pathol 64:389398, 1975 68. Harris .IS: Mucormycosis: report ol'a ease. Pedmlrics 16:857-867, 1955 69. Hauman CHJ, Raubenheimer El: Orothcial mucormycosis. Oral Stag Oral Med Oral Pathol 68:624-627. 1989 70. Hazarika P, Ravikumar \', Nayak RG, et ale Rhinocerebral mycosis. Ear Nose Throal J 63:100-106, 1984" 71. Hemashettar BM, Kagal AE, Patil CS, Nagalotimath SJ:

SURVIVAL

FACTORS

IN MUCORMYCOSIS

Rhino orbital mucormycosis treated with amphotericin B with successful outcome. J ,.Issoc Physicians l,dia 33: 3 0 2 - 3 0 4 , 1985" 72. Henderson L'I', Robbins KT, Weitzner S: Benign nnlcot colonization (fungus ball) associated with chronic sinusitis. South Med ] 81:846-850, 1988 73. Henriquez M, Levy R, Raja RM, et al: Mucormycosis in a renal transplant recipient with successlifl outcome. .]AMA 242:1397-1399, 1979" 74. Ho KL: Acute subdural hematoma and intracerebral henmrrhage. Arch OIoho3,ngol Head Neck Stag 105:279281, 1979* 7:5. Hu XH, Meng X-k: Nasal mucormycosis with a case report. Re(, Lao, ngol OIol Rlnimd 104:279-281, 1983" 76. Huddle KRL, Hale MJ, Joseph CA, Chang KL: Rhinocerebral mucormycosis in diabetic keto-acidosis. S .-!fr MedJ 72:713-714, 1987" 77. Humphry Re, Wright C;, Rich wJ, Simpson R: Acute proptosis and blindness in a patient with orbital phycomycosis. J R Soc Med 82:304-305, 1989" 78. Johnson EV, Kline LB, Julian BA, Garcia.J H: Bilateral cavernous sinus thrombosis due to llltlcornlycosis. ,.Itch Ophlhahmd 106: 11189-1092, 1988* 79. Jones DB, Steinkuller I'G: Strategies tin" the initial management of acute preseptal and orbital cellulitis. Trans Am Ophtlmhnol Soc 86:94- I 12, 1988 80. Kaplan AH. l'oza-Juncal E, Shapiro R, Staple(on JT: Cure of lntlCOl'lllycosis ill a renal Iransplallt patient receiving ciclosporin with maintenance of imnmnosuppression. ,-Im .] Neph rol 8:139-142, 1988* 81. Kaplan AL, Huerta AR, Chiou SJ: Rhinocerebral muCOrlllycosis. H:est.] Med 135.'326-329, 1981 * 82. Karam F, Chmel H: Rhino-orbital cerebral nmcormycosts. Ear Nose Throat J 69:187-193, 1990* 8Y,. Kaufman L, Padhye :L-k, Parker S: Rhinocerebral zygomycosis caused by Saksenaea vasilormis.J Med Vet Mycol 26:237-241, 1988 84. Kohn R, Hepler R: Management of limited rhino-orbital mucornlycosis without exenteration. Ophthahnolo4q., 92:144/)-1444, 1985" 85. Kotzanlanogh)u K, lzallakakis G, Micllalopoulos E, Stathopoulou M: Orbilal celhditis due to mucormycosis. Grae.[~,sArch Clin E.xl~Ophthahno1226:539-54 I, 1988* 86. Kumar S, Trivcdi H L, Smith EKM: Rhim)cerebral nlucormycosis in a renal transplant patient. Oral Stog Oral Med Oral Pathol 34.'583, 1976" 87. Lazzaro EC, Sh>an B: Mucm-mycosis: case presentation and discussion...Inn Ophthahnol 14:660-1562, 1982" 88. Lehrer RI, Howard DH, Syphcrd PS, et al: Mucormycosts. :In n Inh, r+t Med 93(Parl /):93- 1118, 1981) 89. Lie-Klan-Joe, Eng NT, "l'jokronegoro S, et al: Phycomycosts of'the cenll+al IICI'VOLIS SySlCnl associated with diabetes mellitus in Indonesia. AmJ Patho132.'62-71/, 1959 90. Lopez-Berestein (;, Fainstein V, Hopfer R, et al: Liposolna] amphotericin B lot tile treatment of systemic tiingal infections in patients with cancel': a preliminary study. J Infect Dis /5/:704-7 I0, 1985 91. Louria DB: Some aspects of tile absorption, distribution, and excretion ofAmphotericin B in nlan. ,-Inlibiol Med 5.'295, 1958 92. IVlaniglia AJ, IVlintz DH, Novak S: Cephalic phycomycosis: a report of eight cases. I~nyngoscope 92:755-760, 1982" 9",. IVlargo C, Rabinowicz M, Kwon-C'hung KJ, Zimmerman LE: Subacute zygomycosis of the orbit. Arch Ophthahmd 101.'1580-1585, 1983 94. M a r r ' l ] , Traislnan HS, Davis AT, Kernahan D: Rhinocerebral mttcormvcosis and juvenile diabetes mellitus: report of a case with recovery. Diabetes Care/:250-251, 1978" 95. McDevitt GRJr, Brantley MJ, Cawthon MA: Rhinocerebral nltlCOl'lllycosis: a case report with magnetic resonance imaging tindings. Clin Imaging 13:317-320, 1989"

21 96. Meyers BR, Wornlse," G, Hirschman SZ, Blitzer A: Rhinocerebral nmcormycosis pt'enmrtem diagnosis and therapy. Arch l,tern Med 139:557-560, 1979" 97. Miller RD, Steinkuller PG, Naegele D: Nonfhtal maxilIocerebral mucormycosis with orbital involvement in a dehydrated inl:ant...bin Ophthahmd 12."11165-1068, 1980 98. Morduchowicz G, Shmueli D, Shapira Z, et al: Rhinocerebral nmc,n'mycosis in n'ena] transplant recipients: report of three cases and review of'the Jiterature. Hey h!#'cl D/s 8 : 4 4 1 - 4 4 6 . 1986" 99. Nagalotimath SJ, Patti PV, Pal N: Intraoperative cytodiagnosis o[" paranasal sinus nllucol'mycosis iX1 an immunocompetent host. ,.Iota Cylol 31:533-534, 1987 100. Narang AK, Dina TS: Cerebral mucormycosis: a case report. Compul Med hnaging Graph /2.'259-262, 1988 101. Norden G, Bjorck S, Persson H, et a]: Cure ofzygomycosts caused by a lipase-produci,lg rhizopus rhizopodi[ornlis strain i.n a renal transplant patient, scanJ InJecl Dis 23.'377-382, 1991 1112. Ochi .]W, Harris J P, Feldman J I, Press GA: Rhinocerebn'al mucol'mycosis; resuhs of aggressive surgical clebriclement ancl amphotericin B. Lmyngoscope 98:13391342, 1988 103. O'Keefe M, Haining WM, YoungJDH, Guthrie W: O f bital mucormycosis with survival. BrJ opln 70.'634-636, 1986 104. del Palacio Hernanz A, Fereres J, Larregla G, et al: Nosocomial infection by Rhizomucor pusillus in a clinical haematology unit. J Hosp h(fi,cl 4:45-49, 1983 105. PahaufA: Mycosis mucorin~i; ein Beitrag zur Kenntniss den" menschlichen Fadenpilzerkrankungen. l'irchows Arch 102:543-564, 1885 106. Parfi'ey NA: hnproved diagnosis and prognosis of mucormycosis: a clinico-pathologic study ot"°,3 cases. Meditim, 65:113-123, 1986" 107. Pennisi AK, Parenti DM, Stevens A, et al: Paranasal sirens mucormycosis in an imnmnologically competent host. A m J OIola~yngol 6:47 I~173, 1985* 108. Perillie PE, Nolan JP, Finch SC: Studies o1" the resistance to infection in diabetes mellitus. Local exudative cellular response. J Lab Clin Med 59:1008, 1962 109. Pillsbury HC, Fischer N D: Rhinocerebral mucormvcosis. Arch Olola~yngol Head Neck Stag 103:6011-6(14, 19'77* 110. Polli C: On the incidence of ketone reductase in microorganisms. Pathol Microbiol 28.'93, 1965 I 11. Press GA, Weindling SIVl, Hesselink jR, et al: Rhinocerebral mucormycosis: MR manifestations.J Comput Assist 7)mtogr /2.'744-749, 1988" 112. Qingli L, Orcutt JC, Seifter LS: Orbital mucormycosis with retinal ancl ciliary artery occlusions. BrJ Oplnthaltool 73:680-683, 1989' 113. Quattrocolo G, Pignatta P, Dimanico U, et al: Rhinocerebral mucornlycosis and internal carotid artery thrombosis in a previously healthy patient. Acta Nem'ol Belg 90:20-26, 1990" 114. Rakovcr Y, Vered I, Garzuziz H, Rosen G: Rhinocerebral phycomycosis; combined approach therapy: case report. J Lrnsngol Olol 99:1279-1280, 1985* 115. Rangel-Gucrra R, Martinez H R, Saenz C: Mucormycosis report of I I cases. Arch Neurol 42.'578-581, 1985 116. Rao VRK, PillaiSM, MathewsG, Radhakrishnan VV: Cerebral mucormycosis -- a case report. Neuroradiolo~, 15:291-293, 1978 117. Reich H, Behr W, Barnett J: Rhinocerebral nmcormycosts in a diabetic ketoacidotic patient..] Neurol 232: 115-117, 1985" 118. Rex.J H, Ginsberg AM, Fries LF, el al: Cunninghamella bertholletiae infection associated with deferoxamine therapy. Rev Infi'ct Dis 10:1187-1194, 1988 I 19. Rosenberg SW, LepleyJ B: Mucormycosis in leukenlia. Oral Surg Oral Med Oral Palhol 54:26-32, 1982" 120. Rosenberger RS, West BC, King JW: Case report survival from sino-orbital mucormycosis clue to rhizopus rhizopoditormis. Am.] Med Sci 286.'25-30, 1983"

22

S u r v O p h t h a l m o l 39 (I) J u l y - A u g u s t 1994

YOHAI ET AL

121. Ryder NS: Mechanism of action and biochemical selectivity of allylamine antimycotic agents. Ann NYAcad Sci 544:208-220, 1988 122. SchwartzJN, Donnelly EH, Klintworth GK: Ocular and orbital phycomycosis. Surv Ophthahno122:30-28, 1977* 123. Scully RE, Mark EJ, McNeely BU: Case records ofthe Massachusetts General Hospital. N Engl J Med 307: 806-814, 1982 124. Scully RE, Mark EJ, McNeely WF, McNeely BU: Case records of the Massachusetts General Hospital. N EngIJ Med 323:1823-1833, 1990" 125. Severo LC, Guindani C, Geyer GR: Chronic sinusitis caused by zygomycosis and aspergillosis [letter]. EurJ Clin Microbiol Infect Dis 8:317-318, 1989 126. Shadomy S, Espinel-lngroff, Gebhart RJ: In-vitro studies with SF-327, a new orally active allylamine derivative. Sabouraudia:J Med I/et Mycology 23:125-132, 1985 127. Shadomy S, Pfaller MA: Laboratory studies with antifungal agents: susceptibility tests and quaqtitation in body fluids, in Balows A, et al (ed): Manual of Clinical Microbiology, Chapter 117, Wash, DC, American Society for Microbiology, 1991, ed 5, pp 1173-1179 128. Sheils WSJr, IVlarano GD, Nelson J, Scbochet SS: Manifestation of atypical cerebral mucormycosis. Scientific Newsfront 83:115-117, 1987" 129. Sheldon WH, Bauer H: The development of the acute inflantntatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med 110:845-852, 1959 130. Slade MP, McNab APt: Fatal mucormycosis therapy associated with deferoxamine [letter]. Am J Ophthahnol 112:594-595, 1991 131. Small A, Reeser F, Deeb Z: Rhino-orbital cerebral mucormycosis. Ear Nose Throat J 56:38-46, 1977" 132. SmithJL, Stevens DA: Survival in cerebro-rhino-orbital zygomycosis and cavernous sinus thrombosis with combined therapy. South MedJ 79:501-504, 1986" 133. Soloniuk DS, Moreland DB: Rhinocerebral mucormycosis with extension to the posterior fossa: case report. Neurosurge~y 23:641-643, 1988 134. Sponsler TA, Sassani JW, Johnson LN, Towfighi J: Ocular invasion in mucormycosis. Sum, Ophthahnology 36:345-350, 1992 135. Stelani FH, Mehraein P: Acute rhiqo-orbito-cerebral mucormycosis. Ophthahnologica 172:38--44, 1976" 136. Straatsnta BR, Zimmerman LE, GassJ DM: Phycomycosis: a clinicopathologic study of fifty-one cases. Lab hn,est 11 (Part I):963-985, 1962 137. Succar M B, Nichols RD, Burch KH: Rhinocerebral mucormycosis./I rch Otolmyngol 105:212-214, 1979* 138. Tabachnick "IT, Levine B: Mucormycosis of the craniofacial structures. J Oral Surg 33:464-469, 1975 139. Vandepune J, Wachtel J L, Stiller ET: Amphotericins A and B, antifungal antibiotics produced by a streptomycets. I I. The isolation and properties of the crystallinie amphotericins. Antibiotic Annual 1955-56. New York, Medical Encyclopedia, 1956, pp 587-591 140. Van der Westhuijzen AJ, Grotepass FW, Wyma G, Padayachee A, et ah A rapidly fatal palatal ulcer: rhinocerebral mucormycosis. Oral Sitrg Oral Med Oral Pathol 68:32-36, 1989" 141. Vandevelde L, Bondewel C, Duhois M, De Vt, yst M: Mucorales and deferoxamin: fi'om saprophytic to pathogenic state. Acta Otorhinolao,ngol Belg 44:429-433, 1990* 142. VeisJ H, Contiguglia R, Klein M, et ah Mucormycosis in deferoxamine-treated patients on dialysis [letter]. Ann Intern Med 107:258, 1987" 143. Venezio FR, Sexton DJ, Forsythe R, et al: Mucormycosis after open fiacture injury. South Med J 78:15161517, 1985 144. Watson KL, Neame PB: In vitro activity of Amphotericin B on strains of mucor aceae pathogenic to man. J Lab Clin Med 56:251-257, 1960

145. Webb D: New antifungal agents: clinical and laboratory issues. Clin Microbiol Newsletter 13:129-136, 1991 146. Webb J, Colman MF, Thompson K, Westcott WB: Acute, life-threatening disease first appearing as odontogenic pain. J Am Dent Assoc 109:936-938, 1984" 147. Weber PA, Makley TA, Werling K: Cerebro-rhino-orbital phycomycosis: a case report. Ann Ophthalmol 12: 459-463, 1980" 148. Weber RS, Lopez-Berestein G: Treatment of invasive aspergillus sinusitis with liposomal-amphotericin B. Lalyngoscope 97:937-941, 1987 149. Windus DW, Stokes TJ,Julian BA, et ah Fatal Rhizopus infections in hemodialysis patients receiving deferoxamine. Ann Intern Med 107:678-680, 1987" 150. Wong KL, Tai YT, Loke SL, et ah Disseminated zygomycosis masquerading as cerebral lupus erythematosus. Am J Clin Pathol 86:546-549, 1986 151. Yousem DM, Galetta SL, Gusnard DA, Goldberg HI: MR findings in rhinocerebral mucormycosis.J Comput Assist Tomogr 13:878-882, 1989" 152. Zak SM, Katz B: Successfully treated spheno-orbital mucormycosis in an otherwise healthy adult. Ann Ophthalmol 17:344-348, 1985" *Indicates articles that contain cases included in this review.

Outline I. Case reports II. Review of the literature A. U n d e r l y i n g conditions 1. Diabetes mellitus 2. Renal disease 3. D e f e r o x a m i n e t h e r a p y 4. L e u k e m i a 5. Miscellaneous conditions B. Presenting signs and s y m p t o m s 1. O p h t h a l m i c signs and s y m p t o m s 2. N o n o p h t h a l m i c signs and s y m p t o m s C. Interval fi'om s y m p t o m onset to treatment: Effect on survival D, Survival rate as related to o r g a n i s m g r o w n on culture E. Survival rate as related to extent o f p a r a n a sal sinus infection 1. N u m b e r o f sinuses infected 2. Bilateral sinus infection F. Diagnosis 1. S u m m a r y o f clinical features 2. I m a g i n g studies 3. Biopsy G. T r e a t m e n t 1. A m p h o t e r i c i n B 2. Liposomal a m p h o t e r i c i n B 3. S u r g e r y 4. T r e a t m e n t effect of h y p e r b a r i c o x y g e n 5. Local irrigation and packing with Amphotericin B 6. Adjunctive antifungal agents 7. New antifungal agents III. Conclusion

Reprint address: John D. Bullock, M.D., Professor and Chairman, Department of Ophthalmology, Wright State University School of Medicine, 500 Lincoln Park Boulevard, Suite 104, Dayton, OH 45429-3489.