Rhinocerebral mucormycosis is a fungal disease that has a 50% mortality. Its occurrence has increased, possibly because of greater use of chemotherapeutic agents that may compromise the immunologic defenses of the host or alter the normal flora. The earliest signs, ulceration and pain, may appear in the mouth. In the patient described in this report, the autopsy showed that mucormycosis had entered the brain cells.
Rhinocerebral mucormycosis
Gordon Cruickshank, DDS Ronald D. Vincent, DDS, Grand Junction, Colo Henry M. Cherrick, DDS, MSD Kathryn Derby, BA, Los Angeles
It is critical that this fungal disease be diagnosed early to prevent an irreversible process. One case of mucormycosis is reviewed that emphasizes the early signs and symptoms of the disease.
1164 ■ JADA, Vol. 95, December 1977
M ucorm ycosis is an acute, fulminating, and often fatal fungal disease caused by various species of the order Phycom ycetes. F ortunately, hum ans have a natural resistance to these organism s, and m ucorm ycosis is rarely seen in healthy individu als. H ow ever, its occurrence in predisposed pa tients has been increasing in recent years, perhaps because o f the greater use of chem otherapeutic agents which may com prom ise the immunologic defenses of the host or alter norm al flo ra.1,2 R hinocerebral m ucorm ycosis, the m ost com mon o f the four m ajor types (rhinocerebral, pul m onary, gastrointestinal, and dissem inated), is of particular interest to the oral surgeon and general dentist since many o f the earliest clinical signs appear in the mouth. T he clinician m ust be aw are of this disease process for, unless treatm ent is initiated at its earliest onset, prognosis is not en couraging. Organism s o f the order Phycom ycetes can be thought of as opportunists, rather than true pathogens, as they are invasive only when the body physiology is disturbed, as in debilitating diseases and in chem otherapy. Blood dyscrasias, extensive burns, renal disease, m alnutrition, nar cotic addiction, immunologic deficiencies, im m unosuppressive therapy, corticosteroids, an tibiotics, and antim etabolites have been as sociated with the developm ent o f m ucor m ycosis.3'5 T he m ost com m on predisposing fac tor, how ever, is diabetic ketoacidosis, which in volves 40% to 50% of all cases o f m ucorm ycosis and 75% of rhinocerebral m ucorm ycosis. H yperglycem ia, or the subsequent acidosis that
occurs in diabetic ketoacidosis, may be conducive to the proliferation of the fungus. Rhyzopus, the species m ost commonly found in rhinocerebral m ucorm ycosis, grows favorably under conditions that are found in the ketoacidotic patient: acidic p H , high tem perature, and high glucose con ten t.6,7 There also have been studies that indicate that leukocyte function and local tissue accum ula tion of granulocytes are impaired during keto acidosis, thus decreasing the patient’s natural im m unity.8,9 The fungal spores enter through the nose or m outh in inhaled dirt particles and occasionally invade the orbit or open wounds. Rhinocerebral m ucorm ycosis usually begins in the nasal mucosa or palate and spreads into the paranasal sinuses, skin of the face, cribriform plate, and brain. Infec tion may reach the orbit via the nasolacrim al duct. Spread occurs either by direct extension or through vascular channels. A distinctive feature of this organism is its pre dilection for the invasion of arteries. The m ucor mycosis species penetrates the walls of arteries, strips the intima from the media, and eventually spreads into and occludes the lum en.10 This, along with the invasion of veins and lymphatics, results in the characteristic throm bosis, infarc tion, and necrosis seen in the disease. R e p ort o f case A 48-year-old white woman was adm itted to the medical service of the hospital with chief com plaints of lack of coordination, confusion, hal lucinations, excessive thirst, and sciatic nerve pain. The patient had been a brittle diabetic for 20 years and was taking 38 units of protamine in
sulin a day. The patient was relatively well until about a year before admission when carcinom a of the vagina developed, which was treated with radia tion therapy without recurrence. She had had a bilateral cataract extraction and a B artholin’s cyst rem oved from the vulva. F our days before adm ission the patient devel oped an ulceration and severe pain in the maxil lary left vestibule with m oderate swelling and discoloration in the left cheek. This had been treated unsuccessfully by a dentist with boric acid m outhrinse and a topical antifungal agent. The oral ulceration becam e more extensive in the following four days. ■ Physical examination: The patient was obtunded, confused, and in obvious distress. H er breath had a strong odor of acetone. H er lips were blood-encrusted and a large (6 cm) ulceration was found in the maxillary left vestibule that involved the posterior two thirds of the alveolar ridge and corresponding buccal m ucosa. T he lateral wall of the maxilla was exposed and the area was filled with a brownish pigm ented, foul-smelling m ate rial. The right cornea was cloudy and w ithout vision. N o m asses were palpated in the neck or subm ental regions. T here were a few scattered rales in both chest bases, and diffuse tenderness was noted in all quadrants of the abdom en. The liver was felt 3 cm below the right costal margin. N o deep tendon reflexes of the legs were de tected. Blood pressure was 154/80 mm Hg; pulse, 130/ min; tem perature, 97 F; and respiratory rate 40/ min. The patient was edentulous. She had lost 20 pounds in the previous few m onths and weighed 89 pounds.
THE AUTHORS
CRUICKSHANK
VINCENT
Drs. C ruickshank and V incent practice oral surgery in Grand Junction, Colo. Dr. C herrick is associate professor, section of oral pathol
DERBY ogy, and Ms. Derby is a dental student at UCLA. Send re print requests to Dr. Cruickshank, 2721 N 12th St, Grand Junction, C olo 81501.
Cruickshank— others: RHINOCEREBRAL MUCORMYCOSIS ■ 1165
■ Laboratory findings: The hem atocrit was 43%; white blood cell count, 20,000/cu mm with a left shift; blood urea nitrogen, 51 mg/100 ml; serum glucose, 732 m g/100 ml; carbon dioxide combining power less than 10 m Eq/liter; potas sium, 4.7 m Eq/liter; sodium, 126 m Eq/liter; and chloride, 96 m Eq/liter. T he acetone o f the urine was positive 4 + . Radiographs of the facial bones were noncon tributory. R esults of cultures of the urine, mouth w ound, cerebral spinal fluid, sputum , and blood were negative. ■ Clinical course: The immediate plan was to hydrate the patient and restore metabolic equilib rium. During the first 24 hours the patient re ceived 300 units of regular insulin, 9 liters of intravenous fluids with 165 mEq potassium chloride, and 3 ampules o f sodium bicarbonate. Oral surgery consultation with the medical ser vice resulted in a tentative clinical diagnosis of m ucorm ycosis; am photericin B therapy was ini tiated. T en milligrams of am photericin B in 500 cc of 5% dextrose in w ater (D5W ) was given the first day, 30 mg in 1,000 cc D5W was given the second day, and 50 mg in 1,000 cc D5W was given every day thereafter. An initial biopsy of the necrotic oral tissue (Fig 1-2), taken the second hospital day, had negative results for hyphae, and high doses o f streptom y cin and penicillin were given in addition to the am photericin B to cover the possibility of a noma. A second biopsy, taken the fifth hospital day, showed positive results for fungus and the penicillin-streptom ycin treatm ent was discon tinued. T he oral lesion was debrided on the sec ond and the fifth hospital days. T he acidosis was controlled two days after ad mission; how ever, glucose levels remained high, and blood C O 2 levels were below normal. The patient becam e increasingly unresponsive with com a, Kussmaul breathing, and Babinski devel opm ent on the right side by the third day, suggest ing brainstem involvement. On the fourth hospital day the patient devel oped congestive heart failure with pulm onary edem a from fluid overload and had a possible myocardial infarction. T he oral lesion continued to involve more tis sue and extended to the cheek, which became gangrenous (Fig 3). Scalp lesions also were not ed. Swelling on the left side of the face increased, and bilateral periorbital edem a and bilateral prop tosis developed which was more noticeable on 1166 ■ JADA, Vol. 95, December 1977
Fig 1 ■ Necrosis of oral tissue and exposure o f lateral wall of maxilla.
Fig 2 ■ Phycomycetes organism s appearing as large hyphae.
the left side. By the tenth day the hem atocrit fell to 21%. T he patient continued to deteriorate and died 11 days after admission. An autopsy showed the patient had a maxil lary left sinusitis as a result of m ucorm ycosis, with extension into adjacent sinuses, m outh, skin, and brain; diabetic ketoacidosis; and oc clusion of the right coronary artery with emboli associated with myocardial infarction o f the left ventricle and papillary muscle. The latter findings suggest that the infection may have spread into the thorax, although no positive identification of hyphae was made in this area. T here also were
Fig 3 ■ G angrenous area of patient’s cheek eight days after ad mission.
areas of infarction in the left lung. The maxillary left sinus and orbital contents revealed necrosis and inflammatory changes that extended into the brain. Multiple areas of infarc tion were found in the left side of the cerebrum , cerebellum , and brainstem . Brain cultures were positive for m ucorm ycosis.
D iscu ssio n One of the earliest and m ost conspicuous clinical signs o f rhinocerebral mucorm ycosis is the ap pearance o f a reddish-black necrotic turbinate and septum , with a dark nasal discharge. The necrosis usually continues to involve the paranasal sinuses and orbital cavity, with characteristic fistulas and sloughs. T he soft tissue of the cheek may become involved with gangrene and sloughing. O cular involvem ent may include the following sym ptoms: unilateral orbital cellulitis, proptosis, ptosis, conjunctival hem orrhage, internal and ex ternal ophthalm oplegia, corneal anesthesia, and loss of vision.3 M any of the ocular findings are m anifestations of damage to cranial nerves II to VI that occur as the infection proceeds into the cranium . Involvem ent of the seventh nerve also may occur. As the infection continues, the patient becom es increasingly lethargic and nonresponsive with the occasional developm ent of Kussmaul breathing, convulsions, hemifacial anes thesia, hemiplegia, and blurred vision. Coma and death may follow.
D iseases that may be confused with rhinocerebral m ucorm ycosis are fulminating bacterial or viral infections, acute sinusitis, cavernous sinus throm bosis, syphilis, or malig nancies. 2,7,10 Biopsy is the m ost reliable m ethod for diag nosis; how ever, failure to find hyphae in a biopsy from an infected person is not uncom m on, and a second biopsy may be required. N asal swabs are ineffective diagnostic tools because the organism s are frequently present in the upper respiratory tract of healthy individuals. L aboratory testing has also proved useless, as no diagnostic skin test or blood culture exists, and the cerebral spinal fluid contains hyphae only occasionally. Diagnosis of m ucorm ycosis depends on a high degree of clinical suspicion suggested by the pa tient’s history and physical exam ination. Biopsy is perform ed to confirm the diagnosis, but when enough clinical evidence indicates m ucor mycosis, therapy m ust be begun even when initial pathologic findings are negative. Early recogni tion of the disease is im perative as swift aggres sive therapy must begin before the invasion and occlusion of arteries lead to irreversible vascular changes. ■ Prognosis and therapy: U ntreated m ucor mycosis can be fatal in a few days. Form erly, even with treatm ent, m ortality was as high as 90%. This poor prognosis has been attributed to a num ber of factors, including late diagnosis, re sistance of m ucor species to antim ycotic agents, and the fulminating nature of the disease.11 Pres ently, m ortality is 50%. This increase in survival rate is probably a result of an increased aw areness of the disease leading to earlier diagnosis and treatm ent, and to the introduction of potent an timycotic drugs. The most im portant therapeutic m easure, ac cording to many authors,4,5,12 is the control of the underlying predisposing disease. In the patient with diabetes this involves correction of acidosis and restoration of normal electrolyte balance. The use of m edicines, such as steroids, an tim etabolites, and antibiotics, which may com promise the immune response and alter the nor mal flora, is restricted. Surgical intervention is an im portant part of the therapy, having been used for m ost patients who have survived, and may range from debridem ent of the necrotic edges of the wound to the complete removal of the eye. A m photericin B is the preferred antim ycotic Cruickshank— others: RHINOCEREBRAL MUCORMYCOSIS ■ 1167
drug. It has broad spectrum fungistatic activity and has been proved effective against Phycom ycetes organism s in vitro.13 Side effects o f am photericin B include anaphylaxis, throm bocy topenia, chills, fever, phlebitis, arrhythm ias, diarrhea, m elena, arthralgia, and decreased renal function or renal damage. T he renal effects of am photericin B therapy include electrolyte im balance, renal tubular acidosis, hypokalem ia, hyposthenuria, nephrocalcinosis, and azo tem a.14 Blood urea nitrogen, blood creatinine, and creatinine clearance should be m onitored while the patient is on am photericin B therapy. T he drug should be tem porarily discontinued if the B U N level exceeds 50 mg/100 ml o r if the blood creatinine level exceeds 3.0 mg/100 m l.15 Since am photericin is absorbed poorly from the intestine, it is adm inistered intravenously. This is usually done with a pediatric scalp vein needle to minimize throm bophlebitis. T he required am ount is dissolved in 0.5 to 1 liter of 5% dextrose in w ater and infused slowly. Differing schedules o f trea t m ent are used, but the usual recom m endation is adm inistration o f a small am ount of the drug with a gradual increase in dosage to 1.2 mg/kg body w eight a day. A lternate-day therapy is the m ethod m ost fre quently used today. This reduces the total dosage given w ithout lowering the m ean concentration in the b lo o d .14 T herapy has also included, in addition to the foregoing m easures, local irrigation with an tim ycotic drugs such as nystatin or am photericin
1168 ■ JADA, Vol. 95, December 1977
and the concom itant use of other antim ycotic drugs such as clotrim azole.16
1 . Parkhurst, G .F .,an d V lahides, G O . Fatal opportunistic fun gu s d isea se . JAM A 202:279 Oct 23, 1967. 2. Abram son, E., and others. Rhinocerebral p hycom ycosis in association with diabetic ketoacid osis. An Intern Med 6 6 :7 35 April 1967. 3. G in sberg, J ., and others. Cerebral phycom ycosis (m ucor m ycosis) with ocular involvem ent. Ophthalmol Am J 62:900 Nov 1966. 4. Taylor, C .G ., and others. M ucorm ycosis (phycom ycosis) in volving the m axilla. Oral Su rg 27:806 Ju n e 1969. 5. Meyer, R.D., and Arm strong, D. M ucorm ycosis— changin g status. C RC Crit Rev Clin Lab Sci 4 :4 2 1 D ec 1973. 6. G ale, G .R . G as e x ch an g e in rhizopus oryzae. J Infect Dis 10 6 :14 9 , 1960. 7. Long, F.L., and W eiss, D.L. C erebral m ucorm ycosis. Am J Med Sci 26:625, 19 59 . 8. Perillie, P .E .,a n d others. S tu d ies of the resistan ce to infection in d iabetes m ellitus: local exud ative cellular respo n ses. J Lab Clin Med 59 :10 0 8 Ju n e 1962. 9. Bybee, J.D ., and R o ge rs, D.E. The p hagocytic activity of p olym orphonuclear leukocytes obtained from patients with diab etes mellitus. J Lab Clin Med 64:1 Ju ly 1964. 10 . Groote, G.A. Rhinocerebral phycom ycosis. Arch Otolaryn gol 92:288 S e p t 1970. 1 1 . Battock, and others. A lternate-day am photericin B therapy in the treatment o f rhinocerebral ph ycom ycosis (m ucorm ycosis). Ann Int Med 6 8 :12 2 Ja n 1968. 12 . Kaufm an, R .S., and Ston e, G. Osteom yelitis of frontal bone secon d ary to m ucorm ycosis. NY S ta te J Med Ju n e 19 7 3. 1 3 . W atson, K.C., and Neam e, P .B. In vitro activity o f am photeri cin B on strains of m u corraceae p athogen ic to man. J Lab Clin Med 6 :17 5 , 1964. 14 . Butler, W.T., and others. Nephrotoxicity of am photericin B early and late effec ts in 81 patients. Ann Int Med 6 1 :1 7 5 , 1964. 15 . Bergstrom , H.L., and others. Rhinocerebral and otologic m ucorm ycosis. Ann Otol Rhinol Laryngol 79:70, 1970. 16 . Low, A.I., and others. P h ycom ycosis of the kidney associated with a transient immune d efect and treated with clotrim azole. J Urol 1 1 1 : 7 3 2 Ju n e 1974.
Rhinocerebral mucormycosis
Gordon Cruickshank, DDS Ronald D. Vincent, DDS, Grand Junction, Colo Henry M. Cherrick, DDS, MSD Kathryn Derby, BA, Los Angeles
It is critical that this fungal disease be diagnosed early to prevent an irreversible process. One case of mucormycosis is reviewed that emphasizes the early signs and symptoms of the disease.
1164 ■ JADA, Vol. 95, December 1977
M ucorm ycosis is an acute, fulminating, and often fatal fungal disease caused by various species of the order Phycom ycetes. F ortunately, hum ans have a natural resistance to these organism s, and m ucorm ycosis is rarely seen in healthy individu als. H ow ever, its occurrence in predisposed pa tients has been increasing in recent years, perhaps because o f the greater use of chem otherapeutic agents which may com prom ise the immunologic defenses of the host or alter norm al flo ra.1,2 R hinocerebral m ucorm ycosis, the m ost com mon o f the four m ajor types (rhinocerebral, pul m onary, gastrointestinal, and dissem inated), is of particular interest to the oral surgeon and general dentist since many o f the earliest clinical signs appear in the mouth. T he clinician m ust be aw are of this disease process for, unless treatm ent is initiated at its earliest onset, prognosis is not en couraging. Organism s o f the order Phycom ycetes can be thought of as opportunists, rather than true pathogens, as they are invasive only when the body physiology is disturbed, as in debilitating diseases and in chem otherapy. Blood dyscrasias, extensive burns, renal disease, m alnutrition, nar cotic addiction, immunologic deficiencies, im m unosuppressive therapy, corticosteroids, an tibiotics, and antim etabolites have been as sociated with the developm ent o f m ucor m ycosis.3'5 T he m ost com m on predisposing fac tor, how ever, is diabetic ketoacidosis, which in volves 40% to 50% of all cases o f m ucorm ycosis and 75% of rhinocerebral m ucorm ycosis. H yperglycem ia, or the subsequent acidosis that
occurs in diabetic ketoacidosis, may be conducive to the proliferation of the fungus. Rhyzopus, the species m ost commonly found in rhinocerebral m ucorm ycosis, grows favorably under conditions that are found in the ketoacidotic patient: acidic p H , high tem perature, and high glucose con ten t.6,7 There also have been studies that indicate that leukocyte function and local tissue accum ula tion of granulocytes are impaired during keto acidosis, thus decreasing the patient’s natural im m unity.8,9 The fungal spores enter through the nose or m outh in inhaled dirt particles and occasionally invade the orbit or open wounds. Rhinocerebral m ucorm ycosis usually begins in the nasal mucosa or palate and spreads into the paranasal sinuses, skin of the face, cribriform plate, and brain. Infec tion may reach the orbit via the nasolacrim al duct. Spread occurs either by direct extension or through vascular channels. A distinctive feature of this organism is its pre dilection for the invasion of arteries. The m ucor mycosis species penetrates the walls of arteries, strips the intima from the media, and eventually spreads into and occludes the lum en.10 This, along with the invasion of veins and lymphatics, results in the characteristic throm bosis, infarc tion, and necrosis seen in the disease. R e p ort o f case A 48-year-old white woman was adm itted to the medical service of the hospital with chief com plaints of lack of coordination, confusion, hal lucinations, excessive thirst, and sciatic nerve pain. The patient had been a brittle diabetic for 20 years and was taking 38 units of protamine in
sulin a day. The patient was relatively well until about a year before admission when carcinom a of the vagina developed, which was treated with radia tion therapy without recurrence. She had had a bilateral cataract extraction and a B artholin’s cyst rem oved from the vulva. F our days before adm ission the patient devel oped an ulceration and severe pain in the maxil lary left vestibule with m oderate swelling and discoloration in the left cheek. This had been treated unsuccessfully by a dentist with boric acid m outhrinse and a topical antifungal agent. The oral ulceration becam e more extensive in the following four days. ■ Physical examination: The patient was obtunded, confused, and in obvious distress. H er breath had a strong odor of acetone. H er lips were blood-encrusted and a large (6 cm) ulceration was found in the maxillary left vestibule that involved the posterior two thirds of the alveolar ridge and corresponding buccal m ucosa. T he lateral wall of the maxilla was exposed and the area was filled with a brownish pigm ented, foul-smelling m ate rial. The right cornea was cloudy and w ithout vision. N o m asses were palpated in the neck or subm ental regions. T here were a few scattered rales in both chest bases, and diffuse tenderness was noted in all quadrants of the abdom en. The liver was felt 3 cm below the right costal margin. N o deep tendon reflexes of the legs were de tected. Blood pressure was 154/80 mm Hg; pulse, 130/ min; tem perature, 97 F; and respiratory rate 40/ min. The patient was edentulous. She had lost 20 pounds in the previous few m onths and weighed 89 pounds.
THE AUTHORS
CRUICKSHANK
VINCENT
Drs. C ruickshank and V incent practice oral surgery in Grand Junction, Colo. Dr. C herrick is associate professor, section of oral pathol
DERBY ogy, and Ms. Derby is a dental student at UCLA. Send re print requests to Dr. Cruickshank, 2721 N 12th St, Grand Junction, C olo 81501.
Cruickshank— others: RHINOCEREBRAL MUCORMYCOSIS ■ 1165
■ Laboratory findings: The hem atocrit was 43%; white blood cell count, 20,000/cu mm with a left shift; blood urea nitrogen, 51 mg/100 ml; serum glucose, 732 m g/100 ml; carbon dioxide combining power less than 10 m Eq/liter; potas sium, 4.7 m Eq/liter; sodium, 126 m Eq/liter; and chloride, 96 m Eq/liter. T he acetone o f the urine was positive 4 + . Radiographs of the facial bones were noncon tributory. R esults of cultures of the urine, mouth w ound, cerebral spinal fluid, sputum , and blood were negative. ■ Clinical course: The immediate plan was to hydrate the patient and restore metabolic equilib rium. During the first 24 hours the patient re ceived 300 units of regular insulin, 9 liters of intravenous fluids with 165 mEq potassium chloride, and 3 ampules o f sodium bicarbonate. Oral surgery consultation with the medical ser vice resulted in a tentative clinical diagnosis of m ucorm ycosis; am photericin B therapy was ini tiated. T en milligrams of am photericin B in 500 cc of 5% dextrose in w ater (D5W ) was given the first day, 30 mg in 1,000 cc D5W was given the second day, and 50 mg in 1,000 cc D5W was given every day thereafter. An initial biopsy of the necrotic oral tissue (Fig 1-2), taken the second hospital day, had negative results for hyphae, and high doses o f streptom y cin and penicillin were given in addition to the am photericin B to cover the possibility of a noma. A second biopsy, taken the fifth hospital day, showed positive results for fungus and the penicillin-streptom ycin treatm ent was discon tinued. T he oral lesion was debrided on the sec ond and the fifth hospital days. T he acidosis was controlled two days after ad mission; how ever, glucose levels remained high, and blood C O 2 levels were below normal. The patient becam e increasingly unresponsive with com a, Kussmaul breathing, and Babinski devel opm ent on the right side by the third day, suggest ing brainstem involvement. On the fourth hospital day the patient devel oped congestive heart failure with pulm onary edem a from fluid overload and had a possible myocardial infarction. T he oral lesion continued to involve more tis sue and extended to the cheek, which became gangrenous (Fig 3). Scalp lesions also were not ed. Swelling on the left side of the face increased, and bilateral periorbital edem a and bilateral prop tosis developed which was more noticeable on 1166 ■ JADA, Vol. 95, December 1977
Fig 1 ■ Necrosis of oral tissue and exposure o f lateral wall of maxilla.
Fig 2 ■ Phycomycetes organism s appearing as large hyphae.
the left side. By the tenth day the hem atocrit fell to 21%. T he patient continued to deteriorate and died 11 days after admission. An autopsy showed the patient had a maxil lary left sinusitis as a result of m ucorm ycosis, with extension into adjacent sinuses, m outh, skin, and brain; diabetic ketoacidosis; and oc clusion of the right coronary artery with emboli associated with myocardial infarction o f the left ventricle and papillary muscle. The latter findings suggest that the infection may have spread into the thorax, although no positive identification of hyphae was made in this area. T here also were
Fig 3 ■ G angrenous area of patient’s cheek eight days after ad mission.
areas of infarction in the left lung. The maxillary left sinus and orbital contents revealed necrosis and inflammatory changes that extended into the brain. Multiple areas of infarc tion were found in the left side of the cerebrum , cerebellum , and brainstem . Brain cultures were positive for m ucorm ycosis.
D iscu ssio n One of the earliest and m ost conspicuous clinical signs o f rhinocerebral mucorm ycosis is the ap pearance o f a reddish-black necrotic turbinate and septum , with a dark nasal discharge. The necrosis usually continues to involve the paranasal sinuses and orbital cavity, with characteristic fistulas and sloughs. T he soft tissue of the cheek may become involved with gangrene and sloughing. O cular involvem ent may include the following sym ptoms: unilateral orbital cellulitis, proptosis, ptosis, conjunctival hem orrhage, internal and ex ternal ophthalm oplegia, corneal anesthesia, and loss of vision.3 M any of the ocular findings are m anifestations of damage to cranial nerves II to VI that occur as the infection proceeds into the cranium . Involvem ent of the seventh nerve also may occur. As the infection continues, the patient becom es increasingly lethargic and nonresponsive with the occasional developm ent of Kussmaul breathing, convulsions, hemifacial anes thesia, hemiplegia, and blurred vision. Coma and death may follow.
D iseases that may be confused with rhinocerebral m ucorm ycosis are fulminating bacterial or viral infections, acute sinusitis, cavernous sinus throm bosis, syphilis, or malig nancies. 2,7,10 Biopsy is the m ost reliable m ethod for diag nosis; how ever, failure to find hyphae in a biopsy from an infected person is not uncom m on, and a second biopsy may be required. N asal swabs are ineffective diagnostic tools because the organism s are frequently present in the upper respiratory tract of healthy individuals. L aboratory testing has also proved useless, as no diagnostic skin test or blood culture exists, and the cerebral spinal fluid contains hyphae only occasionally. Diagnosis of m ucorm ycosis depends on a high degree of clinical suspicion suggested by the pa tient’s history and physical exam ination. Biopsy is perform ed to confirm the diagnosis, but when enough clinical evidence indicates m ucor mycosis, therapy m ust be begun even when initial pathologic findings are negative. Early recogni tion of the disease is im perative as swift aggres sive therapy must begin before the invasion and occlusion of arteries lead to irreversible vascular changes. ■ Prognosis and therapy: U ntreated m ucor mycosis can be fatal in a few days. Form erly, even with treatm ent, m ortality was as high as 90%. This poor prognosis has been attributed to a num ber of factors, including late diagnosis, re sistance of m ucor species to antim ycotic agents, and the fulminating nature of the disease.11 Pres ently, m ortality is 50%. This increase in survival rate is probably a result of an increased aw areness of the disease leading to earlier diagnosis and treatm ent, and to the introduction of potent an timycotic drugs. The most im portant therapeutic m easure, ac cording to many authors,4,5,12 is the control of the underlying predisposing disease. In the patient with diabetes this involves correction of acidosis and restoration of normal electrolyte balance. The use of m edicines, such as steroids, an tim etabolites, and antibiotics, which may com promise the immune response and alter the nor mal flora, is restricted. Surgical intervention is an im portant part of the therapy, having been used for m ost patients who have survived, and may range from debridem ent of the necrotic edges of the wound to the complete removal of the eye. A m photericin B is the preferred antim ycotic Cruickshank— others: RHINOCEREBRAL MUCORMYCOSIS ■ 1167
drug. It has broad spectrum fungistatic activity and has been proved effective against Phycom ycetes organism s in vitro.13 Side effects o f am photericin B include anaphylaxis, throm bocy topenia, chills, fever, phlebitis, arrhythm ias, diarrhea, m elena, arthralgia, and decreased renal function or renal damage. T he renal effects of am photericin B therapy include electrolyte im balance, renal tubular acidosis, hypokalem ia, hyposthenuria, nephrocalcinosis, and azo tem a.14 Blood urea nitrogen, blood creatinine, and creatinine clearance should be m onitored while the patient is on am photericin B therapy. T he drug should be tem porarily discontinued if the B U N level exceeds 50 mg/100 ml o r if the blood creatinine level exceeds 3.0 mg/100 m l.15 Since am photericin is absorbed poorly from the intestine, it is adm inistered intravenously. This is usually done with a pediatric scalp vein needle to minimize throm bophlebitis. T he required am ount is dissolved in 0.5 to 1 liter of 5% dextrose in w ater and infused slowly. Differing schedules o f trea t m ent are used, but the usual recom m endation is adm inistration o f a small am ount of the drug with a gradual increase in dosage to 1.2 mg/kg body w eight a day. A lternate-day therapy is the m ethod m ost fre quently used today. This reduces the total dosage given w ithout lowering the m ean concentration in the b lo o d .14 T herapy has also included, in addition to the foregoing m easures, local irrigation with an tim ycotic drugs such as nystatin or am photericin
1168 ■ JADA, Vol. 95, December 1977
and the concom itant use of other antim ycotic drugs such as clotrim azole.16
1 . Parkhurst, G .F .,an d V lahides, G O . Fatal opportunistic fun gu s d isea se . JAM A 202:279 Oct 23, 1967. 2. Abram son, E., and others. Rhinocerebral p hycom ycosis in association with diabetic ketoacid osis. An Intern Med 6 6 :7 35 April 1967. 3. G in sberg, J ., and others. Cerebral phycom ycosis (m ucor m ycosis) with ocular involvem ent. Ophthalmol Am J 62:900 Nov 1966. 4. Taylor, C .G ., and others. M ucorm ycosis (phycom ycosis) in volving the m axilla. Oral Su rg 27:806 Ju n e 1969. 5. Meyer, R.D., and Arm strong, D. M ucorm ycosis— changin g status. C RC Crit Rev Clin Lab Sci 4 :4 2 1 D ec 1973. 6. G ale, G .R . G as e x ch an g e in rhizopus oryzae. J Infect Dis 10 6 :14 9 , 1960. 7. Long, F.L., and W eiss, D.L. C erebral m ucorm ycosis. Am J Med Sci 26:625, 19 59 . 8. Perillie, P .E .,a n d others. S tu d ies of the resistan ce to infection in d iabetes m ellitus: local exud ative cellular respo n ses. J Lab Clin Med 59 :10 0 8 Ju n e 1962. 9. Bybee, J.D ., and R o ge rs, D.E. The p hagocytic activity of p olym orphonuclear leukocytes obtained from patients with diab etes mellitus. J Lab Clin Med 64:1 Ju ly 1964. 10 . Groote, G.A. Rhinocerebral phycom ycosis. Arch Otolaryn gol 92:288 S e p t 1970. 1 1 . Battock, and others. A lternate-day am photericin B therapy in the treatment o f rhinocerebral ph ycom ycosis (m ucorm ycosis). Ann Int Med 6 8 :12 2 Ja n 1968. 12 . Kaufm an, R .S., and Ston e, G. Osteom yelitis of frontal bone secon d ary to m ucorm ycosis. NY S ta te J Med Ju n e 19 7 3. 1 3 . W atson, K.C., and Neam e, P .B. In vitro activity o f am photeri cin B on strains of m u corraceae p athogen ic to man. J Lab Clin Med 6 :17 5 , 1964. 14 . Butler, W.T., and others. Nephrotoxicity of am photericin B early and late effec ts in 81 patients. Ann Int Med 6 1 :1 7 5 , 1964. 15 . Bergstrom , H.L., and others. Rhinocerebral and otologic m ucorm ycosis. Ann Otol Rhinol Laryngol 79:70, 1970. 16 . Low, A.I., and others. P h ycom ycosis of the kidney associated with a transient immune d efect and treated with clotrim azole. J Urol 1 1 1 : 7 3 2 Ju n e 1974.
