Rhinocerebral M. Bashar
Succar, MD;
Richard D.
Mucormycosis
Nichols, MD; Keith H. Burch, MD
\s=b\ Rhinocerebral phycomycosis is a serious and commonly fatal fungal infection. The causative organism, ordinarily a saprophyte, becomes pathogenic in persons who are made susceptible by coexisting, debilitating disease. We report a well-documented case of rhinocerebral phycomycosis where early diagnosis led to successful treatment, and we discuss important aspects of the clinical evaluation and management of such cases.
(Arch Otolaryngol 105:212-214, 1979)
demonstration of the or¬ affected tissue. Identifica¬ tion of the specific order and genus of the pathogen is possible only by morphologic examination of growth from a successful culture of affected tissue. Treatment consists of surgical debridement, attention to predisposing factors, and parenteral amphotericin B.
pathologie ganism in
A 52-year-old man
was
referred from the
Henry Ford Hospital, Detroit, with a diagnosis of possible acute left maxillary sinusitis. His chief complaint was progressive left severe facial pain of three days' duration. He had also noticed left infraorbital swelling and numbness. The patient had no past history of diabetes or hypertension. An emergency room physician started therapy with ampicillin sodium and decongestants. Results of emergency room,
initial examination demonstrated redness, swelling, and tenderness over the left maxilla. The nasal mucosa was pink with
rhinocerebral is affects since it both in terms of mortality and residu¬ al disability. Early diagnosis is not difficult. It is only necessary that the physician considers the possibility of the existence of the disease before the obvious full-blown clinical picture de¬ velops. The earliest symptom is facial pain that is severe and out of propor¬ tion to roentgenographic findings of the sinuses. Physical signs are absent at this clinical stage. The diagnosis is confirmed by histo-
phycomycosis, early In diagnosis extremely important positively prognosis,
for publication March 16, 1978. From the Departments of Otolaryngology (Drs Succar and Nichols) and Division of Infectious Diseases (Dr Burch), Henry Ford Hospital, Detroit. Dr Succar is now with Metropolitan Hospital, Detroit. Reprint requests to Department of Otolaryngology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202 (Dr Nichols).
REPORT OF A CASE
no
Accepted
Fig 1—Patient with proptosis, restriction of ocular mobility, and swelling of left side of face.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
purulent
or
serosanguineous drainage.
There was ptosis of his left eye and decreased transillumination of the left maxillary sinus (Fig 1). Extraocular move¬ ments and vision were normal. Roentgenographs showed clouding of the left maxillary sinus, without an airfluid level or bone destruction. Laboratory studies disclosed the following values: urinalysis, with glucose, 4+ and ketone, 2+ ; random blood glucose, 313 mg/dl, with no ketoacidosis; and WBC count, 14.2/cu mm, with 69% polymorphonuclear leuko¬ cytes, 8% monocytes, 18% lymphocytes, and 5% band cells. The differential diagnosis included tumor and infection. On the following day, there were signifi¬ cant changes. The pain was worse and could be controlled only with strong anal¬ gesics. Proptosis and restriction of ocular mobility had developed in all directions in the affected eye. Lateral gaze was particu¬ larly affected. His maxillary cellulitis and intranasal findings remained the same. A
Fig 2—Mucor sp obtained from
of
mucormycosis showing nonseptate mycelia
smear
potassium hydroxide,
biopsy tissue (lactophenol 390).
of
mycotic infection of the antrum was considered, and a diagnostic maxillary antrum lavage was done. Routine and fungal cultures were taken. To date, these have shown no growth. The
patient was admitted for close observation and diagnostic sinusotomy, which was done the following day under local anesthesia. was black discoloration on the medial wall of the sinus, with an edema¬ tous thick mucosa that was removed completely. A large, nasoantral window was created. The diagnosis of mucormyco¬ sis was confirmed by results of an exami¬ nation of a smear that was prepared with lactophenol blue and potassium hydroxide. Successful culture of the surgical specimen has shown nonseptate mycelia with sporefilled sporangia (Fig 2 and 3). Treatment was started. The with amphotericin patient received 50 mg on the first day of treatment. Irrigation of the sinus with 5% acetic acid was done every other day. Insu¬ lin injection was used to control his diabetes. Cerebrospinal fluid was obtained by lumbar puncture but showed no abnor¬
There
mality.
patient was discharged from the hospital after 22 days of treatment with 530 mg of amphotericin B. The BUN and The
monitored during his treatment. At the time of discharge, there was no proptosis or impairment of extraocular movement. The infraorbital numbness was improving. As an outpatient, the amphotericin therapy was continued to a total dose of 2.5 g, and the sinus irrigation was continued weekly for seven weeks.
serum
creatinine levels
were
COMMENT Mucormycosis is a fungal infection that is caused by an organism with
large, irregular, wide, nonseptate my-
blue and
Fig 3—Spore-filled sporangia (lactophenol blue hydroxide, 390).
celia. Three common genera are known: Mucor, Rhizopus, and Absidia. Mucormycosis is present in the envi¬ ronment on vegetables, soil, animal excreta, and decayed fruit. It is ordi¬ narily a saprophyte, but it may become pathogenic under certain clin¬ ical conditions.1 The most common predisposing factors in susceptible persons are diabetic acidosis, renal insufficiency,- or diarrhea in infants.2 It has also occurred in patients with neoplasms, who receive cytotoxic agents and steroids,1 in very wellcontrolled diabetics,4 and in patients
following immunosuppressive therapy after renal transplants.5
There are three types of mucormy¬ cosis: rhinocerebral, pulmonary, and abdominal. We will discuss only the rhinocerebral type. In rhinocerebral mucormycosis, the portal of entry is the nasal mucosa, with a direct spread to the sinuses. It may extend to the orbit via a vascular or neural channel. Extension to the cerebrum could be through the cribri¬ form plate, vessels, or nerves. If there is orbital involvement, it is difficult to rule out cerebral involvement.2 Mucor¬ mycosis has an unusual propensity for invasion of the arterial wall, which produces fungal arteritis. The vascu¬ lar involvement can include the inter¬ nal carotid artery,6 cavernous sinus, or ophthalmic artery. At autopsy, hyphae have been found in the internal carot¬ id artery wall." The Mucor organisms may also invade the perineural tissue, which leads to anesthesia or paralysis.
and
potassium
Histologie examination of tissue that is obtained at autopsy may show a nucleated giant cell reaction of peri¬ neural tissue, the nerves invaded by hyphae, and signs of neuritis. The other structures in the orbit, muscle, vessels, nerves, and fat may also be involved with the inflammatory pro¬ cess.
CLINICAL COURSE
Symptoms
patient usually has a history of facial pain.1 The clinical pro¬ gression of rhinocerebral mucormyco¬ sis includes the following symptoms: swelling over the eyelid; lacrimation; nasal congestion; brownish nasal dis¬ charge; blackening over the turbinate; The
severe
cellulitis of the orbit; weakness
or
paresis of the third, fourth, and sixth
cranial nerves; blindness; mental dete¬ rioration; and death.7
Prognosis
mucormycosis usual¬ ly has a very rapid, aggressive course, Rhinocerebral
which terminates in a fatal outcome. Involvement of the orbit and cere¬ brum is associated with an especially poor prognosis, but two cases of orbit¬ al mucormycosis have been reported with a good recovery after amphoteri¬ cin therapy and ethmoidectomy.8 Cases of cerebral mucormycosis have also been reported with recovery, with only debridement of devitalized nasal tissue without amphotericin thera¬
py-9
There
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
are
two considerations of
importance in the diagnosis of rhino¬ cerebral mucormycosis. The first is that any delay in establishing the diagnosis will negatively affect the prognosis. The second is the ubiqui¬ tous nature of the organism, which makes it difficult, using culture tech¬ niques, to identify it as the pathogen. The only way to confirm the diagnosis is to observe the organism in the
tissue that is taken from the lesion for use as a
biopsy specimen. Histologie
examination of such tissue will show necrosis with acute and chronic inflammatory infiltrates with scat¬
tered, fragmented, large, nonseptate, haphazardly branching hyphae. The
hyphae
can
usually
be shown in
sections that are stained with PAS after diastase treatment. Roentgeno-
graphs may show only slight clouding
of the sinuses without air-fluid lev¬ els.1" A diagnostic clue is that these patients complain of pain that is far out of proportion to the roentgeno¬ graphic findings. Another important
clinical characteristic is the presence of anesthesia or hypesthesia of the face. The CSF may show an increased protein level and inflammatory cells. The organism has never been isolated from the CSF of affected individu¬ als.2 Treatment
In addition to direct treatment of the infection, predisposing factors, such as diabetic acidosis, must be controlled. A total dose of 2.5 to 2.7 g should be given of amphotericin during a four- to eight-week period. Debridement of the necrotic tissue is important. The surgical operation that is necessary to accomplish this may range from a simple CaldwellLuc procedure to a radical ethmoidec¬ tomy and exentration of the orbit and orbital floor, with removal of the hard palate and sphenoidotomy.1113 It may be difficult to judge the exact extent of the infection, but the goal of the operation is not to eradicate the
disease but to remove the dead and necrotic tissue that is a good medium for the fungal growth. Some suggest heparinization with the previously described regimen. CONCLUSION
Mucormycosis is included in the diagnosis of any severe, pain. Predisposing factors
differential acute facial
or may not be obvious. Once the orbital complications and intracranial signs and symptoms occur, the likeli¬ hood of successful therapy is greatly diminished. Whenever the index of suspicion is high, tissue should be removed for use as biopsy specimens, and treatment should be started as
may
soon as
possible. Names and Trademarks of Drugs
Nonproprietary
Amphotericin B—Fungizone. Ampicillin sodium—A mcill-S, Omnipen-N, Penbritin-S, Polycillin-N, Principen IN.
References 1. Eilderton TE: Fatal postextraction: Cerebral mucormycosis in an unknown diabetic. J Oral Surg 32:297-300, 1974. 2. Meyer RD, Armstrong D: Mucormycosis: Changing status. CRC Crit Rev Clin Lab Sci 4:421-449, 1973. 3. Suga J, Hagal A, Kashima H: Autopsy case of disseminated mucormycosis with ossicular involvement. J Clin Ophthalmol 17:365, 1963. 4. Sandler R, Tallman CB, Keany DG, et al: Successfully treated rhinocerebral phycomycosis in well-controlled diabetes. N Engl J Med
285:1180, 1971.
5. Harm S, Better OS, Lichtig C, et al: Rhinocerebral mucormycosis following kidney transplantation. Isr J Med Sci 6:646, 1970. 6. Lowe JT Jr, Hudson WR: Rhinocerebral phycomycosis and internal carotid artery thrombosis. Arch Otolaryngol 101:100-103, 1975. 7. Stefani FH, Mehraein P: Acute rhino-orbital cerebralmucormycosis. Ophthalmologica 172:38\x=req-\ 44, 1976. 8. Bullock JD, Jampol LM, Fezza AJ: Two cases of orbital phycomycosis with recovery. Am J Ophthalmol 78:811-815, 1974. 9. Pollack RA, Pratt RC, Shulman JA, et al:
Nasal
mucormycosis: Early
detection and treat-
ment without radical surgery
or
amphotericin
B.
South Med J 68:1279-1282, 1975. 10. Green WH, Goldberg HI, Wohl GT: Mucormycosis infection of the craniofacial structures. Am J Radiol 101:802-806, 1967.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
11. Eisenberge L, Wood T, Boles R: Mucormycosis. Laryngoscope 87:347-356, 1977. 12. Faila PS, Sube HP, Anderson NH: Mucormycosis of the paranasal sinus and the maxilla. Oral Surg 12:304-309, 1959. 13. Hoagland RJ, Sube J, Bishop RH, et al: Mucormycosis. Am J Med Sci 242:415-422, 1961.
Succar, MD;
Richard D.
Mucormycosis
Nichols, MD; Keith H. Burch, MD
\s=b\ Rhinocerebral phycomycosis is a serious and commonly fatal fungal infection. The causative organism, ordinarily a saprophyte, becomes pathogenic in persons who are made susceptible by coexisting, debilitating disease. We report a well-documented case of rhinocerebral phycomycosis where early diagnosis led to successful treatment, and we discuss important aspects of the clinical evaluation and management of such cases.
(Arch Otolaryngol 105:212-214, 1979)
demonstration of the or¬ affected tissue. Identifica¬ tion of the specific order and genus of the pathogen is possible only by morphologic examination of growth from a successful culture of affected tissue. Treatment consists of surgical debridement, attention to predisposing factors, and parenteral amphotericin B.
pathologie ganism in
A 52-year-old man
was
referred from the
Henry Ford Hospital, Detroit, with a diagnosis of possible acute left maxillary sinusitis. His chief complaint was progressive left severe facial pain of three days' duration. He had also noticed left infraorbital swelling and numbness. The patient had no past history of diabetes or hypertension. An emergency room physician started therapy with ampicillin sodium and decongestants. Results of emergency room,
initial examination demonstrated redness, swelling, and tenderness over the left maxilla. The nasal mucosa was pink with
rhinocerebral is affects since it both in terms of mortality and residu¬ al disability. Early diagnosis is not difficult. It is only necessary that the physician considers the possibility of the existence of the disease before the obvious full-blown clinical picture de¬ velops. The earliest symptom is facial pain that is severe and out of propor¬ tion to roentgenographic findings of the sinuses. Physical signs are absent at this clinical stage. The diagnosis is confirmed by histo-
phycomycosis, early In diagnosis extremely important positively prognosis,
for publication March 16, 1978. From the Departments of Otolaryngology (Drs Succar and Nichols) and Division of Infectious Diseases (Dr Burch), Henry Ford Hospital, Detroit. Dr Succar is now with Metropolitan Hospital, Detroit. Reprint requests to Department of Otolaryngology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202 (Dr Nichols).
REPORT OF A CASE
no
Accepted
Fig 1—Patient with proptosis, restriction of ocular mobility, and swelling of left side of face.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
purulent
or
serosanguineous drainage.
There was ptosis of his left eye and decreased transillumination of the left maxillary sinus (Fig 1). Extraocular move¬ ments and vision were normal. Roentgenographs showed clouding of the left maxillary sinus, without an airfluid level or bone destruction. Laboratory studies disclosed the following values: urinalysis, with glucose, 4+ and ketone, 2+ ; random blood glucose, 313 mg/dl, with no ketoacidosis; and WBC count, 14.2/cu mm, with 69% polymorphonuclear leuko¬ cytes, 8% monocytes, 18% lymphocytes, and 5% band cells. The differential diagnosis included tumor and infection. On the following day, there were signifi¬ cant changes. The pain was worse and could be controlled only with strong anal¬ gesics. Proptosis and restriction of ocular mobility had developed in all directions in the affected eye. Lateral gaze was particu¬ larly affected. His maxillary cellulitis and intranasal findings remained the same. A
Fig 2—Mucor sp obtained from
of
mucormycosis showing nonseptate mycelia
smear
potassium hydroxide,
biopsy tissue (lactophenol 390).
of
mycotic infection of the antrum was considered, and a diagnostic maxillary antrum lavage was done. Routine and fungal cultures were taken. To date, these have shown no growth. The
patient was admitted for close observation and diagnostic sinusotomy, which was done the following day under local anesthesia. was black discoloration on the medial wall of the sinus, with an edema¬ tous thick mucosa that was removed completely. A large, nasoantral window was created. The diagnosis of mucormyco¬ sis was confirmed by results of an exami¬ nation of a smear that was prepared with lactophenol blue and potassium hydroxide. Successful culture of the surgical specimen has shown nonseptate mycelia with sporefilled sporangia (Fig 2 and 3). Treatment was started. The with amphotericin patient received 50 mg on the first day of treatment. Irrigation of the sinus with 5% acetic acid was done every other day. Insu¬ lin injection was used to control his diabetes. Cerebrospinal fluid was obtained by lumbar puncture but showed no abnor¬
There
mality.
patient was discharged from the hospital after 22 days of treatment with 530 mg of amphotericin B. The BUN and The
monitored during his treatment. At the time of discharge, there was no proptosis or impairment of extraocular movement. The infraorbital numbness was improving. As an outpatient, the amphotericin therapy was continued to a total dose of 2.5 g, and the sinus irrigation was continued weekly for seven weeks.
serum
creatinine levels
were
COMMENT Mucormycosis is a fungal infection that is caused by an organism with
large, irregular, wide, nonseptate my-
blue and
Fig 3—Spore-filled sporangia (lactophenol blue hydroxide, 390).
celia. Three common genera are known: Mucor, Rhizopus, and Absidia. Mucormycosis is present in the envi¬ ronment on vegetables, soil, animal excreta, and decayed fruit. It is ordi¬ narily a saprophyte, but it may become pathogenic under certain clin¬ ical conditions.1 The most common predisposing factors in susceptible persons are diabetic acidosis, renal insufficiency,- or diarrhea in infants.2 It has also occurred in patients with neoplasms, who receive cytotoxic agents and steroids,1 in very wellcontrolled diabetics,4 and in patients
following immunosuppressive therapy after renal transplants.5
There are three types of mucormy¬ cosis: rhinocerebral, pulmonary, and abdominal. We will discuss only the rhinocerebral type. In rhinocerebral mucormycosis, the portal of entry is the nasal mucosa, with a direct spread to the sinuses. It may extend to the orbit via a vascular or neural channel. Extension to the cerebrum could be through the cribri¬ form plate, vessels, or nerves. If there is orbital involvement, it is difficult to rule out cerebral involvement.2 Mucor¬ mycosis has an unusual propensity for invasion of the arterial wall, which produces fungal arteritis. The vascu¬ lar involvement can include the inter¬ nal carotid artery,6 cavernous sinus, or ophthalmic artery. At autopsy, hyphae have been found in the internal carot¬ id artery wall." The Mucor organisms may also invade the perineural tissue, which leads to anesthesia or paralysis.
and
potassium
Histologie examination of tissue that is obtained at autopsy may show a nucleated giant cell reaction of peri¬ neural tissue, the nerves invaded by hyphae, and signs of neuritis. The other structures in the orbit, muscle, vessels, nerves, and fat may also be involved with the inflammatory pro¬ cess.
CLINICAL COURSE
Symptoms
patient usually has a history of facial pain.1 The clinical pro¬ gression of rhinocerebral mucormyco¬ sis includes the following symptoms: swelling over the eyelid; lacrimation; nasal congestion; brownish nasal dis¬ charge; blackening over the turbinate; The
severe
cellulitis of the orbit; weakness
or
paresis of the third, fourth, and sixth
cranial nerves; blindness; mental dete¬ rioration; and death.7
Prognosis
mucormycosis usual¬ ly has a very rapid, aggressive course, Rhinocerebral
which terminates in a fatal outcome. Involvement of the orbit and cere¬ brum is associated with an especially poor prognosis, but two cases of orbit¬ al mucormycosis have been reported with a good recovery after amphoteri¬ cin therapy and ethmoidectomy.8 Cases of cerebral mucormycosis have also been reported with recovery, with only debridement of devitalized nasal tissue without amphotericin thera¬
py-9
There
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
are
two considerations of
importance in the diagnosis of rhino¬ cerebral mucormycosis. The first is that any delay in establishing the diagnosis will negatively affect the prognosis. The second is the ubiqui¬ tous nature of the organism, which makes it difficult, using culture tech¬ niques, to identify it as the pathogen. The only way to confirm the diagnosis is to observe the organism in the
tissue that is taken from the lesion for use as a
biopsy specimen. Histologie
examination of such tissue will show necrosis with acute and chronic inflammatory infiltrates with scat¬
tered, fragmented, large, nonseptate, haphazardly branching hyphae. The
hyphae
can
usually
be shown in
sections that are stained with PAS after diastase treatment. Roentgeno-
graphs may show only slight clouding
of the sinuses without air-fluid lev¬ els.1" A diagnostic clue is that these patients complain of pain that is far out of proportion to the roentgeno¬ graphic findings. Another important
clinical characteristic is the presence of anesthesia or hypesthesia of the face. The CSF may show an increased protein level and inflammatory cells. The organism has never been isolated from the CSF of affected individu¬ als.2 Treatment
In addition to direct treatment of the infection, predisposing factors, such as diabetic acidosis, must be controlled. A total dose of 2.5 to 2.7 g should be given of amphotericin during a four- to eight-week period. Debridement of the necrotic tissue is important. The surgical operation that is necessary to accomplish this may range from a simple CaldwellLuc procedure to a radical ethmoidec¬ tomy and exentration of the orbit and orbital floor, with removal of the hard palate and sphenoidotomy.1113 It may be difficult to judge the exact extent of the infection, but the goal of the operation is not to eradicate the
disease but to remove the dead and necrotic tissue that is a good medium for the fungal growth. Some suggest heparinization with the previously described regimen. CONCLUSION
Mucormycosis is included in the diagnosis of any severe, pain. Predisposing factors
differential acute facial
or may not be obvious. Once the orbital complications and intracranial signs and symptoms occur, the likeli¬ hood of successful therapy is greatly diminished. Whenever the index of suspicion is high, tissue should be removed for use as biopsy specimens, and treatment should be started as
may
soon as
possible. Names and Trademarks of Drugs
Nonproprietary
Amphotericin B—Fungizone. Ampicillin sodium—A mcill-S, Omnipen-N, Penbritin-S, Polycillin-N, Principen IN.
References 1. Eilderton TE: Fatal postextraction: Cerebral mucormycosis in an unknown diabetic. J Oral Surg 32:297-300, 1974. 2. Meyer RD, Armstrong D: Mucormycosis: Changing status. CRC Crit Rev Clin Lab Sci 4:421-449, 1973. 3. Suga J, Hagal A, Kashima H: Autopsy case of disseminated mucormycosis with ossicular involvement. J Clin Ophthalmol 17:365, 1963. 4. Sandler R, Tallman CB, Keany DG, et al: Successfully treated rhinocerebral phycomycosis in well-controlled diabetes. N Engl J Med
285:1180, 1971.
5. Harm S, Better OS, Lichtig C, et al: Rhinocerebral mucormycosis following kidney transplantation. Isr J Med Sci 6:646, 1970. 6. Lowe JT Jr, Hudson WR: Rhinocerebral phycomycosis and internal carotid artery thrombosis. Arch Otolaryngol 101:100-103, 1975. 7. Stefani FH, Mehraein P: Acute rhino-orbital cerebralmucormycosis. Ophthalmologica 172:38\x=req-\ 44, 1976. 8. Bullock JD, Jampol LM, Fezza AJ: Two cases of orbital phycomycosis with recovery. Am J Ophthalmol 78:811-815, 1974. 9. Pollack RA, Pratt RC, Shulman JA, et al:
Nasal
mucormycosis: Early
detection and treat-
ment without radical surgery
or
amphotericin
B.
South Med J 68:1279-1282, 1975. 10. Green WH, Goldberg HI, Wohl GT: Mucormycosis infection of the craniofacial structures. Am J Radiol 101:802-806, 1967.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Pennsylvania User on 06/15/2015
11. Eisenberge L, Wood T, Boles R: Mucormycosis. Laryngoscope 87:347-356, 1977. 12. Faila PS, Sube HP, Anderson NH: Mucormycosis of the paranasal sinus and the maxilla. Oral Surg 12:304-309, 1959. 13. Hoagland RJ, Sube J, Bishop RH, et al: Mucormycosis. Am J Med Sci 242:415-422, 1961.
