Rhinocerebral mucormycosis, with invasion of the right cavernous sinus and internal carotid artery;
Diabetic ketoacidosis, partially treated
Based on the presence of hyperglycemia, metabolic acidosis and ketones in her serum and urine, this patient without a previous history of diabetes mellitus was diagnosed with diabetic ketoacidosis. Her condition was stabilized with IV fluids, an insulin drip and correction of electrolyte abnormalities prior to her transfer to The Methodist Hospital. A CT scan performed before transfer showed multiple acute and subacute infarcts in the right middle cerebral artery distribution, as well as a right nasopharyngeal mass and chronic sinusitis. Although her examination at the outside hospital documented a left hemiparesis on admission, a right facial droop was clearly documented after transfer, prompting consultation to rule out an evolving brainstem infarct. A MRI study of the brain confirmed the previously noted infarcts in the cortex and centrum semiovale of the right cerebral hemisphere, and defined an invasive process involving the skull base and extending to involve the right inferior orbital fissure, right cavernous sinus, and the cavernous portion of the right internal carotid artery. Both MRI and MRA suggested occlusion of the right internal carotid artery in this region.
The otolaryngology service was consulted. Flexible laryngyoscopic examination revealed friable gray mucosa in the area of the right nasopharynx, extending to the right lateral wall. Biopsies of this lesion were obtained, showing pseudohyphae with a right-angled (90 degree) branching pattern suggestive of mucormycosis. Fungal cultures of this sample grow Rhizopus species, consistent with this diagnosis. Treatment was initiated with intravenous amphotericin B, with improvement in the patient's neurologic status. She regained strength in her left lower extremity and was able to ambulate in the hall with minimal assistance. A percutaneous gastrostomy tube was inserted as she could not maintain adequate oral intake during her hospitalization. She was discharged to a long term care facility after 20 days in the hospital, with plans to continue treatment with amphotericin B for at least two months.
Mucormycosis is typically a rapidly progressive infection by fungi in the order of Mucoraceae and the class of Zygomyceles. Of three genera in this class (Mucor, Absidia and Rhizopus), species of the genus Rhizopus are most frequently identified in specimens from patients diagnosed with this condition. These fungi are present in air, soil, vegetable matter and bread mold, and are readily cultured from the upper respiratory tracts of healthy individuals where they exist as noninvasive, non-pathogenic opportunists. These fungi, however, may become invasive if an individual is immunodepressed, particularly if mucosal immunity is altered. Eighty percent of cases of mucormycosis are diagnosed in individuals with diabetes mellitus, and the majority of these individuals are diagnosed with ketoacidosis at the presentation of the fungal infection. Other conditions that appear to predispose individuals to mucormycosis include renal disease, cirrhosis, neoplastic processes (such as leukemia and lymphomas), gastrointestinal disorders in infants, heroin abuse and prolonged treatment with immunosuppresive medicines. There are also a few reports in the literature of patients diagnosed with mucormycosis that have no identifiable compromise of their immune system.
Mucormycosis most commonly presents as rhinocerebral infection, but it may also present with pulmonary, gastrointestinal, cutaneous, cardiac and widely disseminated infections. The rhinocerebral variant is the most aggressive and potentially fatal form of mucormycosis. Typically, fungal infections in immunocompromised hosts begin as a sinusitis. Infection spreads by direct extension or by invading the internal elastic layer of penetrating blood vessels to involve the orbit, the cavernous sinus and the brain itself. Thrombosis can occur in arteries after they are violated by infection. Pseudoaneurysms have also been described as a complication of mucormycosis.
Involvement of the carotid arteries is not unusual in this infection. Unfortunately, this complication carries a high mortality rate; only 6 of the 37 patients described in one review (Anaissie and Shikhani, 1985) survived more than 3 weeks. This poor outcome was attributed to the advanced state of infection by the time carotid occlusion typically occurs. Orbital involvement may also occur in mucormycosis, with invasion frequently producing syndromes referable to the orbital apex.
Even though mucormycosis is generally viewed as a rapidly progressive infection, chronic rhinocerebral mucormycosis (CRM) may also occur. One report (Harril et al., 1996) noted that most patients with chronic mucormycosis have symptoms for at least seven months prior to diagnosis of their condition and initiation of appropriate treatment. In contrast, the median duration of symptoms for patients with acute rhinocerebral mucormycosis (ARM) is about ten days. Of particular interest, half of reported patients with CRM have documented narrowing of either internal carotid artery, believed to be secondary to the infection, and eight of 18 patients in this report had involvement of one carotid artery and the ipsilateral cavernous sinus. In general, patients with CRM, even with carotid artery and/or cavernous sinus thrombosis, have a much better prognosis than patients with ARM.
Initial symptoms and signs of rhinocerebral mucormycosis depend upon the site of infection. Initial complaints are usually quite non-specific, and include lethargy and headache, leading to the misdiagnosis of "flu," sinusitis, or tension headache. As the infection progresses, symptoms including orbital edema, decreased visual acuity, ptosis and proptosis have been reported as the orbit becomes involved. Examination of the nasal passages may reveal a black, necrotic eschar of the palatine or nasal mucosa. Histopathological identification of large, irregularly branching non-septate hyphae from biopsied tissue, or identification of Mucoraceae fungi from the genera of Mucor, Absidia or Rhizopus from culture of an infected site, establishes diagnosis of this infection. Imaging studies may help to confirm the diagnosis, but abnormal imaging studies are not required to make the diagnosis. One study (Gamba et al., 1986) noted that mucosal thickening of the paranasal sinuses without an air/fluid level, proptosis, and a thickened medial rectus muscle on CT imaging are highly suggestive of the diagnosis of rhinocerebral mucormycosis. Bony destruction is not generally noted in imaging studies of patients with mucormycosis, as the fungi usually cross through penetrating veins without affecting the underlying bone.
Early identification and aggressive treatment are the keys to improving outcome in patients with mucormycosis. Treatment of underlying illnesses, long term anti-fungal therapy with amphotericin B, surgical debridement (if appropriate), and establishment of adequate sinus drainage are accepted modes of therapy. A few reports also recommend hyperbaric oxygen therapy, but the efficacy of this intervention is not fully established. In general, patients diagnosed with mucormycosis are believed to have a better than 50% chance of survival if they receive early diagnosis, aggressive intervention, and the underlying illness is manageable.
In the case detailed above, we believe that undiagnosed diabetes mellitus and chronic antibiotic treatment likely compromised the patient's immune status, predisposing to development of rhinocerebral mucormycosis. Whether her three-month history of right jaw and ear pain arose from chronic nonfungal otitis media, or represented chronic mucormycosis, is unclear. It is possible that her peripheral right seventh nerve palsy resulted from extension of infection from this location. The patient's right visual loss and ophthalmoplegia, together with her left hemiparesis, are attributable to involvement of nerves passing through the right cavernous sinus and orbital apex, together with cerebral infarction from occlusion of the right internal carotid artery. The limited mobility and reduced visual acuity of her left eye are unexplained by our imaging studies. Very likely, however, the infection had progressed beyond the extent detected on MR imaging. Extension to the contralateral cavernous sinus or orbit, as well as pontine infarction, have been reported in the setting of cavernous sinus mucormycosis infection. For this reason, bilateral cranial nerve signs should not dissuade one from considering the diagnosis of a lesion involving anterior structures.
We thank Albert Davies, M.D., of the Pulmonary and Critical Care Division of the Department of Medicine, Eugene C. Lai, M.D., Ph.D., of the Department of Neurology, and Linda M. Wells, M.D., of the Department of Pathology, for their contributions to this case. After this case was submitted, we noted the publication of a case of mucormycosis in a widely read medical journal (Bienfang DC, Karluk D, New England Journal of Medicine 346:924, 2002). Several readers have also brought this to our attention. We believe that comparison of these two cases may be of value to interested readers.
-- Dennis R. Mosier, M.D., Ph.D.
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