Introduction
Mucormycosis is a rare, acute, fatal, opportunistic fungal infection affecting humans with predisposing conditions such as diabetes mellitus (DM); use of deferoxamine; and immunocompromised states, including leukemia, lymphoma, multiple myeloma, septicemia, and chemotherapy. Since this disease progresses rapidly, prompt and aggressive therapy is essential.2)8)14) Rhinocerebral mucormycosis is the most common form of mucormycosis and is most frequently seen in patients with poorly controlled DM.
Fungi commonly invade the blood vessel walls resulting in vascular occlusion, thrombosis, infarction, and
hematogenous dissemination of the infection from the primary infection site to the central nervous system.8) Vascular occlusion occurs frequently in the internal carotid artery (ICA) and cavernous sinus (CS).8)9)14) Mucormycosis can be suspected on the basis of clinical symptoms, but histopathological identification of the fungal species is an essential element of diagnosis. Diabetes is the most common
underlying disorder seen in these patients.5)
Case Report
A 70-year-old man with insulin dependent diabetes mellitus (IDDM) presented with slowly progressive nasal pain. Contrast-enhanced paranasal sinus magnetic resonance imaging (PNS MRI) showed a polypoid mucocele at the right anterior ethmoid sinus (Fig. 1). The mucocele was removed by an endoscopic paranasal sinus approach. Several days after the operation, the patient complained of pain in the right eye, with associated swelling and redness. On ophthalmological examination, central retinal artery
occlusion, partial obstruction of the choroidal circulation, and central retinal vein occlusion were detected. Cranial and orbital MRI revealed inflammatory infiltration of the right superior oblique muscle and the intraconal space between the optic nerve and the superior oblique muscle. Probable infectious lesion at the right orbital apex was suspected to be causing the arterial spasm or occlusion of the right
ophthalmic artery with venous congestion. There was no difference in pre- and post-infarction contrast-enhanced PNS computed tomography (CT) images in terms of the bilateral contrast filling patterns of the CS. However, contrastenhanced brain CT performed after the onset of ophthalmic
symptoms revealed markedly decreased contrast filling in the right cavernous sinus as compared to that in the left cavernous sinus. This finding was suggestive of CS thrombophlebitis (Fig. 2). Apparent diffusion coefficient (ADC) mapping of the right optic nerve showed hypointensity, indicating optic nerve ischemia (Fig. 3). Histopathological examination of the biopsied sinus tissue sample revealed characteristic aseptate branching hyphae with the invasion of blood vessels, which are consistent with zygomycosis (Fig. 4). The patient had been administered highdose amphotericin B (1mg/kg) for 70 d. During the course of high-dose amphotericin B therapy, the patient developed a left-sided hemiparesis 25 d after initiation of therapy. MRI and MR angiography revealed acute infarction at the right cerebral hemisphere and ICA occlusion at the right cavernous sinus segment (Fig. 5). Thromboembolism associated with
aging could be considered in this patient. However, MRI performed before cavernous ICA occlusion showed no evidence of stenosis or atherosclerotic change in any of the intracranial vessels. This finding suggested that ICA occlusion developed after the infection progressed (Fig. 6). The patient was managed with the conventional treatment for cerebral infarction without surgery. Under careful drug monitoring, additional injections of amphotericin B (60mg/day) had been administered for 15 d. The total period
of amphotericin B injection was approximately 3 mo, and the cumulative amount of amphotericin B used was 5.2g. Despite extensive medical therapy, the patient developed severe neurological sequelae such as complete visual loss, left-sided hemiparesis, impairment of cognitive function, dysphagia, and neuropathic pain in the left side of the body. No evidence of recurrence was found on PNS CT and nasal examination 6 months after the onset of the symptoms. The patient survived, but with severe neurological sequelae.
Discussion
Mucormycosis or zygomycosis is an infection caused by fungi of the class zygomycetes. Zygomycetes are a class of widely-spread filamentous fungi found in soil, plants, mammals, and insects. The fungi produce broad, thichwalled, non-septate or sparsely septate hyphae surrounded by eosinophilic material in human tissue.15)
Infection occurs by inhalation, and zygomycetes are inoculated in the nasopharynx and oropharynx.9)12) The normal immune system can arrest the progression of the infection.6) However, immunocompromised individuals or DM patients may be unable to generate an adequate immune response to zygomycetes.6)12)
Rhinocerebral mucormycosis typically originates in the nasal or oral mucosa, invades the paranasal sinuses, and extends towards the orbit via the ethmoid and maxillary sinuses or via the nasolacrimal duct. Intracerebral extension may occur from the orbit via the orbital apex, orbital vessels, or the cribriform plate. Vascular occlusion may occur in the ophthalmic artery, ICA, or cavernous sinus.8)14)
Mucormycosis is mainly characterized by fungal angiotropic invasion. Mycosis induces proliferation of the tunica intima, resulting in its separation from the tunica media, followed by thrombogenous vasculitis, infarction, hemorrhage, and diffuse tissue necrosis. However, vein and lymph node invasion are rare.10)13)15)
This case demonstrated the typical pathogenesis and pathway of intracranial infections. The symptoms of
mucormycosis include cranial nerve palsy and ocular symptoms such as periorbital pain, orbital inflammation, eyelid edema, blepharoptosis, proptosis, acute ocular motility changes, internal or external ophthalmoplegia, and acute vision loss.1) For the final diagnosis of the disease, histological evidence, including the characteristic finding of tissue invasion by the hyphae, is required. According to available literature, zygomycosis comprises approximately 5~12% of all fungal infections seen in highrisk
populations. The organisms are considered as opportunistic pathogens.11) As is the case with the
Aspergillus species, zygomycetes cause a wide spectrum of clinical diseases involving the sinonasal, rhinocerebral, pulmonary, cardiac, gastrointestinal, and cutaneous systems.8)12)14) Infection with Rhizopus species is the most common form of rhinocerebral zygomycosis and is usually fulminant and fatal, accounting for about 90% of all infections with the zygomycetes.11)15)
The mortality rate of rhinocerebral mucormycosis is approximately 20%.15) Furthermore, involvement of the cavernous sinus increases the mortality rate to 50%.5) DM is the single most common predisposing illness associated with the development of this infection.11) This case highlights the importance of early diagnosis and prompt treatment, including surgical excision and antifungal therapy. If the authors had started treatment earlier that they did, the unwanted sequelae could have been avoided. A review of
currently available literature supports the use of intravenous amphotericin B as the primary antifungal treatment for all forms of zygomycosis.2)3)4) A review of all relevant published articles revealed that the number of major infarctions caused by ICA occlusion was very little, and treatment options have
not yet been examined. Since the pathogenesis involves thromboembolism due to vasculitis, treatment options can include antiplatelet and anticoagulative agents. Netfidou et al.7) reported that secretion of aspartic proteinase is observed in mucormycosis and that this enzyme inactivates antithrombin III leading to a severe hypercoagulative state. Therefore, it may be helpful to combine antithrombin III administration with antiplatelet treatment.
Conclusion
We reported a case of rare and severe cavernous sinus mucormycosis. Zygomycosis should be included in the differential diagnosis of cranial nerve deficit developing after nasopharyngeal surgery in DM patients. Management of the underlying risk factors is also important for successful treatment. Since it is a life-threatening disease, aggressive medical treatment with amphotericin B and surgical removal
of the infection source is necessary.
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