Intracranial Perineural Extension of Invasive Mycosis: A Novel Mechanism of Disease Propagation by Aspergillus fumigatus
- 1 Division of Infectious Diseases, Department of Medicine, University of South Carolina School of Medicine, Palmetto-Richland Memorial Hospital, Columbia, South Carolina
- 2 Department of Radiology, University of South Carolina School of Medicine, Palmetto-Richland Memorial Hospital, Columbia, South Carolina
- 3 Department of Ophthalmology, University of South Carolina School of Medicine, Palmetto-Richland Memorial Hospital, Columbia, South Carolina
- Reprints or correspondence: Dr. Amar Safdar, Div. of Infectious Diseases, Dept. of Medicine, University of South Carolina School of Medicine, 2 Medical Park, Ste. 502, Columbia, SC 29203 (safdar{at}richmed.medpark.sc.edu).
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Presented in part: 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco, California, 25–28 October 2001 (abstract 605).
Abstract
We describe an immunocompetent woman who had refractory, invasive sphenoid sinus Aspergillus fumigatus infection for which there was radiologic evidence of intracranial perineural spread. The patient responded to a combination of antifungal and adjuvant recombinant cytokine therapy.
Invasive mycosis that involves the paranasal sinuses occasionally can lead to severe and disabling complications. Extension of the disease to the orbit and brain is a grave concern and is often seen in patients with immunosuppression [1, 2]. Invasive mold infections may involve contiguous tissue through necrosis and infarction or systemic dissemination via bloodstream invasion [3]. Unlike malignancies of the head and neck, spread of fungi along the nerve sheath [4–6] has not been reported in patients with invasive mycosis. We describe an immunocompetent woman with refractory, invasive, sphenoid sinus Aspergillus fumigatus infection that progressed through perineural involvement and that responded to a combination of antifungals and adjuvant therapy.
A 68-year-old, healthy white woman presented with severe headache of a few days' duration and intractable pain in the right eye. Four months before presentation, she had been given a diagnosis of invasive right sphenoid fungal sinusitis, and A. fumigatus had been isolated. MRI of the orbit and brain showed a retro-orbital mass with ipsilateral temporal lobe involvement. Because the patient had recently experienced a decrease in her visual acuity and had developed new-onset paralysis of cranial nerve (CN) III (CN-III; the oculomotor nerve) and CN-VI (the abducent nerve), emergent craniotomy and temporal lobe biopsy were performed. Histological examination revealed branching, septate hyphae in an area of tissue necrosis. A. fumigatus was isolated from cultures of specimens obtained from this area intraoperatively.
Therapy with AmBisome (Fujisawa Healthcare; 5 mg/kg/day) was initiated. Seven weeks later, the patient presented with right facial nerve lower motor neuron paralysis of new onset; progressive right orbital apex syndrome, including persistent paralysis of CN-III and CN-VI and new-onset paralysis of CN-IV (trochlear nerve) and CN-V2 (second division of the trigeminal nerve); and progressive exophthalamus (figure 1). Retro-orbital pain was severe and refractory to narcotic analgesic treatment. The results of the patient's physical examination were otherwise normal. Laboratory studies revealed the following values: WBC count, 6900 cells/µL; hemoglobin, 9.4 g/dL; platelet count, 257,000 platelets/µL; creatinine, 1.6 mg/dL; lactic dehydrogenase, 396 IU; and erythrocyte sedimentation rate, 65 mm/h. The CD4+ T cell count (1033 cells/µL) and serum levels of alanine aminotransferase and aspartate aminotransferase were within normal ranges. A second MRI showed an enlarged mass in the right cavernous sinus and interval progression of disease that involved the ipsilateral pterygopalatine fossa and the intracanalicular facial nerve (figure 2A–C). Results of serological tests for the detection of HIV-1 and HIV type 2, human T lymphotropic virus types 1 and 2, and antinuclear antibodies were negative. Blood cultures were sterile, and CT of the chest revealed normal findings.
Figure 1
Top, Progressed right exophthalamus and orbital apex syndrome that included paralysis of the oculomotor nerve (CN-III), the trochlear nerve (CN-IV), and the abducent nerve (CN-VI), in addition to new-onset paralysis of the ipsilateral lower motor neuron facial nerve (CN-VII). Bottom, Complete resolution of proptosis and resolution of the right orbital apex syndrome (CN-III, CN-IV, and CN-VI) and CN-VII after 8 weeks of combination therapy.
Figure 2
MRI of the brain, with intravenous gadolinium enhancement. Contrast enhancement and widening of the right pterygopalatine fossa (A, black arrow) and right Meckel's cave (A, black arrowhead) are shown. The right geniculate ganglion and preganglionic intracanalicular right facial nerve are apparent with gadolinium enhancement (B, white arrow). With contrast enhancement, an enlarged right facial nerve appears within the temporal bone (C, white arrow), whereas the left facial nerve appears to have normal dimensions after enhancement with intravenous gadolinium (C, white arrowhead). MRIs obtained 8 weeks after combination therapy was initiated show diminished enhancement of the right pterygopalatine fossa (D, black arrow), reduced dural enhancement of right Meckel's cave (D, black arrowhead), and persistent enhancement of the right geniculate ganglion, whereas the right intracanalicular facial nerve appears to be normal (E, white arrow).
The dosage of AmBisome was increased (to 7.5 mg/kg/day), and itraconazole (400 mg iv daily) was added to the treatment regimen [7]. Two weeks after combination antifungal therapy was initiated because of a lack of improvement in the patient's clinical condition, adjuvant therapy with hyperbaric oxygen (HBO) [8] and recombinant granulocyte macrophage–colony-stimulating factor (GM-CSF; 400 µg sc) was initiated [9, 10]. Exenteration was withheld because of the high associated surgical risk. Ten days after initiation of adjuvant therapy, the patient's headache resolved and her retro-orbital pain had lessened significantly. Four weeks after commencement of adjuvant therapy, right facial nerve motor functions returned to normal and near-complete resolution of right orbital apex syndrome and proptosis was reassuring (figure 1). Because of the development of acute capillary leak syndrome and early pulmonary bullous changes, adjuvant recombinant GM-CSF therapy and HBO therapy were discontinued. Right CN-III, CN-IV, CN-VI motor, and CN-V2 sensory functions returned to normal 4 weeks after adjuvant therapy was discontinued, and MRI showed pronounced improvement in the appearance of the cavernous sinus and retro-orbital mass, in addition to normalization of the appearance of the right optic nerve on gadolinium enhancement (figure 2D and 2E). Treatment with AmBisome (7.5 mg/kg 3 days a week) and oral itraconazole (400 mg/day) was continued for 6 months. No recurrence was observed 12 months after cessation of antifungal therapy.
Perineural spread of tumors has been well documented [4–6, 11, 12]. Perineural extension of sinunasal sarcoidosis has also been described recently [13]. In the case presented here, isolated involvement of the intratemporal portion of the facial nerve was unexpected (figure 2C). The pterygopalatine fossa has direct extension to the orbital apex via the inferior orbital fissure, and it communicates intracranially via the foramen rotundum and the vidian canal. The vidian nerve is a continuation of the greater superficial petrosal nerve, which is a preganglionic, parasympathetic branch of facial nerve that originates at the geniculate ganglion at the genu of facial nerve canal (figure 2B and 2E). The lateral wall of the sphenoid sinus is contiguous to the medial wall of the foramen rotundum, which carries the second division of trigeminal nerve (CN-V2) and which serves as a channel of communication between the sphenoid sinus, the cavernous sinus, and the pterygopalatine fossa. We propose that A. fumigatus spread, via the foramen rotundum, from the right sphenoid sinus into the pterygopalatine fossa and the orbital apex anteriorly (figure 2A and 2B). Isolated involvement of the intracanalicular facial nerve within the temporal bone appears to have occurred along the nerve sheath of the vidian nerve via the vidian canal (figure 2D and 2E), with no bony involvement of the skull base [14].
Invasive fungal rhinosinusitis and, especially, infections of the sphenoid sinus are serious and are not uncommonly associated with life-threatening intracranial progression of the disease [15]. Perineural extension of intracranial aspergillosis appears to be another mechanism of propagation of infection in patients with invasive mycosis. Conventional therapy with amphotericin B alone may not be adequate for the control of severe fungal infections, because the overall response to treatment with amphotericin B is ∼35% among patients with acute invasive aspergillosis [16, 17] and because multimodal treatment may lead to improved outcomes for select cases. The role of adjuvant recombinant cytokine therapy with granulocyte-CSF [10], GM-CSF, macrophage–colony-stimulating factor (M-CSF) [9], IL-12 [18], IL-2, and IFN-γ [10], all of which enhance the compromised immune responses of the host [10, 19, 20], is currently evolving and warrants further clinical investigation for the control of refractory fungal infections in humans.
- Received January 31, 2002.
- Revision received March 20, 2002.
- Accepted August 1, 2002.
- © 2002 by the Infectious Diseases Society of America
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