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Show ORIGINAL CONTRIBUTION Successful Treatment of Invasive Cavernous Sinus Aspergillosis with Oral Itraconazole Monotherapy Andrew C. Browning, FRCOphth, Kuan T. Sim, MRCOphth, Judith M. Timms, MRCP, MRCPath, Stephen A. Vernon, FRCOphth, Norman S. McConachie, FRCR, Richard Allibone, MRCPath, and Nick S. Jones, MD, FRCS Abstract: An 83- year- old woman receiving long-term prednisolone treatment presented with a right optic neuropathy and right third fourth, fifth, and sixth cranial nerve palsies secondary to sino- orbital aspergillosis with cavernous sinus involvement. Because the patient refused conventional treatment, she was given a two- year course of oral itraconazole 200 mg/ day, leading to a complete imaging resolution of the lesion. Three years after completing treatment, there is no clinical or imaging evidence of disease recurrence. Visual and ocular motor function did not recover, but ptosis and proptosis improved. We believe this to be the first documented case of successful treatment of such a lesion with oral itraconazole monotherapy. (/ Neuro- Ophthalmol 2006; 26: 103- 106) Sino- orbital aspergillosis is a life- threatening condition seen predominantly in immunocompromised patients. The organism invades the wall of the affected sinus to enter the orbit and subsequently the intracranial space via the superior orbital fissure and optic canal ( 1). Treatment usually comprises a combination of surgical debridement, either locally or by orbital exenteration, followed by intravenous amphotericin B therapy ( 2- 4). Despite such aggressive treatment, mortality rates of 50%- 80% have been described ( 5- 7). We report an 83- year- old woman with sino- orbital aspergillosis and cavernous sinus involvement who refused conventional intervention but did consent to a prolonged course of oral itraconazole. This treatment led to a complete Department of Ophthalmology ( ACB, KTS, SAV) and Department of Otorhinolaryngology ( NSJ), Eye, Ear, Nose and Throat Centre, Department of Microbiology ( JMT), Department of Neuroradiology ( NSM), and Department of Histopathology ( RA), University Hospital, Queen's Medical Centre, Nottingham, United Kingdom. Address correspondence to Nick S. Jones, MD, FRCS, Department of Otorhinolaryngology, Eye, Ear, Nose and Throat Centre, University Hospital, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom; E- mail: nick. jones@ nottingham. ac. uk resolution of the lesion. The patient remains well three years after cessation of therapy. This is the first documented case of successful treatment of such a lesion with oral itraconazole monotherapy. CASE REPORT An 8 3- year- old woman presented with rapid visual loss in the right eye preceded by a two- month history of right- sided headache and periocular pain. She had a long history of polymyalgia rheumatica for which she had been treated with prednisolone 5 mg every other day. She reported no jaw claudication, neck pain, or recent weight loss. She had primary biliary cirrhosis and hypertension, for which she received ursodeoxycholic acid and felodipine. Visual acuity was hand movements in the right eye and 20/ 40 in the left eye. There was a marked right relative afferent pupil defect. Ophthalmoscopy was normal. The temporal arteries were pulsatile bilaterally, and there was no scalp tenderness. Hemoglobin level was 13.9 g/ dl ( 11- 16.5), white cell count was 9.6 x 109/ L ( 70% neutrophils), platelet count was 404 x 109 ( 140- 400), erythrocyte sedimentation rate was 42 mrn/ hr, and C- reactive protein level was 16 mg/ L ( 0- 10 mg/ L). A provisional clinical diagnosis of posterior ischae-mic optic neuropathy secondary to giant cell arteritis was made, and the patient was treated with predisolone 80 mg on a tapering schedule over several weeks. A temporal artery biopsy performed the day after presentation showed no evidence of giant cell arteritis. The predisolone dose was tapered to the premorbid level. Five weeks after initial presentation, the patient had rapid onset of painless drooping of the right upper lid. Examination revealed no light perception in the right eye and 20/ 40 in the left eye. There was complete right upper lid ptosis, right proptosis, a right afferent pupil defect, absent right corneal and first division trigeminal sensation, and absent right eye ductions. Ophthalmoscopy revealed right optic disc pallor. The examination of the left eye was normal. CT ( Fig. 1A) showed a small mass of heteroge-neously enhancing soft tissue centered on the right orbital J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 103 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Browning et al FIG. 1. Imaging five weeks after initial presentation ( before treatment). Post- contrast axial CT ( A) and T1 MRI ( B) show a heteroge-neously enhancing mass in the right orbital apex, optic canal, and anterior cavernous sinus. apex and proximal right optic canal. There was destruction of the wall of the adjacent sphenoid sinus and lobulated soft tissue within the right lateral sphenoid loculus. The right cavernous sinus was prominent, but there was no evidence of spread beyond it. MRI ( Fig. IB) confirmed involvement of the right anterior cavernous sinus. Given a differential diagnosis of primary or metastatic malignancy or meningioma, the patient underwent a full investigation including chest radiography, mammography, thyroid and abdominal ultrasound examination, and bone marrow biopsy, all of which were negative. CT performed six weeks later showed that the mass had enlarged ( Fig. 2). It now involved the right loculus of the sphenoid sinus and had eroded the right lateral wall of the anterior sphenoid sinus, the medial greater wing of sphenoid, and the right side of the planum sphenoidale. It extended into the right infra- orbital fissure, the superior pterygopalatine fossa, and the right orbit. The orbital component of the mass was predominantly extraconal, displacing the muscle cone and the right optic nerve inferiorly The patient underwent endoscopic biopsy via the sphenoid sinus. The gray- green material appeared necrotic. Extended laboratory culture failed to grow either bacteria or fungi, but histopathologic examination revealed dichoto-mous branching septate hyphae consistent with Aspergillus species ( Fig. 3). Polymerase chain reaction analysis confirmed the presence of Aspergillus. The patient declined standard therapy consisting of extensive surgical debridement and intravenous amphotericin B, but agreed to a prolonged course of oral itraconazole 200 mg/ day After four months of treatment ( Fig. 4A), the lesion had shrunk; after 12 months of treatment, there had been a further dramatic reduction in its size ( Fig. 4B). The patient continued to take oral itraconazole for 36 months. At the conclusion of treatment, MRI revealed only FIG. 2. Imaging 11 weeks after initial presentation ( before treatment). Post- contrast axial CT shows marked enlargement of the lesion relative to Fig. 1. FIG. 3. Sphenoid sinus biopsy. Periodic acid- Schiff stain shows dichotomous branching septate hyphae consistent with Aspergillus species. 104 © 2006 Lippincott Williams & Wilkins Aspergillosis J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 FIG. 4. Post- treatment imaging. CTs performed four months ( A) and 12 months ( B) after starting treatment show progressive reduction in lesion size. C. T1 MRI performed 24 months after starting treatment shows only mild residual thickening and enhancement of the right cavernous sinus, together with mucosal thickening and enhancement in the right loculus of the sphenoid sinus. mild thickening of the right cavernous sinus and slightly prominent enhancement in relation to the right orbital apex, superior orbital fissure, and dura over the right sphenoid wing ( Fig. 4C). No mass was present. There was also persistent mucosal thickening and enhancement in the right loculus of the sphenoid sinus, considered chronic reactive changes. To date, 36 months after cessation of treatment, there is no clinical evidence of disease recurrence. Throughout the 24 months of itraconazole treatment, the patient tolerated the drug without significant side effects. Ptosis and proptosis improved, but the total ophthalmoplegia and visual acuity remained unchanged. The left eye has remained unaffected. Her liver function tests were checked on a monthly basis. DISCUSSION Our patient with sino- orbital aspergillosis is unusual in that the illness responded to oral itraconazole monotherapy. Itraconazole is a highly lipophilic fungicidal drug structurally related to ketoconazole with potent antifungal activity against Aspergillus species. In comparison to ketoconazole, itraconazole is less toxic to the host and has a broader spectrum of antifungal activity against dermatophytes, opportunistic yeasts, and dimorphic fungi ( 8). It has become established as a treatment option in invasive pulmonary aspergillosis, either alone or in combination with other agents such as amphotericin B ( 9,10). In our case, a two- year course of oral itraconazole was used largely on the basis of experience from a series of similar unpublished cases ( personal communication, Dr. Meganadh, Vasavi Hospital, Hyderabad, India). Before this case, reports on the use of itraconazole in sino- orbital invasive aspergillosis have been confined to a small number of cases where attempts to control the disease by surgical debridement and/ or intravenous amphotericin B have failed ( 11- 14). In these cases, itraconazole was continued for up to nine months after failure of standard therapy, and when information about the patients' clinical course is reported, it has indicated a disease- free state for up to 16 months after cessation of treatment. Our case demonstrates that oral itraconazole may be useful in the primary treatment of sino- orbital aspergillosis in patients who refuse other more invasive or toxic treatments or who are either medically unfit for surgical debridement or intravenous amphotericin B. Acknowledgment The authors would like to thank the Mycology Reference Laboratory, Health Protection Agency, Bristol, United Kingdom, for the Aspergillus polymerase chain reaction analysis. REFERENCES 1. Levin LA, Avery R, Shore JW, et al. The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol 1996; 41: 142- 54. 2. Hedges TR, Leung LE. Parasellar and orbital apex syndrome caused by aspergillosis. Neurology 1976; 26: 117- 20. 3. Jahrsdoerfer RA, Ejercito VS, Johns MM. Aspergillosis of the nose and paranasal sinuses. Am J Otolaryngol 1979; 1: 6- 14. 4. Waitzman AA, Birt BD. Fungal sinusitis. J Otolaryngol 1994; 23: 244- 9. 5. Green WR, Font RL, Zimmerman LE. 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