- Email: [email protected]
When to Think of Zebras
DIAGNOSTIC DILEMMA Charles M. Wiener, MD, Section Editor
When to Think of Zebras Roger S. Ho, MS, Rahul M. Kohli, MD, PhD, Lisa L. Maragakis, MD, MPH Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
PRESENTATION During medical training, physicians are often told, “When you hear hoofbeats, think of horses.”1 Recently, however, we treated a 44-year-old man whose chronic otitis eventually evoked thoughts of zebras. The patient presented with worsening otalgia and newonset fever. For the 6 years preceding, he had been treated with intermittent courses of topical steroids and oral antimicrobials for chronic suppurative otitis media. He additionally suffered from diabetes mellitus with associated retinopathy, and his medical care had been compromised by lack of insurance coverage. One month prior to admission, sudden worsening of his right-sided otalgia led to an evaluation that revealed significant tympanic membrane perforation with mucoid discharge. A bone scan suggested osteomyelitis of the middle ear, and surgical debridement and tympanic membrane reconstruction was planned. Prior to the scheduled surgery, however, the patient developed emesis and gait instability that prompted hospital admission.
ASSESSMENT The patient was febrile at presentation. He reported right ear pain and a prominent headache without photophobia. No cranial nerve deficits were noted other than a right-lateralized Weber test indicating conductive hearing loss on that side. Otoscopy revealed 30% inferior perforation of the right tympanic membrane with mucopurulent drainage, which was obtained for culture. The patient had leukocytosis with 18 ⫻ 103 white blood cells/mm3. Piperacillin/tazobactam therapy was initiated to treat possible infection with Pseudomonas aeruginosa, which seemed the most likely pathogen. Funding: Johns Hopkins University School of Medicine. Conflict of Interest: All authors report no conflicts of interest. Authorship: All authors had access to the data and participated in writing the manuscript. Address requests for reprints to Lisa L. Maragakis, MD, MPH, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 425, Baltimore, MD 21287. E-mail address: [email protected]
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.01.008
Magnetic resonance imaging (MRI) revealed a 1-cm rim-enhancing fluid collection at the right petrous apex with associated dural enhancement. Suspecting malignant otitis externa, the otolaryngology team performed a radical mastoidectomy with temporalis flap reconstruction. Despite extensive surgical debridement, the fluid could not be accessed. The patient’s antimicrobial therapy was changed to vancomycin, cefepime, metronidazole, and liposomal amphotericin B to enhance central nervous system penetration and broaden treatment for potential pathogens involved in brain abscess. However, an MRI scan taken 2 days later revealed extension of the fluid collection and new abscesses in the temporal lobe and along the inferior margin of the petrous bone (Figure 1). This progression of disease despite ongoing therapy with broad-spectrum antimicrobial agents prompted an emergent procedure to drain and determine the etiology of the intracerebral fluid collections.
DIAGNOSIS The patient was diagnosed with malignant otitis externa with deep invasion and brain abscesses as an acute complication of chronic suppurative otitis media. A relatively common condition, chronic suppurative otitis media is an infection of the middle ear and mastoid air cells and is characterized by tympanic membrane perforation and persistent otorrhea. It occurs in both immunocompetent and immunocompromised individuals. Malignant otitis externa, however, usually occurs in immunocompromised patients or in those with diabetes mellitus. Malignant otitis externa results from aggressive extension of infection in the external auditory canal to the adjacent soft tissues and bone.2,3 Both chronic suppurative otitis media and malignant otitis externa can progress to the formation of brain abscesses, as seen in our patient. The most common causative organism for both chronic suppurative otitis media and malignant otitis externa is P. aeruginosa; 99.2% of 262 cases of malignant otitis externa reviewed in one report4 were caused by this organism. Filamentous fungi account for most of the remaining cases of malignant otitis externa, mostly in immunosuppressed patients. Malignant otitis externa secondary to zygomycosis
Ho et al
Thinking of Zebras
425
Figure 1 (Left) Axial post-gadolinium contrast T1-weighted MRI image showing a 1.2 cm ⫻ 1.0 cm ring-enhancing fluid collection (black arrow) in the medial aspect of the right temporal lobe. Abscesses were also seen in other views (not shown). (Right) Axial FLAIR image showing hyperintensity within the medial right temporal lobe. The edema surrounding the rim-enhancing lesion suggested a localized infection, given the patient’s history. A, anterior; P, posterior.
is rare, but the majority of reported cases with head and neck involvement have diabetes as the major predisposing factor, prompting us to use liposomal amphotericin B in treating our diabetic patient.5 Cultures of both the pre-surgical auricular drainage and intra-operative debridement specimens grew filamentous fungus with septated hyphae and narrow-angle branching, indicating that the infection was caused by Aspergillus fumigatus rather than by P. aeruginosa as originally suspected (Figure 2). This finding was unexpected; in a 2003 study evaluating the etiology of malignant otitis externa from 1966 to 2001, only 13 cases were caused by Aspergillus spp.; 6 of these were caused by A. fumigatus, and no cases were associated with diabetes mellitus.6 In fact, most cases of malignant otitis externa due to filamentous fungi have affected non-diabetic, immunocompromised patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome or blood dyscrasias, neither of which were found in our patient.7 Aspergillus brain abscess from direct extension of malignant otitis externa also is unusual. Fungal brain abscess is most commonly described in immunocompromised hosts undergoing chemotherapy or with advanced HIV, and Aspergillus brain abscess is usually secondary to disseminated infection with hematogenous seeding.8 However, in our patient, the brain abscesses were a result of direct extension of the A. fumigatus infection.8
MANAGEMENT Because central nervous system Aspergillus infections are associated with a mortality of greater than 90%, we treated
our patient with aggressive surgical and medical interventions.9 While awaiting culture data, a right temporal craniotomy with stereotactic evacuation of extradural and intraparenchymal brain abscesses was performed. Well-encapsulated, purulent abscesses were removed along with necrotic tissue. An MRI scan performed 1 week later showed no evidence of residual abscess or enhancement. When the culture data definitively demonstrated Aspergillus as the causative pathogen, the patient’s regimen was changed to liposomal amphotericin B with voriconazole. In an animal model study, intra-parenchymal concentrations of amphotericin B in the brain were higher with liposomal amphotericin B than with conventional amphotericin deoxycholate, despite the fact that the concentration in the cerebral spinal fluid was relatively low.10 The antifungal agent voriconazole has excellent central nervous system penetration, reaching high concentrations in both cerebral spinal fluid and brain tissue.11 In a recent study, voriconazole was superior to amphotericin deoxycholate in efficacy and survival for treatment of invasive aspergillosis among 277 immunocompromised patients, 10 of whom had central nervous system involvement.12 One month after the initiation of liposomal amphotericin B/voriconazole therapy, a repeat MRI scan demonstrated a new intraparenchymal abscess. The patient immediately underwent another surgical exploration with debridement of the collection and necrotic tissue. Shortly thereafter, the liposomal amphotericin B was stopped due to acute renal failure necessitating hemodialysis, and the voriconazole was stopped due to intractable emesis. Given his intolerance to conventional agents, an alternative antifungal regimen
426
The American Journal of Medicine, Vol 122, No 5, May 2009 posaconazole for central nervous system fungal infections had a clinical response.13 The posaconazole was continued for 1 year, at which point an MRI scan showed no evidence of relapse. Eighteen months after his initial diagnosis, the patient is without complications. In this case, an atypical pathogen was found to cause an uncommon infection in an unexpected host, but aggressive surgical and medical management overcame the normally lethal condition. This case illustrates that when a chronic condition is punctuated by new, rapidly accelerating symptoms, immediate and thorough investigation and management are warranted.
References
Figure 2 (Upper panel) Hematoxylin and eosin staining of a neurosurgical specimen showing inflammatory exudates with fibrin deposition. Acute and chronic inflammatory cells are visible, but not fungal organisms. (Lower panel) Grocott’s Methenamine Silver staining of the neurosurgical specimen revealed the causative agent: narrow-angle branching, septated filamentous fungi consistent with A. fumigatus.
was sought. The patient was started on posaconazole therapy, which has been used previously as a well-tolerated and effective salvage therapy for patients who are intolerant of or refractory to conventional antifungal therapy for invasive aspergillosis; in 1 study, 2 of 4 patients treated with
1. Smith CS, Paauw DS. When you hear hoof beats: four principles for separating zebras from horses. J Am Board Fam Pract. 2000;13:424429. 2. Meltzer P, Lelemen G. Pyocutaneous osteomyelitis of the temporal bone, mandible, and zygoma. Laryngoscope. 1959;169:1300-1316. 3. Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am. 2008;41:537-549, viii-ix. 4. Rubin J, Yu VL. Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy. Am J Med. 1988;85: 391-398. 5. Macdonell RA, Donnan GA, Kalnins RM, Richards MJ, Bladin PF. Otocerebral mucormycosis—a case report. Clin Exp Neurol. 1987;23: 225-232. 6. Bellini C, Antonini P, Ermanni S, et al. Malignant otitis externa due to Aspergillus niger. Scand J Infect Dis. 2003;35:284-288. 7. Slattery WH, 3rd, Brackmann DE. Skull base osteomyelitis: malignant external otitis. Otolaryngol Clin North Am. 1996;29:795-806. 8. Young RC, Bennett JE, Vogel CL, et al. Aspergillosis: the spectrum of the disease in 98 patients. Medicine (Baltimore). 1970;49:147-173. 9. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147-1201. 10. Groll AH, Giri N, Petraitis V, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182:274-282. 11. Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis. 2003;37:728-732. 12. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415. 13. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2-12.
When to Think of Zebras Roger S. Ho, MS, Rahul M. Kohli, MD, PhD, Lisa L. Maragakis, MD, MPH Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
PRESENTATION During medical training, physicians are often told, “When you hear hoofbeats, think of horses.”1 Recently, however, we treated a 44-year-old man whose chronic otitis eventually evoked thoughts of zebras. The patient presented with worsening otalgia and newonset fever. For the 6 years preceding, he had been treated with intermittent courses of topical steroids and oral antimicrobials for chronic suppurative otitis media. He additionally suffered from diabetes mellitus with associated retinopathy, and his medical care had been compromised by lack of insurance coverage. One month prior to admission, sudden worsening of his right-sided otalgia led to an evaluation that revealed significant tympanic membrane perforation with mucoid discharge. A bone scan suggested osteomyelitis of the middle ear, and surgical debridement and tympanic membrane reconstruction was planned. Prior to the scheduled surgery, however, the patient developed emesis and gait instability that prompted hospital admission.
ASSESSMENT The patient was febrile at presentation. He reported right ear pain and a prominent headache without photophobia. No cranial nerve deficits were noted other than a right-lateralized Weber test indicating conductive hearing loss on that side. Otoscopy revealed 30% inferior perforation of the right tympanic membrane with mucopurulent drainage, which was obtained for culture. The patient had leukocytosis with 18 ⫻ 103 white blood cells/mm3. Piperacillin/tazobactam therapy was initiated to treat possible infection with Pseudomonas aeruginosa, which seemed the most likely pathogen. Funding: Johns Hopkins University School of Medicine. Conflict of Interest: All authors report no conflicts of interest. Authorship: All authors had access to the data and participated in writing the manuscript. Address requests for reprints to Lisa L. Maragakis, MD, MPH, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 425, Baltimore, MD 21287. E-mail address: [email protected]
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.01.008
Magnetic resonance imaging (MRI) revealed a 1-cm rim-enhancing fluid collection at the right petrous apex with associated dural enhancement. Suspecting malignant otitis externa, the otolaryngology team performed a radical mastoidectomy with temporalis flap reconstruction. Despite extensive surgical debridement, the fluid could not be accessed. The patient’s antimicrobial therapy was changed to vancomycin, cefepime, metronidazole, and liposomal amphotericin B to enhance central nervous system penetration and broaden treatment for potential pathogens involved in brain abscess. However, an MRI scan taken 2 days later revealed extension of the fluid collection and new abscesses in the temporal lobe and along the inferior margin of the petrous bone (Figure 1). This progression of disease despite ongoing therapy with broad-spectrum antimicrobial agents prompted an emergent procedure to drain and determine the etiology of the intracerebral fluid collections.
DIAGNOSIS The patient was diagnosed with malignant otitis externa with deep invasion and brain abscesses as an acute complication of chronic suppurative otitis media. A relatively common condition, chronic suppurative otitis media is an infection of the middle ear and mastoid air cells and is characterized by tympanic membrane perforation and persistent otorrhea. It occurs in both immunocompetent and immunocompromised individuals. Malignant otitis externa, however, usually occurs in immunocompromised patients or in those with diabetes mellitus. Malignant otitis externa results from aggressive extension of infection in the external auditory canal to the adjacent soft tissues and bone.2,3 Both chronic suppurative otitis media and malignant otitis externa can progress to the formation of brain abscesses, as seen in our patient. The most common causative organism for both chronic suppurative otitis media and malignant otitis externa is P. aeruginosa; 99.2% of 262 cases of malignant otitis externa reviewed in one report4 were caused by this organism. Filamentous fungi account for most of the remaining cases of malignant otitis externa, mostly in immunosuppressed patients. Malignant otitis externa secondary to zygomycosis
Ho et al
Thinking of Zebras
425
Figure 1 (Left) Axial post-gadolinium contrast T1-weighted MRI image showing a 1.2 cm ⫻ 1.0 cm ring-enhancing fluid collection (black arrow) in the medial aspect of the right temporal lobe. Abscesses were also seen in other views (not shown). (Right) Axial FLAIR image showing hyperintensity within the medial right temporal lobe. The edema surrounding the rim-enhancing lesion suggested a localized infection, given the patient’s history. A, anterior; P, posterior.
is rare, but the majority of reported cases with head and neck involvement have diabetes as the major predisposing factor, prompting us to use liposomal amphotericin B in treating our diabetic patient.5 Cultures of both the pre-surgical auricular drainage and intra-operative debridement specimens grew filamentous fungus with septated hyphae and narrow-angle branching, indicating that the infection was caused by Aspergillus fumigatus rather than by P. aeruginosa as originally suspected (Figure 2). This finding was unexpected; in a 2003 study evaluating the etiology of malignant otitis externa from 1966 to 2001, only 13 cases were caused by Aspergillus spp.; 6 of these were caused by A. fumigatus, and no cases were associated with diabetes mellitus.6 In fact, most cases of malignant otitis externa due to filamentous fungi have affected non-diabetic, immunocompromised patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome or blood dyscrasias, neither of which were found in our patient.7 Aspergillus brain abscess from direct extension of malignant otitis externa also is unusual. Fungal brain abscess is most commonly described in immunocompromised hosts undergoing chemotherapy or with advanced HIV, and Aspergillus brain abscess is usually secondary to disseminated infection with hematogenous seeding.8 However, in our patient, the brain abscesses were a result of direct extension of the A. fumigatus infection.8
MANAGEMENT Because central nervous system Aspergillus infections are associated with a mortality of greater than 90%, we treated
our patient with aggressive surgical and medical interventions.9 While awaiting culture data, a right temporal craniotomy with stereotactic evacuation of extradural and intraparenchymal brain abscesses was performed. Well-encapsulated, purulent abscesses were removed along with necrotic tissue. An MRI scan performed 1 week later showed no evidence of residual abscess or enhancement. When the culture data definitively demonstrated Aspergillus as the causative pathogen, the patient’s regimen was changed to liposomal amphotericin B with voriconazole. In an animal model study, intra-parenchymal concentrations of amphotericin B in the brain were higher with liposomal amphotericin B than with conventional amphotericin deoxycholate, despite the fact that the concentration in the cerebral spinal fluid was relatively low.10 The antifungal agent voriconazole has excellent central nervous system penetration, reaching high concentrations in both cerebral spinal fluid and brain tissue.11 In a recent study, voriconazole was superior to amphotericin deoxycholate in efficacy and survival for treatment of invasive aspergillosis among 277 immunocompromised patients, 10 of whom had central nervous system involvement.12 One month after the initiation of liposomal amphotericin B/voriconazole therapy, a repeat MRI scan demonstrated a new intraparenchymal abscess. The patient immediately underwent another surgical exploration with debridement of the collection and necrotic tissue. Shortly thereafter, the liposomal amphotericin B was stopped due to acute renal failure necessitating hemodialysis, and the voriconazole was stopped due to intractable emesis. Given his intolerance to conventional agents, an alternative antifungal regimen
426
The American Journal of Medicine, Vol 122, No 5, May 2009 posaconazole for central nervous system fungal infections had a clinical response.13 The posaconazole was continued for 1 year, at which point an MRI scan showed no evidence of relapse. Eighteen months after his initial diagnosis, the patient is without complications. In this case, an atypical pathogen was found to cause an uncommon infection in an unexpected host, but aggressive surgical and medical management overcame the normally lethal condition. This case illustrates that when a chronic condition is punctuated by new, rapidly accelerating symptoms, immediate and thorough investigation and management are warranted.
References
Figure 2 (Upper panel) Hematoxylin and eosin staining of a neurosurgical specimen showing inflammatory exudates with fibrin deposition. Acute and chronic inflammatory cells are visible, but not fungal organisms. (Lower panel) Grocott’s Methenamine Silver staining of the neurosurgical specimen revealed the causative agent: narrow-angle branching, septated filamentous fungi consistent with A. fumigatus.
was sought. The patient was started on posaconazole therapy, which has been used previously as a well-tolerated and effective salvage therapy for patients who are intolerant of or refractory to conventional antifungal therapy for invasive aspergillosis; in 1 study, 2 of 4 patients treated with
1. Smith CS, Paauw DS. When you hear hoof beats: four principles for separating zebras from horses. J Am Board Fam Pract. 2000;13:424429. 2. Meltzer P, Lelemen G. Pyocutaneous osteomyelitis of the temporal bone, mandible, and zygoma. Laryngoscope. 1959;169:1300-1316. 3. Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am. 2008;41:537-549, viii-ix. 4. Rubin J, Yu VL. Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy. Am J Med. 1988;85: 391-398. 5. Macdonell RA, Donnan GA, Kalnins RM, Richards MJ, Bladin PF. Otocerebral mucormycosis—a case report. Clin Exp Neurol. 1987;23: 225-232. 6. Bellini C, Antonini P, Ermanni S, et al. Malignant otitis externa due to Aspergillus niger. Scand J Infect Dis. 2003;35:284-288. 7. Slattery WH, 3rd, Brackmann DE. Skull base osteomyelitis: malignant external otitis. Otolaryngol Clin North Am. 1996;29:795-806. 8. Young RC, Bennett JE, Vogel CL, et al. Aspergillosis: the spectrum of the disease in 98 patients. Medicine (Baltimore). 1970;49:147-173. 9. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147-1201. 10. Groll AH, Giri N, Petraitis V, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182:274-282. 11. Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis. 2003;37:728-732. 12. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415. 13. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2-12.