Original Paper Audiology Neurotology
Received: August 19, 2013 Accepted after revision: February 5, 2014 Published online: September 18, 2014
Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
Gradenigo Syndrome Caused by Nontuberculous Mycobacteria Pey-Yu Chen a Chen-Chi Wu a Tsung-Lin Yang a Chuan-Jen Hsu a Yi-Tsen Lin a, b Kai-Nan Lin a, c
a Department of Otolaryngology, National Taiwan University Hospital, Taipei, b Department of Otolaryngology, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, and c Department of Otolaryngology, Cardinal Tien Hospital, New Taipei, Taiwan, ROC
Abstract Gradenigo syndrome is a rare but devastating complication of otitis media that involves the petrous apex. Clinically, it is characterized by the triad of suppurative otitis media, deep facial pain, and abducens palsy. Most of the Gradenigo syndrome cases that have been reported in the literature were caused by pyogenic bacteria. In this report, we describe the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012. Mycobacterium abscessus was confirmed in all 4 cases by culturing the pathological tissues obtained during surgical debridement. To the best of our knowledge, this is the first report documenting infections of nontuberculous mycobacteria (NTM) in Gradenigo syndrome. An NTM infection must be considered in chronic otomastoiditis complicated by Gradenigo syndrome. The defi-
© 2014 S. Karger AG, Basel 1420–3030/14/0194–0275$39.50/0 E-Mail [email protected] www.karger.com/aud
nite treatment of Gradenigo syndrome with an NTM infection requires adequate surgical debridement combined with antibiotic treatment for at least 4–6 months. © 2014 S. Karger AG, Basel
Introduction
Gradenigo syndrome is a rare complication of otitis media. Giuseppe Gradenigo [1907] was the first to describe a triad of symptoms related to petrous apicitis. This triad includes suppurative otitis media, deep facial pain over the trigeminal territory, and abducens palsy. The incidence of petrous apicitis has decreased markedly since the 1940s due to the advent of antibiotics. The widespread use of antibiotics has also altered the clinical picture by masking the symptoms [Gradenigo, 1907; Lee et al., 2005; Price and Fayad, 2002; Sethi et al., 2005; Sherman and Buchanan, 2004; van Aarem et al., 1998]. The majority of Gradenigo cases were caused by pyogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa [Sherman and Buchanan, 2004]. The uncommon pathoYi-Tsen Lin or Kai-Nan Lin Department of Otolaryngology, National Taiwan University Hospital 7 Chung-Shan S. Rd. Taipei 10002, Taiwan (ROC) E-Mail yitsen.lin @ gmail.com or klinpie @ ntu.edu.tw
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Key Words Gradenigo syndrome · Petrositis · Nontuberculous mycobacterium · Abducens palsy · Anti-nontuberculosis treatment · Mycobacterium abscessus
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ing the first clinical visit showed two perforations in the eardrum. b Otorrhea progressed despite the initial treatment with otics and oral antibiotics. c Axial postcontrast T1-weighted MR imaging showed a normal nonenhanced Meckel’s cave (arrow) on the right side as well as an ill-defined lesion with enhancement involving the petrous apex, Meckel’s cave (thin arrow), and mastoid air cells on the left side. d Coronal postcontrast T1-weighted MR imaging showed the enhancement of the petrous apex (thin arrow), which is confluent with the enhanced meninges (arrowhead).
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gens included Mycobacterium tuberculosis [Sethi et al., 2005]. Nontuberculous mycobacteria (NTM) are ubiquitous in the soil, water, plants, and animal excreta [TerKonda et al., 1995; van Aarem et al., 1998]. Notably, NTM infections have garnered increased public attention since the 1980s, accompanying the increasing prevalence of acquired immunodeficiency syndrome [van Aarem et al., 1998]. Improvements in culturing techniques also increased the rate of diagnosing NTM infections [Flint et al., 1999]. Cervicofacial lymphadenitis is the most common clinical presentation of an NTM infection [Moerman et al., 1993; Sugimoto et al., 2010; van Aarem A et al., 1998]. Conversely, an NTM infection of the ear is relatively uncommon: NTM-related mastoiditis has been sporadically reported in immunocompetent children [Flint et al., 1999; Stewart et al., 1995; Sugimoto et al., 2010; TerKonda et al., 1995; van Aarem et al., 1998] and is even less common in adults [Franklin et al., 1994; Sugimoto et al., 2010; Wu et al., 2011]. Gradenigo syndrome caused by an NTM infection has never been documented in the literature. Between 2008 and 2012, 4 consecutive cases of Gradenigo syndrome in adults were encountered in a tertiary referral 276
Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
hospital. To our surprise, Mycobacterium abscessus, a species of NTM, was confirmed as the pathogen in all of the cases, indicating that an NTM infection might be an emerging cause of Gradenigo syndrome in the postantibiotics era.
Case Presentations Case 1 Case 1 is a 64-year-old woman who had a history of pulmonary tuberculosis and had been treated 40 years ago, but was otherwise healthy. She presented at our clinic with progressive left-sided otorrhea, otalgia, and hearing impairment of a 2-month duration. She had gradually developed pain over her left parietal and temporal areas. An otoscopic examination showed two perforations of the left eardrum (fig. 1a). Physical examination at our clinic revealed a left-sided cervical lymphadenopathy at level II. High-resolution computed tomography (HRCT) scan of the temporal bone revealed soft-tissue density that filled the left tympanic cavity and the mastoid cavity. Cortical destruction of the petrous ridge was not observed. The symptoms and signs persisted despite treatment with otics and oral antibiotics (fig. 1b). Sudden-onset diplopia, severe headache, and a mild tingling sensation in the left eye occurred 1 month later. M. tuberculosis infection was suspected due to the multiple eardrum perfora-
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Fig. 1. Local findings and imaging findings in case 1. a The otoscopic examination dur-
axial view of the temporal bone taken using HRCT demonstrated the destruction of the cortex of the right petrous apex (arrow) and the opacification of the mastoid air cells (arrowhead). b The coronal view showed the destruction and opacification of the petrous apex air cells (arrow). c Postcontrast T1-weighted MR imaging showed ill-defined soft tissue involving the right petrous apex and Meckel’s cave on the right side (thick arrow) and the abducens nerve in Dorello’s canal, with enhancement of the surrounding meninges (thin arrow). d Postcontrast T1-weighted MR imaging showed the enhancement of the petrous apex surrounding the internal carotid artery (arrowhead).
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tions, cervical lymphadenopathy, history of pulmonary tuberculosis, and the infection being refractory to empiric antibiotic treatment. However, repeated cultures of discharge from her left ear were negative for acid-fast staining. Magnetic resonance (MR) images gave the impression of Gradenigo syndrome, showing ill-defined lesions with a hyperintense signal in the mastoid air cells, cavernous sinus, Meckel’s cave, and the surrounding dura mater (fig. 1c, d). Because the symptoms progressed despite parenteral antibiotic treatment with piperacillin/tazobactam (4,000 g/500 g) for 4 days, the patient underwent a left modified radical mastoidectomy. The granular tissue in the middle ear, the mastoid cavity and its extension to the petrous bone were removed. The cultures of the mastoid cavity content and the left-ear discharge were both found to contain M. abscessus. Based on the culture results, the antibiotics were then replaced with levofloxacin (500 mg, q.d.), doxycycline (100 mg, q.d.), and clarithromycin (500 mg, b.i.d.). Her headache and diplopia subsided gradually. The diplopia completely resolved within 2.5 months after surgery. Two months later, we changed the treatment to a combination of levofloxacin (500 mg, q.d.) and clarithromycin (500 mg, b.i.d.). The otorrhea gradually subsided. She received a revised tympanomastoidectomy to repair the persistent eardrum perforation 1 year after the first surgery. The wound healed smoothly afterward. The patient stopped taking medication 1 month after this surgery and completed a 13-month course of antibiotic treatment.
Case 2 The second case is a 33-year-old woman who had been well except for a history of right-sided chronic otitis media that had been treated with a tympanoplasty 1 year earlier. She presented to our clinic with right otalgia, otorrhea, and mild hearing impairment lasting for 3 months, followed by right-occipital headache and facial palsy. Otoscopic examination showed right-sided ear drainage with a 15% perforation of the right eardrum. The facial palsy improved transiently after oral prednisolone treatment. However, acute-onset diplopia upon rightward gaze developed 2 weeks later and the facial palsy was aggravated. Otoscopic examination showed that the eardrum perforation had enlarged to encompass 40% of the eardrum area. HRCT images of the temporal bone showed cortical bone destruction and coalescence of the air cells of the right petrous apex as well as opacification of the right tympanic cavity and the mastoid air cells (fig. 2a, b). MR images of the brain, which were taken to evaluate the intracranial lesions, revealed prominent fluid collection in the right mastoid air cells with abnormal bright enhancement over the right petrous apex, Meckel’s cave, the meninges of Dorello’s canal, and the clivus (fig. 2c, d). Culturing the ear discharge yielded no bacterial growth. The patient was then admitted and received parenteral antibiotic treatment with ceftriaxone (2,000 mg, every 12 h) and vancomycin ceftazidime (2,000 mg, every 8 h) under the impression of Gradenigo syndrome and central nervous system infection. The cranial nerve VI and VII palsy only minimally improved. Therefore, the patient underwent a right canal wall down mastoidectomy
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Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
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Fig. 2. Imaging findings in case 2. a The
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Fig. 3. Abducens palsy and imaging findings in case 3. a Right abducens palsy was present. b The coronal post-contrast T1-
weighted MR image showed ill-defined soft tissue at the petrous apex of the right temporal bone (white arrow) and an intracranial extension with a focal nodule in the base of the right temporal bone (arrow head). The right abducens nerve was involved at the dural entry site (black arrow).
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Fig. 4. Imaging findings in case 4. a The
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9 days later. As much of the granular tissue that had filled the mastoid cavity and the middle ear cavity as possible was removed. The culture of the granular tissue was positive for M. abscessus. Her facial palsy resolved at 20 days after surgery, and her diplopia resolved 3 weeks later. The patient initially refused antibiotic treatment for the NTM infection after the operation. However, since her headache and otorrhea persisted for 3 months after surgery, she finally agreed to the definite treatment for NTM. Her headache and otorrhea gradually subsided after treatment with levofloxacin (750 mg, q.d.), doxycycline (100 mg, b.i.d.), and clarithromycin (500 mg, b.i.d.) for 12 months. Case 3 A 58-year-old man with a history of well-controlled hypertension presented at our clinic with right otorrhea and hemicrania of 3-month duration and diplopia of 1-month duration. The diplopia was most prominent when he looked to the right (fig. 3a). An otoscopic exam revealed granulation behind the perforated eardrum and a purulent discharge. The bacterial culture of the ear discharge yielded no pathogenic growth. HRCT images of the temporal bone showed soft tissue densities in the middle ear, the mastoid, and the petrous apex, with bony destruction. Postcontrast T1-weighted MR images revealed ill-defined soft tissue at the petrous apex of the right
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b
temporal bone and an intracranial extension with a focal nodule in the right temporal base (fig. 3b). Comparison to the normal left side indicated that the right abducens nerve was involved at the dural entry site (fig. 3b). The patient received ceftriaxone (750 mg, b.i.d.) for 3 days before receiving a right canal wall down mastoidectomy in which the petrous passage was explored through the supralabyrinthine and infralabyrinthine routes. Considerable granular and necrotic tissue was found in the mastoid cavity during the surgery. Culturing of the material from the subperiosteal abscess in the mastoid cavity confirmed the presence of M. abscessus. The patient received anti-NTM treatment with ethambutol (800 mg, q.d.) and levofloxacin (750 mg, q.d.) for 5 weeks, and was then switched to ethambutol (800 mg, q.d.), ciprofloxacin (750 mg, q.d.), and clarithromycin (500 mg, b.i.d.) for another 2 months. His headache subsided approximately 6 weeks later. Complete recovery of eye movement was achieved within 3 months after surgery. The patient then stopped taking antibiotics after a discussion with an infectious disease specialist. Case 4 A 45-year-old man with no significant medical history was referred to our clinic for right otorrhea that had lasted for 2 years. Although he had been treated with numerous courses of orally
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axial view of the temporal bone taken using HRCT demonstrated the destruction of the cortex of the right petrous apex (arrow). b The coronal T2-weighted magnetic-resonance image showed an abscess forming at the cerebellopontine angle (arrowhead).
Table 1. Summary of clinical courses in the 4 patients
Age/ Otorrhea gender
Headache
Abducens Other Previous ear palsy CN signs surgery
Culture of otorrhea
Recovery of CN deficits after operation
Case 1
64/F
3 months
parietal and + temporal
no
no
M. abscessus 2.5 months for diplopia and CoNS (few)
Case 2
33/F
3 months
occipital
+
facial palsy
tympanoplasty
no growth of bacteria
20 days for facial palsy; 41 days for diplopia
Case 3
58/M
3 months
hemicrania
+
ptosis
no
no growth of bacteria
2–3 months for ptosis; 3 months for diplopia
Case 4
45/M
2 years
frontal
+
no
tympanoplasty MRSA and atticoantrotomy
4 months for diplopia
administered antibiotics, he began to have right-sided headaches 1 year earlier. He had undergone a right tympanoplasty and an atticoantrotomy 3 months before presentation. However, his symptoms had not improved. Otoscopic examination of the right ear revealed a polypoid lesion hanging from the posterior canal wall and profuse discharge. The culture of the ear discharge yielded methicillin-resistant S. aureus. HRCT images of the temporal bone showed opacification of the right mastoid air cells and bony destruction of the mastoid cortex, the tegmen, and the petrous bone (fig. 4a). A right radical mastoidectomy was performed, revealing pale granular tissue and pus that filled the middle ear, the mastoid cavity, and the petrous bone. We also found a subperiosteal abscess with a fistula in the mastoid cortex. One month later, a pus culture confirmed the presence of an atypical mycobacterial infection. The patient was treated with orally administered clarithromycin (500 mg, b.i.d.). Nevertheless, the sudden onset of binocular diplopia (particularly upon a rightward gaze), accompanied by a right frontal headache, right otalgia, and fever, occurred 6 weeks later. The subsequent MR images revealed a right cerebellopontine angle abscess (fig. 4b). Revision surgery with a right petrous apicetomy using infralabyrinthine approach was performed. The culture proved positive for M. abscessus infection. The patient received oral clarithromycin (500 mg, b.i.d.) for 6 additional months. His headache and otalgia subsided 1 month later, and the diplopia was completely resolved at 4 months after surgery.
Discussion
This report describes the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012 (table 1). Bacterial cultures of the pathological tissues that were obtained during surgical debridement confirmed M. abscessus as the pathogen in all 4 of the cases. To the best of our knowledge, this is the first report in the Gradenigo Syndrome Caused by NTM
literature documenting an NTM infection in Gradenigo syndrome. The consistent presence of M. abscessus in these cases indicates the clinical significance of an NTM infection in the pathogenesis of Gradenigo syndrome in this postantibiotics era. Moore and Frerichs [1953] first identified M. abscessus in 1953. Until recently (1992), this bacterium was considered a subspecies of Mycobacterium chelonae [Medjahed et al., 2010; Nessar et al., 2012]. M. abscessus is an acid-fast Gram-positive rod belonging to the group of rapidly growing mycobacterium, and it is the most pathogenic and chemotherapy-resistant NTM [Nessar et al., 2012]. Notably, it can cause chronic lung disease, posttraumatic wound infections, and disseminated cutaneous diseases, mostly in patients with compromised immune systems. A localized infection generally occurs in immunocompetent hosts [Franklin et al., 1994]. Additionally, NTM can cross the blood-brain barrier [Medjahed et al., 2010]. Symptoms of NTM infections typically occur at 3–4 weeks after inoculation; however, the incubation period can vary from 1 week to 2 years [Franklin et al., 1994; van Aarem et al., 1998]. Host immunity also plays a role in the onset of symptoms [Muller et al., 2006]. The clinical course of an NTM infection is often indolent and afebrile, and with systemic symptoms [Franklin et al., 1994]. Notably, NTM are an uncommon cause of middle ear or mastoid infections. Several NTM species, including M. chelonae ssp. abscessus, M. chelonae ssp. chelonae, M. fortuitum, M. avium, M. avium-intracellulare, and M. kansasii, have been reported in otomastoiditis cases [Flint et al., 1999; Franklin et al., 1994; Lowry et al., 1988; Muller et al., 2006; Stewart et al., 1995; TerKonda et al., 1995; van Aarem et al., 1998; Wu et al., 2011]. Most otoAudiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
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CN = Cranial nerve; CoNS = coagulase-negative staphylococci; MRSA = methicillin-resistant S. aureus.
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infection, the mastoid and the middle ear are often filled with a rubbery granular tissue; however, caseating necrosis was rarely observed [Flint et al., 1999; Franklin et al., 1994; Wu et al., 2011]. Poor wound healing after surgery is not uncommon [Flint et al., 1999; Stewart et al., 1995; van Aarem et al., 1998]. In this series, all of the patients suffered refractory otorrhea, followed by acuteonset diplopia, headache, and otalgia, thus fulfilling the diagnostic criteria of Gradenigo syndrome. Other neurological signs, such as facial palsy (1/4) or ptosis (1/4), were also noted (table 1). An otoscopic examination revealed polypoid tissue in 2 cases. Profuse granular tissue involving the middle ear and the mastoid cavity was found during surgery in all 4 cases. Briefly, except for headache and abducens palsy, all 4 cases demonstrated otological manifestations similar to those of NTM otomastoiditis cases. Gradenigo syndrome can result from acute or chronic petrous apicitis. CT is useful for evaluating the bony cortex: a subperiosteal lucency implies abscess formation in the periosteum in an acute case; opacification or the coalescence of air cells and bony destruction suggests a chronic case, and erosion of the cortical bone of the petrous pyramid and the skull base implies petrositis [González-García et al., 2009; Marianowski et al., 2001; Sherman and Buchanan, 2004]. MR imaging is sensitive in detecting early marrow changes and intracranial complications, and is helpful in differentiating petrous apicitis from other petrous diseases, including cholesteatoma, mastoiditis, chondroma, clival chordoma, epidural abscess, cholesterol cyst, and metastasis [Connor et al., 2008; Moerman et al., 1993; Sherman and Buchanan, 2004]. The abnormalities that are observed in the MR images may persist [Gibier et al., 2009], and gallium-67 scintigraphy can be utilized to monitor the resolution of infections [Vijayananthan et al., 2008]. The HRCT images for cases 2 and 3 showed breaks in the petrous cortex and the coalesced air cells; whereas the postcontrast T1-weighted MR images for cases 1, 2, and 3 showed an ill-defined soft tissue density with a hyperintense signal around the petrous apex and Meckel’s cave. These findings indicated that the radiological findings for NTM-based Gradenigo syndrome were similar to those for Gradenigo syndrome caused by other pathogens. Because NTM are ubiquitous, distinguishing pathogenic colonization from a true infection is difficult. Pus swab culturing or acid-fast staining of the otorrhea has low sensitivity (≤20%) for the diagnosis of otological tubercular infections [Sethi et al., 2005]. Pus cultures of ear Chen/Wu/Yang/Hsu/Lin/Lin
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logical NTM infections result from inoculation due to trauma, surgery, or an injection [van Aarem et al., 1998]. Other possible sources of such an infection include exposure to contaminated water and transmission via the eustachian tube [Flint et al., 1999; Moerman et al., 1993; Sethi et al., 2005; TerKonda et al., 1995]. No evidence of human-to-human or animal-to-human transmission exists [Flint et al., 1999; Griffith et al., 2007; Medjahed et al., 2010; Muller et al., 2006; Redaelli de Zinis et al., 2003; Sugimoto et al., 2010; TerKonda et al., 1995]. An outbreak of 17 cases of otomastoiditis caused by M. chelonae was attributed to inadequate instrument sterilization [Lowry et al., 1988]. Flint et al. [1999], who reviewed 59 cases of chronic otitis media with NTM infections that occurred between 1976 and 1998, found that 72% (43/59) of the patients had a previous ventilation tube insertion, 13.5% (8/59) of the patients had a chronic eardrum perforation, and only 4 patients had no previous ear surgery. It is believed that a plastic ventilation tube may serve as a suitable microenvironment for biofilm formation. The application of a topical steroid may alter the local immunity, allowing M. abscessus to spread [Franklin et al., 1994]. Topical antibiotics may inhibit bacterial growth and further promote NTM infection. Furthermore, a chronically perforated eardrum may also serve as an entry route. In this series, 2 patients (cases 2 and 4) had undergone a tympanoplasty before the development of full-blown Gradenigo symptoms and their visits to our clinic. However, these 2 patients had suffered from chronic otorrhea before their tympanoplasty, and no new symptoms occurred immediately after the tympanoplasty. Therefore, it is difficult to attribute the NTM infections to a previous ear surgery in these 2 cases. NTM and tuberculous otomastoiditis have similar clinical presentations and imaging findings. The common features of the otoscopic findings include painless and odorless otorrhea, a thickened tympanic membrane, and granulation or a polypoid lesion in the external auditory meatus [Flint et al., 1999; Franklin et al., 1994; Muller et al., 2006; Stewart et al., 1995; van Aarem et al., 1998; Wu et al., 2011]. Patients with an NTM infection may have a normal plain chest film, lack general symptoms (e.g. fever, malaise, and weight loss), and have no previous exposure to pulmonary tuberculosis [Franklin et al., 1994; van Aarem et al., 1998]. Multiple eardrum perforations are often associated with a tubercular infection [Cavallin and Muren, 2000; TerKonda et al., 1995], but as in case 1, a NTM infection can also lead to multiple eardrum perforations. In cases of an NTM
a rapidly growing mycobacterium infection and amikacin is the most active parenteral agent [Griffith and Wallace, 1996; Lowry et al., 1988; Petrini, 2006; Sugimoto et al., 2010]. Other such agents include cefoxitin, imipenem, linezolid, and tigecycline [Griffith et al., 2007; Medjahed et al., 2010; Petrini, 2006]. Single-agent therapy should be avoided to prevent the development of drug resistance. Previous treatment with aminoglycosidecontaining otics may have selected resistant strains because the target 16S rRNA is prone to point mutations in M. abscessus [Franklin et al., 1994; Lowry et al., 1988; Nessar et al., 2012]. The treatment regimen should be based on the sensitivity results for individual isolates, the clinical response to treatment, and the patient’s tolerance of the side effects of the medication. The treatment duration depends on the site of infection and its severity [Griffith et al., 2007], and resolution of the symptoms alone is not a sufficient reason to withdraw the antibiotics [Gibier et al., 2009]. Some authors have suggested maintaining the antibiotics regimen until a disease-free period of 4–6 weeks is obtained [Flint et al., 1999; Moerman et al., 1993], whereas others have recommended a minimum of 2–3 months of treatment after the symptoms have disappeared [Muller et al., 2006; van Aarem et al., 1998]. Still others have suggested a period lasting as long as 12–18 months. Among the cases of NTM-related mastoiditis reported in the literature, the treatment durations were 0.5–18 months, with an average of 7 months [Flint et al., 1999; van Aarem et al., 1998]. NTM-based otomastoiditis or petrositis, i.e. with bony involvement, should be considered a severe infection. According to the 2007 ATA/IDSA guidelines, a minimum of 4 months of therapy is recommended for a serious infection, and 6 months of therapy is suggested for a bony infection [Griffith et al., 2007]. In this series, all of the patients underwent radical surgical debridement, and 3 of them completed a course of oral medication directed against NTM after surgery. All 4 patients recovered from their abducens palsy and their other neurological symptoms within 4 months after surgery, which is comparable to the outcome of Gradenigo syndrome that is caused by other pathogens. Among the 12 cases of Gradenigo syndrome in the literature, those with abducens palsy achieved complete recovery after the appropriate treatment, either with conservative therapy alone or in combination with surgical intervention [Burston et al., 2005; Chole and Donald, 1983; Gillanders, 1983; Hilding, 1987; Minotti and Kountakis, 1999; Price and Fayad, 2002; Sternberg et al., 1980; Woody et al., 1984].
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discharge may also have limited diagnostic utility for otological NTM infections. In this series, culturing ear discharge revealed skin flora in 2 of the cases: one with a few coagulase-negative staphylococci and the other with a few methicillin-resistant S. aureus. Only case 1 had M. abscessus in an ear-discharge culture before surgery. The most reliable method for diagnosis of a mycobacterial infection is a direct histological examination combined with a culture of the infected tissue [Sethi et al., 2005]. An M. abscessus infection was confirmed in the culture of the pathological tissue or the subperiosteal abscess material that was obtained during surgery in all 4 cases. In addition to bacterial culturing, DNA probes for specific mycobacterial species have been developed, and rapid identification of the type of NTM present is now possible using polymerase chain reactions [Muller et al., 2006; van Aarem et al., 1998]. The treatment of petrous apicitis has been primarily surgical intervention; however, several series studies have also reported good outcomes with conservative treatment alone [Burston et al., 2005; Gibier et al., 2009; Marianowski et al., 2001; Minotti and Kountakis, 1999; Kong et al., 2011]. For acute petrositis, conservative therapy with parenteral antibiotics and adequate mastoid drainage, such as a myringotomy or ventilation tube insertion, may be sufficient. When conservative therapy fails or the disease is chronic (e.g. cholesteatoma), surgical intervention is indicated to ensure adequate drainage and decompression. Conversely, chronic petrositis may result in permanent mucosal thickening and the development of a central cystic space trapping the mucopus, making it difficult to cure the disease with medical treatment alone [Minotti and Kountakis, 1999]. Surgical intervention has an important role in the effective treatment of petrositis resulting from NTM infection. As mentioned, culturing NTM from ear discharge is difficult. Surgery allows collecting pathological tissues for culturing and subsequent diagnosis. Moreover, surgical intervention may also relieve the occlusion of the mastoid drainage by removing granulomatous tissue and ameliorate cranial nerve complications through decompression. The ideal surgical treatment of an NTM infection is to excise as much of the affected tissue as possible [Flint et al., 1999; Muller et al., 2006]. After surgery, long-term medical treatment is often required. Patients with an infection of a rapidly growing mycobacterium, such as M. abscessus, should be treated in consultation with an infectious disease specialist. Clarithromycin is currently the mainstay of oral therapy for
Conclusion
NTM infection is an emerging cause of Gradenigo syndrome. Treatment is often delayed due to the failure to identify the pathogens. The diagnosis depends on a high index of suspicion. The definite treatment requires
surgical intervention and the prolonged administration of antibiotics directed against NTM. Patients should be treated in consultation with an infectious disease specialist. An antibiotic treatment for a minimum of 4–6 months is recommended.
References
282
Kong SE, Lee IW, Goh EK, Park SE: Acute otitis media-induced petrous apicitis presenting as the Gradenigo syndrome: successfully treated by ventilation tube insertion. Am J Otolaryngol 2011;32:445–447. Lee YH, Lee NJ, Kim JH, Song JJ: CT, MRI and gallium SPECT in the diagnosis and treatment of petrous apicitis presenting as multiple cranial neuropathies. Br J Radiol 2005;78: 948–951. Lowry PW, Jarvis WR, Oberle AD, Bland LA, Silberman R, Bocchini JA Jr, Dean HD, Swenson JM, Wallace RJ Jr: Mycobacterium chelonae causing otitis media in an ear-nose-andthroat practice. N Engl J Med 1988; 319: 978– 982. Marianowski R, Rocton S, Ait-Amer JL, Morisseau-Durand MP, Manach Y: Conservative management of Gradenigo syndrome in a child. Int J Pediatr Otorhinolaryngol 2001;57: 79–83. Medjahed H, Gaillard JL, Reyrat JM: Mycobacterium abscessus: a new player in the mycobacterial field. Trends Microbiol 2010; 18: 117– 123. Minotti AM, Kountakis SE: Management of abducens palsy in patients with petrositis. Ann Otol Rhinol Laryngol 1999;108:897–902. Moerman M, Dierick J, Mestdagh J, Boedts D, Van Cauwenberge P: Mastoiditis caused by atypical mycobacteria. Int J Pediatr Otorhinolaryngol 1993;28:69–76. Moore M, Frerichs JB: An unusual acid-fast infection of the knee with subcutaneous, abscesslike lesions of the gluteal region; report of a case with a study of the organism, Mycobacterium abscessus, n. sp. J Invest Dermatol 1953; 20:133–169. Muller B, Kemper J, Hartwig NG, Mooi-Kokenberg EA, van Altena R, Versteegh FG: Mycobacterium avium intracellulare otomastoiditis: case report and literature review. Eur J Clin Microbiol Infect Dis 2006;25:723–727. Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B: Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother 2012;67:810–818.
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Petrini B: Mycobacterium abscessus: an emerging rapid-growing potential pathogen. APMIS 2006;114:319–328. Price T, Fayad G: Abducens nerve palsy as the sole presenting symptom of petrous apicitis. J Laryngol Otol 2002;116:726–729. Redaelli de Zinis LO, Tironi A, Nassif N, Ghizzardi D: Temporal bone infection caused by atypical mycobacterium: case report and review of the literature. Otol Neurotol 2003;24: 843–849. Sethi A, Sabherwal A, Gulati A, Sareen D: Primary tuberculous petrositis. Acta Otolaryngol 2005;125:1236–1239. Sherman SC, Buchanan A: Gradenigo syndrome: a case report and review of a rare complication of otitis media. J Emerg Med 2004; 27: 253–256. Sternberg I, Ronen S, Arnon N: Recurrent, isolated, post-febrile abducens nerve palsy. J Pediatr Ophthalmol Strabismus 1980; 17: 323– 324. Stewart MG, Troendle-Atkins J, Starke JR, Coker NJ: Nontuberculous mycobacterial mastoiditis. Arch Otolaryngol Head Neck Surg 1995; 121:225–228. Sugimoto H, Ito M, Hatano M, Nakanishi Y, Maruyama Y, Yoshizaki T: A case of chronic otitis media caused by Mycobacterium abscessus. Auris Nasus Larynx 2010;37:636–639. TerKonda RP, Levine SC, Duvall AJ 3rd, Giebink GS: Atypical mycobacterial otomastoiditis. Laryngoscope 1995;105:1275–1278. van Aarem A, Muytjens HL, Smits MM, Cremers CW: Recurrent therapy resistant mastoiditis by Mycobacterium cheilonae abscessus, a nontuberculous mycobacterium. Int J Pediatr Otorhinolaryngol 1998;43:61–72. Vijayananthan A, Arumugam A, Kumar G, Harichandra D: Mastoiditis secondary to mycobacterium abscessus imaged with gallium-67 scintigraphy. Biomed Imaging Interv J 2008; 4:e23. Woody RC, Burchett SK, Steele RW, Sullivan JA, McConnell JR: The role of computerized tomographic scan in the management of Gradenigo’s syndrome: a case report. Pediatr Infect Dis 1984;3:595–597. Wu KC, Shu MT, Chen BN: Otomastoiditis with acute left facial nerve paralysis caused by Mycobacterium chelonae. Ear Nose Throat J 2011;90:E18–E22.
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Burston BJ, Pretorius PM, Ramsden JD: Gradenigo’s syndrome: successful conservative treatment in adult and paediatric patients. J Laryngol Otol 2005;119:325–329. Cavallin L, Muren C: CT findings in tuberculous otomastoiditis. A case report. Acta Radiol 2000;41:49–51. Chole RA, Donald PJ: Petrous apicitis. Clinical considerations. Ann Otol Rhinol Laryngol 1983;92:544–551. Connor SE, Leung R, Natas S: Imaging of the petrous apex: a pictorial review. Br J Radiol 2008;81:427–435. Flint D, Mahadevan M, Gunn R, Brown S: Nontuberculous mycobacterial otomastoiditis in children: four cases and a literature review. Int J Pediatr Otorhinolaryngol 1999; 51: 121– 127. Franklin DJ, Starke JR, Brady MT, Brown BA, Wallace RJ Jr: Chronic otitis media after tympanostomy tube placement caused by Mycobacterium abscessus: a new clinical entity? Am J Otol 1994;15:313–320. Gibier L, Darrouzet V, Franco-Vidal V: Gradenigo syndrome without acute otitis media. Pediatr Neurol 2009;41:215–219. Gillanders DA: Gradenigo’s syndrome revisited. J Otolaryngol 1983;12:169–174. González-García JÁ, Trinidad A, María Verdaguer J, García-Berrocal JR, Ramírez-Camacho R: Radiological diagnostic of the nonpathological conditions of the petrous apex (in Spanish). Acta Otorrinolaringologica Esp 2009;60:346–351. Gradenigo G: Über die Paralyse des Nervus Abducens bei Otitis. Arch Ohrenheilk 1907;774: 149–187. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K: An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. Griffith DE, Wallace RJ Jr: New developments in the treatment of nontuberculous mycobacterial (NTM) disease. Semin Respir Infect 1996;11:301–310. Hilding DA: Petrous apex and subarcuate fossa maturation. Laryngoscope 1987; 97: 1129– 1135.
Received: August 19, 2013 Accepted after revision: February 5, 2014 Published online: September 18, 2014
Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
Gradenigo Syndrome Caused by Nontuberculous Mycobacteria Pey-Yu Chen a Chen-Chi Wu a Tsung-Lin Yang a Chuan-Jen Hsu a Yi-Tsen Lin a, b Kai-Nan Lin a, c
a Department of Otolaryngology, National Taiwan University Hospital, Taipei, b Department of Otolaryngology, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, and c Department of Otolaryngology, Cardinal Tien Hospital, New Taipei, Taiwan, ROC
Abstract Gradenigo syndrome is a rare but devastating complication of otitis media that involves the petrous apex. Clinically, it is characterized by the triad of suppurative otitis media, deep facial pain, and abducens palsy. Most of the Gradenigo syndrome cases that have been reported in the literature were caused by pyogenic bacteria. In this report, we describe the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012. Mycobacterium abscessus was confirmed in all 4 cases by culturing the pathological tissues obtained during surgical debridement. To the best of our knowledge, this is the first report documenting infections of nontuberculous mycobacteria (NTM) in Gradenigo syndrome. An NTM infection must be considered in chronic otomastoiditis complicated by Gradenigo syndrome. The defi-
© 2014 S. Karger AG, Basel 1420–3030/14/0194–0275$39.50/0 E-Mail [email protected] www.karger.com/aud
nite treatment of Gradenigo syndrome with an NTM infection requires adequate surgical debridement combined with antibiotic treatment for at least 4–6 months. © 2014 S. Karger AG, Basel
Introduction
Gradenigo syndrome is a rare complication of otitis media. Giuseppe Gradenigo [1907] was the first to describe a triad of symptoms related to petrous apicitis. This triad includes suppurative otitis media, deep facial pain over the trigeminal territory, and abducens palsy. The incidence of petrous apicitis has decreased markedly since the 1940s due to the advent of antibiotics. The widespread use of antibiotics has also altered the clinical picture by masking the symptoms [Gradenigo, 1907; Lee et al., 2005; Price and Fayad, 2002; Sethi et al., 2005; Sherman and Buchanan, 2004; van Aarem et al., 1998]. The majority of Gradenigo cases were caused by pyogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa [Sherman and Buchanan, 2004]. The uncommon pathoYi-Tsen Lin or Kai-Nan Lin Department of Otolaryngology, National Taiwan University Hospital 7 Chung-Shan S. Rd. Taipei 10002, Taiwan (ROC) E-Mail yitsen.lin @ gmail.com or klinpie @ ntu.edu.tw
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Key Words Gradenigo syndrome · Petrositis · Nontuberculous mycobacterium · Abducens palsy · Anti-nontuberculosis treatment · Mycobacterium abscessus
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ing the first clinical visit showed two perforations in the eardrum. b Otorrhea progressed despite the initial treatment with otics and oral antibiotics. c Axial postcontrast T1-weighted MR imaging showed a normal nonenhanced Meckel’s cave (arrow) on the right side as well as an ill-defined lesion with enhancement involving the petrous apex, Meckel’s cave (thin arrow), and mastoid air cells on the left side. d Coronal postcontrast T1-weighted MR imaging showed the enhancement of the petrous apex (thin arrow), which is confluent with the enhanced meninges (arrowhead).
a
b
c
d
gens included Mycobacterium tuberculosis [Sethi et al., 2005]. Nontuberculous mycobacteria (NTM) are ubiquitous in the soil, water, plants, and animal excreta [TerKonda et al., 1995; van Aarem et al., 1998]. Notably, NTM infections have garnered increased public attention since the 1980s, accompanying the increasing prevalence of acquired immunodeficiency syndrome [van Aarem et al., 1998]. Improvements in culturing techniques also increased the rate of diagnosing NTM infections [Flint et al., 1999]. Cervicofacial lymphadenitis is the most common clinical presentation of an NTM infection [Moerman et al., 1993; Sugimoto et al., 2010; van Aarem A et al., 1998]. Conversely, an NTM infection of the ear is relatively uncommon: NTM-related mastoiditis has been sporadically reported in immunocompetent children [Flint et al., 1999; Stewart et al., 1995; Sugimoto et al., 2010; TerKonda et al., 1995; van Aarem et al., 1998] and is even less common in adults [Franklin et al., 1994; Sugimoto et al., 2010; Wu et al., 2011]. Gradenigo syndrome caused by an NTM infection has never been documented in the literature. Between 2008 and 2012, 4 consecutive cases of Gradenigo syndrome in adults were encountered in a tertiary referral 276
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hospital. To our surprise, Mycobacterium abscessus, a species of NTM, was confirmed as the pathogen in all of the cases, indicating that an NTM infection might be an emerging cause of Gradenigo syndrome in the postantibiotics era.
Case Presentations Case 1 Case 1 is a 64-year-old woman who had a history of pulmonary tuberculosis and had been treated 40 years ago, but was otherwise healthy. She presented at our clinic with progressive left-sided otorrhea, otalgia, and hearing impairment of a 2-month duration. She had gradually developed pain over her left parietal and temporal areas. An otoscopic examination showed two perforations of the left eardrum (fig. 1a). Physical examination at our clinic revealed a left-sided cervical lymphadenopathy at level II. High-resolution computed tomography (HRCT) scan of the temporal bone revealed soft-tissue density that filled the left tympanic cavity and the mastoid cavity. Cortical destruction of the petrous ridge was not observed. The symptoms and signs persisted despite treatment with otics and oral antibiotics (fig. 1b). Sudden-onset diplopia, severe headache, and a mild tingling sensation in the left eye occurred 1 month later. M. tuberculosis infection was suspected due to the multiple eardrum perfora-
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Fig. 1. Local findings and imaging findings in case 1. a The otoscopic examination dur-
axial view of the temporal bone taken using HRCT demonstrated the destruction of the cortex of the right petrous apex (arrow) and the opacification of the mastoid air cells (arrowhead). b The coronal view showed the destruction and opacification of the petrous apex air cells (arrow). c Postcontrast T1-weighted MR imaging showed ill-defined soft tissue involving the right petrous apex and Meckel’s cave on the right side (thick arrow) and the abducens nerve in Dorello’s canal, with enhancement of the surrounding meninges (thin arrow). d Postcontrast T1-weighted MR imaging showed the enhancement of the petrous apex surrounding the internal carotid artery (arrowhead).
a
c
b
d
tions, cervical lymphadenopathy, history of pulmonary tuberculosis, and the infection being refractory to empiric antibiotic treatment. However, repeated cultures of discharge from her left ear were negative for acid-fast staining. Magnetic resonance (MR) images gave the impression of Gradenigo syndrome, showing ill-defined lesions with a hyperintense signal in the mastoid air cells, cavernous sinus, Meckel’s cave, and the surrounding dura mater (fig. 1c, d). Because the symptoms progressed despite parenteral antibiotic treatment with piperacillin/tazobactam (4,000 g/500 g) for 4 days, the patient underwent a left modified radical mastoidectomy. The granular tissue in the middle ear, the mastoid cavity and its extension to the petrous bone were removed. The cultures of the mastoid cavity content and the left-ear discharge were both found to contain M. abscessus. Based on the culture results, the antibiotics were then replaced with levofloxacin (500 mg, q.d.), doxycycline (100 mg, q.d.), and clarithromycin (500 mg, b.i.d.). Her headache and diplopia subsided gradually. The diplopia completely resolved within 2.5 months after surgery. Two months later, we changed the treatment to a combination of levofloxacin (500 mg, q.d.) and clarithromycin (500 mg, b.i.d.). The otorrhea gradually subsided. She received a revised tympanomastoidectomy to repair the persistent eardrum perforation 1 year after the first surgery. The wound healed smoothly afterward. The patient stopped taking medication 1 month after this surgery and completed a 13-month course of antibiotic treatment.
Case 2 The second case is a 33-year-old woman who had been well except for a history of right-sided chronic otitis media that had been treated with a tympanoplasty 1 year earlier. She presented to our clinic with right otalgia, otorrhea, and mild hearing impairment lasting for 3 months, followed by right-occipital headache and facial palsy. Otoscopic examination showed right-sided ear drainage with a 15% perforation of the right eardrum. The facial palsy improved transiently after oral prednisolone treatment. However, acute-onset diplopia upon rightward gaze developed 2 weeks later and the facial palsy was aggravated. Otoscopic examination showed that the eardrum perforation had enlarged to encompass 40% of the eardrum area. HRCT images of the temporal bone showed cortical bone destruction and coalescence of the air cells of the right petrous apex as well as opacification of the right tympanic cavity and the mastoid air cells (fig. 2a, b). MR images of the brain, which were taken to evaluate the intracranial lesions, revealed prominent fluid collection in the right mastoid air cells with abnormal bright enhancement over the right petrous apex, Meckel’s cave, the meninges of Dorello’s canal, and the clivus (fig. 2c, d). Culturing the ear discharge yielded no bacterial growth. The patient was then admitted and received parenteral antibiotic treatment with ceftriaxone (2,000 mg, every 12 h) and vancomycin ceftazidime (2,000 mg, every 8 h) under the impression of Gradenigo syndrome and central nervous system infection. The cranial nerve VI and VII palsy only minimally improved. Therefore, the patient underwent a right canal wall down mastoidectomy
Gradenigo Syndrome Caused by NTM
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Fig. 2. Imaging findings in case 2. a The
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Fig. 3. Abducens palsy and imaging findings in case 3. a Right abducens palsy was present. b The coronal post-contrast T1-
weighted MR image showed ill-defined soft tissue at the petrous apex of the right temporal bone (white arrow) and an intracranial extension with a focal nodule in the base of the right temporal bone (arrow head). The right abducens nerve was involved at the dural entry site (black arrow).
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b
Fig. 4. Imaging findings in case 4. a The
a
9 days later. As much of the granular tissue that had filled the mastoid cavity and the middle ear cavity as possible was removed. The culture of the granular tissue was positive for M. abscessus. Her facial palsy resolved at 20 days after surgery, and her diplopia resolved 3 weeks later. The patient initially refused antibiotic treatment for the NTM infection after the operation. However, since her headache and otorrhea persisted for 3 months after surgery, she finally agreed to the definite treatment for NTM. Her headache and otorrhea gradually subsided after treatment with levofloxacin (750 mg, q.d.), doxycycline (100 mg, b.i.d.), and clarithromycin (500 mg, b.i.d.) for 12 months. Case 3 A 58-year-old man with a history of well-controlled hypertension presented at our clinic with right otorrhea and hemicrania of 3-month duration and diplopia of 1-month duration. The diplopia was most prominent when he looked to the right (fig. 3a). An otoscopic exam revealed granulation behind the perforated eardrum and a purulent discharge. The bacterial culture of the ear discharge yielded no pathogenic growth. HRCT images of the temporal bone showed soft tissue densities in the middle ear, the mastoid, and the petrous apex, with bony destruction. Postcontrast T1-weighted MR images revealed ill-defined soft tissue at the petrous apex of the right
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b
temporal bone and an intracranial extension with a focal nodule in the right temporal base (fig. 3b). Comparison to the normal left side indicated that the right abducens nerve was involved at the dural entry site (fig. 3b). The patient received ceftriaxone (750 mg, b.i.d.) for 3 days before receiving a right canal wall down mastoidectomy in which the petrous passage was explored through the supralabyrinthine and infralabyrinthine routes. Considerable granular and necrotic tissue was found in the mastoid cavity during the surgery. Culturing of the material from the subperiosteal abscess in the mastoid cavity confirmed the presence of M. abscessus. The patient received anti-NTM treatment with ethambutol (800 mg, q.d.) and levofloxacin (750 mg, q.d.) for 5 weeks, and was then switched to ethambutol (800 mg, q.d.), ciprofloxacin (750 mg, q.d.), and clarithromycin (500 mg, b.i.d.) for another 2 months. His headache subsided approximately 6 weeks later. Complete recovery of eye movement was achieved within 3 months after surgery. The patient then stopped taking antibiotics after a discussion with an infectious disease specialist. Case 4 A 45-year-old man with no significant medical history was referred to our clinic for right otorrhea that had lasted for 2 years. Although he had been treated with numerous courses of orally
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axial view of the temporal bone taken using HRCT demonstrated the destruction of the cortex of the right petrous apex (arrow). b The coronal T2-weighted magnetic-resonance image showed an abscess forming at the cerebellopontine angle (arrowhead).
Table 1. Summary of clinical courses in the 4 patients
Age/ Otorrhea gender
Headache
Abducens Other Previous ear palsy CN signs surgery
Culture of otorrhea
Recovery of CN deficits after operation
Case 1
64/F
3 months
parietal and + temporal
no
no
M. abscessus 2.5 months for diplopia and CoNS (few)
Case 2
33/F
3 months
occipital
+
facial palsy
tympanoplasty
no growth of bacteria
20 days for facial palsy; 41 days for diplopia
Case 3
58/M
3 months
hemicrania
+
ptosis
no
no growth of bacteria
2–3 months for ptosis; 3 months for diplopia
Case 4
45/M
2 years
frontal
+
no
tympanoplasty MRSA and atticoantrotomy
4 months for diplopia
administered antibiotics, he began to have right-sided headaches 1 year earlier. He had undergone a right tympanoplasty and an atticoantrotomy 3 months before presentation. However, his symptoms had not improved. Otoscopic examination of the right ear revealed a polypoid lesion hanging from the posterior canal wall and profuse discharge. The culture of the ear discharge yielded methicillin-resistant S. aureus. HRCT images of the temporal bone showed opacification of the right mastoid air cells and bony destruction of the mastoid cortex, the tegmen, and the petrous bone (fig. 4a). A right radical mastoidectomy was performed, revealing pale granular tissue and pus that filled the middle ear, the mastoid cavity, and the petrous bone. We also found a subperiosteal abscess with a fistula in the mastoid cortex. One month later, a pus culture confirmed the presence of an atypical mycobacterial infection. The patient was treated with orally administered clarithromycin (500 mg, b.i.d.). Nevertheless, the sudden onset of binocular diplopia (particularly upon a rightward gaze), accompanied by a right frontal headache, right otalgia, and fever, occurred 6 weeks later. The subsequent MR images revealed a right cerebellopontine angle abscess (fig. 4b). Revision surgery with a right petrous apicetomy using infralabyrinthine approach was performed. The culture proved positive for M. abscessus infection. The patient received oral clarithromycin (500 mg, b.i.d.) for 6 additional months. His headache and otalgia subsided 1 month later, and the diplopia was completely resolved at 4 months after surgery.
Discussion
This report describes the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012 (table 1). Bacterial cultures of the pathological tissues that were obtained during surgical debridement confirmed M. abscessus as the pathogen in all 4 of the cases. To the best of our knowledge, this is the first report in the Gradenigo Syndrome Caused by NTM
literature documenting an NTM infection in Gradenigo syndrome. The consistent presence of M. abscessus in these cases indicates the clinical significance of an NTM infection in the pathogenesis of Gradenigo syndrome in this postantibiotics era. Moore and Frerichs [1953] first identified M. abscessus in 1953. Until recently (1992), this bacterium was considered a subspecies of Mycobacterium chelonae [Medjahed et al., 2010; Nessar et al., 2012]. M. abscessus is an acid-fast Gram-positive rod belonging to the group of rapidly growing mycobacterium, and it is the most pathogenic and chemotherapy-resistant NTM [Nessar et al., 2012]. Notably, it can cause chronic lung disease, posttraumatic wound infections, and disseminated cutaneous diseases, mostly in patients with compromised immune systems. A localized infection generally occurs in immunocompetent hosts [Franklin et al., 1994]. Additionally, NTM can cross the blood-brain barrier [Medjahed et al., 2010]. Symptoms of NTM infections typically occur at 3–4 weeks after inoculation; however, the incubation period can vary from 1 week to 2 years [Franklin et al., 1994; van Aarem et al., 1998]. Host immunity also plays a role in the onset of symptoms [Muller et al., 2006]. The clinical course of an NTM infection is often indolent and afebrile, and with systemic symptoms [Franklin et al., 1994]. Notably, NTM are an uncommon cause of middle ear or mastoid infections. Several NTM species, including M. chelonae ssp. abscessus, M. chelonae ssp. chelonae, M. fortuitum, M. avium, M. avium-intracellulare, and M. kansasii, have been reported in otomastoiditis cases [Flint et al., 1999; Franklin et al., 1994; Lowry et al., 1988; Muller et al., 2006; Stewart et al., 1995; TerKonda et al., 1995; van Aarem et al., 1998; Wu et al., 2011]. Most otoAudiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
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CN = Cranial nerve; CoNS = coagulase-negative staphylococci; MRSA = methicillin-resistant S. aureus.
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infection, the mastoid and the middle ear are often filled with a rubbery granular tissue; however, caseating necrosis was rarely observed [Flint et al., 1999; Franklin et al., 1994; Wu et al., 2011]. Poor wound healing after surgery is not uncommon [Flint et al., 1999; Stewart et al., 1995; van Aarem et al., 1998]. In this series, all of the patients suffered refractory otorrhea, followed by acuteonset diplopia, headache, and otalgia, thus fulfilling the diagnostic criteria of Gradenigo syndrome. Other neurological signs, such as facial palsy (1/4) or ptosis (1/4), were also noted (table 1). An otoscopic examination revealed polypoid tissue in 2 cases. Profuse granular tissue involving the middle ear and the mastoid cavity was found during surgery in all 4 cases. Briefly, except for headache and abducens palsy, all 4 cases demonstrated otological manifestations similar to those of NTM otomastoiditis cases. Gradenigo syndrome can result from acute or chronic petrous apicitis. CT is useful for evaluating the bony cortex: a subperiosteal lucency implies abscess formation in the periosteum in an acute case; opacification or the coalescence of air cells and bony destruction suggests a chronic case, and erosion of the cortical bone of the petrous pyramid and the skull base implies petrositis [González-García et al., 2009; Marianowski et al., 2001; Sherman and Buchanan, 2004]. MR imaging is sensitive in detecting early marrow changes and intracranial complications, and is helpful in differentiating petrous apicitis from other petrous diseases, including cholesteatoma, mastoiditis, chondroma, clival chordoma, epidural abscess, cholesterol cyst, and metastasis [Connor et al., 2008; Moerman et al., 1993; Sherman and Buchanan, 2004]. The abnormalities that are observed in the MR images may persist [Gibier et al., 2009], and gallium-67 scintigraphy can be utilized to monitor the resolution of infections [Vijayananthan et al., 2008]. The HRCT images for cases 2 and 3 showed breaks in the petrous cortex and the coalesced air cells; whereas the postcontrast T1-weighted MR images for cases 1, 2, and 3 showed an ill-defined soft tissue density with a hyperintense signal around the petrous apex and Meckel’s cave. These findings indicated that the radiological findings for NTM-based Gradenigo syndrome were similar to those for Gradenigo syndrome caused by other pathogens. Because NTM are ubiquitous, distinguishing pathogenic colonization from a true infection is difficult. Pus swab culturing or acid-fast staining of the otorrhea has low sensitivity (≤20%) for the diagnosis of otological tubercular infections [Sethi et al., 2005]. Pus cultures of ear Chen/Wu/Yang/Hsu/Lin/Lin
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logical NTM infections result from inoculation due to trauma, surgery, or an injection [van Aarem et al., 1998]. Other possible sources of such an infection include exposure to contaminated water and transmission via the eustachian tube [Flint et al., 1999; Moerman et al., 1993; Sethi et al., 2005; TerKonda et al., 1995]. No evidence of human-to-human or animal-to-human transmission exists [Flint et al., 1999; Griffith et al., 2007; Medjahed et al., 2010; Muller et al., 2006; Redaelli de Zinis et al., 2003; Sugimoto et al., 2010; TerKonda et al., 1995]. An outbreak of 17 cases of otomastoiditis caused by M. chelonae was attributed to inadequate instrument sterilization [Lowry et al., 1988]. Flint et al. [1999], who reviewed 59 cases of chronic otitis media with NTM infections that occurred between 1976 and 1998, found that 72% (43/59) of the patients had a previous ventilation tube insertion, 13.5% (8/59) of the patients had a chronic eardrum perforation, and only 4 patients had no previous ear surgery. It is believed that a plastic ventilation tube may serve as a suitable microenvironment for biofilm formation. The application of a topical steroid may alter the local immunity, allowing M. abscessus to spread [Franklin et al., 1994]. Topical antibiotics may inhibit bacterial growth and further promote NTM infection. Furthermore, a chronically perforated eardrum may also serve as an entry route. In this series, 2 patients (cases 2 and 4) had undergone a tympanoplasty before the development of full-blown Gradenigo symptoms and their visits to our clinic. However, these 2 patients had suffered from chronic otorrhea before their tympanoplasty, and no new symptoms occurred immediately after the tympanoplasty. Therefore, it is difficult to attribute the NTM infections to a previous ear surgery in these 2 cases. NTM and tuberculous otomastoiditis have similar clinical presentations and imaging findings. The common features of the otoscopic findings include painless and odorless otorrhea, a thickened tympanic membrane, and granulation or a polypoid lesion in the external auditory meatus [Flint et al., 1999; Franklin et al., 1994; Muller et al., 2006; Stewart et al., 1995; van Aarem et al., 1998; Wu et al., 2011]. Patients with an NTM infection may have a normal plain chest film, lack general symptoms (e.g. fever, malaise, and weight loss), and have no previous exposure to pulmonary tuberculosis [Franklin et al., 1994; van Aarem et al., 1998]. Multiple eardrum perforations are often associated with a tubercular infection [Cavallin and Muren, 2000; TerKonda et al., 1995], but as in case 1, a NTM infection can also lead to multiple eardrum perforations. In cases of an NTM
a rapidly growing mycobacterium infection and amikacin is the most active parenteral agent [Griffith and Wallace, 1996; Lowry et al., 1988; Petrini, 2006; Sugimoto et al., 2010]. Other such agents include cefoxitin, imipenem, linezolid, and tigecycline [Griffith et al., 2007; Medjahed et al., 2010; Petrini, 2006]. Single-agent therapy should be avoided to prevent the development of drug resistance. Previous treatment with aminoglycosidecontaining otics may have selected resistant strains because the target 16S rRNA is prone to point mutations in M. abscessus [Franklin et al., 1994; Lowry et al., 1988; Nessar et al., 2012]. The treatment regimen should be based on the sensitivity results for individual isolates, the clinical response to treatment, and the patient’s tolerance of the side effects of the medication. The treatment duration depends on the site of infection and its severity [Griffith et al., 2007], and resolution of the symptoms alone is not a sufficient reason to withdraw the antibiotics [Gibier et al., 2009]. Some authors have suggested maintaining the antibiotics regimen until a disease-free period of 4–6 weeks is obtained [Flint et al., 1999; Moerman et al., 1993], whereas others have recommended a minimum of 2–3 months of treatment after the symptoms have disappeared [Muller et al., 2006; van Aarem et al., 1998]. Still others have suggested a period lasting as long as 12–18 months. Among the cases of NTM-related mastoiditis reported in the literature, the treatment durations were 0.5–18 months, with an average of 7 months [Flint et al., 1999; van Aarem et al., 1998]. NTM-based otomastoiditis or petrositis, i.e. with bony involvement, should be considered a severe infection. According to the 2007 ATA/IDSA guidelines, a minimum of 4 months of therapy is recommended for a serious infection, and 6 months of therapy is suggested for a bony infection [Griffith et al., 2007]. In this series, all of the patients underwent radical surgical debridement, and 3 of them completed a course of oral medication directed against NTM after surgery. All 4 patients recovered from their abducens palsy and their other neurological symptoms within 4 months after surgery, which is comparable to the outcome of Gradenigo syndrome that is caused by other pathogens. Among the 12 cases of Gradenigo syndrome in the literature, those with abducens palsy achieved complete recovery after the appropriate treatment, either with conservative therapy alone or in combination with surgical intervention [Burston et al., 2005; Chole and Donald, 1983; Gillanders, 1983; Hilding, 1987; Minotti and Kountakis, 1999; Price and Fayad, 2002; Sternberg et al., 1980; Woody et al., 1984].
Gradenigo Syndrome Caused by NTM
Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
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discharge may also have limited diagnostic utility for otological NTM infections. In this series, culturing ear discharge revealed skin flora in 2 of the cases: one with a few coagulase-negative staphylococci and the other with a few methicillin-resistant S. aureus. Only case 1 had M. abscessus in an ear-discharge culture before surgery. The most reliable method for diagnosis of a mycobacterial infection is a direct histological examination combined with a culture of the infected tissue [Sethi et al., 2005]. An M. abscessus infection was confirmed in the culture of the pathological tissue or the subperiosteal abscess material that was obtained during surgery in all 4 cases. In addition to bacterial culturing, DNA probes for specific mycobacterial species have been developed, and rapid identification of the type of NTM present is now possible using polymerase chain reactions [Muller et al., 2006; van Aarem et al., 1998]. The treatment of petrous apicitis has been primarily surgical intervention; however, several series studies have also reported good outcomes with conservative treatment alone [Burston et al., 2005; Gibier et al., 2009; Marianowski et al., 2001; Minotti and Kountakis, 1999; Kong et al., 2011]. For acute petrositis, conservative therapy with parenteral antibiotics and adequate mastoid drainage, such as a myringotomy or ventilation tube insertion, may be sufficient. When conservative therapy fails or the disease is chronic (e.g. cholesteatoma), surgical intervention is indicated to ensure adequate drainage and decompression. Conversely, chronic petrositis may result in permanent mucosal thickening and the development of a central cystic space trapping the mucopus, making it difficult to cure the disease with medical treatment alone [Minotti and Kountakis, 1999]. Surgical intervention has an important role in the effective treatment of petrositis resulting from NTM infection. As mentioned, culturing NTM from ear discharge is difficult. Surgery allows collecting pathological tissues for culturing and subsequent diagnosis. Moreover, surgical intervention may also relieve the occlusion of the mastoid drainage by removing granulomatous tissue and ameliorate cranial nerve complications through decompression. The ideal surgical treatment of an NTM infection is to excise as much of the affected tissue as possible [Flint et al., 1999; Muller et al., 2006]. After surgery, long-term medical treatment is often required. Patients with an infection of a rapidly growing mycobacterium, such as M. abscessus, should be treated in consultation with an infectious disease specialist. Clarithromycin is currently the mainstay of oral therapy for
Conclusion
NTM infection is an emerging cause of Gradenigo syndrome. Treatment is often delayed due to the failure to identify the pathogens. The diagnosis depends on a high index of suspicion. The definite treatment requires
surgical intervention and the prolonged administration of antibiotics directed against NTM. Patients should be treated in consultation with an infectious disease specialist. An antibiotic treatment for a minimum of 4–6 months is recommended.
References
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Kong SE, Lee IW, Goh EK, Park SE: Acute otitis media-induced petrous apicitis presenting as the Gradenigo syndrome: successfully treated by ventilation tube insertion. Am J Otolaryngol 2011;32:445–447. Lee YH, Lee NJ, Kim JH, Song JJ: CT, MRI and gallium SPECT in the diagnosis and treatment of petrous apicitis presenting as multiple cranial neuropathies. Br J Radiol 2005;78: 948–951. Lowry PW, Jarvis WR, Oberle AD, Bland LA, Silberman R, Bocchini JA Jr, Dean HD, Swenson JM, Wallace RJ Jr: Mycobacterium chelonae causing otitis media in an ear-nose-andthroat practice. N Engl J Med 1988; 319: 978– 982. Marianowski R, Rocton S, Ait-Amer JL, Morisseau-Durand MP, Manach Y: Conservative management of Gradenigo syndrome in a child. Int J Pediatr Otorhinolaryngol 2001;57: 79–83. Medjahed H, Gaillard JL, Reyrat JM: Mycobacterium abscessus: a new player in the mycobacterial field. Trends Microbiol 2010; 18: 117– 123. Minotti AM, Kountakis SE: Management of abducens palsy in patients with petrositis. Ann Otol Rhinol Laryngol 1999;108:897–902. Moerman M, Dierick J, Mestdagh J, Boedts D, Van Cauwenberge P: Mastoiditis caused by atypical mycobacteria. Int J Pediatr Otorhinolaryngol 1993;28:69–76. Moore M, Frerichs JB: An unusual acid-fast infection of the knee with subcutaneous, abscesslike lesions of the gluteal region; report of a case with a study of the organism, Mycobacterium abscessus, n. sp. J Invest Dermatol 1953; 20:133–169. Muller B, Kemper J, Hartwig NG, Mooi-Kokenberg EA, van Altena R, Versteegh FG: Mycobacterium avium intracellulare otomastoiditis: case report and literature review. Eur J Clin Microbiol Infect Dis 2006;25:723–727. Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B: Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother 2012;67:810–818.
Audiol Neurotol 2014;19:275–282 DOI: 10.1159/000360413
Petrini B: Mycobacterium abscessus: an emerging rapid-growing potential pathogen. APMIS 2006;114:319–328. Price T, Fayad G: Abducens nerve palsy as the sole presenting symptom of petrous apicitis. J Laryngol Otol 2002;116:726–729. Redaelli de Zinis LO, Tironi A, Nassif N, Ghizzardi D: Temporal bone infection caused by atypical mycobacterium: case report and review of the literature. Otol Neurotol 2003;24: 843–849. Sethi A, Sabherwal A, Gulati A, Sareen D: Primary tuberculous petrositis. Acta Otolaryngol 2005;125:1236–1239. Sherman SC, Buchanan A: Gradenigo syndrome: a case report and review of a rare complication of otitis media. J Emerg Med 2004; 27: 253–256. Sternberg I, Ronen S, Arnon N: Recurrent, isolated, post-febrile abducens nerve palsy. J Pediatr Ophthalmol Strabismus 1980; 17: 323– 324. Stewart MG, Troendle-Atkins J, Starke JR, Coker NJ: Nontuberculous mycobacterial mastoiditis. Arch Otolaryngol Head Neck Surg 1995; 121:225–228. Sugimoto H, Ito M, Hatano M, Nakanishi Y, Maruyama Y, Yoshizaki T: A case of chronic otitis media caused by Mycobacterium abscessus. Auris Nasus Larynx 2010;37:636–639. TerKonda RP, Levine SC, Duvall AJ 3rd, Giebink GS: Atypical mycobacterial otomastoiditis. Laryngoscope 1995;105:1275–1278. van Aarem A, Muytjens HL, Smits MM, Cremers CW: Recurrent therapy resistant mastoiditis by Mycobacterium cheilonae abscessus, a nontuberculous mycobacterium. Int J Pediatr Otorhinolaryngol 1998;43:61–72. Vijayananthan A, Arumugam A, Kumar G, Harichandra D: Mastoiditis secondary to mycobacterium abscessus imaged with gallium-67 scintigraphy. Biomed Imaging Interv J 2008; 4:e23. Woody RC, Burchett SK, Steele RW, Sullivan JA, McConnell JR: The role of computerized tomographic scan in the management of Gradenigo’s syndrome: a case report. Pediatr Infect Dis 1984;3:595–597. Wu KC, Shu MT, Chen BN: Otomastoiditis with acute left facial nerve paralysis caused by Mycobacterium chelonae. Ear Nose Throat J 2011;90:E18–E22.
Chen/Wu/Yang/Hsu/Lin/Lin
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/4/2015 2:11:25 PM
Burston BJ, Pretorius PM, Ramsden JD: Gradenigo’s syndrome: successful conservative treatment in adult and paediatric patients. J Laryngol Otol 2005;119:325–329. Cavallin L, Muren C: CT findings in tuberculous otomastoiditis. A case report. Acta Radiol 2000;41:49–51. Chole RA, Donald PJ: Petrous apicitis. Clinical considerations. Ann Otol Rhinol Laryngol 1983;92:544–551. Connor SE, Leung R, Natas S: Imaging of the petrous apex: a pictorial review. Br J Radiol 2008;81:427–435. Flint D, Mahadevan M, Gunn R, Brown S: Nontuberculous mycobacterial otomastoiditis in children: four cases and a literature review. Int J Pediatr Otorhinolaryngol 1999; 51: 121– 127. Franklin DJ, Starke JR, Brady MT, Brown BA, Wallace RJ Jr: Chronic otitis media after tympanostomy tube placement caused by Mycobacterium abscessus: a new clinical entity? Am J Otol 1994;15:313–320. Gibier L, Darrouzet V, Franco-Vidal V: Gradenigo syndrome without acute otitis media. Pediatr Neurol 2009;41:215–219. Gillanders DA: Gradenigo’s syndrome revisited. J Otolaryngol 1983;12:169–174. González-García JÁ, Trinidad A, María Verdaguer J, García-Berrocal JR, Ramírez-Camacho R: Radiological diagnostic of the nonpathological conditions of the petrous apex (in Spanish). Acta Otorrinolaringologica Esp 2009;60:346–351. Gradenigo G: Über die Paralyse des Nervus Abducens bei Otitis. Arch Ohrenheilk 1907;774: 149–187. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K: An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. Griffith DE, Wallace RJ Jr: New developments in the treatment of nontuberculous mycobacterial (NTM) disease. Semin Respir Infect 1996;11:301–310. Hilding DA: Petrous apex and subarcuate fossa maturation. Laryngoscope 1987; 97: 1129– 1135.
