Malignant otitis externa is an invasive, potentially life-threatening infection of the external ear and skull base that requires urgent diagnosis and treatment. It affects immunocompromised individuals, particularly those who have diabetes. The most common causative agent remains Pseudomonas aeruginosa. Definitive diagnosis is frequently elusive, requiring a high index of suspicion, various laboratory and imaging modalities, and histologic exclusion of malignancy. Long-term oral antipseudomonal agents have proven effective; however, pseudomonal antibiotic resistance patterns have emerged and therefore other bacterial and fungal causative agents must be considered. Adjunctive therapies, such as aggressive debridement and hyperbaric oxygen therapy, are reserved for extensive or unresponsive cases.
Malignant (necrotizing) otitis externa (MOE) was first described as a case of progressive Pseudomonas osteomyelitis in the temporal bone of a patient who had diabetes nearly a half century ago . Chandler published the first series of patients with progressive osteomyelitis of the temporal bone and termed the condition malignant otitis externa . Other authors have advocated using the term necrotizing otitis externa to reflect the fact that the process is not neoplastic . Skull base osteomyelitis perhaps most accurately describes the pathophysiology of the disease process and has been used to indicate infection that has spread to the skull base, beyond the external auditory canal . Although perhaps less precise, malignant otitis externa has been used most extensively in the literature and common vernacular, and will be the term used in this article.
Before effective antibiotic regimens, MOE was frequently fatal, with mortality rates of nearly 50% . Originally managed surgically, MOE is now effectively treated with antibiotics in most cases, with surgery reserved for biopsy and local debridement. Prompt identification and diagnosis of MOE and appropriate culture-directed therapy can prevent serious complications and mortality.
Epidemiology
Diabetes mellitus remains the most important associated condition. Although only 65% of subjects had diabetes in a recent review of 46 cases of malignant otitis externa , the prevalence of diabetes in MOE is more commonly 90% to 100% of patients . Any condition causing immunosuppression, including HIV/AIDS , chemotherapy-induced aplasia, refractory anemia, chronic leukemia, lymphoma, splenectomy, neoplasia, and renal transplantation, may predispose a patient to MOE . As recognized in Chandler’s seminal review, however, patients who have diabetes (and especially elderly patients) are particularly vulnerable to MOE because of the associated endarteritis, microangiopathy, and small vessel obliteration, which, coupled with the ability of Pseudomonas to invade vessel walls and cause a vasculitis with thrombosis and coagulation necrosis of surrounding tissue, underlies the pathophysiology of this disease.
Patients who have HIV-associated MOE are younger than the average patient who has diabetes. MOE should be suspected in all patients who have HIV and otitis externa that does not improve with appropriate therapy. MOE in patients who have HIV may lack typical granulation tissue along the floor of the external auditory canal (EAC) . Fungal MOE is found in patients who have HIV more commonly than in those who have diabetes, particularly patients who have severe AIDS . Fungal MOE often originates in the middle ear or mastoid in contrast to pseudomonal MOE. Pseudomonas infections in HIV occur with CD4 levels less than 100 cells/mm and Aspergillus -associated MOE with CD4 counts less than 50 cells/mm .
Although rare, MOE has been reported in children who have diabetes and other immunocompromised states, including IgG subclass deficiency , IgA deficiency , acute monocytic leukemia , iatrogenic neutropenia secondary to induction chemotherapy for acute lymphoblastic leukemia , and bone marrow transplantation . Compared with adults, diabetes is not as common a comorbidity in children (21% in one review ) as are other immunocompromised states.
The course of MOE in children has an acute onset, with more toxic initial symptoms of fever, malaise, and leukocytosis. Although one review reported a lower incidence of facial nerve paralysis in children , another cited a higher incidence earlier in the course of the disease because of the less-developed mastoid process and closer proximity of the facial nerve and stylomastoid foramen to the EAC . Facial paralysis has no prognostic significance to overall recovery, because both studies agree that children generally have a more favorable prognosis than adults . Prognosis for facial nerve recovery in children is poorer, however . P aeruginosa is also the most common causative agent in children. Complications in children include necrosis of the tympanic membrane , stenosis of the EAC, auricular deformity, and sensorineural and conductive hearing loss . Most pediatric cases resolve with several weeks of intravenous antibiotics, although longer courses can be required . Quinolones are generally avoided in children because of damage to weight-bearing joints in juvenile animal studies. However, ciprofloxacin has been successfully used to treat resistant MOE in a child after other intravenous therapy failed .
Pathophysiology
MOE affects immunocompromised individuals; its presentation in an otherwise healthy individual should prompt an investigation for diabetes mellitus or other immunodeficiency. MOE originates as a soft tissue infection of the EAC. Water irrigation for cerumen disimpaction in elderly patients who have diabetes is a proposed inciting event . Histologic studies of the EAC show inflammation of the epidermis with acute and chronic inflammatory reaction in the dermis . Patients who have diabetes show poor chemotaxis and phagocytosis of polymorphonuclear leukocytes, monocytes, and macrophages, leading to susceptibility to P aeruginosa infection . Another contributing factor may be the higher pH of cerumen in individuals who have diabetes .
Infection from the EAC spreads to the skull base through the fissures of Santorini, small perforations in the cartilaginous portion of the EAC found along the floor of the canal. Once out of the canal, infection spreads medially to the tympanomastoid suture, and along venous canals and fascial planes. The compact bone of the skull base becomes replaced with granulation tissue, leading to bone destruction. Progressive spread of infection to skull base foramina causes cranial neuropathies. The most commonly involved nerve is the facial nerve because of the proximity of the stylomastoid foramen to the EAC. Nerves of the jugular foramen are the next most commonly affected. As disease spreads more medially, petrous apex involvement can affect the abducens and trigeminal nerves and, more medially, the optic nerve . Spread of infection to the sigmoid sinus can lead to septic thrombosis of the sigmoid sinus and internal jugular vein; meningitis and cerebral abscess may also complicate MOE . Skull base osteomyelitis can also spread to the contralateral side and include the cervical spine . Finally, extracranial spread of infection may involve the infratemporal fossa, parotid, and neck, leading to involvement of surrounding structures and abscess formation. The otic capsule is typically spared and middle ear involvement is usually a late finding .
Pathophysiology
MOE affects immunocompromised individuals; its presentation in an otherwise healthy individual should prompt an investigation for diabetes mellitus or other immunodeficiency. MOE originates as a soft tissue infection of the EAC. Water irrigation for cerumen disimpaction in elderly patients who have diabetes is a proposed inciting event . Histologic studies of the EAC show inflammation of the epidermis with acute and chronic inflammatory reaction in the dermis . Patients who have diabetes show poor chemotaxis and phagocytosis of polymorphonuclear leukocytes, monocytes, and macrophages, leading to susceptibility to P aeruginosa infection . Another contributing factor may be the higher pH of cerumen in individuals who have diabetes .
Infection from the EAC spreads to the skull base through the fissures of Santorini, small perforations in the cartilaginous portion of the EAC found along the floor of the canal. Once out of the canal, infection spreads medially to the tympanomastoid suture, and along venous canals and fascial planes. The compact bone of the skull base becomes replaced with granulation tissue, leading to bone destruction. Progressive spread of infection to skull base foramina causes cranial neuropathies. The most commonly involved nerve is the facial nerve because of the proximity of the stylomastoid foramen to the EAC. Nerves of the jugular foramen are the next most commonly affected. As disease spreads more medially, petrous apex involvement can affect the abducens and trigeminal nerves and, more medially, the optic nerve . Spread of infection to the sigmoid sinus can lead to septic thrombosis of the sigmoid sinus and internal jugular vein; meningitis and cerebral abscess may also complicate MOE . Skull base osteomyelitis can also spread to the contralateral side and include the cervical spine . Finally, extracranial spread of infection may involve the infratemporal fossa, parotid, and neck, leading to involvement of surrounding structures and abscess formation. The otic capsule is typically spared and middle ear involvement is usually a late finding .
Microbiology
In most cases, the causative agent of MOE is Pseudomonas aeruginosa , which is a gram-negative obligate aerobe not normally found in the EAC. This organism will colonize the EAC in a moist environment or after trauma and is only a pathogen in the absence of effective host defenses. It also commonly causes benign acute otitis externa (swimmer’s ear). Conditions leading to more invasive MOE must also involve impaired host immunity to allow the organism to spread out of the external canal. More virulent Pseudomonas species contain a mucoid surface layer that protects the bacterium from phagocytosis. They also produce lytic enzymes, including endotoxin, collagenase, and elastase, causing a necrotizing vasculitis and endarteritis that enable invasion of surrounding tissue. Other bacteria, including Staphylococcus aureus , S epidermidis , Proteus mirabilis , Klebsiella oxytoca , and P cepacia , have also been reported to cause MOE, although these organisms may have been colonizers and not true pathogens.
Fungal pathogens can also cause MOE, particularly in immunocompromised patients who are not diabetic, including those who have HIV/AIDS . The most common fungal organism is Aspergillus fumigatus , although other species have been isolated, including A flavus , A niger (in a patient who was immunocompetent and one who was diabetic ), and Scedosporium apiospermum (in a patient who had end-stage AIDS ). The possibility of fungal MOE must be considered if a patient who has classic signs and symptoms of MOE is unresponsive to appropriate antimicrobial therapy and cultures have been negative. Fungal MOE should also be considered and cultures retaken in patients who do well initially on antimicrobial therapy but experience recrudescence . Several studies point out the clinical differences between bacterial and fungal MOE ( Table 1 ).
| Etiologic agent | Age | Diabetes | Immunosuppression | Granulation tissue | Middle ear/mastoid involvement | Histology |
|---|---|---|---|---|---|---|
| Bacteria ( Pseudomonas aeruginosa ) | Older | Common | Common | + | − | Gram-negative rod |
| Fungus ( Aspergillus spp) | Younger | Less common | More common, especially cellular immunity, AIDS | − | + | Branching septated hyphae; calcium oxalate crystals |
Finally, the diagnosis and treatment of MOE in the absence of an identifiable pathogen (culture-negative specimen) has been described. These studies diagnosed MOE based on clinical history, signs and symptoms, biopsy to rule out malignancy, markedly elevated erythrocyte sedimentation rate (ESR), and imaging studies, such as CT and radionuclide (gallium and technetium bone) scanning . Previous treatment with oral or topical antibiotics before evaluation and wound culture may be responsible for this scenario, because many patients had already experienced failed response to a short course of oral ciprofloxacin and various topical antibiotic preparations before undergoing otolaryngologic evaluation. Treatment included intravenous ceftazidime (aztreonam for penicillin allergic patients), high-dose oral ciprofloxacin (750 mg twice daily), and topical aminoglycoside–steroid drops .
Clinical presentation
Typical patients who have MOE are elderly individuals who have diabetes and severe, unremitting otalgia, aural fullness, otorrhea, and hearing loss. Otalgia in these patients may be worse at night and more severe than what is usually associated with otitis externa. Hearing loss is conductive in nature. Headache, temporomandibular joint pain, and decreased oral intake secondary to trismus may also be present. Patients may provide a history of minor ear canal trauma associated with irrigation or cleaning. Many patients will have already taken short courses of oral antibiotics or been prescribed topical antibiotic drops. This antecedent history of antimicrobial therapy should not deter clinicians from pursuing and diagnosing MOE (and ruling out malignancy).
On examination, purulent otorrhea with a swollen, tender external auditory canal are hallmarks. Skin of the concha may be erythematous and tender. Granulation tissue or exposed bone is frequently seen on the floor of the canal at the bony–cartilaginous junction. Usually the tympanic membrane and middle ear appear healthy and uninvolved if not obstructed by granulation tissue or polyp in the canal. Periaural lymphadenopathy may also be present. Associated cranial neuropathies are caused by spread of infection through the skull base. Involvement of the stylomastoid foramen will lead to facial paralysis in 25% of patients; less frequently, involvement of the jugular foramen leads to deficits in cranial nerves IX, X, and XI . Fever and leukocytosis are frequently absent. Dural sinus thrombosis, meningitis, and cerebral abscess may also complicate MOE and are late findings that portend a grave prognosis. The diagnosis of MOE should be considered in all immunocompromised patients, especially those who have diabetes, who have external otitis and severe otalgia.
Diagnosis
The diagnosis of MOE relies on specific elements of the history and physical examination and laboratory and imaging studies. Findings of pain disproportionate to the examination, otorrhea, and granulation tissue along the floor of the ear canal at the bony–cartilaginous junction are usually the first nonspecific signs and symptoms of MOE. Differential diagnosis includes carcinoma of the ear canal, granulomatous diseases, Paget’s disease, nasopharyngeal malignances, clival lesions, and fibrous dysplasia . Carcinoma of the ear canal has similar clinical and radiologic findings, and biopsy is absolutely necessary to rule out this disease. Additionally, repeat biopsy and cultures are warranted to rule out an occult malignancy if inflammatory disease persists despite appropriate antibiotic therapy. Fever and leukocytosis are typically absent in adults who have MOE. ESR is always elevated and has been advocated as a nonspecific inflammatory marker for diagnosis and resolution of disease .
Even if patients have used antibiotic drops, cultures should be taken for aerobic, anaerobic, and fungal organisms and for bacterial sensitivity. Tissue biopsies should be sent to pathology to rule out malignancy and to microbiology for culture. Silver stain on histologic sections may identify fungal pathogens. Repeat cultures are necessary if the first set of cultures is negative, but withholding therapy until cultures are positive is not recommended.
No imaging modality provides adequate anatomic and physiologic detail sufficient to diagnose and follow MOE. CT is sensitive to bone erosion and decreased skull base density, a later finding in MOE ( Fig. 1 ) . CT scanning is also sensitive in diagnosing abscess formation and involvement of the mastoid, temporomandibular joint, infratemporal fossa, nasopharynx, petrous apex, and carotid canal. Demineralization of the skull base of 30% or greater is identifiable on CT scan, but because these changes persist despite resolution of disease, CT is therefore a poor choice for measuring treatment response. CT is also inadequate for showing intracranial extension and bone marrow involvement.
