Deadly Diabetic Earache

NEWSLETTER 21: DEADLY DIABETIC EARACHE

Malignant External Otitis
MEO
How an earache in a diabetic can lead to: bacteria invading the bones inside the ear; spreading to the base of the skull causing osteomyelitis; cranial nerve palsy; brain abscess; meningitis; sepsis and death

Synonyms and related keywords: malignant external otitis of the external ear, MEO, invasive external otitis, necrotizing external otitis, progressive external otitis, skull base osteomyelitis, ear infection, pseudomonal osteomyelitis of the temporal bone, Pseudomonas aeruginosa, P aeruginosa, diabetes, malignant external otitis.

A rare but serious infection called malignant external otitis can develop if bacteria invade the bones inside the ear canal and spread to the base of the skull. Not many people get this infection-it is mainly seen in older adults who also have diabetes, people who have HIV, and children who have impaired immune systems - but it can be fatal. Symptoms include ear pain with sudden facial paralysis, hoarseness, and throat pain. Antibiotics are used to treat this infection.

Necrotizing (malignant) external otitis, an infection involving the temporal and adjacent bones, is a relatively rare complication of external otitis. It occurs primarily in immunocompromised persons, especially older persons with diabetes mellitus, and is often initiated by self-inflicted or iatrogenic trauma to the external auditory canal. The most frequent pathogen is Pseudomonas aeruginosa. Patients with necrotizing external otitis complain of severe otalgia that worsens at night, and otorrhea. Clinical findings include granulation tissue in the external auditory canal, especially at the bone-cartilage junction. Facial and other cranial nerve palsies indicate a poor prognosis; intracranial complications are the most frequent cause of death. Diagnosis requires culture of ear secretions and pathologic examination of granulation tissue from the infection site. Imaging studies may include computed tomographic scanning, technetium Tc 99m medronate bone scanning, and gallium citrate Ga 67 scintigraphy. Treatment includes correction of immunosuppression (when possible), local treatment of the auditory canal, long-term systemic antibiotic therapy and, in selected patients, surgery. Family physicians and others who provide medical care for immunocompromised patients should be alert to the possibility of necrotizing external otitis in patients who complain of otalgia, particularly if they have diabetes mellitus and external otitis that has been refractory to standard therapy. Susceptible patients should be educated to avoid manipulation of the ear canal (i.e., they should not use cotton swabs to clean their ears) and to minimize exposure of the ear canal to water with a high chloride concentration. Appropriate patients should be referred to an otolaryngologist.

In 1968, Chandler discussed the clinical characteristics of MEO and defined it as a distinct clinical disease. He described this external otitis as malignant because he observed an aggressive clinical behavior, poor treatment outcome, and a high mortality rate for the patients affected by this disease. Malignant (necrotising) external otitis is an invasive infection of the external auditory canal. Although elderly patients with diabetes remain the population most commonly affected, immunosuppressed individuals (eg, from HIV infection, chemotherapy, etc) are also susceptible to malignant external otitis. Pseudomonas aeruginosa is isolated from the aural drainage in more than 90% of cases. The pathophysiology is incompletely understood although aural water exposure (eg, irrigation for cerumen impaction) has been reported as a potential iatrogenic factor. The typical patient presents with exquisitely painful otorrhoea. If untreated, cranial neuropathies (most commonly of the facial nerve) can develop due to subtemporal extension of the infection. The diagnosis of malignant external otitis is based on a combination of clinical findings, an increased erythrocyte sedimentation rate, and radiographic evidence of soft tissue with or without bone erosion in the external canal and infratemporal fossa. Treatment consists of prolonged administration (6-8 weeks) of an antipseudomonal agent (typically an orally administered quinolone). With the introduction and widespread use of both oral and topical quinolones, there are reports of less severe presentation of malignant external otitis and even the emergence of ciprofloxacin resistance. Systemic quinolones for the treatment of invasive Pseudomonal ear infections is recommended.

Pathophysiology: MEO is an infection that affects the external auditory canal and temporal bone. The causative organism is usually Pseudomonas aeruginosa, and the disease commonly manifests in elderly patients with diabetes. The infection begins as an external otitis that progresses into an osteomyelitis of the temporal bone. Spread of the disease outside the external auditory canal occurs through the fissures of Santorini and the osseocartilaginous junction.

Frequency:

In the US: MEO is more common in humid and warm climates than in other climates.

Mortality/Morbidity:

Cranial neuropathy

Cranial nerves can be affected by inflammation along the skull base or by a neurotoxin produced by Pseudomonas species. The facial nerve (VII) is affected most commonly, usually at the stylomastoid foramen. As the disease progresses, cranial nerves IX, X, and XI can be affected at the jugular foramen, followed by XII at the hypoglossal canal. Cranial nerves V and VI can be affected if the disease extends to the petrous apex.
In 1977, Chandler reported a 32% incidence of facial nerve paralysis. The incidence of facial nerve paralysis appears to have decreased with the development of more effective medical therapy. The development of cranial neuropathy generally was thought to reflect advanced-stage disease associated with a worse prognosis. More recently, Corey et al suggested that the presence of facial nerve paralysis alone does not worsen the prognosis. The other cranial nerves are affected much less frequently than the seventh cranial nerve, but these neuropathies still are associated with an 80-100% mortality rate. The recovery of nerve function is unpredictable and should not be used as an indicator of successful treatment.

Intracranial complications: These complications rarely occur in the absence of cranial nerve palsies. Meningitis, brain abscess, and dural sinus thrombosis may ensue. Cranial neuropathies related to the jugular foramen should raise concern for sigmoid sinus thrombosis. Cavernous sinus thrombosis should be considered if cranial nerves V or VI are affected. Intracranial complications reflect severe disease and are commonly fatal.
Comorbid conditions: Patients with MEO almost always have diabetes, often with other multiple medical problems. During the course of therapy, Chandler found some deaths related to pneumonia, uremia, myocardial infarction, strokes, and liver failure.

Sex: MEO is more common in males than in females.

Age: MEO has been reported in all age groups but is most common in patients who are elderly (age, >60 y).

History:

Diabetes (90%) or immunosuppression (illness or treatment related)
Severe, unrelenting, deep-seated otalgia
Temporal headaches
Purulent otorrhea
Possibly dysphagia, hoarseness, and/or facial nerve dysfunction

Necrotizing external otitis should be suspected when patients with diabetes mellitus (or another condition that compromises the immune system) complain of persistent external otitis that causes severe pain, especially at night.

Physical:

Inflammatory changes are observed in the external auditory canal and the periauricular soft tissue.
The pain is out of proportion to the physical examination findings.

Marked tenderness is present in the soft tissue between the mandible ramus and mastoid tip.

Granulation tissue is present at the floor of the osseocartilaginous junction. This finding is virtually pathognomonic of MEO. Otoscopic examination may also reveal exposed bone.

The cranial nerves (V-XII) should be examined.

Mental status examination should be performed. Deterioration of the mental status may indicate intracranial complication.

The tympanic membrane is usually intact.

Fever is uncommon.

Patients with osteitis of the base of the skull sometimes have extra-auricular manifestations, such as cervical lymphadenopathy, trismus (because of temporomandibular joint involvement), or irritation of the masseter muscle. As the infection spreads in the temporal bone, it may extend into the cranium and result in cranial nerve palsies. These palsies generally are caused by the secretion of neurotoxins or the compressive effect of the destructive process through the relevant foramina. Because of its anatomic location in the temporal bone, the facial nerve is usually the first nerve to become involved.

Causes:

Diabetes (90% of patients)

Diabetes is the most significant risk factor for developing MEO.
Small-vessel vasculopathy and immune dysfunction associated with diabetes are primarily responsible for this predisposition.
The cerumen of patients with diabetes has a higher pH and reduced concentration of lysozyme, which may impair local antibacterial activity.
No difference in predisposition is found between diabetes types I and II.
The predisposition is not necessarily related to the severity of glucose intolerance or periods of hyperglycemia.

Immunodeficiencies, such as lymphoproliferative disorders or medication-related immunosuppression
AIDS

MEO associated with AIDS may have a different pathophysiology than classic MEO.
Patients present with similar symptoms but are generally younger and do not have diabetes.
Granulation tissue may be absent in the external auditory canal.
Pseudomonas is not necessarily the dominant causative organism.
Patients with AIDS generally have a poorer outcome than patients with diabetes.

Aural irrigation: As many as 50% of cases of MEO have been reported to be preceded by traumatic aural irrigation in patients with diabetes.

Pathogenesis and Clinical Manifestations

Infection of the soft tissue of the external auditory canal ("swimmer's ear") is common, especially in hot, humid climates. The usual initiating events are trauma (often self-inflicted with cotton swabs) and exposure to swimming-pool water, which has a high concentration of halogens. The most frequently cultured pathogen, Pseudomonas aeruginosa, is not a normal inhabitant of the auditory canal. Other possible pathogens include Staphylococcus epidermidis, gram-negative bacteria, and fungi.

Patients with external otitis complain of otalgia and sensitivity to auricular movement. Otorrhea may be present, and obliteration of the external auditory canal by edema and secretions may cause hearing loss or a sensation of fullness in the ear.

The infection may extend to the cartilaginous skeleton of the ear canal and through Santorini's fissures to reach the temporal bone, causing osteitis. One of the hallmarks of this extension is granulation tissue in the bone-cartilage junction of the external auditory canal. This otoscopic finding is of extreme importance.

Because of significant differences in natural course and treatment, it is crucial to differentiate severe otitis externa and necrotizing external otitis. Involvement of structures beyond the soft tissues of the auditory canal occurs only in necrotizing external otitis. Osteitis of the base of the skull usually follows external otitis but also may begin with a middle-ear infection.

Lab Studies:

Leukocyte count

The leukocyte count is usually normal or mildly elevated.
A left shift is not commonly found.

Erythrocyte Sedimentation Rate (ESR)

Erythrocyte sedimentation rate (ESR) is invariably elevated, with an average of 87 mm/h.
It begins to decrease within 2 weeks of initiating therapy but takes many months to return to normal.
ESR can be used to support the clinical diagnosis since acute external otitis or ear canal malignancy usually does not cause a rate elevation in this lab test.

Serum chemistry

Patients with known diabetes need an evaluation of the serum chemistry to determine if the infection is affecting their baseline glucose intolerance.
Patients without a history of diabetes should be tested for glucose intolerance.

Culture and sensitivities from the external auditory canal

Culture from the ear drainage should be performed ideally before antimicrobial therapy is initiated.
The most common causative organism is P aeruginosa (95%). This organism is an aerobic, gram-negative rod. Pseudomonas species has a mucoid coating that deters phagocytosis. Exotoxins (ie, exotoxin A, collagenase, and elastase) can cause tissue necrosis, and some strains produce a neurotoxin that may be partially responsible for cranial neuropathies.
Less common organisms identified include Aspergillus and Proteus species, Staphylococcus aureus, and Staphylococcus epidermidis.

Imaging Studies:

These are important adjuncts for determining the presence of osteomyelitis, the extent of disease, and response to therapy.
Technetium Tc 99 methylene diphosphonate bone scanning is based on binding to osteoblasts.

This scan depicts as little as a 10% increase in osteoblastic activity. However, this test is not specific since tumors or bony dysplasias, in addition to osteomyelitis, can cause osteoblastosis.
It is useful in the initial evaluation because a positive finding in the correct clinical context can lead to confirmation of the diagnosis.
The test is not useful for assessing the response to therapy since results remain persistently positive long after clinical improvement because of continuous bone remodeling and reformation.
This test may also have limited usefulness for patients with a prior history of mastoiditis or otologic surgery.
The application of single-photon emission computed tomography (SPECT) technology has improved the poor spatial resolution traditionally associated with this test.

Gallium citrate Ga 67 scan is very sensitive but is not specific because gallium binds to actively dividing cells, including inflammatory cells, tumor cells, and osteoblasts.

Uncertainty is possible regarding whether a positive test result represents an inflammatory condition, soft tissue, or bone disease.
This test is most helpful when used as a monitor of successful treatment. Improvement of a positive test result correlates with therapeutic response.
A baseline test is usually obtained at the initial diagnosis for comparison with follow-up studies during treatment.
A quantitative comparison of the lesion to the nonlesion side may improve the interpretation of these studies for distinguishing acute external otitis from MEO and for determining the efficacy of therapy.
The application of SPECT technology has improved the poor spatial resolution traditionally associated with this test.

Indium In 111�labeled leukocyte scan attempts to provide the same sensitivity as a gallium citrate Ga 67 scan but is more specific to an inflammatory process.

It does not appear to provide an improvement in scintographic technique for helping to establish the diagnosis.
It may be better than gallium citrate Ga 67 scans for assisting in establishing the correct timing of disease resolution.
This test can be unreliable for imaging chronic osteomyelitis in other areas of the body. Thus, the accuracy of this application needs further study.

CT scanning and MRI are both useful for evaluating the anatomic extent of soft tissue inflammation, abscess formation, and intracranial complications.

CT scanning fails to diagnose early osteomyelitis because 30-50% of bone destruction is required to detect osteomyelitis by CT scanning.
MRI provides poor bone resolution.
The soft tissue manifestations regress on CT scanning and MRI with response to therapy.
Bone changes remain persistently abnormal on CT scans for at least one year and are not well demonstrated by MRI studies. Thus, neither of the tests can be used to determine osteomyelitis resolution.
Most authors advocate obtaining a CT scan with the initial evaluation for all patients, whereas Benecke advocates obtaining this test selectively for patients with cranial neuropathy, extensive bone changes on technetium scan, or poor clinical response to treatment. Grandis et al and Okpala et al support obtaining a CT scan early in the diagnostic/treatment algorithm.
MRI and CT scanning are equally sensitive in detecting the soft tissue extent of the disease, but MRI is more sensitive for detecting intracranial complications.

Procedures:

Obtain a biopsy of the external auditory canal to exclude carcinoma or other etiologies.

Histologic Findings:

Staging:

Levenson et al, Corey et al, Benecke, and Davis et al have proposed staging systems for MEO.

These staging systems are generally based on extent of soft tissue/bony involvement or development of neurologic complications.
None of these staging systems has been widely adopted.

Medical Care:

meticulous glucose control,

aural toilet,

systemic and ototopic antimicrobial therapy,

hyperbaric oxygen therapy.

Local treatment of the auditory canal

Treatment should be continued for at least four weeks,

night pain, physical findings

ESR, and imaging studies

Systemic antibiotic choice: Until the development of third-generation antipseudomonal cephalosporins, long-term intravenous antibiotics using an antipseudomonal penicillin and aminoglycoside were the mainstay of medical treatment.

Several authors have demonstrated the effectiveness of intravenous Fortaz (ceftazidime) monotherapy in the treatment of malignant external otitis (MEO).
Fluoroquinolones that attain high soft tissue and bone levels with oral doses were then developed. Subsequently, several authors have demonstrated the efficacy of oral ciprofloxacin monotherapy.
Although no established treatment guidelines are available, case series and anecdotal experience suggest that initial outpatient therapy with oral ciprofloxacin is efficacious for patients without a fluoroquinolone allergy, cranial neuropathy, or intracranial complication and who do not require hospital admission for diabetes or pain management.
The widespread use of fluoroquinolones for upper respiratory infections and simpler ear infections is beginning to confound the typical clinical spectrum of MEO. Ciprofloxacin-resistant P aeruginosa has been increasingly isolated in patients with MEO, accounting for as many as 33% of isolates in patients who failed outpatient management in a study by Berenholz et al. Most notably in this patient population, 63% of isolates from 1998-2001 were resistant to ciprofloxacin, whereas only 15% of isolates were found to be resistant in the 10 years before this 3-year period. No increased morbidity or mortality was found in patients with ciprofloxacin-resistant Pseudomonas. Patients with resistant P aeruginosa require parenteral antibiotics with antipseudomonal beta-lactam antibiotics with or without an aminoglycoside.

Duration of therapy

Symptoms and examination findings improve with appropriate therapy, but these changes do not correlate with the length of needed therapy. Despite symptom relief, prolonged antimicrobial treatment as indicated for osteomyelitis is still indicated.
Imaging studies

are helpful in determining the adequate length of treatment for each patient.

Treatment response should be evaluated with a gallium citrate Ga 67 scan every 4-6 weeks during treatment. Benecke recommended ending treatment 1 week after the gallium citrate Ga 67 scan findings return to normal and confirming this with a repeat scan 1 month after the treatment is stopped. Using this protocol for 13 patients, the average duration of treatment was 8.8 weeks with a range of 4-17 weeks.

Hyperbaric oxygen therapy

This should be used only as an adjunct to antimicrobial therapy; it should not be used alone.
Hyperbaric oxygen therapy may be helpful for patients with complications, experiencing a poor response to therapy, or with recurrent cases.

Surgical Care:

Chandler advocated surgery in his original report when appropriate antimicrobials were not available; he had very poor results, with a 50% mortality rate.
Surgical removal of the lesion requires resection of large portions of the temporal bone.
Because of the histopathology of MEO, removal of contiguous areas of bone may not be sufficient because of the spread of infection through vascular and fascial planes.
Surgery is now reserved for local debridement, removal of bony sequestrum, or abscess drainage.
Facial nerve decompression is not indicated for patients with facial paralysis.

Consultations:

Consultation with internal medicine specialists is required for the management of diabetes and other comorbidities.
Infectious-disease consultants may help with the choice of antibiotics in complicated cases.

Prognosis:

Disease recurrence

Disease recurrence is reported in 9-27% of patients.
It usually is related to inadequate length of therapy and manifests as recurrent headaches and otalgia, not as otorrhea.
The ESR begins increasing again.
MEO can recur as long as one year after treatment is completed; thus, a patient should not be considered cured until that time.

Mortality

Chandler reported a mortality rate of 50% in the original series.
The mortality rate has decreased to 20% with the introduction of appropriate antibiotics, improved imaging modalities, and increased awareness of the disease.
Most current studies report a mortality rate.

Medical/Legal Pitfalls:

Failure to exclude a malignant neoplastic process via biopsy of the external auditory canal.
Failure to place MEO in the differential diagnosis of a diabetic with an earache.
Failure to pick up on the symptom of night-time ear ache (severe otalgia at night).
Failure to pick up pain out of proportion to physical exam findings.
Failure to pick up on the sign ear discharge (otorrhea).
Failure to advise not to clean ears with Q-Tip.
Failure to order an ESR.
Failure to order timely imaging studies.
Failure to obtain sequential Gallium citrate 67 scans every 4 weeks during treatment and repeating it a month after treatment is stopped to confirm cure.
Failure to recognize cranial nerve palsies are associated with advanced MEO.
Failure to acquire timely ENT consultation in a resistant hard to treat earache.
Failure to acquire early cultures and Infectious Disease consultation.
Failure to acquire timely neurology and neurosurgery consultations in the presence of cranial nerve palsies.
Failure to appreciate the granulation tissue in the external auditory canal, especially at the bone-cartilage junction, on otoscopic exam.
Failure to see exposed bone in the ear canal.
Failure to see in the ear canal due to pain and swelling.
Failure to recognize the difference between severe otitis externa and MEO.
Failure to recommend adjunctive hyperbaric oxygen therapy.

Special Concerns:

Infants and children

In 1988, Rubin et al reported MEO in 15 children. Most did not have diabetes, and the more common predisposing risk factor was immune dysfunction.
The facial nerve was affected more frequently than in adults, and other cranial neuropathies were not found. This is likely related to the underdeveloped mastoid process and the more medial location of the fissures of Santorini in children. Tympanic membrane involvement was common, and bacteremia was more common than in adults.
Long-term morbidity was uncommon.
Fluoroquinolones are not approved by the Food and Drug Administration (FDA) for use in the management of MEO in the pediatric population, but they have been used widely and safely in the management of cystic fibrosis in children.

Possible impact of managed care and delayed diagnosis because of late referrals: Insufficient duration of therapy by primary care physicians treating MEO as an uncomplicated otitis externa may lead to emergence of drug resistance.

Prevention

In many patients with necrotizing external otitis, the initiating event may be self-inflicted or iatrogenic trauma to the ear canal. Therefore, susceptible patients should be instructed to avoid manipulation of the external auditory canal (i.e., they should not use cotton swabs to remove cerumen). Cleaning of the external auditory canal, including aural irrigation by medical staff, should be carried out with extreme caution to avoid injuring delicate skin in the canal. Eczematous conditions involving the meatus of the canal should be treated topically, because these conditions may result in pruritus that leads to scratching of the irritated skin. And you can�t make a diagnosis if you don�t think about it. It is imperative to remember in immunocompromised patients like a diabetic who have an earache that is worse than usual; worse at night; and possible associated with cranial neuropathy; to order a ESR, imaging studies, culture the drainage, begin anti-pseudomonal topical and systemic antibiotics, and obtain early help from ENT colleagues.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science)
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PI (Principal Investigator), DSI (Drug Study Institute)
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