Skull Base Osteomyelitis
Etai Funk, M.D.
January 27, 2005

We will start off with our case report.  C.O. is an 89-year-old white male who presented on March 11th with a five-week history of right otalgia, otorrhea, and aural fullness.  He was placed on otic drops and an oral antibiotic.  He returned on March 31st with worsening pain and facial paresis.  His past medical history is significant for coronary artery disease and mild dysplasia, for which he has received multiple blood transfusions.  He denied any history of diabetes.  His past surgical history is significant for a coronary artery bypass and aortic valve replacement.  His medications include Aciphex, Plavix, Celebrex, multiple vitamins, metaprolalol, and Nystatin. 

On physical exam, his right external canal demonstrated granulation tissue at the inferior aspect.  His right tympanic membrane was clear.  It was tender to palpation over the right mastoid and preauricular area.  His left ear was clear.  His oral cavity and oropharyngeal exam was clear with symmetric uvula and soft palate elevation.  His tongue is midline on protrusion.  His hypopharynx and larynx demonstrated bilateral vocal cords were mobile.  He had a grade 3 cranial nerve VII paresis. 

The patient was admitted and started on IV ciprofloxacin but subsequently was changed to p.o. Tequin by the IV service.  He was discharged on p.o. Tequin once his pain had resolved and improved.  However, he returned to the clinic on June 1st with worsened 7th nerve paresis and with a grade 5 out of 6.  His cultures grew out Pseudomonas.  His biopsy demonstrated acute inflammation.  His labs from December demonstrated an elevated sed rate.  His glucose was slightly elevated, however, subsequently, he was noted not to have diabetes.  His white count was within normal limits, and he was slightly anemic. 

You can see his audiogram here—the one on the left from May, the one on the right from this January.  You can see his mixed hearing loss worsened over these seven months, and his discriminations worsened as well.  His left ear remained stable.

A CT exam demonstrated soft tissue swelling and edema in the right external canal.  He had mastoid air cell opacification and thinning of the cortex with some disruption here.  His gallium scan from April 1st demonstrated an increased uptake in the right temporal bone.  This was repeated in June, which demonstrated a more prominent uptake of gallium in the right temporal bone.  He was taken to the operating room on June 17th for a right tarsal strip and gold weight placement to his right eye for his 7th nerve paresis. 

He tolerated the procedure well and was subsequently followed in clinic. He began to develop a small micro-abscess in his outer external canal, which had a periodic leak that drained.  Yet his pain was controlled while continuing on p.o. Tequin.  Serial cultures during these visits were negative for bacteria or fungus.  He returned for regular follow-up to the clinic until December 14th when he arrived with increasing otalgia that now extended toward his right eye.  A myringotomy was performed at this time in his right thickened TM, which demonstrated no effusion.  Otherwise, his exam was unchanged. 

He was admitted for pain control, repeat scans, and IV antibiotics.  His repeat gallium scan was unchanged to that in June; and his MRI did not demonstrate any intradural extension.  Due to his poor health, it was decided that surgical intervention would not be appropriate in this case.  He was subsequently discharged off on antibiotics and his pain currently is being treated by the Pain Management service. 

The first reference to skull base osteomyelitis was made in 1838. In 1959 Meltzer and Keleman first described pseudomonas chondritis with osteomyelitis of the EAC and temporal bone.  In 1968, Chandler,who is considered the godfather of skull base osteomyelitis, coined the term “malignant otitis externa”.  He used this name to designate the high mortality associated with the disease at the time.  In 1974, Conn proposed the name change to “necrotizing otitis externa”. 

A little bit on the terminology.  There are three main terms used in skull base osteomyelitis.  Necrotizing otitis externa is frequently used interchangeably with malignant otitis externa.  However, most used this term throughout the literature to designate only the soft tissue inflammation that occurs with this infection.  Objections to the term “malignant” have been raised, as this is an infectious process and not an immunoplastic one.  Chandler considers skull base osteomyelitis to be a complication of malignant otitis externa.  One must keep in mind that skull base osteomyelitis can be caused by entities other than malignant otitis externa, such as chronic inner ear disease or sphenoid sinusitis.  Therefore, it would be wrong to consider malignant otitis externa and skull base osteomyelitis as one and the same.  However, they are used interchangeably throughout the literature. 

For clarity, skull base osteomyelitis will be used as the term throughout this presentation, which may be seen abbreviated as SBO.

It begins as a soft tissue infection in the external canal.  Granulation tissue may be seen at the osseo-cartilaginous junction.  The epidermis and dermis will be inflamed, which is more common to be seen in the osseous portion of the canal as opposed to the cartilaginous portion, as seen in acute otitis externa.  The infection will spread through the skull base by the fissures of Santorini and the tympanomastoid suture.  The response in the bone is an osteoblastic and an osteoplastic one, and micro-abscesses will be seen.

You can see a diagram of how this proceeds, starting with an infection, leading to a cellulitis, chondritis and osteitis, and ultimately, osteomyelitis. 

This is a cross-section coronal of the external canal.  You can see the fissures of Santorini here and the osseous canal where this is most affected.  Again, the pattern of spread of osteomyelitis in the skull base occurs through the fissures of Santorini and the tympanomastoid suture line.  It may spread inferior medially to the carotid, jugular foramen, or the sigmoid sinus; anteriorly, it may spread to the parotid, the TMJ, and the stylomastoid foramen; posteriorly, to the mastoid and descending vertical segment of the 7th nerve. 

Here you can see the diagram of the spread from the external canal to the stylomastoid foramen, the jugular foramen, and hypoglossal canal. 

Eighty to 90 percent of patients with skull base osteomyelitis will have diabetes.  The other 10 to 20 percent will have some sort of immunocompromised state.  There are multiple reasons for why diabetics are more prone to having skull base osteomyelitis.  One is they have a decreased cell-mediated immunity.

Cerumen is known to be bacteria cytolymph; and one of the reasons for this is its acidity.  Driscoll demonstrated that the cerumen pH in diabetics is more alkalyine compared to controls.  Diabetics have a micro-angiopathy leading to tissue necrosis and decreased immunologic delivery.  Their granulocytes have impaired migration and phatocytosis.  This is why it is extremely important to control the glucose very well in these patients, as improved control of glucose improves the acidic activity of these granulocytes.  There is no correlation that has been found between the severity of the skull base osteomyelitis and the severity of the diabetes. 

Pseudomonas is the most common culture to isolate in terms of bacteria in skull base osteomyelitis in over 99.2 percent of the cases.  It is an aerobic gram negative bacillus and enjoys a warm, humid, moist environment, making the external canal ideal.  It has a protein thick membrane that prevents phagocytosis and penetration of certain antibiotics.  It also contains exotoxins and enzymes to break down tissue and possibly contains a neurotoxin, which may lead to the cranial nerve palsies. 

Aspergillus is actually the next most common organism seen.  It more commonly causes 7th nerve palsy and it, as opposed to Pseudomonas, begins in the middle ear and the mastoid, not the external canal. Treatment for it is Amphotericin B. 

This is a typical presentation of a patient with skull base osteomyelitis.  It is an elderly, chronically diabetic male with otalgia, which is worse at night; otorrhea; and possibly a history of trauma.  There are multiple case series of patients who underwent ear syringing and subsequently developed skull base osteomyelitis.  On exam, granulation tissue may be seen at the osseo-cartilaginous junction.  A serous otitis media may be seen and a conductive hearing loss on audiogram.  It is important to understand that skull base osteomyelitis is diagnosed once otitis externa is treated and does not respond to local treatment.  In the literature, it varies in terms of how long this treatment should occur, from 8 to 21 days. It has been described that the differences on presentation between an acute otitis externa and malignant otitis externa and denoted that these differences included granulation tissues of the osseocartilaginous junction and a positive bone scan. 

Complications in terms of skull base osteomyelitis include a serous otitis media in 50 percent of the patients.  This is most likely due to nasopharyngeal inflammation causing Eustachian tube dysfunction.  Spread anteriorly may lead to parotitis or severe trismus from spread to the TMJ.  Seventh nerve is the most common nerve affected in 25 percent of the cases, subsequently followed by a jugular foramen syndrome of 9th and 11th, and 12th nerve palsy.  Other nerves have been noted, but these are fairly rare. 

There is an increased mortality rate noted with cranial nerve palsy.  Other complications may include a sigmoid or cavernous sinus thrombosis, meningitis, or cerebral abscess. 

There are four staging systems that have been proposed throughout the literature, each dividing stages into three levels.  In 1985 Corey first described a staging system: stage 1 is an infection; stage 2 involving cranial nerves; and stage 3 with intradural spread.  Another staging system in 1989 (Benecke) split these three:  the first as a necrotizing otitis externa, which designates the soft tissue infection.  Stage 2 is a limited skull base osteomyelitis, and stage 3 is an extensive skull base osteomyelitis with spread to the occipital bones, facial bones, and contralateral extension.  Benecke made a table denoting the effects of gallium and technetium scans based on his stages and noted that the gallium scan would be positive throughout all three of these stages, making it a fairly sensitive test.  The technetium scan will only be positive for patients with skull base osteomyelitis, making it the most specific test. 

Levenson’s staging system was very similar to Davis’s most recent staging system in 1992.

The diagnosis of skull base osteomyelitis has multiple criteria, as described by Levenson.  These patients must have a calcitrate otitis externa that does not respond to antibiotics, otic drops, and local treatment.  They have a severe otalgia, which is worse at night; and otorrhea.  Granulation tissue should be seen at the osseocartilaginous junction and a positive bone scan.  The recovery of Pseudomonas in an immunocompromised state is not necessarily required for the diagnosis; however, these are very common in skull base osteomyelitis.  Differential diagnosis for skull base osteomyelitis includes herpes zoster, necrotizing otitis externa, carcinoma, nasopharyngeal malignancy, metastases to the clivus, Paget’s disease, virus dysplasia, and a chronic granulomatous disease. 

There is an entity termed “benign necrotizing otitis externa.”  In this case, you will see the granulation tissue or avascular necrosis of the tympanic plate.  The patient may have otorrhea; however, there is no otalgia involved, no cranial nerves or Pseudomonas involved.  These patients respond well to local treatment with otic drops and removal of the ulcerated external canal skin.

The labs most commonly ordered are slightly elevated white count; again, Pseudomonas will be found in 99.2 percent of cases.  The glucose must always be ordered when a patient presents with a possible skull base osteomyelitis, as this may be the way a diabetic presents for the first time.  The sed rate can be used to monitor not only the disease progression but also the response to treatment.  Biopsy must be performed of the external canal to rule out malignancy. 

There are multiple radiologic studies that need to be ordered for skull base osteomyelitis.  We will start off with a CT scan.  It delineates inflammatory changes.  The most common findings are external canal swelling, middle ear opacification, and mastoid air cell opacification.  It demonstrates the progression of bone erosion only once demineralization has occurred and requires a minimum destruction of 30 to 50 percent of the bone to have radiologic evidence of osteomyelitis.  Therefore, Damiani demonstrated that 26 percent of patients on presentation will not have x-ray or MRI findings of skull base osteomyelitis.  This exam rarely returns to normal, therefore making it a poor tool to evaluate the response to treatment. 

Here you can see the inferior aspect of the external canal eroded, superior and attic here.  The attic eroded here with the tegmen intact.  Here you can see mastoid air cell opacification with external canal edema and some erosion of the cortex, and here you can see a stage 3 or a central disease, into the occipital nodes. 

The MRI is superior to the CT in evaluating the anatomic extent of soft tissue changes.  It is an excellent tool to assess for any intradural involvement or any venous thromboses.  It should be ordered for severe disease in all cases.  This is another test that remains positive after clinical resolution of skull base osteomyelitis; therefore, again, making it a poor tool to evaluate the response to treatment. 

Here you can see enhancement of the right skull base with increased intensity of the dura lining right here, and here you can see enhancement with contrast of the petrous bone. 

In terms of nuclear radiology, the technetium bone scan is the most specific test for skull base osteomyelitis.  It is picked up by osteoblasts and osteocytes, and it is positive well in advance to CT and MRI.  Quantitative methods using pixel density have been described to better differentiate acute otitis externa from skull base osteomyelitis, and it is demonstrated that the evaluation of the technetium bone scan at 4 and 24 hours post injection increases sensitivity.  There is poor resolution of this type of modality, and there is decreased specificity in previously operated patients.  This test will remain positive for 6 to 12 months secondary to new bone formation and remodeling; therefore, again, making it a poor tool to evaluate for response to treatment. 

You can see a typical bone scan with the temporal bone lighting up here, here, and there. 

The gallium scan is the most sensitive test in terms of radiologic exams.  It binds to granulocytes early in the course of disease and images the effective insult rather than the reaction to it, as the bone scan does.  This exam takes 48 to 72 hours to perform, and it will demonstrate the inflammatory process not only in the bone but also in the soft tissue; again, making it a sensitive test but a nonspecific one.  It has poor resolution. However, this test is the best radiologic tool to monitor the response to treatment.  Serial gallium scans are recommended at three to six week intervals. A quantitative approach using pixel density has been described to provide a more accurate evaluation of the response to treatment. 

Here you can see uptake in the temporal bone; and this is the same patient four weeks later, and you can see a good response to treatment with decreased uptake. 

The indium scan is a type of white blood cell scintigraphy.  It is more reliable than CT in detection, and, when combined with the technetium scan, it can improve the usefulness of both studies.  It can also be used to monitor the response to treatment; however, further work needs to be performed on this modality to elucidate its role in skull base osteomyelitis. 

Moving on to treatment.  Originally, Chandler described a wide local debridement and radical resection for treatment of skull base osteomyelitis.  This ended with a 60 percent mortality rate, which he believed was due to the risk of exposing uninfected structures in spreading of the pseudomonal infection.  Subsequently, this has fallen out of favor.

Topical antibiotics are controversial in the treatment of skull base osteomyelitis, as their efficacy is questioned and many feel that they may alter future culture specimens.  However, if proper cultures and biopsy are taken prior to treatment, this should not be an issue and they may actually help decrease edema.  Since the 1970s, IV and oral antibiotics are the gold standard primary treatment for skull base osteomyelitis.  Hyperbaric oxygen has been described for use in recalcitrant, advanced cases.  It works by elevating the oxygen partial pressure in tissues allowing increased phagocytic oxidative killing.

In terms of antibiotics, most recommend duration of treatment from six to nine weeks depending on the results of the gallium scan.  Initially, a synthetic penicillin, such as Carbenicillin, Ticarcillin, or Piperacillin, was used with an aminoglycoside for double coverage.  Chandler preferred Tobramycin.  This decreased the mortality rate to 23% as reported by Meyerhoff.  Everyone must also keep in mind that many of these patients are elderly, with diabetes and chronic renal disease.  Therefore, nephrotoxicity and ototoxicity must be a concern.

In the last 1980s, an incredible drug emerged for treatment for skull base osteomyelitis: ciprofloxacin.  It inhibits DNA gyrase, and it can be taken by an oral route.  It reaches concentration 5 to 7 times in bone and cartilage compared to serum.  Its use with a synthetic penicillin has been demonstrated to act synergistically against Pseudomonas in 20 to 55 percent of isolates.  However, in 2002, in a retrospective review, increasing resistance to ciprofloxacin was demonstrated in one-third of cases.  It is believed that the widespread community use of ciprofloxacin for respiratory tract infections and its topical use for external ear infections may be contributing to this resistance.

In 1989, the emergence of a third-generation cephalosporin was recommended by Kimmelman and has an excellent effect as an IV drug against Pseudomonas.

Currently, surgery is considered to have a more complementary role, mainly with conservative goals.  Sreepada et al and Pederson et al described these conservative goals as soft tissue debridement with daily debridement of external canal, removal of bony sequestrum, and biopsy to rule out malignancy or abscess drainage.  A predicament arises when the patient does not respond to these conservative measures, and this dilemma is even more concerning when the patient is an elderly diabetic with poor renal function and, most likely, multiple medical problems when one is considering more extensive surgery.  However, many advocate more extensive surgery once these patients are unresponsive to conservative treatment of antibiotics or hyperbaric oxygen. 

Many believe that bone biopsy is essential in terms of obtaining the correct pathogen.  Kraus described the use of the simple mastoidectomy in terms of treating skull base osteomyelitis not responsive to conservative measures.  Others refer to modified radical and radical mastoidectomies, facial nerve decompressions, and even petrous apicectomies.  Some believe that this type of surgery may lower the infectious load in the bone allowing the antibiotics to penetrate a non-infected bone.  Fortunately, however, we don’t have to consider surgery in many of these cases, as mortality rates have decreased to less than 5 percent, as reported, with antibiotics and other conservative treatment modalities.  However, with cranial nerve neuropathies, such as a 7th nerve palsy, the mortality rate increases to close to 50 to 63 percent, and with other cranial nerve palsies, the mortality rate increases to 80 percent. 

Most of these patients should be hospitalized for multiple reasons.  One is the laborious and time-consuming exams that need to be ordered. Others are control of glucose in these cases.  Many of these patients are fairly sick with a severely compromised status.  One must start IV antibiotics to obtain the radiographic nuclear studies, a biopsy, and obtain sequential cultures; and, of course, any patient with extensive disease should be hospitalized.

Children with skull base osteomyelitis will appear with more acute and toxic onset.  They usually have a preceding traumatic event and most are immunocompromised; however, less than a third have diabetes.  Their tympanic membrane and middle ear are also commonly involved in addition to the external canal.  Seventh nerve palsy is more common in these cases.  This does not carry the negative prognostic significance that it does in adults.  Usually, the 7th nerve palsy is permanent.  They require short duration of treatment—anywhere from two to three weeks—and no mortality has ever been reported with a skull base osteomyelitis in children. 

With the emergence of HIV in the 1980s, there has been increased cases of skull base osteomyelitis with HIV.  They lack the granulation tissue at the osseo-cartilaginous junction and the presence of granulation tissue in these patients is actually a good sign, as it may indicate more intact immunity.  Pseudomonas is the most common isolate and Aspergillus must also be considered in these cases.  Again, Aspergillus is more common in the middle ear or mastoid and there may be an increased mortality rate in these patients who are so immunocompromised and who have increased comorbidities. 

In summary, skull base osteomyelitis is a serious invasive infection, usually originating from a malignant otitis externa.  Presentation is typically in an elderly diabetic with otitis externa recalcitrant to local treatment.  Diagnostic physical exam finding is granulation tissue at the osseo-cartilaginous junction.  Pseudomonas is the most common isolate, and technetium bone scan is the most specific test for it.  CT and MRI are helpful to evaluate the bony-soft tissue extension, and a gallium scan and an ESR are essential to evaluate the response to treatment.  Seventh nerve is the most common complication, and long-term treatment with antibiotics, specifically oral ciprofloxacin, have decreased mortality rates significantly. 

 Case Presentation

CO is an 89 year-old white male with PMH of CAD and myelodysplasia who presented on March 11, 2004, with a five-week history of right otalgia, otorrhea, and aural fullness.  He was placed on otic drops and an oral antibiotic yet returned on March 31st with worsening pain and facial paresis.

His physical exam demonstrated right external auditory canal (EAC) granulation tissue at the inferior aspect of the canal.  His right TM was clear.  There was tenderness to palpation over the right mastoid/preauricular area.  His left ear was clear.  His oral cavity and oropharynx were clear with symmetric uvula/soft palate elevation.  His tongue was midline on protrusion.  His bilateral vocal cords were mobile.  He had a right cranial nerve (CN) VII grade III paresis.
Culture of the right external ear grew Pseudomonas aeruginosa while biopsy of the same site demonstrated acute ulceration with prominent acute inflammation.  His labs were within normal limits aside from an elevated ESR.

His audiogram demonstrated a right sided moderate to profound mixed loss with poor speech discrimination.  He had a left sided sloping mild to profound sensorineural hearing loss. 
CT scan from March 31, 2004, demonstrated fluid throughout the mastoid and middle ear with soft tissue thickening of the EAC and fat plane distortion around the stylomastoid foramen at the base of skull.  His Gallium scan from April 1, 2004, demonstrated increased uptake in the right temporal bone. 

He was admitted and started on IV Ciprofloxacin but changed to oral Tequin by the Infectious Disease service.   He was subsequently discharged on oral Tequin once his pain improved.  However, he returned to the clinic on June 1, 2004, with worsened CN VII paresis at a grade 5/6.  Repeat gallium scan on June 14, 2004, demonstrated more prominent uptake of gallium in the right temporal bone.  He was taken to the operating room on June 17, 2004, for a right tarsal strip and gold weight placement.  He tolerated the procedure well and was subsequently followed in clinic. 

He began to develop a micro-abscess in his outer EAC which had to periodically be drained, yet his pain was controlled while continuing on the oral Tequin.  Serial cultures during these clinic visits were negative for bacteria or fungus. 

He returned to the clinic on December 14, 2004, with increasing right otalgia that now extended toward his right eye.  Myringotomy was performed on his thickened right TM which demonstrated no effusion.  Otherwise, his exam was unchanged.  He was admitted for pain control, repeat scans, and IV antibiotics.  Repeat gallium study on December 15, 2004, demonstrated persistent and approximately the same uptake as seen on June 14, 2004.  MRI did not demonstrate intracranial extension.  Due to his poor health, it was decided that surgical intervention would not be appropriate.  His pain was more controlled.  He was subsequently discharged and his pain is currently being treated by the pain management service. 

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