Osteomyelitis of the skull base, etiology unknown KATHLEEN C.Y. SIE, MD, MICHAEL G. GLENN, MD, ALLEN H. HILLEL, MD, and CHARLES W. CUMMINGS, MD, Seattle, Washington

Osteomyelitis of the skull base (OSB), in the absence of contiguous infection or microvascular disease, has not previously been reported. We have recently seen two cases of this infection. In each case, the diagnosis was elusive, requiring multiple biopsies. Once the diagnosis was confirmed and appropriate antibiotic therapy was instituted, both patients had resolution of symptoms, normalization of blood variables, and radiographic evidence of bone healing. Clinical symptoms, diagnostic evaluation, treatment, and follow-up for OSB are discussed, on the basis of both our experience and a review of the current literature. OSB has classically been considered a complication of necrotizing external otitis.''l OSB is typically encountered in elderly patients with diabetes, small vessel disease, and an impaired immune system. OSB has also been described in patients with chronic infection of the middle ear, mastoid, and paranasal sinuses.' These patients usually have persistent unilateral headaches and other nonspecific symptoms, such as low-grade fevers and malaise. The infection may progress to cranial neuropathy and sigmoid sinus thrombosis. Pseudomonas aeruginosa is the organism most frequently found in these patients. Despite broad-spectrum antibiotics, OSB remains potentially fatal. Treatment requires accurate diagnosis and systematic assessment of response to therapy. Nasopharyngeal malignancy, metastatic le-

From the Department of Otolaryngology-Head and Neck Surgery, University of Washington. Resented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, New Orleans, La., Sept. 24-28, 1989. Received for publication Jan. 8, 1990; accepted July 1 1 , 1990. Reprint requests: Michael G . Glenn, MD, Department of Otolaryngology-Head and Neck Surgery, RL-30, University of Washington, Seattle, WA 98195.


sions to the clivus, Paget's disease, fibrous dysplasia, and basilar skull fractures can show similar symptoms and must be excluded. In their classic publication, Waldvogel et a1.6 defined osteomyelitis as an infection of bone fulfilling two of the following three diagnostic criteria: characteristic radiographic changes, characteristic histologic changes, and isolation of a pathogenic organism. An elevated erythrocyte sedimentation rate (ESR) and a normal or minimally elevated white blood cell count (WBC) are characteristicbut nonspecific findings. Waldvogel et aL6 also described three main factors in the pathogenesis of osteomyelitis: contiguous focus of infection, hematogenous seeding, and microvascular disease. We describe the cases of two patients with OSB of unclear origin. They had no obvious contiguous infection or other predisposing factors. These patients were examined at the University of Washington Hospitals between 1986 and 1987. CASE REPORTS

Case I. A 45-year-old nondiabetic man had a 2-month history of progressive postauricular pain and night sweats. He denied visual-field defects, dysphagia, hoarseness, facial numbness, recent upper respiratory infection, otorrhea, or otalgia. He also denied previous ear infections, chronic sinusitis, head trauma, radiation exposure, or exposure to tuberculosis. Results of a detailed physical examination were normal. His WBC was 11,OOO cells1 p1 and his ESR was 45 mm hr. Results of serum protein electrophoresis were normal. A technetium bone scan revealed a lytic lesion of the left skull base. A computerized tomographic (CT) scan of the head and skull base demonstrated a lytic lesion of the left occipital condyle and clivus, with adjacent soft-tissue fullness in the nasopharynx (Fig. 1, A). He was referred to the University Hospital, where his physical examination was only notable for palpable spasm of the left paraspinous muscles. Cranial nerve function was normal and symmetric. Blood studies were repeated, with results un-

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Fig. 1. A, CT scan in case 1 shows lylic lesion (arrow)of left occipital condyle and clhrus. B, CT scan of same patient 1 yeor after completion of therapy shows small persistent defect of the clivus with evidence of bone healing [arrow].

Fig. 2. A, CT scan in case 2 shows lesion of the rigM jugular foramen and clius [arrow).B, CT scan of same patient 8 months after completion of therapy shows evidence of bone healing [arrow). changed. except for an ESR of 120 rnni/hr. Examination of the anesthetized patient failed to reveal any abnormalities. Pathologic examination of samples from directed nasopharyngeal biopsies showed both chronic and active inflammation. One week later, he had a repeated biopsy of the naso-

pharynx, which was again nondiagnostic. Finally, a percutaneous CT-guided line-needle aspiration of the lytic lesion was performed. Culture of the aspirate yielded Propionobacrcriitm granulosum. Diagnosis of OSB was made and the patient was treated with a 6-week regimen of intravenous

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Table 1. Commonly used antibiotics Bacteriostatic ~~~

Bocterlcidai ~

Clindamycin Chiorarnphenicol Erythromycin Sulfamethoxazole Tetracycline Trimethoprirn





Aminoglycosides Bacitracin Cephalosporins Fluoroquinolones Metronidazole Penicillins Rifampin Vancomycin

imipenem. On completion of therapy, his WBC was 9,000 cells/ p,1 and his ESR was 25 mm hr. Technetium scan 1 year after completion of therapy showed a small amount of persistent uptake at the left skull base. CT scan at that time showed a persistent defect of the clivus but with evidence of bone healing (Fig. 1, B ) . He has had no recurrence of symptoms 3 years after completion of therapy. Case 2. An 80-year-old nondiabetic man had dysphagia and a right-sided hearing loss. Physical examination revealed a right jugular foramen syndrome, including asymmetric palatal elevation, hypesthesia of the right tonsil, right vocal cord paralysis, and right trapezius weakness. His ears appeared normal on examination. An audiogram showed a right-sided 75-dl3 sensorineural hearing loss and a left-sided 40-dB sensorineural hearing loss. WBC was 9000 cells/ pl and ESR was 111 mm/hr. A CT scan of the head and skull base was suggestive of a lesion of the right jugular foramen (Fig. 2, A), with bony abnormalities of the ipsilateral sigmoid sinus. A tomographic technetium radionuclide scan showed increased blood flow to the same area. Two attempts at CT-guided percutaneous fine-needle aspiration were inconclusive. Transparotid approach to the skull base revealed necrotic tissue without gross sequestration. Transmastoid approach to the sigmoid sinus revealed no evidence of mastoiditis, though there was osteitis over the sigmoid sinus. Biopsy samples from the area of osteitis were sent to both the pathology and microbiology departments. Pathologic examination showed chronic and active inflammation. Routine bacterial cultures were negative, but fungal cultures produced a single colony of P. aeruginosa. A nuclear medicine blood-flow study showed patent sigmoid sinus bilaterally with increased flow to the area of infection. He was treated with a 21-day regimen of intravenous imipenem, followed by a 21-day regimen of oral ciprofloxacin. ESR and WBC returned to normal. His cranial nerve deficits were essentially unchanged after treatment. Follow-up CT scan 8 months after completion of therapy showed evidence of bone healing (Fig. 2, B). DISCUSSION OSB in the absence of obvious contiguous infection or underlying vasculopathy has not previously been

described. Because of this lack of similar reported cases, diagnosis in both cases was considerably delayed. These patients may have had subclinical otologic, sinus, or dental infections. We present these cases to describe the clinical manifestation, diagnosis, and management of this unusual infection. The clinical symptoms of these patients were similar to those in well-described cases of OSB caused by necrotizing external otitis, except that neither patient had findings or history of ear disease. Both patients had persistent unilateral headache; one had a jugular foramen syndrome. Objective findings included a markedly elevated ESR, normal WBC, and an osteolytic skull-base lesion observable on radiographic studies. Diagnosis was confirmed by histopathologic study and isolation of an infecting organism. Once the diagnosis is established (by the criteria of Waldvogel et a1.6 of radiographic findings, histologic appearance of the bone, and isolation of a pathogen), appropriate antibiotic therapy should be initiated. Treatment of OSB requires prolonged intravenous antibiotic therapy. The antibiotic regimen should be directed against the pathogenic organism identified by culture. Staphylococcus aureus and P. aeruginosa appear to have a predilection for infecting bone’; they are the organisms most commonly isolated in osteomyelitis.6 Pseudomonal infections require dual antibiotic coverage to minimize the possibility of selecting resistant organisms. Hyperbaric oxygen therapy may play a role in the management of chronic refractory OSB .*-lo Surgical debridement, with its attendant morbidity and mortality, is not generally indicated. Traditionally, treatment of OSB has included parenteral bactericidal antibiotic therapy (Table 1). However, there have been recent reports of successful management of OSB secondary to necrotizing external otitis with an oral bactericidal agent, ciprofloxacin.1 1 ~ 1 2Although these reports support the efficacy of oral fluoroquinolones in the management of OSB, followup has been limited, and intravenous antibiotic therapy remains the recommended treatment for skull base infections. l 3 * I 4 Duration of therapy is determined by response, as measured by improvement of symptoms, normalization of laboratory values, resolution of inflammatory changes demonstrated by radionuclide scintigraphy, and evidence of bone repair on CT scan. Objective evidence of inflammation resolution and bone healing, in addition to clinical improvement of symptoms, guides the clinician in determining the appropriate length of therapy for each patient. The gallium citrate radionuclide scan is particularly

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useful in detecting infection and in monitoring the response to treatment. Gallium is absorbed by macrophages and reticuloendothelial cells, including granulocytes. The study is very sensitive in detecting infection. Activity in successfully treated lesions promptly returns to normal, with the delay seen with CT scan or technetium bone scan.” Noyek et al.I6 and Parisier et al.” suggest that serial gallium scans are the most sensitive method of monitoring response to antibiotic therapy during the treatment of OSB. A gallium scan should be obtained at diagnosis and thereafter at 6-week intervals. Antibiotic therapy should be continued until the results of the gallium scan return to normal. However, gallium scans are also very sensitive in the detection of malignancies; therefore, their primary role in the management of OSB is in determination of adequate treatment rather than confirmation of diagnosis. Technetium phosphate radionuclide scans are more sensitive to changes in the bone itself than are gallium scans. Technetium is primarily absorbed by osteocytes. But since technetium is also absorbed by osteoblasts, abnormal results may persist beyond the period of active inflammation.Is Whereas abnormal results of a gallium scan may reflect an inflammatory process in the soft tissue or bone, abnormal results of a technetium scan are more specific for the involvement of a bony process. However, neither gallium nor technetium radionuclide scans are specific for OSB. Malignancy, fibrous dysplasia, Paget’s disease, fractures, and surgical trauma can also yield positive results with these radionuclide scans. Is-’’ CT imaging is useful in defining location and extent of disease, information unavailable from radionuclide scanning. However, radiographic changes lag behind both the pathologic osteoclastic and the reparative osteoblastic processes. CT-image abnormalities, reflecting ongoing bone healing, may persist up to 2 years after adequate treatment.”.” Magnetic resonance imaging may also be useful in defining location and extent of disease in combination with the radionuclide scans. l9 Radionuclide and CT scans, and possibly magnetic resonance imaging, are useful in the evaluation and management of OSB . However, histopathologic study and isolation of a pathogenic organism are paramount in excluding malignancy and thus firmly establishing the diagnosis of OSB. SUMMARY

OSB can occur in the absence of an obvious contiguous source of infection. When a patient has persistent unilateral headache, elevated ESR, and radiographic ev-

idence of a lytic skull-base lesion, the clinician should consider OSB as a potential diagnosis. A baseline gallium scan should be obtained before biopsy, since surgery or trauma can also produce positive results on radionuclide scans. Technetium-phosphate bone scans should also be performed before any surgical manipulation. However, positive results from a gallium or technetium scan in this setting are not conclusive evidence of infection. At biopsy, the otolaryngologist-head and neck surgeon should consider sending a specimen to the microbiology department for culture in addition to the specimen sent for routine pathologic study; this procedure could minimize delay in diagnosis. Establishing the diagnosis in these patients without obvious contiguous infection can be difficult, demanding perseverance and an appropriate index of suspicion. Once the diagnosis is confirmed, intravenous antibiotic therapy should begin immediately. The duration of therapy must be individualized; patients may require from 4 weeks to several months of treatment. Response to therapy is indicated by resolution of symptoms, normalization of ESR, and reversal of abnormalities on radionuclide scans. Serial gallium scans are particularly useful in following response to treatment. REFERENCES

1 . Meltzer PE, Kelemen G. Pyocyaneous osteomyelitis of the temporal bone, mandible, and zygoma. Laryngoscope 1959;69: 1300-16. 2. Chandler JR. Malignant external otitis. Laryngoscope 1968;78: 1257-94. 3. Chandler JR. Malignant external otitis: further considerations. Ann Otol Rhino1 Laryngol 1977;86:417-28. 4. Chandler JR, Grobman L, Quencer R, Serafini A. Osteomyelitis of the skull base. Laryngoscope 1986;96:245-51. 5 . Bullitt E, Lehman RAW. Osteomyelitisof the skull. Surg Neurol 1979;11:163-6. 6. Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations, and unusual aspects. Parts 1-111. N Engl J Med 1970;282:198-206, 260-6, 31622. 7 . Norden CW. Lessons learned from animal models of osteomyelitis. Rev Infect Dis 1988;10:103-10. 8. Davis JC, Heckman JD, DeLee JC, Buckwold FJ. Chronic nonhematogenous osteomyelitis treated with adjuvant hyperbaric oxygen. J Bone Joint Surg [Am] 1986;66:1210-7. 9. Shupak A, Greenberg E, Hardoff R, et al. Hyperbaric oxygenation for necrotizing (malignant) otitis externa. Arch Otolaryngol Head Neck Surg 1989;115:1470-5. 10. Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy. JAMA 1990;263:2216-20. 1 1 . Norden CW, Shinners E. Ciprofloxacin as therapy for experimental osteomyelitis caused by Pseudomoms ueruginosu. J Infect Dis 1985;151:291-4. 12. Rubin J, Stoehr G, Yu VL, et al. Efficacy of oral ciprofloxacin plus rifampin for treatment of malignant external otitis. Arch Otolaryngol Head Neck Surg 1989;115:1063-9.

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13. Kraus DH, Rehm SJ, Kinney SE. The evolving treatment of necrotizing external otitis. Laryngoscope 1988;98:934-9. 14. Chandler JR. Malignant external otitis and osteomyelitis of the base of the skull. Am J Otol 1989;10:108-10. 15. Greyson ND, Noyek AM. Nuclear medicine in otolaryngologic diagnosis. Otolaryngol Clin North Am 1978;2:541-60. 16. Noyek AM, Kirsh JC, Greyson ND, et al. The clinical significance of radionuclide bone and gallium scanning in osteomyelitis of the head and neck. Laryngoscope 1984;94(suppl 34):l-21.

17. Parisier SC, Lucente FE, Som PM, et al. Nuclear scanning in necrotizing progressive “malignant” otitis. Laryngoscope 1982; 92:1016-9. 18. Gold S, Som PM, Lucente FE, et al. Radiographic findings in

progressive necrotizing “malignant”external otitis. Laryngocope 1984;94:363-6. 19. Gherin SG, Brackman DE, Bradley WG. Magnetic resonance imaging and computerized tomography in malignant external otitis. Laryngoscope 1986;96:542-8.

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Osteomyelitis of the skull base, etiology unknown.

OSB can occur in the absence of an obvious contiguous source of infection. When a patient has persistent unilateral headache, elevated ESR, and radiog...
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