What is the Best Test for Diagnosis and Monitoring Treatment Response in Malignant Otitis Externa?

Abstract

Malignant Otitis Externa (MOE), or skull base osteomyelitis, is an aggressive infection that predominantly affects elderly, diabetic, or immunocompromised patients, and is associated with high disease-specific mortality. MOE is suspected in the setting of external otitis associated with granulation tissue and pain; biopsy is obtained to rule out malignancy. CT and/or MRI imaging is useful to delineate bony and soft tissue involvement, respectively. Diagnosis of MOE is supported by a positive methylene diphosphonate (MDP)-technetium-99 m (Tc99m) bone scan and Gallium-67 (Ga67) scan. Sequential Ga67 scans have been traditionally used to assess response to antibiotic therapy. More recently, concern has been raised regarding the accuracy and cost-effectiveness of the current imaging paradigm for diagnosis and assessment of treatment response in MOE. The dominance of Tc99m and Ga67 as the gold standard for the diagnosis of MOE is based on a case series of 18 patients with apparent MOE who were evaluated with CT, Tc99m, and Ga67 studies.1 In this series, 100% of patients had abnormal bone uptake on Tc99m scan, whereas, only 75% of patients had bony abnormalities on CT. This is likely due to the fact CT only demonstrates bone changes when demineralization of bone is >30%—a feature commonly absent in early disease. The authors promoted Tc99m as the more sensitive test for the diagnosis of MOE. A subset of patients in the study (6 of 18) also underwent baseline and post-treatment Ga67 studies; serial Ga67 universally showed either resolution or substantial reduction in uptake after systemic antibiotic therapy. Thus, Ga67 uptake, which normalizes after an infection resolves, was deemed a superior measure of treatment response. In contrast, Tc99m uptake persists for an indefinite period as it is related to osteogenic activity, and consequently is not appropriate for monitoring treatment response. Unlike Tc99m and Ga67 studies, which offer poor anatomic resolution, CT and MRI provide fine-scale details on bony and soft tissue involvement, respectively. Al-Noury and Lotfy2 assessed the role of CT and MRI in monitoring disease progression and resolution. They prospectively followed 18 patients with apparent MOE, performing CT and MRI at presentation, and 6 and 12 months after treatment. They found that many patients exhibited persistent skull base abnormalities despite clinical recovery. Cortical bone abnormalities in the skull base were evident on CT at presentation in 44% of patients (8 of 18), and medullary changes were present on MRI in 66% (12 of 18). Of the six patients who completed 6-month follow-up scans, 100% (6 of 6) had persistent cortical skull base abnormalities on CT and 100% (6 of 6) had persistent medullary skull base abnormalities on MRI. Thus, while CT and MRI offer excellent and complementary anatomic resolution, their sensitivity for detecting treatment-related changes in MOE is limited. The utility of Tc99m and Ga67 studies as the standard for the diagnosis and monitoring of MOE has recently been drawn into question. Moss et al.3 conducted a systematic review and meta-analysis of 20 studies that evaluated the accuracy of Tc99m and Ga67 in the diagnosis and assessment of treatment response in MOE. Their analysis of 608 patients reported pooled sensitivities for Tc99m and Ga67 of 85% (95% CI, 72–98.1%) and 71.2% (95% CI, 55.1–87.3%), respectively. The specificities for Tc99m and Ga67 could not be evaluated, because studies examining this measure did not meet the inclusion criteria of >10 patients with standard OE necessary to calculate specificity. The authors point out that since the specificity of Tc99m for MOE is not known, the test cannot be reliably used to “rule in” the disease. Instead, the primary role of Tc99m had been to “rule out” MOE (which requires high sensitivity). However, given the sub-par sensitivity of Tc99m reported in this analysis, its ability to “rule out” MOE may also be limited. They also questioned the utility of Ga67 imaging to assess treatment response as it has limited sensitivity to detect the disease initially. In this analysis, comparisons to CT, MRI, leukocyte scintigraphy such as Indium-111 labeling, or to hybrid nuclear studies such as 2-deoxy-2-[fluorine-18] fluoroglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) were not performed. Hybrid nuclear studies have shown great promise as accurate diagnostic tools for osteomyelitis. When Termaat et al.4 compared the diagnostic accuracy of multiple imaging modalities in chronic osteomyelitis, they found that FDG-PET/CT offered the highest sensitivity and specificity. In this systemic review and meta-analysis of 23 studies, FDG-PET/CT had a pooled sensitivity of 96% (95% CI, 88–99%), compared to 82% for bone scintigraphy (95% CI, 70–89%]), 61% for leukocyte scintigraphy (95% CI, 43–76%), 78% for combined bone and leukocyte scintigraphy (95% CI, 72–83%) and 84% for MRI (95% CI, 69–92%). The pooled specificity for FDG-PET/CT was also the highest at 91% (95% CI, 81–95%), compared to 25% for bone scintigraphy (95% CI, 16–36%), 77% for leukocyte scintigraphy (95% CI, 63–87%), 84% for combined bone and leukocyte scintigraphy (95% CI, 75–90%) and 60% for MRI (95% CI, 63–87%). However, specific cases of MOE were not included. Stern Shavit et al.5 recently described the utility of 18F-FDG-PET/CT specifically in the diagnosis and monitoring of MOE. In this case-series of 12 patients with physical evidence of MOE, 100% of patients showed abnormal FDG uptake. After at least 6 weeks of systemic antibiotic therapy, imaging was repeated to assess treatment response. Out of the eight patients who completed follow-up imaging, four patients showed no FDG uptake and three patients showed substantially reduced uptake. A single patient had persistent FDG uptake, which later resolved on a third PET/CT after completion of an additional 6 weeks of antibiotics. Their findings indicate that 18F-FDG-PET/CT may be a reliable imaging modality for both diagnosis and assessment of treatment response in MOE. Additionally, compared to traditional paradigms (eg, Tc99m/Ga67/CT), 18F-FDG-PET/CT was determined to be more cost effective and involved less radiation exposure. It should be noted, however, that no comparisons to other imaging modalities were performed. Tc99m and Ga67 nuclear studies have historically been used to diagnose and monitor disease progression in MOE, respectively. However, the sensitivity and specificity of these studies is more limited than once imagined. Furthermore, they provide little anatomic detail, entail high costs and radiation exposure, and are not widely available. By contrast, CT and MRI are widely available and afford excellent anatomic resolution but are neither sufficiently sensitive nor specific as standalone modalities. 18F-FDG-PET/CT is a promising hybrid imaging modality for diagnosing and assessing treatment response in MOE. Future, prospective trials comparing 18F-FDG-PET to traditional nuclear imaging paradigms in the management of MOE are necessary. Three case series (level 4) and two meta-analyses of case series (level 4) were evaluated.

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