Paradoxical Reaction Syndrome Complicating Aural Infection Due to Mycobacterium tuberculosis during Therapy

A patient with an aural mass and progressive unilateral deafness caused by a locally extensive process due to Mycobacterium tuberculosis was evaluated. A discussion of this uncommon infection [1] and an early complication during antituberculosis therapy are presented. A 21-year-old Pakistani man presented with an aural mass and hearing loss in the right ear. The patient complained of right ear pain, headache, tinnitus, and recurring mucopurulent discharge from the external ear for 3 months. His medical history was un-remarkable, except for bilateral retinal detachment during early childhood. He denied cough, weight loss, or night sweats. He may have received bacille Calmette-Guérin vaccine as a child. The patient was well nourished and afebrile. Physical examination revealed a pale fungating mass that bled easily and totally obliterated the right external auditory canal. Cervical and periauricular lymph nodes were nonpalpable. The mastoid process was normal. Neurological examination was unremarkable, except for complete conductive deafness. Laboratory studies disclosed the following: leukocyte count, 4400/µL; hemoglobin level, 13.8 g/dL; platelet count, 201,000/µL; and erythrocyte sedimentation rate, 13 mm H2O/h. Serological testing for HIV type 1 was negative. A chest radiogram was normal, and an MRI of the head with iv gadolinium contrast (figure 1A) showed dense infiltration of the right middle ear cavity, mastoid air cells, ossicle disarticulation, erosion of the tegmen tympani, and an epidural collection encircling the right cerebral hemisphere, as well as associated calvarial and dural thickening. Biopsy of the external auditory canal mass showed numerous acid-fast bacilli and necrotizing granulomas. Analysis of smears of the right ear discharge was positive for acid-fast bacilli, and, 3 weeks later, M. tuberculosis was isolated and identified. This strain of M. tuberculosis was resistant to isoniazid, streptomycin, and ethionamide. Aside from an opening pressure of 29 cm H2O during lumbar puncture, examination of CSF was negative, and culture of CSF for mycobacteria was negative. Cultures of multiple induced sputum specimens were negative for mycobacteria. The patient was treated for 24 months with daily oral rifampin (600 mg), ethambutol (1200 mg), and ofloxacin (400 mg twice a day). Within 10 days after initiation of treatment with antituberculous medications, the patient's course was complicated by the new onset of complex partial seizures and worsening headache. Repeat MRI of the head showed a new ischemic infarction in the temporoparietal area, and magnetic resonance venography revealed thrombosis of the left parietal superficial cortical veins. A persistently high opening pressure of 27 cm H2O was noted during repeated lumbar puncture, although CSF examination and CSF cultures remained negative. No change was noted during the neurological examination. Treatment with high doses of dexamethasone was instituted, and the headaches resolved. The corticosteroid dose was tapered over 5 months and then was discontinued. He did not have a symptomatic recurrence. The mass in the auditory canal resolved completely, although scarring of the tympanic membrane and discontinuity of the middle ear ossicles were permanent. At the end of therapy, complete resolution of the intracranial process was noted during repeated MRI (figure 1B). However, the unilateral conductive hearing loss failed to improve. By the turn of the 20th century, the natural progression of this locally destructive infection due to M. tuberculosis was well established [2]. After the introduction of antimycobacterial agents, the rate of M. tuberculosis infection among pediatric patients with otitis media had significantly declined from 3%–4% to 0.05%–0.9% [3–5]. Expansion of a cerebral mass (tuberculoma) after therapy for M. tuberculosis infection or development of multiple new brain lesions during treatment of tuberculous meningitis has been reported in the literature and has been termed as a “paradoxical response” [6–8]. Within the first 10 days after starting antituberculous therapy, our patient had significant morbidity due to an unclear mechanism. It is possible that persistent compression of the cerebral cortex by a stable epidural mass was responsible for cerebral venous thrombosis, ischemia, and/or infarction and vasogenic or cytotoxic edema of subjacent white matter, leading to seizures and headache in this 21-year-old man. In addition, a type IV hypersensitivity reaction may have developed within the unchanged abscess, resulting in cerebral vasculitis, infarction, edema, and clinical seizure [9]. The improvement seen during steroid therapy may have been due to a reduction in cerebral edema (i.e., a mechanical effect) and/or to a direct anti-inflammatory mechanism on the cerebral vasculature [10]. However, MRI during this acute phase revealed no change in cerebral edema or in a midline shift to the left. Paradoxical reaction syndrome complicating therapy for M. tuberculosis infection involving the intracranial fossa (other than meningitis) is still ill defined, and the role of preemptive glucocorticosteroid therapy is uncertain. However, early recognition and treatment of this complication with systemic corticosteroids may result in a more favorable outcome. Intravenous gadolinium—enhanced MRIs of the head of a patient with paradoxical reaction syndrome complicating aural infection due to Mycobacterium tuberculosis during therapy. A, Pretherapy image that shows infiltration of mastoid air cells and the middle ear cavity with complete disarticulation of the ossicles (arrow) and a right cerebral hemisphere epidural abscess (arrowheads). B, Image after 24 months of therapy that shows complete resolution of the inflammatory process (arrowheads) with residual scarring (arrow) and a calvarial reaction.