Case Report Immune Reconstitution Syndrome in a Patient with AIDS with Paradoxically Deteriorating Brain Tuberculoma CHEN-HSIANG LEE, M.D.,1 CHUN-CHUNG LUI, M.D.,2 and JIEN-WEI LIU, M.D.1
ABSTRACT A 54-year-old man with an underlying AIDS experienced fever and lethargy. Magnetic resonance imaging (MRI) showed multiple small ring-enhancement lesions over pons, basal ganglion, thalami, and bilateral cerebral hemisphere. Because of the concurrent pulmonary tuberculosis (TB), presumptive diagnosis of tuberculous meningitis and brain tuberculoma was made. The patients condition clinically improved after a 3-month anti-TB treatment coupled with highly active antiretroviral therapy (HAART), and his CD4-T lymphocyte count was increased from 17 cells/mm3 (HIV viral load, 294,000 copies per milliliter) to 153 cells/mm3 (HIV viral load, 5930 copies per milliliter). However, the follow-up MRI disclosed disappearance of some old brain lesions and development of some new ones; some previously identified tuberculoma became smaller in size, while some other enlarger. Of note, ring-enhanced brain lesions were found over the left frontal lobe and left posterior fossa with perifocal edema and hyperintensity in diffusion weighted MRI indicating abscess formation. Steroid was added based on the presumed paradoxical reaction of brain tuberculoma. Complete resolution of brain lesions was found on MRI 9 months later. Tuberculoma should be considered in a patient with AIDS with numerous intracranial lesions if TB involving other site(s) is definitively diagnosed, especially when the patient is receiving prophylactic trimethoprim-sulfamethoxazole and/or serologically negative for toxoplasmosis. Our report demonstrated the peculiar phenomenon of paradoxical reaction of brain tuberculoma during immune reconstitution and strengthens the belief that additional use of steroids for paradoxical reaction of brain tuberculoma is indicated after exclusion of other causes for the progressively enlarging brain lesions. INTRODUCTION
to make a definitive diagnosis
of pathologic conditions in central nervous system (CNS) in patients with AIDS, because T IS DIFFICULT
the clinical and radiologic manifestations are
both nonspecific.1 In patients with AIDS, a great variety of etiologies for brain lesions have been reported, which include Toxoplasma gondii, fungi, Mycobacterium tuberculosis, and
1Division
of Infectious Diseases, Department of Internal Medicine, and 2Department of Radiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China.
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other bacterial species, as well as Kaposis sarcoma and malignant lymphoma.2 Being severely immunocompromised, patients with AIDS may simultaneously suffer from opportunistic infections as a result of multiple infectious etiologies.2 Under these circumstances, only resorting to an invasive procedure for brain biopsy can reach a definitive diagnosis.2 We herein report a case involving a patient with AIDS whose magnetic resonance imaging (MRI) disclosed numerous lesions throughout the cortex of cerebra and cerebellum; tuberculosis meningitis with multiple CNS tuberculoma was presumptively diagnosed because the patient had coexistent pulmonary tuberculosis (TB). Clinical and serological improvements were noticed under anti-TB therapy and highly active antiretroviral therapy (HAART). However, MRI detected that some original brain lesions were enlarging, others were newly developed, and still some other evolved into brain abscess. Paradoxical reaction at immune reconstitution was suspected, and steroid was added. All intracranial lesions resolved after additional short-course steroids therapy.
CASE REPORT A 54-year-old man was admitted via our emergency service because of high fever and progressive lethargy for 1 week. The patient had an underlying AIDS and once refused to receive HAART; he had previously experienced Pneumocystis carinii pneumonia, and began to take daily prophylactic trimethoprimsulfamethoxazole thereafter. Upon admission, his CD4-T lymphocyte count was 17 cells/mm3 and HIV viral load was 294,000 copies per milliliter (Amplicor HIV-1 Monitor Test, Roche Diagnostic, Pleasonton, CA). Neurologic examination revealed poor memory and concentration, as well as dysarthric speech. Hemogram disclosed a normochromic and normcytic anemia as well as leucopenia. Chest radiograph showed infiltrations on his left upper lung field, suggestive of pulmonary TB. Gadolinium-enhanced T1-weighted MRI showed multiple small ( 5 mm) ring-enhancement lesions over the patients pons, basal ganglion, thalami, and bilateral cerebral
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hemisphere (Fig. 1A), and some lesions with
target sign (dot in rim-enhancement lesion).3 His serologic test was negative for toxoplamosis. Cerebrospinal fluid (CSF) was found to have 70 white blood cells/mm3 (22% neutrophil, 66% lymphocyte and 12% monocyte), protein 57 mg/dL and glucose 55 mg/dL (blood glucose, 108 mg/dL). Cytopathological examination of CSF disclosed some lymphocytes suggesting CNS chronic inflammation and absence of malignant cells. Sputum and CSF smears were negative for acid-fast bacilli and Cryptococcus. Serum and CSF were both negative for cryptococcal antigen. Blood and CSF cultures were negative for growth of bacteria and fungi. The polymerase chain reaction (PCR) assay of CSF was negative for TB. Proposed stereotactic brain biopsy was refused by the patient and his family. Based on pulmonary TB suggested by his chest radiography, an assumption of CNS multiple tuberculoma with meningoencephalitis was made. In addition to HAART (zidovudine/lamivudine and efavirenz), anti-TB agents including isoniazid, rifampin, ethambutol, and pyrazinamide, as well as prednisone (30 mg/d) were prescribed. The patients neurologic deficits recovered 1 week later and was released 2 weeks after hospitalization. Steroid was tapered the following month before discontinuation. M. tuberculosis subsequently grew from his sputum, which was susceptible to the prescribed anti-TB agents. The patient was well adherent to antiTB treatment and HAART and was regularly assessed on outpatient basis. Three months later when the patients peripheral CD4-T lymphocyte count was 153 cell/mm3 and HIV viral load was 5930 copies per milliliter indicating a favorable response to HAART, despite being clinically absent of focal neurologic deficit and cerebella ataxia, the follow-up brain MRI showed diminution of the number of the old CNS tuberculoma and development of the new ones; some previously identified tuberculoma diminished in size, while some other became enlarging (Fig. 1B). Of note, ring-enhancement brain lesions were found over the left frontal lobe and left posterior fossa, with perifocal edema and hyperintensity in diffusion weighted MRI indicating abscess formation. Stereotactic brain biopsy was deferred be-
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FIG. 1. A: Axial view of T1-weighted magnetic resonance imaging (MRI) with gadolinium injection showing multiple ring-enhancement lesions, some with central hypodense signal with contrast enhancement rim (arrow). B: Sagittal view of T2-weighted MRI showing hyperintensity lesions in frontal region and posterior fossa with obvious perifocal edema. C: Sagittal view of T2-weighted MRI showing complete resolution of brain lesions.
cause of the familys disapproval. Dexamthasone (30 mg/d) was added because of persistent clinical improvement and because of suspicion of paradoxical reactions resulting from the inflammatory process at the hosts immune-restoration. The prescribed dexamthasone was discondtinued 8 weeks later. At the completion of the 12-month anti-TB therapy, repeat brain MRI showed disappearance of the brain lesions (Fig. 1C).
DISCUSSION With respect to etiologies of CNS lesions among patients with AIDS, toxoplasmosis was once reported to be the most commonly encountered one (approximately 40%), followed by CNS lymphoma (approximately 10%)1,4; progressive multifocal leukoencephalopathy (PML), TB, cryptococcosis and other opportunistic infections were less frequently seen.1
BRAIN TUBERCULOMA IN IMMUNE RECONSTITUTION
Therefore, an proposed algorithm was once put
forward recommending empirical antitoxoplasmosis therapy for a patient with AIDS with brain lesion(s) for at least 2 weeks before reevaluation of his or her clinical and neuoradiographic responses to determine if an invasive diagnostic approach is needed.2,5 A later report by Ammassari et al.6 indicated a significantly lower incidence of toxoplasmosis, suggesting the need for alternative strategy for approaching brain lesion(s) in patients with AIDS. Rapid brain biopsy may unveil the etiologies of the brain lesions. If the invasive brain biopsy is not feasible for whatever reason, the location and contrast-medium enhancement characteristics of brain lesions coupled with PCR assay of CSF may provide important diagnostic clues.7 When it comes to differential diagnosis with MRI, CNS lymphoma is more likely when the enhanced lesion located in the subependymal or periventricular area or in corpus callosum. PML lesions are typically hypointense in T1-weighted imaging and hyperintense in T2-weighted imaging, and are not enhanced by gadolinium.8 Ring-enhanced cortical and subcortical lesions in MRI in our patient are infrequently seen in PML or primary CNS lymphoma. Clinical information may also be helpful in making differential diagnosis. This reported patient had received a prior 21-day therapy for P. carinii pneumonia and ensuring prophylactic trimethoprim-sulfamethixazole, and was serologically negative for toxoplasmosis; brain lesions due to etiologies other than toxoplasmosis should therefore be considered. CNS cryptococcosis is unlikely because in the presence of diffused brain lesions, cryptococcalantigen testing of blood and CSF, as well as Indian-ink smear and culture of CSF were all negative for Cryptococcus species, and because seizure, a frequently encountered manifestation in cryptococcal meningitis, was clinically absent.9 Given the slim possibility of the abovementioned entities and the presence of pulmonary TB, it was reasonable to assume that the brain lesions were tuberculoma. The incidence of TB involving CNS among patients with HIV-infection was reported to be five-fold higher than that in those without.10 Albeit rare, abscess may develop in CNS tuberculoma.10
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Among the diverse patterns of MRI signals for
brain tuberculoma reported previously,11 the target sign as shown in this case was suggested to be pathognomonic.3 In spite of its high specificity, target sign is unfortunately of low sensitivity when it is used in diagnosis of brain tuberculoma.11 Culture is the gold standard for diagnosis of CNS TB, although CSF culture has a lower yield for M. tuberculosis when comparing to sputum and/or lung-tissue culture,12,13 Brain biopsy is an invasive approach, yet is not necessarily conclusive in making a diagnosis of CNS TB.14,15 PCR was reported to be a useful diagnostic tool for tuberculous meningitis or brain tuberculoma in one small series inclusive of 5 patients.13 Another series indicated that PCR had a specificity of 100% and a relatively low sensitivity of 72% in diagnosis of extrapulmonary TB in general.16 Given the limitations of these diagnostic modalities, more often than not clinicians have to empirically start anti-TB therapy for patients with subacute or chronic meningitis while trying to exclude other etiologies, and then make further therapeutic plan based on the clinical and/or laboratory and/or imaging response of the affected patients. In general, patients with cerebral tuberculoma usually began to have a good clinical response to an effective anti-TB therapy within 2 months.17 Paradoxical reactions with neurological symptoms resulting from development of tuberculoma were previously reported in immunity-restoring AIDS patients who were receiving anti-TB therapy for either tuberculous meningitis or disseminated TB.18 To our knowledge, paradoxically enlarging tuberculoma and newly emerging liquefied brain lesions (abscess) during chemotherapy as shown in this case has never reported. The plausible explanation for the brain abscess found in the follow-up MRI at the third month is that the liquefaction of original tuberculoma resulted from the vigorous interactions between the hosts restoring immunity and the microbes and/or debris during the scavenging process. In the scenario of immune reconstitution, TH1 cell regain it pivot role in the hosts inflammatory reaction resulting in alterations of cytokine profile, and of which interferon (IFN)- acts
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(along with other nonspecific cytokine, e.g., interleukin-6) against the invading M. tuberculosis sparking another inflammatory process and thereby changing the inflammatory responsive patterns.18,19 Paradoxical reaction often clinically mimics deteriorations (e.g., prolonged fever and/or exacerbation of already improvement the original infection),18 leading to differentiation between immune reconstitution inflammatory syndrome and progression of infection difficult and challenging.20 Once immune reconstitution syndrome is suspected, it is unjustifiable to change the prescribed antiTB regimen; instead, steroid should be added for control of increased intracranial pressure and suppression of the vigorous inflammatory reaction, which usually leads a favorable outcome.18 The absence of neurologic symptoms and signs in our patient when paradoxical reaction of brain tuberculoma detected by MRI might result from the functionally noncritical locations involved in brain abscess; furthermore, the intracranial spaces home to the occipital as well as frontal lobes and cerebellum are comparatively large and thereby did not produce any compression effect on vital CNS structures. In summary, this case illustrates the clinically asymptomatic paradoxical reaction of brain tuberculoma disclosed by MRI in an AIDS patient with restoring immunity during HAART, and the large brain abscess evolved from the tuberculoma completely resolved after further short-course steroids therapy. Our report strengthens the belief that additional use of steroids for paradoxical reaction of brain tuberculoma is indicated after exclusion of other causes for the seemingly progressively enlarging brain lesions.
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Dr. Jien-Wei Liu Division of Infectious Diseases Chang Gung Memorial Hospital-Kaohsiung Taiwan Republic of China E-mail: 88b0@adm.cgmh.org.tw
