NIH Public Access Author Manuscript J Magn Reson Imaging. Author manuscript; available in PMC 2011 June 1.

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1 NIH Public Access Author Manuscript Published in final edited form as: J Magn Reson Imaging June ; 31(6): doi: /jmri Eccentric Target Sign in Cerebral Toxoplasmosis neuropathological correlate to the imaging feature GG Sharath Kumar, MD 1, A Mahadevan, MD 2, AS Guruprasad, MD 1, Jerry ME Kovoor, MD 1, P Satishchandra, DM, Neurol 3, Avindra Nath, MD 4, Ranga Uday Kumar, PhD 5, and SK Shankar, MD 2 1 Department of Neuroimaging & Interventional Radiology, National Institute of Mental Health & Neurosciences, Bangalore , India 2 Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore , India 3 Department of Neurology, National Institute of Mental Health & Neurosciences, Bangalore , India 4 Department of Neurology, The Johns Hopkins University, Baltimore, Maryland, USA 5 Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore, India Abstract Cerebral toxoplasmosis remains one of the most common focal brain lesions in patients with acquired immune deficiency syndrome (AIDS). Diagnosis is a challenge as on cranial imaging, it closely mimics central nervous system lymphoma, primary and metastatic CNS tumors or other intracranial infections like tuberculoma or abscesses. An MR imaging feature on post contrast T1 weighted sequences considered pathognomonic of toxoplasmosis is the eccentric target sign. The pathological correlate of this imaging sign has been speculative. Herein we correlate the underlying histopathology to the MR feature of eccentric target sign in a patient with autopsy proven HIV/AIDS related cerebral toxoplasmosis. The central enhancing core of the target seen on MR imaging was produced by a leash of inflamed vessels extending down the length of sulcus that was surrounded by concentric zones of necrosis and a wall composed of histiocytes and proliferating blood vessels with impaired permeability producing the peripheral enhancing rim. Keywords cerebral toxoplasmosis; MR imaging; eccentric target sign; pathological correlation; HIV Introduction Toxoplasmosis, a protozoan infection, is one of the most common causes of focal brain lesions in patients with Human Immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) particularly in developing countries (1,2). Cerebral toxoplasmosis produces multifocal lesions, frequently affecting the basal ganglia, cerebral cortex, brain stem and cerebellum. Differentiation is critical as it has therapeutic implications and early institution of therapy is curative in toxoplasmosis. An MR imaging feature considered Corresponding author: Dr. S.K. Shankar, Prof & Head, Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore , India, Tel: , Fax: , shankarsk2004@gmail.com.

2 Sharath Kumar et al. Page 2 Clinical details pathognomonic of toxoplasmosis is the eccentric target sign a ring shaped zone of peripheral enhancement with a small eccentric nodule along the wall with 95% specificity and 25% sensitivity (3). This sign, demonstrable on post contrast CT or MRI scans, is however found in less than 30% of cases (3). The pathological correlate of this eccentric target sign remained speculative, though Ramsay and Gean suggested that it might be caused by focal invagination or folding of the cyst wall on itself (4). We describe the histopathological correlate of eccentric target sign by comparing the imaging findings with large whole mount sections of the lesions sampled from autopsied brain from a histologically confirmed case of cerebral toxoplasmosis with AIDS who succumbed to the disease. A 30 year old male presented to the neurological services with complaints of fever, headache and blurred vision, left focal motor seizures with secondary generalization (3 4 episodes) for 9 days. Initially he was evaluated at another hospital and received anticonvulsants for 5 days as the multiple lesions seen cranial CT scan were interpreted as cerebral metastasis. He had recurrence of left motor seizures and persistent headache and was referred to our center. On admission, he was found to have left upper motor neuron facial palsy and left sided hemiplegia. An MR scan revealed multiple ring enhancing lesions with prominent perilesional edema involving basal ganglia, frontal and parietal lobes. The lesions in right frontal and parietal lobes revealed a ring enhancing eccentric target sign on post contrast T1 weighted spin echo imaging (Fig. 1a). T2W fast spin echo image highlighted the hypointense ring like lesion in the frontal and parietal areas with the central area remaining hypointense and perilesional edema (Fig. 1b). Routine hematological and biochemical parameters were within normal limits. Serum was reactive for HIV-1 and serum and brain tissue were positive for HIV-1 Subtype C by tat specific PCR. Antitoxoplasma antibody (IgG) was detected in serum. CD4/CD8 counts and viral load could not be estimated, because of logistic problems. Based on the MRI features and positive toxoplasma serology, diagnosis of cerebral toxoplasmosis was made and antitoxoplasma therapy was initiated. The patient succumbed, fourteen days followed hospital admission. A partial autopsy confined to examination of the brain alone was conducted, with informed consent of the close relatives. The brain revealed bilateral mild frontal atrophy, and diffuse cerebral edema, with cerebellar tonsillar herniation. Multiple discrete toxoplasma lesions, mostly in necrotizing encephalitis stage or as organizing abscesses were noted in cerebral cortex, diencephalic nuclei and cerebellum bilaterally. The lesions corresponding to the eccentric target sign on MRI were seen as organizing abscesses at grey white junction encircling the depth of the sulci in right superior frontal gyrus, and superior parietal lobule, with perilesional edema (Fig. 1c e). MRI imaging findings were correlated with whole mount histological preparation stained with Haematoxylin-eosin, Luxol Fast Blue stain for demyelination and Masson s trichrome for collagen with CD68 immunostaining for histiocytes. The eccentric target sign noted on MRI in right frontal and parietal cortex corresponded histologically to large necrotizing abscess (Fig 2). Concentrically thickened vessels traversing the sulcus produced the curved eccentric target sign (Fig. 1e arrow, Fig. 2a,d). The surrounding zone of necrosis produced the intermediate zone of hypointensity (Fig. 2b,c,e) while the enhancing rim histologically corresponded to a dense band of histiocytic response (Fig. 2f g) with inflamed (Fig. 2i) and proliferating vessels delineated by immunostaining to Factor VIII related antigen of vascular endothelium (Fig. 2h). The perilesional white matter edema with demyelination was reflected as intense hyperintensities on T2W images.

3 Sharath Kumar et al. Page 3 Discussion Acknowledgments The periphery of the ring enhancing lesion had occasional tissue cysts with bradyzoite of Toxoplasma gondii, while the inflamed vascular zone bordering necrosis had diffusely dispersed tachyzoite forms detected by immunohistochemistry using antibodies to tachyzoite specific antigen (p30) (Fig. 2j). The varying host response to the temporal evolution of toxoplasma lesions, anatomical location and local vascularity appears to determine the patterns observed on MR imaging. Multinucleate giant cells suggestive of HIV encephalitis were not found. Cerebral toxoplasmosis is a common opportunistic infection in patients with HIV/AIDS that is fatal if left untreated making early diagnosis critical. As serological tests are often unhelpful, cranial imaging is relied upon for diagnosis. In earlier studies, Navia et al and others correlated ring enhancement on CT with pathological features seen in the brain at postmortem or following biopsy (5) and suggested that vascular proliferation and inflammation surrounding the abscess was necessary to produce contrast enhancement (6). Chang and colleagues proposed that macrophage infiltration of the vessel wall disrupts the blood barrier producing contrast enhancement (7). Contrast enhancement on imaging has also been reported to be closely correlated to the CD4 count, being absent or faint with counts below 50 and pronounced as the count increased (8,9). MR imaging was noted to be superior in detecting small lesions. The imaging patterns produced by the three morphologic types of toxoplasma lesions - necrotizing, organizing or chronic abscesses depend to a large extent on host s immune response and tissue damage caused by the protozoan infection (5). The rare disseminated form of toxoplasmosis (microglial nodule encephalitis) produces no contrast enhancement unlike all other stages. Brightbill and colleagues demonstrated that T2-weighted hyperintensity corresponded histologically to necrotizing abscesses and isointensity with organizing abscesses with a progression from hyperintensity to isointensity with intermediate period of mixed intensities on T2 W MRI following antibiotic treatment corresponding to the sequential histological patterns (10). An imaging feature termed eccentric target sign is considered highly suggestive of toxoplasmosis. This sign, demonstrable on post contrast CT (asymmetric target sign) or T1W MRI scans, is however found in less than 30% of cases(3). This has three alternating zones: an innermost enhancing core (more often eccentric than central) surrounded by intermediate hypointense zone and a peripheral hyperintense enhancing rim. In the present study, for the first time the imaging features of the eccentric target sign on T1 weighted post contrast are correlated with pathological findings. The original reports of asymmetric/ eccentric target sign illustrate cortical based lesions (3,4) though occasional report of thalamic lesion is on record (11). These however have no histopathological correlation attempted. This study illustrates that in cortical based lesions, the eccentric core is produced by leash of inflamed leaky vessels entering through a sulcus into the lesion. Similar relationship to inflamed tortuous vessels in basal ganglia and thalamus is most likely responsible and needs to be established unequivocally. In conclusion, similar correlative studies are needed to better understand the pathobiology underlying evolution of imaging characteristics in MR imaging sequences. The authors wish to acknowledge Mr. K. Manjunath, Human Brain Tissue Repository (Human Brain Bank), Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore, India for help

4 Sharath Kumar et al. Page 4 with photography and illustrations and Ms. Deepashri, Mrs V. Rajysakti, and Mr. Shivaji Rao for technical assistance. References Funding source: This publication was partly supported by a subaward from The Johns Hopkins University, with funds provided from National Institute of Neurological Disorders and Stroke (NINDS) [Grant no: 1RO1NS A2]. Its contents of the study are solely the responsibility of the authors and do not represent the official view of NINDS or JHU. 1. Satishchandra P, Nalini A, Gourie-Devi M, et al. Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India ( ). Indian J Med Res. 2000; 111: [PubMed: ] 2. Shankar SK, Mahadevan A, Satishchandra P, et al. Neuropathology of HIV/AIDS with an overview of the Indian scene. Indian J Med Res. 2005; 121: [PubMed: ] 3. Ramsay R, Gerenia GK. CNS complications of AIDS: CT and MRI findings. Am J Radiol. 1988; 151: Ramsay R, Gean AD. Central nervous system Toxoplasmosis. Neuroimaging Clinics of North America. 1997; 7: [PubMed: ] 5. Navia BA, Petito CK, Gold JWM, Cho E, Jordan BD, Price RW. Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: clinical and neuropathological findings in 27 patients. Ann Neurol. 1986; 19: [PubMed: ] 6. Enzmann DR, Brant-Zawadzki M, Britt RH. CT of central nervous system infections in immunocompromised patients. Am J Neuroradiol. 1980; 1: Chang L, Cornford ME, Chiang FL, Ernst TM, Sun NCJ, Miller BL. Radiologic-pathologic correlation. Cerebral toxoplasmosis and lymphoma in AIDS. Am J Neuroradiol. 1995; 16: [PubMed: ] 8. Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clinical Radiology. 2006; 61: [PubMed: ] 9. Hansman Whiteman, ML.; Holz, AJ. CNS manifestations of AIDS. In: Reeders, JWAJ.; Goodman, PC., editors. Radiology of AIDS: practical approach. Berlin: Springer; p Brightbill TC, Post JDM, Hensely GT, Ruiz A. MR of Toxoplasma encephalitis: signal characteristics on T2 weighted images and pathologic correlation. J Computer Assisted Tomography. 1996; 20: Rumboldt Z, Thurnher MM, Gupta RK. Central nervous system infections. Semin Roentgenol. 2007; 42: [PubMed: ]

5 Sharath Kumar et al. Page 5 Fig.1. Post-contrast T1-weighted coronal image shows characteristic eccentric target sign of cerebral toxoplasmosis in right superior frontal gyrus (a, arrow). T2 weighted image highlights alternating hyper and hypointense zones (b, arrow) with marked perilesional edema. Corresponding coronal slice of the brain highlights organizing abscess enclosing a sulcus (c, arrow) with surrounding edema. Note vessels traversing the sulcus. Another similar lesion is noted in superior parietal lobule (d, arrow) with close up view and whole mount preparation (e) showing a curved vessel (e, arrow) passing through the sulcus encircled by the Toxoplasma abscess. [e: Masson trichrome x 8]

6 Sharath Kumar et al. Page 6 Fig.2. Lesion in right superior frontal gyrus (a) on histology shows an organizing abscess surrounding the depth of sulcus with concentric zones (b). The center has a vessel traversing the sulcus (asterix) bordered by zone of necrosis with surrounding edematous inflamed wall reflected in whole mount preparation (b,c). Thickened sclerosed vessels are evident traversing the sulcus (d, asterix) and thrombosed vessels in the necrotic center (e). Concentric bands of histiocytic aggregates are seen bordering the necrotic zone and the inflamed wall of the abscess highlighted by CD68 immunostaining (f,g). Leash of vessels forming the wall (h, arrowheads) corresponding to ring enhancement on imaging is highlighted by immunostaining to factor VIII related antigen of vascular endothelium. These vessels are inflamed and thickened (i) with tachyzoites of T gondii surrounding it (j, arrow head). [b:hex4, c:masson trichromex4, d:masson trichrome xobj.10, e:hexobj.20, f:cd68x4, g: CD68xObj.20, h:immunostain to Factor VIII related antigenx4, i:hexobj.20, j:immunostain for T gondii xobj.20] (n-necrosis, w-wall, v-vessel)