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Neuroradiology Case of the Week

Case 74

Deepa Popuri, Rose Ketonen, Leena M. Ketonen, MD, PhD,
Vaseem Chengazi, MD, PhD, Amy Harrow, MD,
and P-L Westesson MD, PhD, DDS

Clinical Presentation:
HPI: Patient is a 36-year-old female who presents with left lower extremity weakness, ataxia, and chronic falling. She has slurred speech and increased difficulty finding words. She also suffers from pain in lower back, hip, and knees. Patient has history of HIV, with CD4 count of 95 and viral load>100,000.
PMH: She has history of chronic right upper extremity and global weakness. She also has history of neuropathy, incontinence, hypertension, hypothyroidism, valvular dysplasia, renal insufficiency, depression, and panic disorder. She has had numerous infections including meningitis, LLB pneumonia, and varicella.
Social History: Patient currently smokes and used IV drugs in the past.
Family History: Her mother has diabetes and her father suffers from Alzheimer’s disease.
Physical Exam: Patient continues to suffer from existing right upper extremity and global weakness. She is unable to walk. She has decreased sensation to knee and wrists bilaterally. She has elevated liver enzymes (AST=158,ALT=124) and toxic antigen titer=8192.

Radiological, Pathological, and Clinical Findings:  
Head CT 6/2/03:  There is a left frontal lobe ring-enhancing lesion measuring 2.3 cm (AP) x 1.8 cm (T), surrounded by a significant amount of vasogenic edema, which is producing mass effect over the adjacent structures and effacing the overlying sulci, partially collapsing the left frontal lobe and producing subfalcine herniation towards the right.
     A second area of vasogenic edema is visualized in the right corona radiata and right centrum semiovale; a ring-enhancing lesion is not visualized.
    There is minimal prominence of the ventricular system, sulci, and basal cisterns, consistent with mild diffuse volume loss. Anti-toxoplasmosis treatment is implemented.
MR Head, MR Spectroscopy 6/5/03: T2 and FLAIR hyperintensities are seen at the left frontal lobe and right parietal lobe with mass effect on the left frontal horn of the lateral ventricle and right occipital horn respectively due to vasogenic edema (Fig. 1).
    Post-contrast study shows ring-enhancing lesions measuring 2.8 (AP) x 2.2 (T) x 2.7 (CC) cm at the left frontal lobe and 2.8 (AP) x 2.2 (T) x 2.6 (CC) cm at the right parietal lobe (Fig. 1B). No other enhancing lesion is seen.
    MR spectroscopy reveals increase in choline (Cho) peak with decrease in N-acetyl-aspartate (NAA) peak suggesting of a tumor process such as lymphoma in voxels placed at the left frontal lobe lesion. Procedure not performed in right parietal lobe lesion because patient could not finish second spectroscopy.
Thallium SPECT Scan 6/9/03:  There are foci of thallium avidity in the left frontal and right parietal regions which correspond to the areas of abnormality on the MR examination. Pattern of thallium uptake on this examination is suggestive, but not unequivocally conclusive, of lymphoma.
Lumbar puncture 6/11/03:  Numerous lymphocytes and occasional neutrophils present in the CSF.
MR Head 6/19/03: There is significant improvement in both cortical lesions with decreased mass effect and ring-enhancement (Fig. 2A-C) while patient was on toxoplasmosis treatment. Patient exhibits improvement in speech and lower extremity weakness. Treatment for toxoplasmosis is suspended and patient is released.
6/20 Pt. suffers from 5-second seizure.
MR Head, MR Spectroscopy 7/1/03:  T1- weighted images show areas of high-signal in the left frontal lesion that may represent a tiny amount of hematoma or laminar necrosis. It may also be similarly seen on the right side. There is some degree of volume loss with dilatation of the third and lateral ventricles (Fig. 3A-C). The sizes of the lesions have not changed since the last MR study on 6/19/03.
    MR spectroscopy (MRS) through left frontal lesion shows increased Cho and decreased NAA. Cho/Cr ratio is larger than 2:1, suggesting a malignant process such as lymphoma (Fig 4A-C). MRS and increased uptake in thallium scan on 6/9/03 favor lymphoma over toxoplasmosis [7]. White matter MRS shows decreased NAA. This is consistent with ADC (AIDS Dementia Complex).
Surgical pathology 7/10/03:  Biopsy from right parietal lesion reveals nonspecific findings with possible reactive astrocytosis and mild chronic perivasculitis. There are vessels within the meninges and leptomeninges with lymphocytic aggregates.
    Toxo antibody stain is negative.

    Results clearly demonstrate the difficulties in making the differential diagnosis of various ring-enhancing lesions in immunocompromised patients.

Differential Diagnosis: Toxoplasmosis, lymphoma

     Three months later there is no indications of new intracranial mass lesions. Final diagnosis is considered to be toxoplasmosis.

Diagnosis: Toxoplasmosis

Discussion: 
Clinical Discussion: Brain lesions develop in 15-20% of all AIDS patients. The etiologies of these lesions from most to least common are toxoplasmosis, lymphoma, PML, and cryptococcomas. Toxoplasmosis is responsible for 33% of neurologically symptomatic cases while primary CNS lymphoma is responsible for 2-6% [1,2]. It is often difficult to diagnose lesions as toxoplasmosis as opposed to lymphoma due to their similar clinical and radiologic presentations.
Presentation:  Patients with toxoplasmosis or lymphoma may present similarly with focal symptoms involving sensory motor deficit or nonfocal symptoms such as headache, altered mental status, nausea, vomiting, and seizure. Fever, drenching night sweats, and weight loss are also common to both conditions. CNS lymphoma is associated with faster neurological deterioration. Toxoplasmosis may produce normal glucose or mildly high protein levels in CSF; a titer 1:256 or greater suggests recent infection. Lymphoma may result in low glucose or high protein levels in CSF [2,3].
Etiology/Pathology: Multiple lesions are more suggestive of toxoplasmosis, occurring in 70% of cases. Multiple lesions are less common in lymphomas, occurring in only 30% of cases [1]. Types of lymphoma include large cell, immunoblastic, noncleaving, and Burkitt’s lymphoma. Lymphoma lesion has central necrosis similar to necrotic abscess present in toxoplasmosis lesions [3,4]. Coagulative necrosis occurs in the innermost zone of the toxoplasmosis lesion and few organisms are present. The intermediate zone is hypervascular with a large number of inflammatory cells, tachyzoites, and encysted organisms. Encysted organisms and vasogenic edema surround the intermediate zone [5]. Despite the different cellular composition of toxoplasmosis and lymphoma, separating the two radiologically can be difficult. Note that it is possible for toxoplasmosis to grow within lymphoma [1].
Treatment: A solitary mass that is hypointense on T2WI or ADC<1.0 should increase suspicion of lymphoma as opposed to toxoplasmosis [3,6]. Routine management of AIDS patient with questionable diagnosis of toxoplasmosis versus lymphoma involves initiation of toxoplasmosis treatment. MR and CT studies follow on a serial basis to monitor response to treatment. Note that decrease in enhancement may be due to steroid effect, injection rate, or time of imaging. Edema and mass effect in addition to enhancement must be examined to assess treatment response [3]. If patient does not improve, a biopsy for lymphoma is indicated. MR spectroscopy and thallium study may also help in making lymphoma diagnosis and localizing lymphoma from other concurrent lesions prior to surgery. Early CNS radiotherapy after an early biopsy improves survival rates for lymphoma patients. The differentiation of toxoplasmosis vs. lymphoma is critical to management of the patient since neurological deterioration in lymphoma can be rapid and devastating [2,6].
Neuroimaging Discussion:  Toxoplasmosis lesions rarely show hyperattenuation while lymphoma appears isodense or moderately hyperdense on noncontrast CT. With contrast, toxoplasmosis shows solitary or multiple ring-enhancement with edema and smaller lesions (<1 cm) may show uniform hyperattenuation throughout; lymphoma lesion demonstrates strong homogeneous enhancement in immunocompetent individuals while nonhomogeneous ring-enhancement may occur in AIDS patients [3,5].
     Both toxoplasmosis and lymphoma lesions are hypointense on MR T1WI. Surrounding edema may be of lower intensity. Toxoplasmosis or lymphoma may have a hyperintense core on noncontrast FLAIR and T2WI. Toxoplasmosis demonstrates less ring-enhancement than lymphoma after administration of gadolinium. Enhancement of lymphoma is more heterogeneous and nodular in AIDS patients than in immunocompetent individuals. T2WI and FLAIR are useful for detection of multiple lesions. Although multiple lesions may occur in either condition, presence of thick walled, solitary lesion favors lymphoma [3,5]. Mass effect and edema tend to be less pronounced in lymphoma as compared to toxoplasmosis lesion [4]
     Subependymal, periventricular, and corpus callosum lesions favor lymphoma. Subependymal cases may appear to encase a portion of the ventricle. Toxoplasmosis lesions are more likely to occur at the corticomedullary junction or basal ganglia. These lesions will appear to resolve after to 2-4 weeks of anti-toxo treatment. Residual encephalomalacia, calcification, and focal atrophy may occur [2,3].
     ADC mapping reveals restricted diffusion in lymphoma due to high cellularity. It has been proposed that ADC value<1.0 should increase suspicion of lymphoma and indicate biopsy [6].
     MR spectroscopy reveals increased choline peak in lymphoma reflecting increased membrane synthesis and turnover. Choline is decreased in toxoplasmosis due to cell loss. N-acetylaspartate peak, which is a measure of neuronal integrity, has greater decreases in toxoplasmosis than lymphoma. Myo-inositol, which is a precursor for second messenger systems, may be absent in toxoplasmosis and decreased in lymphoma [1,4]. Cho/Cr ratio larger than 2:1 suggests increased cell membrane turnover and thus malignant lesion [7].
     Thallium functional imaging study (T1-201) may be useful in toxoplasmosis versus lymphoma differentiation. Sensitivity ranges from 60-100%. Lymphoma diagnosis may be made after ring or solid homogeneous enhancement on CT, thick irregular ring surrounded by vasogenic edema on MRI, negative Toxo IgG, and increased T1-201 uptake. False negative results may occur if the size of the lesion is below the resolution of the SPECT gamma camera, if small lesion is in close proximity to highly active area, or there has been subtle, nonfocal spread of lymphoma to subependymal or leptomeningeal areas. The mechanism of T1-201 uptake in lymphoma may involve ATP dependent transport into actively dividing cells, increased vascular flow, and alteration in the blood-brain barrier [2].

References:

1. Chang L, Miller BL, McBride D, et al. Brain lesions inpatients with AIDS:H-1 MR spectroscopy. Radiology 1995;197:525-531.
2. Ketonen L, De La Pena RC, and Villanueva-Meyer J. MR and TL-201 SPECT imaging with pathologic correlation for the assessment of CNS lymphoma vs. toxoplasmosis in AIDS patients. Journal of Neuro-AIDS 1998;2:21-42.
3. Dina, TS. Primary central nervous system lymphoma versus toxoplasmosis in AIDS. Radiology 1991; 179:823-828.
4. Chinn RJS, Wilkinson ID, Hall Craggs MA, et al. Toxoplasmosis and primary central nervous system lymphoma in HIV infection: Diagnosis with MR spectroscopy. Radiology 1995; 197:649-654.
5. Osborn A. Diagnostic Neuroradiology. St. Louis: CV Mosby, 1994.
6. Camacho DLA, Smith KJ, Castillo M. Differentiation of toxoplasmosis and lymphoma in AIDS patients by using apparent diffusion coefficients. AJNR 2003; 24:633-637.
7. Tien RD, Lai PH, Smith JS, and Lazeyras F. Single-voxel proton brain spectroscopy exam (PROBE/SV) in patients with primary brain tumors. AJR 1996; 167:201-209.