Teaching Case

A 25-year-old HIV-seropositive man presented with raised intracranial tension, seizures and multiple cerebral enhancing lesions on MR imaging.

A 25-year-old man presented with features of raised intracranial tension and seizures, which had been occurring over the past one month. Four months previously, he had been detected to be HIV seropositive during investigations for unexplained fever, weight loss and generalized lymphadenopathy. On physical examination, his vitals were stable and there were no signs of meningeal irritation. Fundoscopy was performed, which showed mild papilledema. A cerebrospinal fluid (CSF) analysis revealed normal glucose and protein levels and was negative for acid fast bacilli and fungal organisms. The CSF bacterial cultures were negative. His CD4 lymphocyte counts were 169/mm³ with a CD4: CD8 lymphocyte ratio of 0.14. MR imaging (Fig. 1) was done, which revealed the presence of multiple enhancing lesions involving the frontal lobes and the basal ganglia region. The MR spectroscopy of the right frontal lesion revealed a dominant lipid peak with the suppression of other metabolite peaks. A diffusion weighted MR imaging procedure revealed a hypointense center, suggestive of increased diffusion. The apparent diffusion coefficient (ADC) values of the center were 2.09 x 10-3 mm²/s with normalized ADC ratios of 2.64. On perfusion MR imaging, the right frontal lesion was found to be hypovascular. Serum IgG antibody titers for toxoplasmosis were found to be markedly raised and were considered strongly positive. Based on the radiological findings and the raised IgG antibody titers, a presumptive diagnosis of toxoplasmosis was made and the patient was treated with anti-toxoplasmosis therapy (a combination of sulfadiazine and pyrimethamine). The patient tolerated the therapy well and showed significant clinical improvement in the second week. Repeat MR imaging was performed (Fig. 2) after four weeks revealed a significant resolution of the lesions.

Toxoplasmosis gondii is an obligate intracellular protozoan and the most common organism affecting the brain in patients with the acquired immunodeficiency syndrome (AIDS) (1). Toxoplasmosis usually occurs due to the reactivation of latent infection as a consequence of immunosuppression. The neuropathological features of this disease consist of a multifocal necrotizing encephalitis. Less commonly, a diffuse encephalitic form is seen. Three stages of focal cerebral involvement have been described. Initially, the lesions consist of a mixture of free living tachyzoites and encysted organisms, with surrounding vascular reaction, inflammation and petechial hemorrhage. In the second stage after 2–4 weeks, a fibrous capsule forms around a necrotic center. The third stage consists of the formation of a chronic abscess in which necrosis and free organisms constitute most of the lesion. The T.gondii tachyzoites are better demonstrated with immunoperoxidase staining than with hematoxylin and eosin staining. The neurological manifestations of toxoplasmosis consist of headache, alteration of mentation, fever, seizures, focal neurological deficit, ataxia and cranial nerve deficits. The clinical presentation is usually subacute but may be acute and occurs when the CD4 lymphocyte levels fall below 200/mm³. The neuroimaging technique demonstrates the presence of multifocal cerebral enhancing lesions. Suggestive diagnostic features on conventional MR imaging are the presence of multiple rim-enhancing lesions having uniform thin walls, distributed typically at the cortico-medullary junction and basal ganglia with the absence of meningeal enhancement. The lesions show variable signal intensity on T2-weighted images and can have a target, ring or nodular appearance. Hyperintensity within the lesions in T2-weighted images has been shown to correlate histopathologically with the initial necrotizing encephalitis, while T2 iso-intensity suggests an organizing abscesses (2). On T1-weighted images, the lesions are hypointense to gray matter due to their necrotic nature. During the course of the disease or with treatment, the lesions often show focal hyperintensity on T1-weighted images due to petechial hemorrhage or calcification. On conventional contrast-enhanced imaging, the lesions typically show rim enhancement without any evidence of meningeal involvement. An asymmetric target sign resembling a pea pod has been described as a characteristic appearance of toxoplasmosis lesions. Toxoplasmosis needs to be differentiated from other diseases producing multifocal lesions in AIDS patients. The most notable of these is cerebral lymphoma. Lymphoma lesions in AIDS patients can have an atypical distribution and may show necrosis. Although a therapeutic trial of anti-toxoplasmosis treatment may help in differentiating toxoplasmosis from lymphoma, a significant number of toxoplasmosis lesions may reveal an evidence of improvement as late as six weeks after the start of the treatment. During such time, the lymphoma lesions can grow rapidly and cause a clinical deterioration. The other important condition that produces multiple cerebral focal lesions in AIDS patients is progressive multifocal leukoencephalopathy (PML). The absence of a mass effect and the lack of contrast enhancement helps in differentiating PML from toxoplasmosis and lymphoma. Advanced MR techniques of diffusion weighted imaging, MR spectroscopy, and perfusion MR imaging have been found useful in characterizing toxoplasmosis lesions. The MR spectroscopy procedure typically reveals a large lipid peak with the suppression of other metabolite peaks. The lipid peak has been related to the destructive nature of the lesions and super-added infiltration with lipid-laden macrophages. Although more commonly found in toxoplasmosis lesions, a lipid peak has also been reported from the center of necrotic lymphoma lesions in AIDS patients (3). The perfusion MR imaging technique can serve as an important tool for the diagnosis of toxoplasmosis and has been used to differentiate toxoplasmosis from lymphoma in AIDS patients. Toxoplasmosis lesions are seen to be extremely hypovascular on perfusion MR imaging, due to the lack of vasculature within the abscesses. Occasionally, a thin rim of low vascularity may be seen surrounding the lesions, as a consequence of the inflammatory response offered by the host. In contrast to toxoplasmosis, lymphoma lesions are usually hypervascular. Ernst et al. (4) reported significant differences between relative cerebral blood volume values of toxoplasmosis (44 ± 24%) and lymphoma lesions (258  99%). Diffusion weighted MR imaging has been reliably used to differentiate cerebral necrotic tumors from abscesses. Pyogenic abscess cavities reveal increased signal intensity on DWI due to restricted diffusion and have lower ADC values as compared to necrotic or cystic tumors. Toxoplasmosis lesions however, have increased rather than restricted diffusion, and higher central ADC values as compared to pyogenic abscesses. Diffusion MR imaging has also been recently demonstrated to reliably differentiate toxoplasmosis lesions from necrotic lymphoma lesions (5). The diagnosis of toxoplasmosis can be established on the basis of the radiological findings along with ancillary laboratory tests. The latter include the detection of rising titers of IgG antibodies to toxoplasmosis, detection of IgM antibodies in the first week of infection and polymerase chain reaction (PCR), and the detection of T. gondii DNA in the cerebrospinal fluid. A rapid clinical and radiological response to specific anti-toxoplasmosis therapy can also be considered as an important tool for diagnosis especially in patients with typical imaging features. Although the definite diagnosis can be established only with a histopathological examination, a brain biopsy is unappealing due to the associated morbidity and low life expectancy of the patients. Moreover, AIDS patients are known to have multiple lesions that may be of differing etiologies and a biopsy of each lesion may be impossible. Hence, biopsy is usually advisable for atypical lesions or lesions which do not resolve on specific antitoxoplasmosis therapy. Toxoplasmosis is treated with a combination of sulfadiazine and pyrimethamine for six weeks and subsequent life-long secondary prophylaxis to prevent recurrence. Primary prophylaxis is recommended especially when the CD4 lymphocyte counts fall below 100/mm³.