Journal of Hematology & Thromboembolic Diseases
Open Access

Discrimination between Toxoplasmic Encephalitis and Central Nervous System Lymphoma: An Updated Review

Shingen Nakamura^1* and Hirokazu Miki^{2 *}Correspondence: Shingen Nakamura, Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan, Email:

Author info »

Abbreviations

HIV: Human Immunodeficiency Virus; CNS: Central Nervous System; ML: Malignant Lymphoma; TE: Toxoplasmic Encephalitis; SPECT: Single Photon Emission Computed Tomography; FDG-PET/CT: 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography; CSF: Cerebrospinal Fluid; PCR: Polymerase Chain Reaction; AIDS: Acquired Immunodeficiency Syndrome; EBV: Epstein-Barr virus; PCNSL: Primary Central Nervous System Lymphoma; ²⁰¹Tl: 201Thallium; SUV: Standardized Uptake Value

Introduction

Various opportunistic infections can develop in compromised hosts. Differential diagnosis of Central Nervous System (CNS) lesions includes Malignant Lymphoma (ML), metastatic tumors, and infectious diseases. Diseases that form space-occupying lesions are difficult to diagnose. Standard treatments for Primary CNS Lymphoma (PCNSL) and Toxoplasmic Encephalitis (TE) are quite different; therefore, their discrimination is critical. These diseases tend to develop in patients with Human Immunodeficiency Virus (HIV) infection. Therefore, the importance of considering and ruling out HIV infection when suspecting certain conditions like TE (Toxoplasma Encephalitis) or PCNSL (primary central nervous system lymphoma). Both TE and PCNSL are more likely to manifest in individuals with weakened immune systems, and HIV infection can significantly compromise the immune system. Therefore, in diagnosing TE or PCNSL, it's essential to evaluate for HIV infection as it could be a contributing factor or a potential cause for the compromised immune state leading to these conditions. By excluding HIV infection from consideration, healthcare professionals can ensure a more accurate diagnosis and appropriate management of patients presenting with symptoms suggestive of TE or PCNSL. Toxoplasmosis is transmitted to humans through the ingestion of infectious oocytes from the soil or feces of cats and insufficiently heated meat of infected animals. Toxoplasma gondii infection is prevalent in approximately one-third of the global population [1]. After the initial acute infection, the latent infection persists throughout the life of the host. Immunocompromised individuals, such as HIV-infected patients with CD4 count <100/μL, tend to have reactivation mostly in the CNS [2]. In addition, TE rarely occurs in immunosuppressed patients such as recipients of hematopoietic stem cell transplantations. Here, we summarize the options for diagnosing and discriminating between TE and ML in HIV-infected patients.

Malignant lymphoma is known as one of the defining diseases that occur in AIDS patients. PCNSL can develop in both immunocompetent and immunosuppressed patients 63% of PCNSL cases develop in immunocompetent individuals [3]. However, individuals with AIDS have a noticeably increased risk of malignancies, such as diffuse large B-cell lymphoma (98-fold compared with the general population) and CNS lymphoma (5,000-fold) [4]. Brain biopsy is the gold standard method for diagnosis; however, it is invasive and is not possible to perform for all locations. Additionally, TE is likely to develop in HIVinfected individuals; therefore, it is important to differentiate between TE and PCNSL. Furthermore, at the point of treatment, anti-parasitic therapy is the best treatment for TE, and HD-MTX-based systemic chemotherapy is essential for PCNSL. A study showed that the median Overall Survival (OS) was 0.3 years in HIV-associated PCNSL, both with and without chemotherapy (when analyzed limited to patients who received chemotherapy, the median OS was 1.5 years) [5]. Therefore, diagnostic delay leads to worse prognosis in HIV-associated PCNSL.

Literature Review

Here, we summarize the options for diagnosing and discriminating between TE and ML in HIV-infected patients (Table1).

Table1: Options for discrimination between TE and PCNSL. Note: Magnetic resonance imaging (MRI); Single Photon Emission Computed Tomography (SPECT); 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT); Cerebrospinal Fluid (CSF); Polymerase Chain Reaction (PCR); Acquired Immunodeficiency Syndrome (AIDS); Epstein-Barr virus (EBV); Primary Central Nervous System Lymphoma (PCNSL); 201Thallium (²⁰¹Tl); Standardized Uptake Value (SUV).

Imaging

CNS lesions in patients with AIDS may include PCNSL, mycobacterial infection, cytomegalovirus encephalitis, cryptococcosis, bacterial abscesses, metastatic cancer, and, uncommonly, progressive multifocal leukoencephalopathy. Brain magnetic resonance imaging is often performed as a first-line diagnostic imaging modality. Both TE and PCNSL lesions are enhanced by contrast agents and appear ring shaped. Therefore, other modalities must be considered for more accurate discrimination (Table1).

Single Photon Emission Computed Tomography (SPECT)

²⁰¹Tl-SPECT is frequently performed to differentiate CNS lesions. Some studies have reported discrimination based on the uptake of Tl, CNS mass number/size, and other parameters in combination. Miller et al. reported a discrimination method for patients with AIDS using a combination of ²⁰¹Tl uptake and number of CNS lesions. Isolated lesions with the uptake of ²⁰¹Tl indicated PCNSL, whereas lesions without the uptake indicated TE. In patients with multiple lesions and high ²⁰¹Tl uptake (uptake ratio>2.9), all lesions were of PCNSL, and ²⁰¹Tl uptake of all lesions in patients with TE was 2.1 [6]. Lorberboym et al. reported discrimination between PCNSL and TE by combining the uptake and retention indices of ²⁰¹Tl [7]. If the lesion had accumulated ²⁰¹Tl in the early phase, a low retention index suggested a benign lesion, and the retention index, in addition to the early uptake of ²⁰¹Tl, increased the specificity of malignant lesions [7]. Robert TC, et al. [8], reported differentiation between lesion size and Tl index; the Tl index is a significant predictor of malignancy in lesions ≥ 2 cm (P<0 .01) with 100% sensitivity and 89% specificity but is not a significant predictor of malignancy in lesions <2 cm. However, there are some exceptions. We experienced a case with HIV infection with multiple brain lesions [9]. One of the CNS lesions had high ²⁰¹Tl uptake with a T/N ratio of 3.034 and a retention index of 0.9, while the others had low ²⁰¹Tl uptake and retention; therefore, we suspected synchronous development of PCNSL with TE. We biopsied both the high- and low-retention index lesions, but they were eventually diagnosed as TE [9]. Discrimination between ML and TE remains challenging in SPECT.

18F-Fluorodeoxyglucose-Positron Emission Tomography/ Computed Tomography (FDGPET/ CT)

FDG-PET/CT is widely used in clinical practice, particularly in oncology. FDG-PET/CT is useful in discriminating between PCNSL and TE. A previous study reported that the usefulness of the Standardized Uptake Value (SUV)_max of the lesion was significantly lower in cerebral toxoplasmosis or tuberculoma than in PCNSL (SUV)_max, 3.5 (1.9-5.8) vs. 18.8 (12.4-29.9) [10].

Discussion

Cerebrospinal Fluid (CSF) test

Polymerase Chain Reaction (PCR) of CSF has high specificity (100%) but low sensitivity (50%-60%) for detecting toxoplasmosis [11,12]. However, the availability of PCR tests may be limited in clinical practice. A study reported a combined approach using ²⁰¹Tl-SPECT and Epstein Barr Virus (EBV) DNA in the CSF of 13 patients with PCNSL and 18 patients without tumors [13]. In PCNSL patients, a ²⁰¹Tl lesion/ background ratio <1.95 was found only in one case, and EBV DNA was never detected in patients without neoplasms; therefore, the presence of increased uptake and/or positive EBV DNA had 100% sensitivity and 100% negative predictive value for the diagnosis of PCNSL [13]. Therefore, PCR testing for EBV DNA and Toxoplasma may aid in the final diagnosis.

Serological test

In most patients with reactivation of Toxoplasma, both serum IgM and IgG antibodies against Toxoplasma gondii are positive; however, false-negative serological IgM results rarely occur and are typically observed in patients who are significantly immunocompromised [14]. Moreover, the absence of IgG antibodies does not completely exclude the possibility of TE in immunocompromised individuals.

Therapeutic diagnosis

Empiric diagnostic treatment is performed if the patient has a CD4 count of <100/μL, without prophylaxis for toxoplasmosis, with compatible clinical features, positive T. gondii IgG antibody, and typical brain imaging, such as multiple ringenhancing lesions. If these criteria are present, there is a 90% probability that the diagnosis is TE [15,16]. A study reported on 136 consecutive patients with HIV infection who presented with focal CNS lesions [17]. Following 3 weeks of empiric therapy for TE, brain biopsy was performed in patients with progression. The probability of TE was 0.87 in Toxoplasma-seropositive patients with a mass effect, who were not treated with trimethoprim-sulfamethoxazole, but only 0.59 for those receiving prophylaxis. Thus, empirical therapy for toxoplasmosis may be considered as an alternative method to discriminate between PCNSL and TE in patients with characteristic radiographic findings.

Brain biopsy

Brain biopsy is the gold standard method for the diagnosis of focal lesions in the CNS; however, it is an invasive procedure that is influenced by the location of the lesions and whether a brain biopsy can be performed [17]. Therefore, rapid diagnostic procedures are required to differentiate between PCNSL and TE. Moreover, brain biopsies revealed inflammatory cell infiltration with a few toxoplasmas in our case [6]. Therefore, in addition to histological examination, PCR of biopsy specimens can aid in the diagnosis of TE.

Conclusion

We described the discrimination between TE and PCNSL diagnosis. These diseases develop in patients with HIV infection, and the status of HIV infection should be confirmed when TE or PCNSL is suspected. If the definitive diagnosis of CNS lesions in patients with HIV infection is uncertain, a combination of multiple tests, including MRI, SPECT, FDGPET/ CT, CSF test, PCR test, anti-parasitic therapy for TE (therapeutic diagnosis), and brain biopsy should be performed as soon as possible, which may aid in an accurate diagnosis and better prognosis.

Acknowledgement

We would like to thank editage proofreading services for the English language editing.

Conflicts of Interest

The authors declare no conflicts of interest associated with this manuscript.

Funding

No funding was received to assist with the preparation of this manuscript.

References

1. Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: From animals to humans. Int J Parasitol Parasites Wildl. 2000;30(12-13):1217-1258.

   [Crossref] [Google Scholar]

2. Belanger F, Derouin F, Grangeot-Keros L, Meyer L, HEMOCO and SEROCO study groups. Incidence and risk factors of toxoplasmosis in a cohort of human immunodeficiency virus-infected patients: 1988-1995. Clin Infect Dis. 1999;28(3):575-581.

   [Crossref] [Google Scholar] [PubMed]

3. D'Angelo CR. diagnostic, pathologic, and therapeutic considerations for primary CNS lymphoma. JCO Oncol Pract. 2024;20(2):195-202.

   [Crossref] [Google Scholar] [PubMed]

4. Brandsma D, Bromberg JE. Primary CNS lymphoma in HIV infection. Handb Clin Neurol. 2018;152:177-186.

   [Crossref] [Google Scholar] [PubMed]

5. Olszewski AJ, Fallah J, Castillo JJ. Human immunodeficiency virus‐associated lymphomas in the antiretroviral therapy era: Analysis of the National Cancer Data Base. Cancer. 2016;122(17):2689-2697.

   [Crossref] [Google Scholar] [PubMed]

6. Miller RF, Hall-Craggs MA, Costa DC, Brink NS, Scaravilli F, Lucas SB, et al. Magnetic resonance imaging, thallium-201 SPET scanning, and laboratory analyses for discrimination of cerebral lymphoma and toxoplasmosis in AIDS. Sex Transm Infect. 1998;74(4):258-264.

   [Crossref] [Google Scholar] [PubMed]

7. Lorberboym M, Wallach F, Estok L, Mosesson RE, Sacher M, Kim CK, et al. Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med. 1998;39(8):1366-1369.

   [Google Scholar] [PubMed]

8. Young RJ, Ghesani MV, Kagetsu NJ, DeRogatis AJ. Lesion size determines accuracy of thallium-201 brain single-photon emission tomography in differentiating between intracranial malignancy and infection in AIDS patients. Am J Neuroradiol. 2005;26(8):1973-1979.

   [Google Scholar] [PubMed]

9. Nakamura S, Hara K, Kobayashi T, Sumitani R, Oura M, Maeda Y, et al. Toxoplasmic encephalitis with high ²⁰¹Tl uptake and retention mimicking malignant lymphoma in a patient with human immunodeficiency virus infection. Parasitol Int. 2024:102895.

   [Crossref] [Google Scholar] [PubMed]

10. Lewitschnig S, Gedela K, Toby M, Kulasegaram R, Nelson M, O’Doherty M, et al. 18F-FDG PET/CT in HIV-related central nervous system pathology. Eur J Nucl Med Mol Imaging. 2013;40:1420-1427.

    [Crossref] [Google Scholar] [PubMed]

11. Roberts TC, Storch GA. Multiplex PCR for diagnosis of AIDS-related central nervous system lymphoma and toxoplasmosis. J Clin Microbiol. 1997;35(1):268-269.

    [Crossref] [Google Scholar] [PubMed]

12. Tachikawa N, Goto M, Hoshino Y, Gatanaga H, Yasuoka A, Wakabayashi T, et al. Detection of Toxoplasma gondii, Epstein-Barr virus, and JC virus DNAs in the cerebrospinal fluid in acquired immunodeficiency syndrome patients with focal central nervous system complications. Intern Med. 1999;38(7):556-562.

    [Crossref] [Google Scholar] [PubMed]

13. Antinori A, De Rossi G, Ammassari A, Cingolani A, Murri R, Di Giuda D, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol. 1999;17(2):554-560.

    [Crossref] [Google Scholar] [PubMed]

14. Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis. 2002;185(Supplement_1):S73-S82.

    [Crossref] [Google Scholar] [PubMed]

15. Cohn JA, McMeeking A, Cohen W, Jacobs J, Holzman RS. Evaluation of the policy of empiric treatment of suspected Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Am J Med. 1989;86(5):521-527.

    [Crossref] [Google Scholar] [PubMed]

16. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis. 1992;15(2):211-222.

    [Crossref] [Google Scholar] [PubMed]

17. Antinori A, Ammassari A, de Luca A, Cingolani A, Murri R, Scoppettuolo G, et al. Diagnosis of AIDS-related focal brain lesions: A decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997;48(3):687-694.

    [Crossref] [Google Scholar] [PubMed]