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Reactivated Toxoplasmic Encephalitis-A case report with histopathology, ultrastructure and pathogenesis analysis

1 Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Department of Infectious Diseases, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

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Date of Submission24-May-2021
Date of Acceptance16-Jul-2021
Date of Web Publication07-Jun-2022


We report a patient who developed reactivated toxoplasmic encephalitis due to human immunodeficiency (HIV)-associated immune compromise, resulting in a breakdown of the balance between the host immunity and toxoplasma cyst. Through detailed pathological analysis, spilling of tachyzoites from the ruptured wall of toxoplasma cyst can be identified. It was also proved that Toxoplasma gondii would infect endothelial cells of blood vessels, leading to vasculitis and brain ischemic necrosis. By transmission electron microscope (TEM), apical complex of the parasite can be identified, as well as tachyzoites in rapid reproduction through fission. Rhoptry, a club-shaped specialized organelle, which is characteristic of the motile stages of Apicomplexa protozoans, was also identified. The prevention of toxoplasma infection is still an issue to be emphasized in public health. This article is special in its pathophysiology-based description of the morphology. 'Form ever follows function' is a famous quote from the architect Louis Sullivan. In this case report, we make effort to depict a pathophysiology-based or a 'form-function correlation' interpretation of the histopathological findings by light microscope, IHC and ultrastructural examination. We believe such an approach should also be included in the daily pathology resident training program.

Keywords: Electron microscope, encephalitis, Toxoplasma gondii, toxoplasmosis

How to cite this URL:
Wu SR, Liang JS, Weng YW, Wang JS. Reactivated Toxoplasmic Encephalitis-A case report with histopathology, ultrastructure and pathogenesis analysis. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Feb 5]. Available from:

   Introduction Top

Most cases with acquired toxoplasmosis infection do not have apparent symptoms, but reactivation of the latent infection might occur for those with compromised immunity or under immunosuppressive treatment, with brain being the most susceptible site.[1] We report a case of reactivated toxoplasmic encephalitis by brain biopsy, with detailed histopathology, ultrastructural, and pathogenesis analysis.

   Case Report Top

A 29-year-old men lost consciousness for seconds after falling from two stories height, with spontaneous recovery. He was sent to the emergency department of nearby hospital, receiving wound suture and computed tomography (CT) scan of brain. There was no specific finding through brain CT examination and he was discharged under stable condition. Two days later, he started presenting with blurred vision and intermittent headache. There was no fever, nausea, photophobia, or limb movement abnormality. Twenty-five days later, due to persistent visual blurriness, he went to the emergency department of Kaohsiung Veteran General Hospital for help. Bilateral right hemianopia was noticed through physical examination.

The initial blood test revealed pancytopenia as follows: WBC: 3200/μL; Hemoglobin: 9.6 g/dL; Platelet: 148000/μL. A 4.2 cm sized lesion at left occipital lobe was identified on brain CT image, with suspicion of high-grade glioma, hematoma, or abscess formation [Figure 1]a. The patient then received brain magnetic resonance image (MRI) examination which being more in favor of multifocal brain abscess instead of intracerebral hemorrhage [Figure 1]b. Owing to pancytopenia with absolute lymphocyte count lower than 1500 cell/mm3, as well as multifocal brain abscess with unknown etiology, HIV-1 was checked and demonstrated HIV-1 infection. HIV-1 viral load was 2,240,000 copies/mL. The CD4 count was 46.8 cells/mm3 and acquired immune deficiency syndrome (AIDS) was confirmed. Opportunistic infection of brain, such as Cryptococcus neoformans and T. gondii, was considered. HIV-associated lymphoma was also considered in AIDS patient with brain space-occupying lesion. For decompression and differential diagnosis, debridement and biopsy of the left occipital lobe lesion were performed. Through hematoxylin and eosin stain, Toxoplasma cyst was seen [Figure 2]a, and revealed positive for T. gondii specific IHC stain [Figure 2]b. Part of the formalin-fixed, paraffin-embedded tissue blocks was retrieved for transmission electron microscopy (TEM) examination, and intracellular tachyzoites were identified [Figure 2]c. The final diagnosis was reactivated toxoplasmic encephalitis. During admission, antibiotics with Trimethoprim/Sulfamethoxazole (TMP/SMX) were administered for toxoplasmosis. Anti-retroviral therapy was administered as well for HIV infection. After stabilization, the patient was discharged with oral antibiotics (TMP/SMX) for 10 weeks for treatment of toxoplamic encephalitis, and later on as secondary prophylaxis. The follow-up brain CT and MRI disclosed regression of the cerebral Toxoplasmosis [Figure 1]c and [Figure 1]d.
Figure 1: Pretreatment images. (a) Diffuse white matter edema in left temporal-occipital-parietal lobes, with mass effect (arrow) (CT). (b) A lesion over left occipital lobe, with perifocal edema and mass effect (arrow) (MRI). Post-treatment images. (c) Remission of edema after treatment (CT). (d) Partial regression of Toxoplasmic encephalitis after treatment (MRI)

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Figure 2: Toxoplasma reactivation. (a) Toxoplasma cyst in brain with cyst wall (arrow) may contain hundreds of bradyzoites (H & E, ×400). (b) Toxoplasma cyst positive for T. gondii-specific immunostain (IHC, ×400). (c) Multiple tachyzoites, some under fission, in an infected host cell (TEM). (d) Reactivation leading to cyst rupture (arrows) and spilling of the tachyzoites. Marcophages with engulfted tachyzoites (circles) (H & E, ×1000). (e) Tachyzoites spilling out from ruptured cyst (arrow) (PAS, ×1000)

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   Discussion Top

Pathological analysis of parasite with associated immune response

One-third of HIV-infected patients whose CD4 count is less than 100 cells/mm3, toxoplasmosis reactivation occurs. The presence of a toxoplasma cyst indicates a latent infection.[2] Inside a Toxoplasma gondii cyst are hundreds of bradyzoites. Bradyzoites are a slow-growing form of the parasite, and by cyst formation, may incubate in the brain cells for a long period of time, especially in the neurons which serve as immune privilege sites for the parasites. The neurons are not good at processing and presenting antigen, due to lack of MHC class I and class II immune-related molecules.[3] With neuronal infection, the host's behavior would also be manipulated by the parasites. The bradyzoites reach a delicate balance with the host immune system and may persist in the cells for years and even decades in the latent period, analogous to an armed peace. However, after the breakdown of the host-immune system, the slow-growing bradyzoites will transform into fast-growing tachyzoites, leading to cyst rupture with numerous tachyzoites swarming out from the cyst [Figure 2]d and [Figure 2]e. The breakpoint of cyst wall can be better identified through periodic acid-Schiff's stain [Figure 2]e. The parasite starts infecting surrounding host cells with rapid intracellular proliferation, resulting in cellular death. As infection and proliferation keep going on, the number of tachyzoites would increase tremendously in a short period of time. Enormous tachyzoites can be seen in the brain tissue by the IHC stain [Figure 4]a. Balance between the host and the parasite collapsed, turning to a fierce battle from the cold war status.
Figure 3: (a) Disrupted activated T. cyst (arrow), with released tachyzoites (circles) and inflammation (H & E, ×1000). (b) Neutrophils with engulfed tachyzoites (×1000). (c) Infected neurons (arrows) with cell lysis (lower) and released tachyzoites (x1000). (d) Many plasma cells (×400). (e) Necrotizing vasculitis. (f) Numerous Toxoplasma remnants in necrotic brain tissue (some indicated by circles) (×400). G: Endotheliitis with perivascular lymphoid cuffing mimicking lymphoma (×400)

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Figure 4: Immunohistochemical (IHC) stains. (a) Numerous parasites identified by T. gondii IHC stain. (b) Positive T. gondii in blood vascular endothelial cells (IHC, ×400). (c) Dense CD3-positive T-cells in the inflammatory infiltrate. (d) Lesser amount of CD20-positive B-cells in the inflammatory infiltrate (IHC, ×400)

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The host cells embark on a series of immune reaction. The white blood cells, for example, neutrophils and monocytes, move toward and attack the tachyzoites that break the cyst [Figure 3]a. The released tachyzoites are engulfed by macrophages [Figure 2]d and neutrophils [Figure 3]b. The infected cells, such as neurons, are eventually lysed with release of more parasites into the periphery [Figure 3]c. Aside from the aforementioned immune cells, antibody-generating plasma cells also join the battle [Figure 3]d. The parasites also infect endothelial cells and cause necrotizing vasculitis [Figure 3]e with red blood cells extravasation, and ischemic brain tissue necrosis. Numerous remains of the parasites can be seen within the necrotic brain tissue as if a cruel fight had occurred [Figure 3]f.

Pathological differential diagnosis

Under light microscopy, endotheliitis with concentric multilayered perivascular lymphoid cuffing similar to lymphoma was seen, and may lead to misdiagnosis as a lymphoma [Figure 3]g. Presence of mixed population of inflammatory cells and T. gondii can be of great help for the correct diagnosis. The best way is to use IHC stain with T. gondii specific antibody [Figure 4] and [Figure 4]b. Among the mixed population of the inflammatory cells, T lymphocytes outnumber B cells [Figure 4]c and [Figure 4]d.

Ultrastructural characteristics and parasitic strategies of Toxoplasma gondii

Under TEM, tachyzoites were seen in single host cell with rapid reproduction through fission manner [Figure 2]c. Apical complex [Figure 5]a of the parasite can also be identified; however, the ultrastructure was not well-preserved due to limitation of the paraffin block tissue. Toxoplasma gondii can penetrate cell membrane of host cell by apical complex and then reside inside of it. After penetrating intestinal mucosa, through the infected dendritic cells and white blood cells, the parasites can migrate and translocate within brain tissue. Generally speaking, T. gondii cannot penetrate blood brain barrier (BBB). Then how does it work? Some studies indicate that the parasite can penetrate BBB by infecting endothelial cells.[4] The hypothesis is supported by identifying many parasites in the endothelial cells of blood vessel in this case by IHC stain [Figure 4]b. After reaching brain tissue, T. gondii can then disseminate fast within brain through infected microglia.
Figure 5: Transmission electron microscopy (TEM) retrieved from paraffin-embedded block. (a) Apical complex (circle), the special organelle of Apicomplexa. (b) Rhoptries (circle), the special rod-shaped secretion organelles of tachyzoite. (c) Reproduction of intracellular tachyzoite through binary fission (arrow), splitting into two tachyzoites. (d) Magnification view of the splitting tachyzoite

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Sexual reproduction occurs in intestine of Feline but no other intermediate hosts. One study indicates that the lack of enzymatic reactivity of delta-6-desaturase in the guts of feline animals would lead to accumulation of linoleic acid, which promotes sexual reproduction of the T. gondii in their definite hosts.[5] Through sexual reproduction, two millions to twenty millions of oocysts would be excreted in the feces of a cat each day for 5-10 days. Asexual reproduction is applied by the parasite in intermediate hosts through fission [Figure 5]c and [Figure 5]d. The bradyzoites incubate in the cyst with a long period through extremely slow growth and autophagy-digestion of aged/impaired organelle by lysosomes.[6] Rhoptry, a club-shaped organelle, is a specialized secretory organelle characteristic of motile stages of apicomplexa protozoans, including T. gondii [Figure 5]b.[7] The inner content of the rhoptry would be released into a new host cell, and the proteins it contains can promote the interaction between the host cell and the parasite, including the formation of parasitophorous vacuole.[8] Interestingly, the intermediate host of the parasite would also have certain degree of behavioral change, being more inclined to take risks. The infected mice would get close to the territory of cat instead of fleeing from it.[9],[10] The infected chimpanzee would also be fond of smelling or licking the urine of leopard, a feline animal.[11] Such behavioral changes prompt the intermediate host to approach feline animal and then be hunted as a prey and ingested, a process helpful for completion of reproductive life cycle of the T. gondii. According to statistic data, about 1/3 of the global population have been infected by T. gondii. However, it seems a dead end for this parasite to reside in human as there is no way of modern human to be hunted or ingested by feline animal. Then how come the infection rate is still so high? From the point of revolution, human were used to be the prey of feline animals, such as leopard and cougar, before we become hunters later.[12] The high infection rate of human by this parasite, even nowadays, might be some sort of imprint of the revolution.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Goncharov DB, Gubareva EV, Kobets NV, Domonova EA, Ievleva ES. [Toxoplasmosis in HIV infection: Invasion reactivation criteria]. Zh Mikrobiol Epidemiol Immunobiol 2012;:88-92.  Back to cited text no. 1
Pittman KJ, Knoll LJ. Long-term relationships: The complicated interplay between the host and the developmental stages of Toxoplasma gondii during acute and chronic infections. Microbiol Mol Biol Rev 2015;79:387-401.  Back to cited text no. 2
Blanchard N, Dunay IR, Schlüter D. Persistence of Toxoplasma gondii in the central nervous system: A fine-tuned balance between the parasite, the brain and the immune system. Parasite Immunol 2015;37:150-8.  Back to cited text no. 3
Franklin-Murray AL, Mallya S, Jankeel A, Sureshchandra S, Messaoudi I, Lodoen MB. Toxoplasma gondii dysregulates barrier function and mechanotransduction signaling in human endothelial cells. mSphere 2020;5:e00550-19. doi: 10.1128/mSphere. 00550-19.  Back to cited text no. 4
Martorelli Di Genova B, Wilson SK, Dubey JP, Knoll LJ. Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction. PLoS Biol 2019;17:e3000364.  Back to cited text no. 5
Martorelli Di Genova B, Wilson SK, Dubey JP, Knoll LJ. Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction. PLoS Biol 2019;17:e3000364.  Back to cited text no. 6
Boothroyd JC, Dubremetz JF. Kiss and spit: The dual roles of Toxoplasma rhoptries. Nat Rev Microbiol 2008;6:79-88.  Back to cited text no. 7
Bradley PJ, Ward C, Cheng SJ, Alexander DL, Coller S, Coombs GH, et al. Proteomic analysis of rhoptry organelles reveals many novel constituents for host-parasite interactions in Toxoplasma gondii. J Biol Chem 2005;280:34245-58.  Back to cited text no. 8
Kaushik M, Knowles SC, Webster JP. What makes a feline fatal in Toxoplasma gondii's fatal feline attraction? Infected rats choose wild cats. Integr Comp Biol 2014;54:118-28.  Back to cited text no. 9
Berdoy M, Webster JP, Macdonald DW. Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci 2000;267:1591-4.  Back to cited text no. 10
Poirotte C, Kappeler PM, Ngoubangoye B, Bourgeois S, Moussodji M, Charpentier MJ. Morbid attraction to leopard urine in Toxoplasma-infected chimpanzees. Curr Biol 2016;26:R98-9.  Back to cited text no. 11
Hart D, Sussman RW. Man the Hunted: Primates, Predators, and Human Evolution. American: Perseus Books Group; 2005.  Back to cited text no. 12

Correspondence Address:
Jyh-Seng Wang,
Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung City
Ya-Wei Weng,
Department of Infectious Diseases, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_463_21


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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