Journal of Health Care and Prevention
Open Access

Toxoplasma gondii; Toxoplasmic encephalitis; Neuroinflammation; Neurodegeneration; Seizure

Introduction

Toxoplasma gondii (T. gondii) is an intracellular protozoan parasite with a pronounced neurotropism, capable of infecting and persisting in neural tissues throughout the lifetime of its host [1]. It is one of the most prevalent parasitic infections globally, with a seroprevalence that suggests that up to one-third of the world’s population has been exposed this it [2]. Human infection occurs primarily through the ingestion of oocysts shed in the feces of infected felines, the definitive hosts, or through the consumption of undercooked meat containing tissue cysts. Additional routes include organ transplantation, blood transfusion, and vertical transmission from mother to fetus during pregnancy [3].

Once introduced into the host, T. gondii rapidly disseminates via the bloodstream and preferentially encysts in muscle and neural tissues, particularly within the brain. In immunocompetent individuals, the infection is usually asymptomatic or manifests as a mild, self-limiting illness resembling a flu-like syndrome. However, in immunocompromised hosts, especially those with advanced HIV/AIDS, undergoing chemotherapy, or receiving immunosuppressive therapy, reactivation of latent infection can result in life-threatening complications, most notably toxoplasmic encephalitis [4, 5].

Beyond the acute manifestations seen in immunodeficient patients, increasing evidence suggests that chronic or latent T. gondii infection may have insidious effects on the central nervous system. While much attention has been directed toward the parasite’s association with neuropsychiatric disorders, such as schizophrenia and bipolar disorder [6], its purely neurological impacts—independent of psychiatric sequelae—remain underappreciated in clinical practice and scientific literature. These include direct neuropathological outcomes such as focal or generalized seizures, chronic neuroinflammation, cerebrovascular events, and, potentially, a contributory role in neurodegenerative processes [7].

The persistence of T. gondii in neural tissues is facilitated by its ability to evade host immune responses, modulate cytokine signaling, and form cysts that are highly resistant to therapeutic eradication. These cysts can remain dormant for decades, maintaining a latent inflammatory environment within the brain and interfering with normal neuronal and glial function [8]. Furthermore, the parasite’s influence on neurotransmitter systems, mitochondrial metabolism, and synaptic integrity provides mechanistic insights into how chronic infection may subtly alter central nervous system (CNS) physiology [9].

This article aims to explore the non-psychiatric neurological implications of T. gondii infection. By examining the clinical syndromes associated with CNS toxoplasmosis, the immunological and molecular mechanisms that lay at the basis of the parasite persistence and pathogenicity, and the potential links to long-term neurological deterioration, this review highlights the urgent need for increased awareness, improved diagnostic strategies, and innovative therapeutic approaches to limit the burden of this often-overlooked neurotropic pathogen.

Material and Method

This article is structured as a narrative literature review, designed to synthesize existing scientific evidence on the neurological (non-psychiatric) consequences of T.gondii infection. The focus was placed on clinical manifestations such as toxoplasmic encephalitis, seizures, neuroinflammation, cerebrovascular complications, and potential neurodegenerative mechanisms, while explicitly excluding studies primarily addressing psychiatric or behavioral associations.

A comprehensive search was conducted across major biomedical databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering publications from 1990 to 2025. The search strategy used free-text terms using Boolean operators. The following keywords and phrases were used in various combinations: "T. gondii" AND "seizures" OR "epilepsy", "Toxoplasma gondii" AND "neuroinflammation", "CNS toxoplasmosis" AND "HIV" OR "immunosuppression", "T. gondii" AND "microglia" OR "astrocytes", "Toxoplasma" AND "neurodegeneration" OR "neuronal damage". Only articles published in English and appearing in peer-reviewed journals were considered. Additional studies were identified through manual searches of the reference lists of relevant publications.

To ensure relevance and quality, articles were selected based on the following inclusion criteria: studies investigating the direct neurological impact of T. gondii on the CNS, excluding psychiatric/behavioral endpoints, original research articles (in vivo, in vitro, clinical, and epidemiological studies), case series, and systematic reviews, studies involving both immunocompetent and immunocompromised human subjects, as well as relevant animal models, publications providing mechanistic insights into parasite-host interactions in neural tissue. We used as exclusion criteria: articles focusing primarily on psychiatric or behavioral disorders (e.g., schizophrenia, depression, risk behavior), studies unrelated to CNS involvement (e.g., ocular toxoplasmosis, congenital transmission without neurological discussion), non-peer-reviewed literature, editorials, or commentary pieces without original data extraction and synthesis.

Due to the heterogeneity of study designs and outcomes, a qualitative synthesis approach was adopted. Studies were categorized thematically based on their contribution to understanding acute neurological presentations, chronic CNS infection, and mechanistic pathways of neuroinflammation and neuronal damage. This allowed for an integrative discussion of how T. gondii may influence CNS integrity across different host immune statuses.

Results and Discussion

Mechanisms of CNS entry and persistence

The CNS is protected by the blood-brain barrier (BBB), a specialized endothelial structure that prevents pathogens from accessing the brain parenchyma. However, T. gondii is capable of breaching the BBB using several mechanisms. The parasite can infect endothelial cells directly, disrupt tight junction proteins, or exploit leukocytes as "TroJul horses" to cross into the CNS [10].

Once inside the brain, T. gondii forms tissue cysts predominantly in neurons and astrocytes. The parasite can manipulate host cell signaling to prevent apoptosis, ensuring long-term persistence [11]. These cysts may remain dormant for years but can reactivate under conditions of immunosuppression.

Toxoplasmic encephalitis and immunosuppression

Toxoplasmic encephalitis (TE) is the most well-recognized neurological manifestation of T. gondii, primarily occurring in immunocompromised patients. Clinically, TE presents with focal neurological deficits, seizures, headaches, altered mental status, and fever. Radiologically, TE is often characterized by multiple ring-enhancing lesions on MRI, most commonly located in the basal ganglia and corticomedullary junction [12].

The pathophysiology involves reactivation of latent bradyzoites into tachyzoites, leading to widespread tissue necrosis and inflammatory infiltrates. TE is a medical emergency and requires immediate treatment with pyrimethamine, sulfadiazine, and leucovorin to prevent fatal outcomes [4].

Seizures and epileptogenesis

1. gondii infection is increasingly associated with the development of seizures and epilepsy. The mechanisms are multifactorial and include chronic neuroinflammation, gliosis, disruption of neurotransmitter homeostasis, and direct cytotoxic effects on neurons [13].

Additionally, T. gondii may alter the expression of glutamate and GABA transporters, contributing to a pro-excitatory neural environment [14]. These findings underscore the importance of considering toxoplasmosis in the differential diagnosis of new-onset epilepsy, especially in endemic regions.

Neuroinflammation and immune-mediated damage

A hallmark of T. gondii CNS infection is robust neuroinflammation. The immune response involves activation of microglia and astrocytes, production of cytokines such as interferon-gamma (IFN-γ), and recruitment of peripheral immune cells. While these responses are essential for parasite control, excessive or chronic inflammation can lead to bystander neuronal damage and synaptic remodeling [15].

Recent work has shown that persistent low-level inflammation in the CNS due to latent T. gondii may contribute to subtle neurocognitive deficits and increased vulnerability to other neurodegenerative processes [16].

Neurodegeneration and long-term effects

Although acute encephalitis is the most dramatic manifestation, latent toxoplasmosis may also have long-term consequences. Studies in murine models demonstrate that even in the absence of overt symptoms, T. gondii cysts can interfere with synaptic signaling and dendritic spine morphology [17]. This subclinical damage has raised concerns about a possible link to progressive neurological conditions such as multiple sclerosis (MS) or Alzheimer's disease (AD), although direct causal relationships remain speculative.

One study found increased seroprevalence of T. gondii in patients with MS, possibly due to shared immune pathways or impaired pathogen clearance mechanisms [19]. However, more rigorous longitudinal research is needed to confirm these associations.

Diagnostic and therapeutic implications

Given the diagnostic limitations and therapeutic complexities, early detection and targeted treatment remain critical components in reducing morbidity and mortality associated with CNS toxoplasmosis.

Early detection of CNS toxoplasmosis remains a challenge, especially in resource-limited settings. Diagnosis typically involves neuroimaging, serology (IgG/IgM), and in some cases PCR detection of T. gondii DNA in cerebrospinal fluid (CSF). However, false negatives may occur in localized infections or immunosuppressed patients [3]. Antiparasitic therapy is highly effective when administered promptly, but latency and cyst formation complicate eradication. Research into vaccines and cyst-targeted treatments is ongoing, with promising preclinical results [19].

The early diagnosis of central nervous system (CNS) toxoplasmosis remains a clinical challenge, particularly in settings with limited access to advanced diagnostic infrastructure. The disease often presents with nonspecific neurological symptoms, necessitating a high index of suspicion, especially in immunocompromised individuals. Diagnostic approaches typically integrate neuroimaging (e.g., MRI or CT scans), serological assays targeting T. gondii-specific immunoglobulins (IgG and IgM), and, in select cases, molecular techniques such as polymerase chain reaction (PCR) for the detection of T. gondii DNA in cerebrospinal fluid (CSF) ([3]). Despite its high specificity, PCR-based testing may yield false negatives, especially in cases of localized CNS involvement or when parasite loads are low, further complicating diagnostic accuracy.

From a therapeutic standpoint, antiparasitic regimens—typically involving pyrimethamine, sulfadiazine, and leucovorin—are effective when administered promptly. However, treatment efficacy may be limited by parasite latency and the formation of resilient tissue cysts, which allow the parasite to persist within the brain in a dormant state [1]. These cysts are largely refractory to conventional therapies, presenting a major hurdle for complete eradication and posing risks for reactivation, particularly in patients with compromised immune systems. Research into novel therapeutic approaches, including cyst-targeted drugs and immunomodulatory agents, is ongoing. In recent years, vaccine development has emerged as a promising avenue, with several preclinical studies reporting encouraging outcomes in animal models [19]. However, no human vaccine is currently available, and further translational research is needed to bridge experimental data with clinical application.

Conclusion

The neurological consequences of T. gondii infection are increasingly recognized as a significant and complex public health concern. While traditionally associated with psychiatric conditions, accumulating evidence highlights its broader impact on the central nervous system, including the development of toxoplasmic encephalitis, seizure disorders, chronic neuroinflammation, and possibly even long-term neurodegenerative changes. These manifestations are particularly concerning in immunocompromised individuals, but growing data suggest that even latent infections in immunocompetent hosts may not be entirely benign.

At the cellular level, T. gondii exhibits a remarkable ability to persist within neural tissue, modulate host immune responses, and alter neurotransmitter pathways, all of which contribute to its neuropathogenicity. Such findings not only challenge earlier notions of the parasite’s dormancy in the brain but also call for a paradigm shift in how its long-term effects are understood and addressed. The interplay between T. gondii and host microglial activation, cytokine profiles, and neuronal integrity remains an area of active investigation, with significant implications for understanding broader CNS disease mechanisms.

Despite advances in our understanding, many questions remain unanswered. The mechanisms through which T. gondii contributes to chronic neurological dysfunction, its potential role in accelerating or precipitating neurodegenerative diseases, and the variability in clinical outcomes among infected individuals require further exploration. Current diagnostic methods often fall short in detecting latent or subclinical infections, and treatment options remain limited, especially in cases of CNS involvement where parasite persistence poses therapeutic challenges.

As such, there is a pressing need for the development of more sensitive diagnostic tools, improved neuroimaging techniques, and novel antiparasitic agents capable of crossing the blood-brain barrier. Furthermore, interdisciplinary research combining neurology, immunology, and parasitology is essential to unravel the multifaceted impact of T. gondii on the brain. By deepening our understanding and expanding the available therapeutic arsenal, we may be better equipped to reduce the neurological burden of this globally prevalent, yet frequently underestimated, pathogen.

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