The geographic distribution of Chagas disease, caused by the protozoan parasite T. cruzi, is predominantly concentrated in Latin America, where it remains endemic. However, globalization, migration and changing ecological factors have facilitated its spread to non-endemic regions, making it a global health concern. The highest prevalence rates are observed in rural areas where poor housing conditions and inadequate access to healthcare services create conducive environments for transmission. Triatomine bugs, the primary vectors of T. cruzi, thrive in these settings, nesting in the cracks and crevices of substandard housing and feeding on human blood during the night (6,10). Within Latin America, the distribution of Chagas disease exhibits considerable heterogeneity, with some regions experiencing higher prevalence rates than others. The ‘Gran Chaco region’, spanning parts of Argentina, Bolivia and Paraguay, is one of the most heavily affected areas, with prevalence rates >20% in some communities. Other endemic regions include the Amazon basin, the Andean highlands and parts of Central America, where environmental conditions favor the proliferation of vector populations (11,12).

Beyond Latin America, Chagas disease has gained recognition as an emerging health threat in non-endemic regions, including North America, Europe and the Western Pacific. Migration plays a pivotal role in the global dissemination of Chagas disease, as infected individuals carry the parasite to new geographical areas. In the USA, Chagas disease is increasingly recognized, particularly among immigrants from endemic countries. Cases have been reported in states with large immigrant populations, such as Texas, California and Florida (13,14). The Western Pacific region, encompassing countries, such as Australia and Japan, has also reported sporadic cases of Chagas disease, often linked to travel or migration from endemic areas. While transmission through local vector populations is rare in these regions, importing infected triatomine bugs or infected blood products poses a potential risk. Thus, the geographical distribution of Chagas disease spans across Latin America, where it remains endemic, and extends to non-endemic regions through migration and globalization (4,6).

Europe has also witnessed a rise in cases of Chagas disease, primarily attributed to migration from Latin America. Countries such as Spain, Italy and Switzerland have reported autochthonous cases, indicating local transmission through infected triatomine bugs or congenital transmission from infected mothers. Moreover, blood transfusion and organ transplantation have emerged as potential routes of Chagas disease transmission in non-endemic regions, underscoring the importance of screening blood donors and implementing stringent donor selection criteria (15,16). Therefore, the routes of T. cruzi infection are vector-borne transmission, blood transfusion, congenital or transplacental transmission from infected mothers to infants, organ transplants, the ingestion of foods contaminated with T. cruzi, and accidental infection in laboratories (4,6,10).

The prevalence and incidence of neurochagas present complex challenges in estimation due to underreporting, misdiagnosis and varying degrees of disease severity. However, several studies have provided insight into the burden of neurochagas, particularly in endemic regions of Latin America (4,6,14,15). Estimates of the prevalence of neurochagas vary widely across different studies and regions, ranging from <1 to >30% among individuals with chronic Chagas disease, according to different reviews and cohorts, which reflects the vast difference between socioeconomic backgrounds in South America. A summary of the variable prevalence and incidence of Chagas disease according to geographical distribution is presented in Table I (4-6,8,14,15). Neurological complications may manifest years or even decades following the initial infection, contributing to the challenges of accurately estimating prevalence rates. Additionally, the diversity of neurological manifestations further complicates efforts to capture the entire burden of neurochagas. Incidence data for neurochagas are limited, primarily due to the need for longitudinal studies tracking new cases of neurological involvement over time. However, it is generally considered that the incidence of neurochagas is lower than the prevalence, reflecting the chronic and progressive nature of neurological complications in Chagas disease (4,6).

Several factors influence the prevalence and incidence of neurochagas, including the geographic distribution of T. cruzi, the virulence of parasite strains, host immune responses, and access to healthcare services for early diagnosis and treatment. Inadequate vector control measures and socio-economic disparities exacerbate the burden of Chagas disease, increasing the risk of neurological complications among affected populations (7,17).

Identifying risk factors for neurochagas is crucial for understanding disease progression, guiding clinical management and implementing targeted preventive measures. While the exact mechanisms underlying neurochagas remain incompletely understood, several factors have been implicated in increasing the likelihood of neurological complications in Chagas disease. Prolonged exposure to T. cruzi is one of the most critical risk factors for developing neurological manifestations with Chagas disease. Chronic infection, often lasting decades, increases the likelihood of parasite invasion into neural tissues and subsequent neuroinflammatory responses. Chronic peripheral inflammation is considered to lead to decreased protection of the central nervous system (CNS), facilitating the dissemination of the parasite to central neural tissues (4,5,18).

Variability in the virulence and genetic diversity of T. cruzi strains may influence the risk of chronic infection and dissemination to the CNS. Some parasite genotypes have been associated with increased neurotropism and an enhanced ability to invade neural tissues. Furthermore, the host immune responses may play a critical role in determining the clinical course of Chagas disease, including the development of neurological manifestations (19-21). Dysregulated immune responses, characterized by the excessive inflammation or impaired immune surveillance, may exacerbate neuronal damage and contribute to the progression of neurochagas (21-23).

The age at which individuals acquire Chagas disease may influence their risk of developing neurological complications. Early childhood infections are often associated with milder disease manifestations, whereas infections acquired during adulthood may lead to more severe and symptomatic neurochagas. Moreover, underlying medical conditions, such as immunosuppression, diabetes mellitus and cardiovascular disease, can exacerbate the risk of developing neurological complications due to impairment in the immune function and vascular integrity, facilitating the dissemination of T. cruzi to the CNS (2,5,8,9,14,18).

Genetic factors may predispose some individuals to an increased risk of neurochagas. Polymorphisms in genes involved in immune regulation, neuronal function and parasite recognition have been implicated in modulating susceptibility to Chagas disease and its severe neurological manifestations. In addition, socioeconomic disparities, including poverty, inadequate housing and limited access to healthcare services, contribute to the burden of Chagas disease and increase the risk of developing neurological complications. Poor living conditions favor the proliferation of vector populations and enhance the likelihood of parasite transmission, particularly in endemic regions (2,4,5).

The mechanisms underlying the neural invasion of T. cruzi involve a complex interplay between the parasite, host immune responses and neural tissues. While the exact pathways of neural invasion remain incompletely understood, several mechanisms have been proposed. T. cruzi may exploit various strategies to disrupt the integrity of the BBB, including releasing proteases and inflammatory mediators, leading to increased permeability and facilitating its entry into neural tissues. T. cruzi exhibits neurotropism by recognizing specific surface receptors or exploiting chemotactic signals in the nervous system environment. Once inside neural tissues, T. cruzi can evade host immune surveillance and establish chronic infections, contributing to neurological complications (22,24,25).

As hypothesized from experimental models, T. cruzi may utilize retrograde axonal transport as a mechanism for neural invasion. Following entry into peripheral nerve endings or muscle cells, the parasite can hijack the transport machinery of the host cell, including microtubules and molecular motors, to travel along axons toward the CNS. This retrograde transport allows T. cruzi to bypass local immune defenses and gain access to neuronal cell bodies within the spinal cord or brain (26,27). In addition, T. cruzi can directly invade neurons through interactions with surface receptors and host cell signaling pathways. The parasite may utilize adhesion molecules, such as gp82 and gp35/50, to adhere to and penetrate neural cells, triggering intracellular signaling cascades that facilitate its internalization. Once inside neurons, T. cruzi can replicate and spread to neighboring cells, leading to neuronal damage and inflammation (28,29). The methods of the neural invasion of T. cruzi are illustrated in Fig. 2. The early invasion stage of peripheral nerves, as well as the inflammatory process, can give rise to peripheral neuropathy syndromes.

Another possible explanation for neuronal damage is the ‘Trojan horse’ strategy, in which T. cruzi enters the CNS by infecting circulating immune cells, such as monocytes and macrophages. These infected immune cells carry the parasite, allowing it to evade immune surveillance and disseminate to neural tissues upon extravasation from the bloodstream (30,31). Once inside the CNS, T. cruzi can infect resident glial cells and neurons, perpetuating chronic inflammation and tissue damage. Rodent models have raveled CNS abnormalities and parasite presence in the brain following T. cruzi infection, despite peripheral entry via the skin. The presence of the parasite in different brain regions has been demonstrated in animal models, as presented in Table II (10,17,19,20,32-36).

The immune response and neuroinflammation play pivotal roles in the pathogenesis of neurochagas, the neurological manifestations of Chagas disease. Upon the invasion of neural tissues by T. cruzi, the parasite responsible for Chagas disease, a cascade of immune-mediated processes is initiated, leading to neuroinflammation and neuronal damage. Molecular interactions occur between T. cruzi and host molecules in the CNS, as presented in Table III (21,23,25,32,37-39).

The innate immune system is the first line of defense against T. cruzi invasion in the CNS. Innate immune cells, such as microglia, astrocytes and infiltrating macrophages, recognize parasite-derived molecules, known as pathogen-associated molecular patterns, through pattern recognition receptors. The activation of these receptors triggers the production of pro-inflammatory cytokines, chemokines and reactive oxygen species, contributing to neuroinflammation and tissue damage (17,32,33). The adaptive immune response is critical in controlling T. cruzi infection and modulating neuroinflammatory processes in neurochagas. T-lymphocytes, including CD4⁺ T-helper cells and CD8⁺ cytotoxic T-cells, infiltrate neural tissues in response to parasite antigens and contribute to the clearance of infected cells. However, dysregulated T-cell responses, characterized by excessive inflammation or immune evasion, can exacerbate neuronal damage and contribute to the progression of neurochagas (17,32,33).

The dysregulated production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6, is a hallmark of neuroinflammation in neurochagas. These cytokines are secreted by activated immune cells and glial cells in response to T. cruzi infection and contribute to neuronal dysfunction, BBB disruption and tissue damage. Conversely, anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β (TGF-β), may serve as regulatory mechanisms to dampen excessive inflammation and limit tissue injury (21,25,38,39).

Glial cells, including microglia and astrocytes, play crucial roles in neuroinflammation and neuroprotection in neurochagas. Upon activation by parasite-derived factors or inflammatory mediators, glial cells undergo morphological and functional changes, producing pro-inflammatory cytokines, chemokines and neurotoxic molecules. Additionally, activated glial cells can phagocytose T. cruzi parasites and infected cells, contributing to parasite clearance and tissue repair. Furthermore, disrupting the BBB allows immune cells, cytokines and neurotoxic molecules to infiltrate neural tissues, exacerbating neuroinflammation and neuronal damage (29,30,37,39).

T. cruzi can invade neural tissues, leading to a cascade of pathophysiological processes that disrupt neuronal homeostasis and integrity. T. cruzi infection can directly impair neuronal function by disrupting ion homeostasis, neurotransmitter release and synaptic transmission. The parasite invasion of neurons may lead to alterations in neuronal excitability, synaptic plasticity and neuronal network activity, contributing to neurological deficits (4,9,14).

Neurochagas is characterized by chronic neuroinflammation, the infiltration of immune cells, the activation of glial cells, and the production of pro-inflammatory cytokines and chemokines. Neuroinflammatory processes contribute to neuronal dysfunction and damage by releasing neurotoxic molecules, oxidative stress and excitotoxicity, leading to synaptic loss, dendritic remodeling and neuronal death. T. cruzi infection can cause axonal degeneration and demyelination, disrupting neuronal connectivity and impairing signal transmission. Axonal pathology may result from direct parasite invasion of axons, neuroinflammatory responses, or immune-mediated mechanisms (1,4,17,27,28).

Neuronal injury and apoptosis occur in neurochagas due to various pathogenic mechanisms, including excitotoxicity, mitochondrial dysfunction and oxidative stress. T. cruzi infection may induce neuronal apoptosis by activating intrinsic and extrinsic apoptotic pathways, leading to neuronal loss and gliosis. The extent of cellular and cerebrovascular affection determines the localization and nature of pathology, elucidating the clinical syndrome of the CNS. In addition, chronic neuroinflammation and neuronal injury in neurochagas can culminate in progressive neurodegeneration, characterized by the gradual loss of neurons and synaptic connections. Neurodegenerative changes may manifest as cortical atrophy, white matter lesions, and subcortical degeneration, contributing to cognitive decline, motor impairment and functional disability in affected individuals. Moreover, the disruption of the BBB in neurochagas facilitates the infiltration of immune cells, cytokines and neurotoxic molecules into neural tissues, exacerbating neuronal dysfunction and damage. BBB dysfunction may further compromise neuronal integrity and exacerbate neuroinflammatory responses, perpetuating a cycle of neuronal injury and dysfunction (4-7,9,14,35).

CNS manifestations of neurochagas encompass a broad spectrum of neurological complications resulting from T. cruzi invasion and subsequent inflammatory responses. Although these manifestations can vary in severity and presentation, they collectively contribute to significant morbidity and mortality in affected individuals. The mortality related for CNS Chagas disease is high. It depends on the disease phase, in which the mortality is almost 10% in the acute phase and >80% during reactivation (4,6). Shelton and Gonzalez (6) reviewed the literature regarding the neurological symptoms of individuals with CNS Chagas disease. They found, in order of frequency, motor deficit, seizures, altered mental status, focal neurologic deficits, meningismus, dysarthria, aphasia, ataxia, disorientation, facio-brachio-crural paresis, intracranial hypertension signs, hemianopsia, Babinski sign and hyperreflexia (6).

One of the most extensively studied neurological manifestations associated with Chagas disease is stroke. Studies examining the risk factors for stroke in patients with Chagas disease are summarized in Table IV (2,3,5,7-9,18,22,41-46). Some individuals with neurochagas may develop stroke-like syndromes characterized by focal neurological deficits, such as hemiparesis, dysphasia, or visual disturbances. These deficits may result from ischemic or hemorrhagic strokes secondary to vasculopathy, thromboembolic events, or inflammatory vasculitis affecting cerebral blood vessels. Classically, stroke etiology in patients with Chagas disease is considered to be cardioembolic due to cardiac structural diseases, such as apical aneurysm and mural thrombus. Other etiologies have been observed in Chagas disease, and it is deemed that pro-inflammatory and prothrombotic disease states are the main factors associated with these etiologies. Factors associated with stroke recurrence and stroke mortality in Chagas disease are summarized in Table V (2,41,45).

Meningoencephalitis may present with symptoms, such as headache, fever, altered mental status, seizures and focal neurological deficits. Meningoencephalitis can result from direct parasite invasion, immune-mediated responses, or secondary infections. Notably, seizures have been reported with Chagas disease. They can manifest as focal and generalized epileptic events. Seizures may result from neuronal hyperexcitability, cortical scarring, or inflammatory processes affecting brain regions involved in seizure generation and propagation (4,14,40,41). Notably, meningoencephalitis is considered the most common symptom of acute neurological involvement in Chagas disease, and also occurs during reactivation, prompting urgent treatment; otherwise, it is almost fatal (46,47).

Cognitive impairment and dementia, manifesting as deficits in memory, attention, executive function and visuospatial abilities, are frequently observed in individuals with chronic infection with Chagas disease. These cognitive deficits may result from neuronal dysfunction, white matter abnormalities and neuroinflammatory processes affecting cortical and subcortical brain regions (48). These individuals usually have other clinical manifestations of Chagas, such as megacolon and congestive heart failure, at the time of their diagnosis of cognitive impairment associated with Chagas disease. Furthermore, various movement disorders associated with Chagas disease have already been reported, including Parkinsonism, chorea, dystonia and tremor. These movement disorders may result from basal ganglia dysfunction, dopaminergic depletion, or the disruption of corticostriatal circuits secondary to neuronal injury and neuroinflammation (23,49).

Psychiatric symptoms, such as depression, anxiety, psychosis and personality changes, are common in neurochagas and can significantly impair the social functioning and quality of life of affected individuals. These psychiatric manifestations may result from the direct effects of T. cruzi on brain neurotransmitter systems, neuroinflammatory responses, or psychosocial factors related to chronic illness and disability (50,51).

Peripheral neuropathy is a common complication of chronic-stage neurochagas, characterized by damage to peripheral nerves, resulting in sensory, motor, or mixed neuropathies. Peripheral neuropathy in neurochagas often manifests asymmetrically and may involve both upper and lower extremities. Neurochagas can also lead to autonomic nervous system dysfunction, resulting in various symptoms affecting cardiovascular, gastrointestinal, genitourinary and sudomotor function (50,52,54-56).

Rare cases of cranial neuropathies associated with Chagas disease have already been reported. The most frequently affected cranial nerves include the trigeminal and oculomotor nerves. The involvement of other cranial nerves, such as the facial or vestibulocochlear nerve, may also occur (50,54-56).

Neurochagas can affect the neuromuscular junction, leading to myasthenia gravis-like symptoms, such as weakness, fatigue and fluctuating muscle strength. The dysfunction of the neuromuscular junction may result from autoimmune mechanisms, antibody-mediated injury, or direct effects of T. cruzi on neuromuscular transmission. Neurochagas may cause sensory abnormalities, including hypoesthesia, hyperesthesia, or neuropathic pain, affecting dermatomes or peripheral nerve distributions (23,49,55).

Benznidazole is a first-line antiparasitic agent commonly used in the treatment of Chagas disease. It is a nitroimidazole derivative that disrupts the replication and metabolism of T. cruzi parasites. Benznidazole has exhibited efficacy in reducing parasite burden and preventing disease progression in individuals with acute and early chronic Chagas disease. However, its effectiveness in treating neurochagas, particularly in individuals with advanced neurological complications, remains uncertain (60,61). While benznidazole has been shown to clear T. cruzi in PCR-positive patients with non-neurological chronic Chagas disease, this clearance does not necessarily translate into clinical benefit for the patients (4,57,61).

Nifurtimox is another antiparasitic agent used to treat Chagas disease. As with benznidazole, nifurtimox is a nitroimidazole compound that exerts trypanocidal effects by generating toxic free radicals within T. cruzi parasites. While nifurtimox has demonstrated efficacy in treating acute and early chronic Chagas disease, limited data regarding its effectiveness in managing neurochagas are available (4,57,61).

The detailed description of antiparasitic choices is presented in Table VI (64-76). While antiparasitic drugs may exhibit efficacy in Chagas disease, their efficacy in cases with neurochagas is limited by the limited available clinical data on such efficacy in human patients, as well as the extent of their penetration to the CNS, apart from their known adverse events.

Analgesic medications, such as non-steroidal anti-inflammatory drugs, opioids and neuropathic pain agents, may be prescribed to alleviate neuropathic pain and discomfort associated with neurochagas. Antiseizure medications may be used to control seizures and manage epilepsy in individuals with neurochagas. Antidepressants and anxiolytics may be prescribed to manage depression, anxiety and other psychiatric symptoms associated with neurochagas (4,53,57).

Corticosteroid medications may suppress neuroinflammatory responses and alleviate symptoms in individuals with neurochagas-associated meningoencephalitis, vasculitis, or other autoimmune-mediated complications. However, corticosteroids should be carefully monitored due to the risk of exacerbating immunosuppression and promoting parasite dissemination. Furthermore, immunomodulatory agents may be considered in selected cases of neurochagas with autoimmune or inflammatory etiologies. These agents aim to modulate immune responses and attenuate neuroinflammation, but should be used judiciously and with caution (77-79).