Neuroleishmaniasis: A Comprehensive Review of the Neurologic Manifestations of Leishmania spp. Infection

1. Introduction

1.1. Overview of Leishmaniasis

Leishmaniasis, a neglected tropical disease caused by protozoan parasites of the Leishmania genus, remains a significant public health concern globally, particularly in tropical and subtropical regions [1]. This complex disease manifests in various clinical forms, presenting unique diagnosis, treatment, and control challenges.

The etiological agents of leishmaniasis belong to the Leishmania genus, with over 20 species known to infect humans [2]. These parasites have a dimorphic life cycle alternating between motile promastigotes in the sand fly vector and intracellular amastigotes in mammalian hosts (Figure 1). Transmission occurs through the bite of infected female sand flies, primarily belonging to the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World [3].

Clinical forms of leishmaniasis primarily include cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL), with mucocutaneous leishmaniasis (MCL) representing a severe complication of CL [4]. Cutaneous leishmaniasis manifests in various presentations, from localized cutaneous lesions to diffuse forms characterized by ulcers and nodules on the skin. Mucocutaneous leishmaniasis, predominantly found in South America, affects mucous membranes, leading to destructive nose, mouth, and throat lesions [5]. Visceral leishmaniasis, known as kala-azar, affects internal organs such as the spleen, liver, and bone marrow, causing systemic symptoms including fever, weight loss, and hepatosplenomegaly [6].

The clinical presentation of leishmaniasis varies depending on the Leishmania species involved, the host's immune response, and environmental factors. Diagnosis relies on clinical evaluation, parasitological confirmation through microscopy or culture, serological tests, and molecular techniques such as polymerase chain reaction. However, accurate diagnosis remains challenging, particularly in resource-limited settings where diagnostic tools may be scarce [7].

Treatment options for leishmaniasis are limited and vary depending on the clinical form and geographical location [8]. Antimonials have been the mainstay of treatment for decades but are associated with toxicities and increasing resistance. Alternatives include liposomal amphotericin B, miltefosine, and pentamidine, each with efficacy and safety profile. However, access to these drugs may be limited in endemic regions, further complicating disease management. Preventive measures focus on vector control strategies, including insecticide spraying, environmental management, and bed nets to reduce sand fly bites. Additionally, efforts to develop vaccines against leishmaniasis continue, although none are available for widespread use [9]. This study aims to narratively review the epidemiological features, pathophysiology, and management of neuroleishmaniasis.

1.2. Epidemiology and Global Burden

Leishmaniasis affects millions worldwide, particularly in tropical and subtropical regions. Understanding its epidemiology and global burden is crucial for effective disease control and public health interventions [10]. Leishmaniasis is endemic in 98 countries, with most cases occurring in developing regions of Africa, Asia, Latin America, and the Mediterranean Basin [11]. The distribution of the disease is closely linked to environmental factors, such as temperature, humidity, and the presence of suitable vectors.

The global incidence of leishmaniasis is estimated to be around 0.7 to 1.2 million cases annually, with approximately 20,000 to 30,000 deaths attributed to the disease each year [12]. However, these numbers are likely underestimated due to underreporting and challenges in diagnosis, particularly in resource-limited settings. Leishmaniasis exhibits geographic variation in its clinical manifestations and Leishmania species involved. Cutaneous leishmaniasis (CL) is more prevalent in the Middle East, Central Asia, and parts of Africa and Latin America. In contrast, visceral leishmaniasis (VL) is endemic in East Africa, the Indian subcontinent, and Latin America [13].

Various socio-economic and environmental factors contribute to the risk of leishmaniasis transmission. These include poverty, malnutrition, displacement due to conflict or natural disasters, urbanization, deforestation, and climate change, which can alter the distribution and abundance of vectors [14]. Some populations are at higher risk of leishmaniasis, including rural communities living in endemic areas, migrant workers, refugees, and immunocompromised individuals such as those co-infected with HIV/AIDS. Children are also disproportionately affected, particularly by visceral leishmaniasis [15].

1.3. Classification of Leishmania spp.

Leishmania is a genus of protozoan parasites belonging to the family Trypanosomatidae and the order Kinetoplastida. Several species have distinct characteristics within the genus Leishmania, including morphology, geographical distribution, and clinical manifestations in humans and other mammalian hosts. Classification of Leishmania spp. is primarily based on molecular phylogenetic analyses, biochemical characteristics, and clinical features [16]. Classification within the Leishmania genus continues to evolve as new species are discovered and characterized through molecular techniques and epidemiological studies. Understanding the diversity and distribution of Leishmania spp. is essential for disease surveillance, diagnosis, treatment, and control efforts in endemic regions worldwide (Table 1) [17].

1.4. Importance of Understanding Neurologic Manifestations

Recognition of neurologic symptoms allows for timely diagnosis and appropriate treatment initiation [18]. Prompt management can prevent disease progression, reduce morbidity, and improve patient outcomes. Also, neurologic complications can significantly impact affected individuals’ quality of life. Understanding these manifestations ensures comprehensive patient care, addressing the disease's systemic and neurological aspects. Moreover, neurologic manifestations of leishmaniasis may mimic other neurological conditions, such as meningitis, encephalitis, or peripheral neuropathy. Knowledge of these presentations aids in accurate differential diagnosis, preventing misdiagnosis and inappropriate treatment.

Some neurologic manifestations, such as meningoencephalitis or myelitis, may indicate severe disease and poorer prognosis [19]. Recognizing these indicators allows healthcare providers to implement appropriate monitoring and management strategies to optimize patient outcomes. In addition, neurologic manifestations of leishmaniasis may pose challenges for disease control and prevention efforts. Understanding these complications' epidemiology and clinical impact informs public health strategies to reduce disease burden and transmission.

2. Pathogenesis of Neuroleishmaniasis

2.1. Mechanisms of Central Nervous System Invasion

The invasion of the CNS by Leishmania parasites, leading to neuroleishmaniasis, involves complex mechanisms that are not fully understood. Leishmania parasites may enter the CNS through the bloodstream, crossing the blood-brain barrier (BBB) either by passive diffusion or through infected immune cells [20]. Once in the CNS, parasites can infect resident cells such as microglia, astrocytes, and neurons, leading to neuroinflammation and tissue damage [21].

Some Leishmania species exhibit neurotropic properties facilitating their invasion and survival within the CNS. This neurotropism may be mediated by specific surface molecules or receptors on neuronal cells that interact with parasite ligands, allowing for adhesion and entry into neural tissues [22]. Inflammatory mediators released during the host immune response to Leishmania infection can disrupt the integrity of the BBB, facilitating the entry of parasites and immune cells into the CNS. This BBB disruption may be mediated by cytokines, chemokines, matrix metalloproteinases, and other inflammatory molecules produced in response to infection [23].

Leishmania parasites can exploit host immune cells, such as monocytes and dendritic cells, such as “Trojan horses,” to penetrate the CNS. Infected immune cells carrying intracellular parasites may cross the BBB and release parasites into the brain parenchyma, initiating local infection and inflammation [24]. Also, leishmania parasites produce various virulence factors and immune evasion mechanisms, contributing to their ability to invade and survive within the CNS. These factors may include surface glycoconjugates, proteases, lipophosphoglycan, and other molecules that modulate host immune responses and promote parasite persistence in neural tissues [25].

The host immune response is critical in determining the outcome of CNS invasion by Leishmania parasites. Dysregulated immune responses, including excessive inflammation or immunosuppression, can contribute to neuroinflammation, tissue damage, and clinical manifestations of neuroleishmaniasis [26].

Figure 2. Leishmania species neural invasion. Leishmania species breach the blood-brain barrier via interaction with the host immune system and the interplay of various cytokine factors. Macrophages and microglial cells play critical roles in immune response. Central nervous system manifestations of Leishmania can be acute and chronic.

Figure 2. Leishmania species neural invasion. Leishmania species breach the blood-brain barrier via interaction with the host immune system and the interplay of various cytokine factors. Macrophages and microglial cells play critical roles in immune response. Central nervous system manifestations of Leishmania can be acute and chronic.

2.2. Immune Response in Neuroleishmaniasis

In neuroleishmaniasis, the immune response plays a crucial role in the disease's pathogenesis, control, and outcome. The interaction between Leishmania parasites and the host immune system within the CNS is complex and dynamic, involving various immune cells, cytokines, chemokines, and other immune mediators.

Microglia are central in initiating the innate immune response against Leishmania parasites [27]. Upon infection, microglia recognize parasite-associated molecular patterns through pattern recognition receptors, producing pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1 β, and interleukin-6 [28]. Astrocytes also contribute to the innate immune response by producing cytokines and chemokines in response to Leishmania infection, thereby recruiting immune cells to the site of infection and modulating local inflammation [29].

T-lymphocytes, particularly CD4+ T cells, are critical in orchestrating the adaptive immune response against Leishmania parasites in the CNS. CD4+ T cells produce cytokines such as interferon-gamma and interleukin-12, which activate macrophages and promote parasite clearance [30]. Regulatory-T cells and T-helper 17 cells also influence the balance of immune responses in neuroleishmaniasis, regulating inflammation and tissue damage [31]. B lymphocytes and antibody responses may contribute to host defense against Leishmania parasites in the CNS, although their role in neuroleishmaniasis is less well-characterized than in systemic leishmaniasis [32].

Leishmania parasites have evolved various immunomodulatory strategies to evade host immune responses and establish chronic infection in the CNS [33]. These include suppressing macrophage activation, inhibiting pro-inflammatory cytokine production, and induction of anti-inflammatory and regulatory pathways. Parasite-derived molecules such as lipophosphoglycan and glycoprotein 63 contribute to immunomodulation by interfering with host signaling pathways and immune cell functions [34].

Excessive or dysregulated immune responses in the CNS can lead to neuroinflammation, tissue damage, and clinical manifestations of neuroleishmaniasis, including meningitis, encephalitis, and myelitis. Chronic inflammation and tissue destruction may result from the persistence of parasites within neural tissues, sustained immune activation, and the recruitment of inflammatory cells [35].

2.3. Factors Influencing Neurological Complications

Several factors can influence the development and severity of neurological complications in leishmaniasis. These factors include host-parasite interaction, host immune response, parasite biology, and clinical features. Understanding these factors is essential for effectively predicting, preventing, and managing neurological complications.

Different Leishmania species and strains exhibit varying neurotropism and virulence, influencing the likelihood and severity of neurological complications. For example, some strains of Leishmania donovani and Leishmania braziliensis have been associated with an increased risk of neuroleishmaniasis [36]. Also, the host immune response is critical in determining susceptibility to neurological complications. Immunocompromised individuals, such as those with HIV/AIDS or receiving immunosuppressive therapy, are at higher risk of developing severe neuroleishmaniasis due to impaired immune surveillance and parasite control [37]. Moreover, the balance between pro-inflammatory and anti-inflammatory responses within the CNS influences the pathogenesis of neuroleishmaniasis. Dysregulated immune responses, characterized by excessive inflammation or immunosuppression, can contribute to neuronal damage, tissue destruction, and clinical manifestations of neurological disease.

The magnitude of parasite burden within neural tissues and the distribution of parasites within the CNS can impact the severity and clinical presentation of neurological complications [38]. Higher parasite loads and widespread tissue involvement are associated with more severe disease manifestations. In addition, genetic factors in both the host and the parasite can influence susceptibility to neurological complications and the clinical course of neuroleishmaniasis. Host genetic polymorphisms related to immune function, inflammation, and neuronal susceptibility may modulate individual susceptibility to neurological disease [39].

Concurrent infections, such as HIV/AIDS, tuberculosis, or other opportunistic infections, can exacerbate neurological complications in individuals with leishmaniasis [40]. Additionally, underlying comorbidities such as malnutrition, diabetes, or chronic systemic diseases may impact disease severity and treatment outcomes [41]. Interestingly, delayed diagnosis and inadequate access to healthcare services can lead to advanced disease progression and more severe neurological complications in individuals with leishmaniasis [42]. Early detection, prompt treatment initiation, and comprehensive healthcare are crucial for effectively preventing and managing neurological sequelae.

3. Clinical Presentation

3.1. Forms of Neuroleishmaniasis

The clinical presentation of neuroleishmaniasis can vary widely depending on several factors, including the species of Leishmania involved, the immune status of the host, and the extent of CNS involvement. Neuroleishmaniasis can present as several distinct clinical syndromes, each with characteristic features [43].

Meningoencephalitis is the most common and severe form of neuroleishmaniasis, characterized by meningitis and encephalitis [19]. Neuroimaging may reveal meningeal enhancement, parenchymal lesions, and signs of cerebral edema. Also, encephalitis can occur as a primary manifestation of neuroleishmaniasis or as a complication of meningoencephalitis. MRI findings may show diffuse or focal brain parenchymal abnormalities, including edema, hemorrhage, and white matter lesions. Also, there are some reports of myelitis and peripheral neuropathy secondary to Leishmaniasis [44]. Moreover, neuroleishmaniasis can also present with cognitive impairment, behavioral changes, and psychiatric symptoms [45].

The clinical presentation of neuroleishmaniasis can be nonspecific and may overlap with other infectious, inflammatory, or neoplastic CNS disorders, posing diagnostic challenges [46]. A thorough clinical evaluation, including history-taking, neurological examination, imaging studies, and laboratory investigations, is essential for accurate diagnosis and appropriate management of neuroleishmaniasis. Prompt recognition and treatment of neuroleishmaniasis are crucial for preventing disease progression and improving patient outcomes [47].

3.2. Symptomatology and Disease Progression

The symptomatology and disease progression of neuroleishmaniasis can vary depending on factors such as the Leishmania species, host immune status, and extent of CNS involvement. While the clinical presentation can be diverse, neuroleishmaniasis typically follows a progressive course with various neurological manifestations. Neuroleishmaniasis often presents with nonspecific symptoms such as fever, headache, malaise, and fatigue, which may mimic other infectious or inflammatory conditions [48]. These initial symptoms may precede the onset of neurological manifestations in days to weeks. Patients may develop neurological symptoms related to CNS involvement as the disease progresses. But, these symptoms can vary widely.

Neuroleishmaniasis can progress rapidly, leading to worsening neurological deficits and systemic complications if left untreated [49]. The severity and rate of disease progression can vary depending on factors such as the host's immune status and the Leishmania species' virulence. In some cases, neuroleishmaniasis can take a chronic course with relapsing or persistent neurological symptoms despite treatment. Residual neurological deficits, including cognitive impairment, motor weakness, and sensory disturbances, may persist even after successful resolution of acute infection.

3.3. Variations Based on Leishmania Species

The clinical presentation and manifestations of neuroleishmaniasis can vary depending on the species of Leishmania involved. Different Leishmania species exhibit varying neurotropism, virulence, and propensity to cause neurological complications.

Leishmania donovani is primarily associated with visceral leishmaniasis (VL), but it can also cause neuroleishmaniasis, particularly in regions where VL is endemic. Neurological complications of L. donovani infection may include meningoencephalitis, encephalopathy, seizures, and focal neurological deficits. Visceral leishmaniasis caused by L. donovani can lead to hematogenous dissemination of parasites to the CNS, resulting in neurological involvement [50].

Leishmania infantum, also known as Leishmania chagasi, is another species associated with visceral leishmaniasis and can cause neuroleishmaniasis. Neurological manifestations of L. infantum infection may include meningoencephalitis, encephalopathy, and myelitis, similar to those observed with L. donovani infection [51].

Leishmania braziliensis and other species within the L. braziliensis complex are primarily associated with cutaneous and mucocutaneous leishmaniasis but can also cause neuroleishmaniasis. Neurological complications of L. braziliensis infection may include meningoencephalitis, encephalopathy, and myelitis, often presenting as severe and progressive [52].

Leishmania tropica is primarily associated with cutaneous leishmaniasis, particularly in the Middle East and Central Asia. While neurological complications of L. tropica infection are less commonly reported compared to other species, isolated cases of neuroleishmaniasis have been documented, typically presenting as meningoencephalitis [53].

Various other Leishmania species, including L. major, L. mexicana, L. amazonensis, L. guyanensis, and L. peruviana, have been associated with cutaneous and mucocutaneous leishmaniasis but may rarely cause neuroleishmaniasis [54]. Neurological complications associated with these species may include meningoencephalitis, encephalopathy, and myelitis, although their frequency and clinical significance may vary.

4. Diagnostic Challenges

Neuroleishmaniasis is a challenging diagnosis due to several factors, including the nonspecific nature of symptoms, limitations of available diagnostic tests, and the complexity of CNS involvement in the disease.

Neuroleishmaniasis often presents with nonspecific symptoms such as fever, headache, and altered mental status, which can mimic other infectious, inflammatory, or neoplastic CNS disorders. This can lead to delays in diagnosis and treatment initiation. Also, unlike systemic leishmaniasis, which can be diagnosed by detecting Leishmania parasites in tissue samples or by serological tests, neuroleishmaniasis lacks specific biomarkers for diagnosis. CSF analysis may show nonspecific abnormalities such as pleocytosis and elevated protein levels but does not provide definitive evidence of CNS involvement by Leishmania parasites [55]. Moreover, diagnostic tests for neuroleishmaniasis, such as CSF microscopy, culture, PCR, and antibody detection assays, may have limited sensitivity, especially in low parasite burden or atypical clinical presentations. False-negative results can occur, leading to missed diagnoses.

The diverse clinical presentations of neuroleishmaniasis further complicate diagnosis and may require a high index of suspicion. In addition, patients with neuroleishmaniasis may have concurrent infections, such as HIV/AIDS or tuberculosis, or underlying comorbidities that complicate diagnosis and management. Coexisting conditions can mask or exacerbate neurological symptoms, making it challenging to attribute them solely to Leishmania infection.

Obtaining diagnostic samples from the CNS, such as CSF, brain biopsy, or nerve biopsy, often requires invasive procedures that carry risks of complications and may not be feasible in all patients. Access to specialized diagnostic tools, such as PCR or advanced imaging modalities, may be scarce in resource-limited settings where leishmaniasis is endemic. This can hinder accurate diagnosis and appropriate management of neuroleishmaniasis.

5. Management Strategies

5.1. Pharmacological Interventions

Medications for neuroleishmaniasis aim to eradicate Leishmania parasites from the CNS, reduce neurological symptoms, prevent disease progression, and improve patient outcomes. Treatment approaches typically involve the use of antiparasitic drugs, adjunctive therapies to manage neurological complications and supportive care.

Pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate have been the mainstay for visceral and cutaneous leishmaniasis treatment [56]. However, their efficacy in treating neuroleishmaniasis is limited due to poor CNS penetration and potential toxicity. Liposomal amphotericin B formulations are considered the first-line treatment for neuroleishmaniasis due to their superior efficacy and safety profile [57]. These formulations have better CNS penetration and are effective against Leishmania parasites resistant to other drugs. Oral miltefosine, an alkylphosphocholine compound, has shown efficacy in treating visceral and cutaneous leishmaniasis and may also be used for neuroleishmaniasis [58]. However, its CNS penetration is limited, and combination therapy with other antiparasitic drugs may be required. Other antileishmanial medications, such as paromomycin, pentamidine, and azoles, have been used in some cases of neuroleishmaniasis, although their efficacy and CNS penetration vary (Table 2) [59].

Systemic corticosteroids may be adjunctive therapy in neuroleishmaniasis to reduce inflammation, alleviate neurological symptoms, and prevent complications associated with immune-mediated pathology [60]. However, their use should be cautious due to the risk of immunosuppression and exacerbation of underlying infection. Close monitoring of patients undergoing treatment for neuroleishmaniasis is essential to assess treatment response, monitor for adverse effects of medications, and manage complications such as electrolyte imbalances, renal toxicity, and infusion-related reactions associated with antiparasitic drugs.

5.2. Challenges in Treatment

Treatment of neuroleishmaniasis poses several challenges due to the complex nature of the disease, limitations of available therapies, and difficulties associated with CNS penetration of antiparasitic drugs. Some antileishmanial drugs, particularly pentavalent antimonials, have limited efficacy in treating neuroleishmaniasis due to poor CNS penetration and resistance. Resistance to amphotericin B and miltefosine also have been reported, further limiting treatment options and effectiveness [61].

Achieving adequate drug concentrations in the CNS to eradicate Leishmania parasites is challenging due to the BBB, which restricts the entry of drugs into the brain and CSF [62]. Liposomal formulations of amphotericin B have improved CNS penetration compared to conventional formulations but may still be inadequate in some cases.

There is a lack of consensus on the optimal treatment regimens for neuroleishmaniasis, including the choice of antiparasitic drugs, dosing schedules, and duration of therapy. Combination therapy with multiple antileishmanial drugs or drug classes may be necessary to enhance efficacy, overcome resistance, and improve treatment outcomes, but optimal combinations have yet to be established [63].

6. Prevention and Control Measures

6.1. Vector and Reservoir Control

Preventing leishmaniasis involves integrated strategies to reduce human-vector contact, control reservoir hosts, improve diagnosis and treatment, and implement vector control measures. In this context, the distribution of bed nets treated with insecticides, such as pyrethroids, can reduce the biting rate of sand flies and prevent transmission of Leishmania parasites [64]. Applying residual insecticides to indoor surfaces can kill sand flies resting inside houses and reduce vector populations. Removing organic matter, vegetation, and animal shelters from peri-domestic areas can reduce sand fly breeding sites and decrease vector densities. Individuals can protect themselves from sand fly bites by wearing long-sleeved clothing and insect repellents and staying indoors during peak biting times [65]. Also, treating domestic animals, such as dogs, with insecticides or systemic medications can reduce their susceptibility to Leishmania infection and decrease the risk of transmission to humans. Implementing measures to control stray animal populations, such as dog culling or vaccination campaigns, can help reduce the reservoir of Leishmania parasites in endemic areas [66].

6.2. Public Health Strategies

Educating communities about the transmission, symptoms, and prevention of leishmaniasis can promote early detection, treatment-seeking behavior, and adoption of preventive measures [67]. Engaging local communities in vector control activities, environmental sanitation, and animal reservoir management can enhance the effectiveness and sustainability of control efforts. Screening high-risk populations, such as individuals with HIV/AIDS, migrants, and travelers to endemic areas for leishmaniasis, can facilitate early diagnosis and treatment [68]. Strengthening healthcare systems to improve access to diagnostic tests and treatment for suspected leishmaniasis cases can reduce morbidity and mortality associated with the disease. Monitoring sand fly populations, infection rates, and distribution can provide valuable information for targeting vector control interventions and assessing the effectiveness of control measures [69].

6.3. Research Needs and Future Directions

Research efforts focused on developing vaccines against leishmaniasis aim to provide long-term protection against infection and reduce disease transmission [70]. Continued research into new antileishmanial drugs, drug combinations, and treatment regimens is needed to overcome drug resistance, improve efficacy, and minimize side effects [71]. Collaboration between health authorities, veterinary services, environmental agencies, research institutions, and community organizations is essential for implementing integrated control strategies and addressing the multifaceted nature of leishmaniasis.

8. Conclusion

In conclusion, neuroleishmaniasis presents unique challenges in diagnosis, treatment, and management due to its involvement in the CNS and the potential for severe neurological complications. Despite advancements in our understanding of the disease, there are still significant gaps in knowledge regarding its pathogenesis, optimal treatment regimens, and long-term outcomes. The complexity of neuroleishmaniasis underscores the importance of multidisciplinary approaches.