Cerebral malaria

Cerebral malaria (CM) is a life-threatening complication of malaria caused by Plasmodium falciparum parasites, characterized by the sequestration of infected erythrocytes within cerebral microvasculature.

According to the World Health Organization (WHO), Malaria Report (WHO 2024) in 2023, there were 263 million cases of malaria, resulting in ∼600 000 deaths, More than three-quarters of children who die from malaria are less than 5 years of age, in sub-Saharan Africa and almost exclusively by P. falciparum, indicating immature immunity and limited access to timely diagnosis and treatment (Rowe et al., Reference Rowe, Rowe, Snow, Korenromp, Schellenberg, Stein, Nahlen, Bryce, Black and Steketee2006; Bizet et al., Reference Bizet, Tadess, Tegegne, Tilahun and Atnafu2022; Alharbi and Ahmed, Reference Alharbi and Ahmed2026). CM accounts for ∼0.5 million cases per year, while NC affects 50 million people worldwide and is often a cause of chronic epilepsy (Roca-Feltrer et al., Reference Roca-Feltrer, Carneiro and Armstrong Schellenberg2008).

Plasmodium is the most widespread vector-borne disease in endemic countries, and P. falciparum malaria represents the most severe form in terms of morbidity and mortality. Forms of malaria due to other Plasmodium species are generally less severe (Lou et al., Reference Lou, Lucas and Grau2001). In non-endemic countries, malaria is the most important imported disease, mainly linked to travel to tropical areas and increased migration flows.

CM is characterized by cerebrovascular dysfunction. Typically, its neuropathology results from the cytoadherence of P. falciparum-infected red blood cells (iRBCs) to the endothelium, a phenomenon called sequestration (Barnwell, Reference Barnwell1989; Lou et al., Reference Lou, Lucas and Grau2001). The sequestration of brain iRBCs not only leads to a mechanical obstruction of blood flow in capillaries and post-capillary venules (Sharma, Reference Sharma1991) but also contributes to endothelial activation and pathology not only in the brain but also in other organs, leading to dramatic consequences such as congestion, hypoxia, tissue swelling, coma and ultimately, death. Brain capillaries and post-capillary venules are somehow more vulnerable to iRBC sequestration than those from other organs (Sharma, Reference Sharma1991; Wiser, Reference Wiser2023). In fact, iRBCs expose proteins (such as PfEMP1) that act as ‘hooks’ that bind to specific receptors present on the cells lining the capillaries of the brain much more than in other organs (Wiser, Reference Wiser2023). In this setting, knobs play an important role in the pathophysiology of falciparum malaria as act as the focal junction between iRBC and host endothelial cell. Understanding the biology of knobs, cytoadherence and sequestration-mediated pathology may provide insights into the management of severe falciparum malaria (Sharma, Reference Sharma1991; Wiser, Reference Wiser2023).

In CM, intracerebral inflammation caused by a heightened proinflammatory immune response also occurs. Some proinflammatory cytokines, such as TNF-α, lymphotoxin α (LTα), interferon-γ (IFN-γ), interleukin-1α (IL-1α) and IL-1β, are increased during CM and are involved in disease exacerbation. CD8+ T cell-mediated immune responses during CM contribute to endothelial injury and BBB disintegration, highlighting potential roles for therapies that target T cell recruitment, activation and cytotoxicity (Dunst et al., Reference Dunst, Kamena and Matuschewski2017; Brejt and Golightly, Reference Brejt and Golightly2019; Trivedi and Chakravarty, Reference Trivedi and Chakravarty2022; Okullo et al., Reference Okullo, Ouma, John, van Hensbroek, Ojiambo, Otike, Kinengyere, Conroy, Ocan, Ekwaro, Obuku and Idro2026).

A particular role in BBB disruptment is played by matrix metalloproteinases, produced by inflammatory cells. These molecules, along with tissue inhibitor metalloproteinases, are involved in the pathogenesis of malaria with different mechanisms: (1) degradation of BBB substrates and (2) functioning as effectors and regulators of the |immune response (Bruschi et al., Reference Bruschi, Brunetti and Pozio2013).

CM includes clouding of consciousness, cerebral seizures and coma, and may lead to the death of the infected individual. Individuals who survive CM may develop residual neurological abnormalities, including cognitive impairment, behavioural disturbances and neurological deficits. A mortality rate ranging between 10% and 20% in children under 5 years of age in sub-Saharan Africa, even when treated. In children who survive an episode of CM, the risk of developing long-term neurological and psychomotor sequelae is estimated at around 10% (Okullo et al., Reference Okullo, Ouma, John, van Hensbroek, Ojiambo, Otike, Kinengyere, Conroy, Ocan, Ekwaro, Obuku and Idro2026). There is also a clear association with epilepsy, as reported in some epidemiological studies in endemic areas of Africa (Ngugi et al., Reference Ngugi, Bottomley and Kleinschmidt2013). CM is part of a multi-organ disease. Patients develop fever, headache and body ache, which can progress to delirium and coma. Anaemia, haemoglobinuria, jaundice, shock, renal failure, lactic acidosis, abnormal bleeding, pulmonary oedema and adult respiratory distress syndrome may also develop (Idro et al., Reference Idro, Marsh, John and Newton2010).

CM’s diagnosis is that of malaria in general. Diagnostic methods range from conventional procedures such as microscopy (Wilson, Reference Wilson2012; Calderaro et al., Reference Calderaro, Piccolo and Chezzi2024) – peripheral blood smear, routine quantitative buffy-coat and rapid diagnostic tests to more advanced techniques like polymerase chain reaction (PCR) tests, loop-mediated isothermal amplification, molecular-based point-of-care test, including lateral flow immunochromatographic tests for the detection of plasmodial antigens. There are also evolved PCR (digital droplets PCR or real-time-PCR), for the study of genetic polymorphisms associated with resistance to antimalarial (Wongsrichanalai et al., Reference Wongsrichanalai, Pickard, Wernsdorfer and Meshnick2002). Other techniques include CRISPR-based diagnostics (in development), which use CRISPR gene editing systems (such as Cas12/Cas13) to detect parasite DNA. They are extremely sensitive and specific and have the potential for rapid, point-of-care use. There are also Smartphone-based microscopes and artificial intelligence algorithms analysing blood smears, which reduces reliance on expert microscopists (Maturana et al., Reference Maturana, Dantas de Oliveira, Nadal, Bilalli, Serrat, Soley, Igual, Bosch, Lluch, Abelló, Codina, Suñé, Clols and Munné2022)

For the haemoscopic examination, it is recommended to obtain at least 3 smears 6 h apart. All 3 smears should be negative before excluding CM (Akafity et al., Reference Akafity, Kumi and Ashong2023).

Recent research showed magnetic resonance imaging (MRI) and fundus fluorescein angiography retinal imaging as useful both as a clinical tool for the assessment of CM and as a scientific instrument to aid the understanding of the clinical condition (Wilson et al., Reference Wilson, Dhalla, Meng, Tu, Zheng, Mhango, Seydel and Beare2023). The characteristic features of retinopathy due to CM include retinal whitening (macula whitening sparing central fovea and peripheral whitening of the fundus), retinal vessel discoloration to pink–orange or white, retinal haemorrhages (Figure 1) and papilloedema (Hora et al., Reference Hora, Kapoor, Thind and Mishra2016). In general, MRI is superior for detecting characteristic brain swelling and structural changes. Typically, T2/FLAIR Hyperintensities are seen in the bilateral periventricular white matter, corpus callosum, basal ganglia and thalamus (Figure 2).

Figure 1.

Fundus of the left eye of a 28-month-old boy with cerebral malaria. Retinal haemorrhages are present (black arrows) (From Hora et al., Reference Hora, Kapoor, Thind and Mishra2016).

Figure 2.

MRI is the most advanced and sensitive imaging tool for studying cerebral malaria. The examination shows widespread abnormalities affecting both the white matter and the deep nuclei of the brain. T2-weighted and FLAIR hyperintensity. Abnormal, bilateral light signals located primarily in the basal ganglia (e.g. Globus pallidus), thalamus, corpus callosum and periventricular white matter. They indicate areas of tissue damage, ischaemia or toxic injury.

Treatment of CM

According to the WHO, parenteral artesunate is recommended as the first-line treatment for CM (WHO 2019). In vitro studies have shown that prompt administration of Artesunate kills parasites before they can mature and sequester in the microvasculature (Barradell and Fitton, Reference Barradell and Fitton1995). However, even with early artesunate, 15–25% of patients still die, and many survivors suffer long-term neurological deficits. Therefore, administration with artemisinin derivatives alone is insufficient to protect against cell death, nerve damage and cognitive impairment (Brejt and Golightly, Reference Brejt and Golightly2019). Therefore, artemisinin-based combination therapies (ACTs) were introduced to improve clinical outcomes, reduce mortality, prevent long-term neurocognitive deficits and delay the onset of artemisinin resistance. ACT also reduces parasitaemia but fails to adequately target the pathogenetic mechanisms underlying CM, including BBB disruption, endothelial activation/dysfunction and hyperinflammation (Wongsrichanalai et al., Reference Wongsrichanalai, Pickard, Wernsdorfer and Meshnick2002). Hence, there is an urgent need for additional therapies to specifically treat this severe form of malaria, as hundreds of thousands of people continue to die each year from this disease (Bensalel and Gallego-delgado, Reference Bensalel and Gallego-delgado2024).

Because CM is a multifactorial disorder, adjuvant therapy targeting multiple physiological processes of CM is needed to improve clinical outcomes, prolong survival and reduce neurological damage in survivors. Studies of malaria patients have revealed increased levels of kynurenine and its metabolites – quinolinic acid, quinurenic acid and picolinic acid in CSF (Gál and Sherman, Reference Gál and Sherman1980). Quinolinic acid (an excitotoxin that exerts its toxic effects on astrocytes, microglia and neurons) and picolinic acid (a proinflammatory mediator that induces chemokine production by macrophages) levels correlate with disease severity (Medana et al., Reference Medana, Day, Salahifar-sabet, Stocker, Smythe, Bwanaisa, Njobvu, Kayira, Turner, Taylor and Hunt2003). In addition, there are possible therapeutic options to maintain BBB integrity during CM. In patients with CM, increased CSF levels of kynurenine and metabolites (quinolinic acid, quinurenic acid and picolinic acid) can alter the integrity and cohesion of the BBB and have been shown to be correlated with disease severity (Gál and Sherman, Reference Gál and Sherman1980; Guillemin, Reference Guillemin2012). Chemokines, in turn, could recruit leukocytes, further promoting BBB breakdown. Therefore, the use of quinolinic and picolinic acid inhibitors could be an option to maintain the integrity of the BBB during malaria (Datta and John, Reference Datta and John2025). New potential antimalarial compounds against P. falciparum, which represent exciting but still experimental frontiers, are rosiglitazone (a PPAR-γ agonist), which reduces inflammation, improves endothelial function and accelerates parasite clearance (Varo et al., Reference Varo, Crowley, Mucasse, Sitoe, Bramugy, Serghides, Weckman, Erice, Bila, Vitorino, Mucasse, Valente, Ajanovic, Balanza, Zhong, Derpsch, Gladstone, Mayor, Bassat and Kain2023); moreover, rapamycin/sirolimus, in late-stage CM models, enhances survival and preserves the BBB by inhibiting mTOR, a pathway downstream of leptin, which is implicated in cerebral damage (Portier et al., Reference Portier, Denorme, Tolley, Kosaka, Andrianova, Sigala, Lamb and Zimmerman2026).

The administration of antibiotics for co-infections during CM may also be important. Up to 25% of children with CM symptoms also have bacterial infections; starting empiric antibiotics upon hospital admission alongside antimalarials could prevent ∼15 000 deaths annually (Myo Aung et al., Reference Myo Aung, Nyein, Htut, Htet, Kyi, Anstey, Kyi and Hanson2018).

The future of CM treatment lies in combination therapies that associate rapid-acting antiparasitic drugs with additional interventions targeting inflammation, endothelial preservation, metabolic regulation and co-infections (Bensalel and Gallego-delgado, Reference Bensalel and Gallego-delgado2024).

Cerebral toxoplasmosis

Toxoplasma gondii, the causative agent of toxoplasmosis, has a marked tropism for the nervous system once the parasite crosses the BBB (Ross et al., Reference Ross, Olivera and Barragan2022).

In the congenital form, toxoplasmosis, contracted through vertical transmission of a first infection from mother to foetus, can cause brain calcifications and hydrocephalus, which are rare, thanks to screening during pregnancy and early treatment of the mother and newborn (Colombo et al., Reference Colombo, Vidal, Penalva de Oliveira, Hernandez, Bonasser-filho, Nogueira, Focaccia and Pereira-chioccola2005; Bénard et al., Reference Bénard, Petersen, Salamon, Chêne, Gilbert and Salmi2008).

Screening strategies for T. gondii in Europe vary greatly, especially for pregnant women, ranging from mandatory national programs to risk-based screening. France is leading the way in mandatory monthly or quarterly active screening, while in other countries (such as Italy) screening is common practice but not uniformly mandatory at the national level. Thanks to active screening of pregnant women in areas where raw meat consumption is widespread, France accounted for the majority of reported cases in Europe (∼83% in 2020), followed by Poland and Germany (2.53 and 1.81 cases per 100 000 live births, respectively). However, the incidence of congenital toxoplasmosis in France has now decreased, largely thanks to the timely administration of treatment to pregnant women, foetuses and newborns (Bénard et al., Reference Bénard, Petersen, Salamon, Chêne, Gilbert and Salmi2008; Mandelbrot et al., Reference Mandelbrot, Kieffer, Wallon, Winer, Massardier, Picone, Fuchs, Benoist, Garcia-meric, L’ollivier, Paris, Piarroux, Villena and Peyron2021).

Universal screening is not available in the United Kingdom and Scandinavian countries, as the prevalence of infection is considered very low and the cost-effectiveness is not considered favourable. Italy, on the other hand, is considered a country with a medium prevalence of toxoplasmosis, with ∼30% of women having already contracted the infection before pregnancy and possessing protective antibodies, resulting in a much lower risk of congenital forms. The incidence of new infections during pregnancy (seroconversions) is estimated at between 1 and 6 cases per 1000 pregnancies (Bollani et al., Reference Bollani, Auriti, Achille, Garofoli, De Rose, Meroni, Salvatori and Tzialla2022). The global incidence rate of congenital infection is estimated to be 1.5 cases per 1000 live births with higher burdens in South America, in some Middle Eastern countries and low-income countries and lower burdens in European countries (Bollani et al., Reference Bollani, Auriti, Achille, Garofoli, De Rose, Meroni, Salvatori and Tzialla2022).

In immunocompromised hosts and in AIDS patients, the CNS is the site most typically affected by infection, and toxoplasmic encephalitis (TE) is the most common manifestation. It still accounts for high mortality and morbidity despite free access to antiretroviral therapy in some countries (Liu et al., Reference Liu, Liu, Wang, Lv, Fan and Pan2017). In individuals with AIDS and a CD4 T-cell count of 100 cells μL⁻¹, the incidence of TE is 28% in seropositive patients not taking prophylaxis (Richards et al., Reference Richards, Kovacs and Luft1995). In these subjects, as in transplant patients or those with malignant haemolymphopathies or solid tumours, ocular and pulmonary diseases are the most common extra-cerebral sites of infection. The presence of latent bradyzoite cysts, along with the ability of bradyzoites to reconvert into the active and rapidly growing tachyzoites that can result in often-fatal injury, explains the high incidence of acute toxoplasmosis observed in immunocompromised persons (Contini, Reference Contini2020).

Most cases result from reactivation of latent infection, although reinfection with different T. gondii strains can also occur (Nayeri et al., Reference Nayeri, Sarvi and Daryani2024).

Patients with TE typically present with headache, confusion, altered mental status and motor weakness. Focal neurologic deficits or seizures, weakness, sensory abnormalities, cerebellar signs and neuropsychiatric manifestations are also common. Fever may be present. Accompanying nausea or vomiting usually indicates elevated intracranial pressure (Contini, Reference Contini2008; Rostami et al., Reference Rostami, Karanis and Fallahi2018). Computed tomography (CT) scan or MRI of the brain typically shows multiple contrast-enhancing lesions, often with associated oedema. These should be distinguished from other infectious or non-infectious CNS diseases in the course of AIDS.

In immunocompromised persons and AIDS patients with TE, indirect serologic methods widely used in immunocompetent patients are unreliable because they fail to produce significant titres of specific antibodies and anti-Toxoplasma IgM antibodies are usually absent (Contini, Reference Contini2020).

This protozoan can persist in the form of brain cysts throughout the host’s life, in a latent phase once the acute phase of infection has passed. It is disputable whether it is more appropriate to consider the existence of a chronic toxoplasmosis instead of a latent one, since infected people have an increased risk to develop neuropsychiatric diseases, such as s schizophrenia, Parkinson’s disease, bipolar disorder and suicidal/aggressive behaviours, according to several studies carried out in different geographical regions (Del Grande et al., Reference Del Grande, Contini, Schiavi, Rutigliano, Maritati, Seraceni, Pinto, Dell’osso and Bruschi2017; Bruschi, Reference Bruschi2025). The relationship between toxoplasmosis and neuropsychiatric diseases has been a matter of debate for many years (Bruschi, Reference Bruschi2025).

In clinical practice, the diagnosis of TE is presumptive and is primarily based on clinical presentation, imaging (CT or MRI) and response to specific anti-T. gondii therapy, in the absence of a probable alternative diagnosis (Figure 3). Generally, the evidence of a low CD4 + T-lymphocyte count (<150–200 mm⁻³) and the presence of anti-T. gondii IgG antibodies are generally accepted as a good predictor of TE reactivation. However, the absence of IgG antibodies does not definitively exclude the diagnosis of TE (Rostami et al., Reference Rostami, Karanis and Fallahi2018).

Figure 3.

CT scan: large hydatid cyst in the left frontal hemisphere with irregular cystic wall (from Padayachy and ozek, Reference Padayachy and ozek2023). A hydatid cyst typically presents as a round, well-defined, hypodense lesion. The cyst is often single, but it can be multiloculated (with daughter cysts within it). It can develop in various areas of the brain, often causing compression of surrounding brain tissue due to its mass effect. The lesion usually does not show enhancement after contrast injection, unless there is an inflammatory reaction or rupture.

Imaging shows isodense or hypodense single or multiple lesions with a mass effect, taking up the contrast dye in a ring-like or nodular manner in more than 90% of cases. However, as neither computed tomography (CT) nor MRI can reliably distinguish CNS infections, such as toxoplasmosis, from lymphoma in HIV-1-positive patients, and the use of fluorine-18-fluorodeoxyglucose–positron emission tomography (FDG-PET) has been shown to offer better sensitivity to noninvasively differentiate cerebral toxoplasmosis and other infectious diseases from primary CNS lymphoma (Marcus et al., Reference Marcus, Feizi, Hogg, Summerfield, Castellani, Sriwastava and Marano2021). FDG-PET has great potential in the evaluation of a variety of inflammatory and infectious disorders and possibly other benign disorders. This technique is also very helpful in differentiating toxoplasmosis from lymphoma in the CNS in HIV-positive patients. (Zhuang et al., 2005). Moreover, FDG-PET-CT demonstrates a very high sensitivity and specificity for the detection of melanoma metastases (Ivanova et al., Reference Ivanova, Glatz, Zippelius, Nicolas and Itin2012).

If the suspected diagnosis of toxoplasmosis is correct, clinical or radiographic improvement should become evident by more than 50% within 7–14 days following treatment (Liu et al., Reference Liu, Liu, Wang, Lv, Fan and Pan2017). Brain biopsy should be considered in immunocompromised patients with presumed CNS toxoplasmosis with a single MRI lesion, absence of IgG antibodies or an unsatisfactory clinical response to specific anti-T. gondii treatment. Diagnosis of TE is crucial because other brain diseases, such as CNS lymphoma, bacterial abscess, progressive multifocal leukoencephalopathy, viral or fungal encephalitis, neurotuberculosis, cytomegalovirus encephalitis and focal lesions caused by fungi (Cryptococcus neoformans, Aspergillus spp. and Nocardia spp.), could share similar clinical and CT scan signs. In general, no imaging technique is completely specific. Thallium single-photon emission computed tomography (SPECT) and PET can be useful in distinguishing toxoplasmosis or other infections from CNS lymphoma (Sanjaume et al., Reference Sanjaume, Rodríguez-carballeira, Mauri, Martínez-lacasa, García and Garau1997). CNS lymphoma has greater thallium uptake on SPECT and greater glucose and methionine metabolism on PET than neurotoxoplasmosis or other infections (Marcus et al., Reference Marcus, Feizi, Hogg, Summerfield, Castellani, Sriwastava and Marano2021).

The use of molecular techniques is principally appropriate for immunocompromised patients, such as HIV/AIDS, transplant patients or other immunocompromised hosts, because these techniques are not affected by the immunologic status of the host.

PCR-based assays, in particular, have been shown to be rapid, sensitive and specific enough to be used as a front-line test for detecting CSF and blood T. gondii DNA in most patients with CNS infection, thus avoiding invasive and expensive brain biopsy procedures (Robert-Gangneux and Belaz, Reference Robert-Gangneux and Belaz2016; Fadel et al., Reference Fadel, El-hady, Ahmed and Tolba2024). However, results are usually negative once specific anti-Toxoplasma therapy has been started. Moreover, parasite levels in blood and CSF may be very poor in some patients and cause difficulties in interpreting the PCR product. For this reason, a number of quantitative real-time PCRs with specific T. gondii genome sequences, including molecular markers based on the B1 gene, have been developed in the last decades and used in blood or CSF samples from patients with AIDS and CNS damage or in aqueous humour from those with toxoplasmic retinochoroiditis with different rates of sensitivity and specificity (Colombo et al., Reference Colombo, Vidal, Penalva de Oliveira, Hernandez, Bonasser-filho, Nogueira, Focaccia and Pereira-chioccola2005; Contini et al., Reference Contini, Seraceni, Cultrera, Incorvaia, Sebastiani and Picot2005; Khanaliha et al., Reference Khanaliha, Bokharaei-salim, Hedayatfar, Esteghamati, Alemzadeh, Asgari, Garshasbi and Salemi2021; Fadel et al., Reference Fadel, El-hady, Ahmed and Tolba2024). In Table 2 are shown the most important molecular techniques developed in the last decades. In this setting, the sensitive and specific real-time PCR technique targeting the 529-bp repeat fragment of the AF146527 element repeated 300 times in the genome of T. gondii has been demonstrated to exactly quantify the parasite load, allowing correlation with clinical symptoms and impact of treatment (Homan et al., Reference Homan, Vercammen, De Braekeleer and Verschueren2000). A study investigated whether targeting the 529-bp repeat element gives better sensitivity and accuracy than can be obtained when targeting the B1 gene (35 copies) when concentrations of T. gondii DNA are low. The results demonstrated that detection of the 529-bp fragment of the AF146527 element repeated 300 times in the genome of T. gondii has been demonstrated to exactly quantify the parasite load, allowing correlation with clinical symptoms and impact of treatment and increasing diagnostic sensitivity and accuracy. Moreover, the use of RT-qPCR with primers targeting the SAG4 and MAG1 genes (localized in bradyzoites) and SAG1 (localized in tachyzoites) has proven to be useful for identifying T. gondii DNA in patients with recurrent ET in whom PCR with the B1 gene failed to detect DNA, both in patients with AIDS and in immunocompromised patients, especially when prophylaxis or treatment was initiated (Contini et al., Reference Contini, Seraceni, Cultrera, Incorvaia, Sebastiani and Picot2005; Del Grande et al., Reference Del Grande, Contini, Schiavi, Rutigliano, Maritati, Seraceni, Pinto, Dell’osso and Bruschi2017). Diagnosis of TE in AIDS patients can also be supported by demonstration of intrathecal antibody production based on detection of oligoclonal bands in CSF with antibody-specific index and affinity-mediated immunoblot techniques. This approach has also been shown to discriminate TE from other opportunistic CNS infections in AIDS (Contini et al., Reference Contini, Fainardi, Cultrera, Canipari, Peyron, Delia, Paolino and Granieri1998).

Table 2.

Molecular techniques used in toxoplasmic encephalitis (TE) diagnosis and research

Table 2 Long description

The table compares molecular methods for detecting or characterizing Toxoplasma in suspected encephalitis, listing target sequences, specimen types, aims, advantages, and limitations. Conventional PCR targets B1 or REP-529 in CSF, blood, or brain tissue and is specific but less sensitive than qPCR. Nested PCR uses similar targets across CSF, blood, PBMCs, and brain biopsy to improve detection at low parasite load, but it has a higher contamination risk. Real-time PCR targets B1, REP-529, SAG4, or MAG1 in CSF, blood, and PBMCs for rapid detection and quantification, with high sensitivity and specificity but needs specialized equipment. Multiplex PCR can detect multiple pathogens from CSF, blood, or PBMCs efficiently, though it requires careful optimization. RT-PCR detects parasite messenger RNA in brain tissue or CSF to suggest active infection, but RNA is unstable and may degrade. LAMP provides rapid REP-529 DNA detection from CSF or blood but is not yet standardized for broad clinical use. Digital PCR on CSF is described as extremely sensitive and precise but is costly and less available. Sequencing from brain tissue or CSF supports strain identification and genotyping with high accuracy and epidemiologic value, but it is not typically used for routine diagnosis.

CSF, cerebrospinal fluid; PBMCs, peripheral blood mononuclear cells; dPCR, droplet digital PCR.

Cerebral amoebiasis

Cerebral amebiasis refers to brain infections caused by various amoebae, including Acanthamoeba spp. and Balamuthia mandrillaris, which are free-living amoebae that can cause granulomatous amoebic encephalitis. N. fowleri (brain-eating amoeba) is a rare but deadly pathogen that has emerged as an important global public health concern, causing an acute, usually fatal CNS disease called PAM (Alanazi et al., Reference Alanazi, Younas, Ejaz, Alruwaili, Alruwaili, Zainab Mazhari, Atif and Junaid2025).

Most infections occur in the Southern United States following exposure to fresh water lakes and rivers, especially in summer, and to inadequately chlorinated swimming pools, which harbour free-living amoebae that can infect humans when contaminated water enters the nose (Berger, Reference Berger2022; Alanazi et al., Reference Alanazi, Younas, Ejaz, Alruwaili, Alruwaili, Zainab Mazhari, Atif and Junaid2025). This typically occurs during recreational activities such as swimming or diving, or when the nose is rinsed with untreated fresh water (Güémez and García, Reference Güémez and García2021).

The disease can be prevented by avoiding swimming or immersion in warm, fresh water and by inhaling water during ablutions, especially during the hot season.

If N. fowleri is involved, it migrates through the olfactory nerve to the brain, causing inflammation and massive destruction of brain tissue. Initial symptoms of PAM may be similar to those of bacterial meningitis and include fever, headache, nausea, vomiting, neck stiffness and altered mental status. Later, confusion, hallucinations, seizures and coma may occur (Güémez and García, Reference Güémez and García2021; Alanazi et al., Reference Alanazi, Younas, Ejaz, Alruwaili, Alruwaili, Zainab Mazhari, Atif and Junaid2025).

The disease progresses rapidly, often unresponsive to any treatment, and leads to death within days of symptom onset. Although rare, PAM has a mortality rate of over 95%.

Diagnosis is difficult and often post-mortem, as the initial symptoms are similar to other diseases.

Diagnosis of N. fowleri is based primarily on analysis of CSF obtained by lumbar puncture, to search for the amoeba and on brain imaging tests (CT scan, MRI) to assess damage. CSF analysis is performed using direct microscopy to identify motile trophozoites that move via pseudopodia. Stain techniques, such as Giemsa, Wright–Giemsa or haematoxylin–eosin, are used to highlight the typical amoeba morphology (nucleus with a large central nucleolus) (Mungroo et al., Reference Mungroo, Khan and Siddiqui2019). Molecular and advanced tests such as PCR are also available, which can detect N. fowleri DNA in CSF or tissue samples with high specificity and rapidity (Madarova et al., Reference Madarova, Trnkova, Feikova, Klement and Obernauerova2010). Next-generation sequencing is also used to rapidly identify the pathogen in complex cases, although it is more expensive and less widespread than PCR (Wang et al., Reference Wang, Li, Ji, Yang, Chen, Zhou, Yang, Zheng, Yuan, Li, Bi, Gao, Ma and Liu2018). Loop-mediated isothermal amplification technique, even if not more recent, amplifies specific regions of DNA (Mahittikorn et al., Reference Mahittikorn, Mori, Popruk, Roobthaisong, Sutthikornchai, Koompapong, Siri, Sukthana and Nacapunchai2015). This technique is rapid and has proven to be more cost-effective, sensitive and reproducible, capable of producing various amplification products at a constant temperature. Furthermore, it does not require expensive equipment, making it suitable for use in developing countries for field investigations (Mahittikorn et al., Reference Mahittikorn, Mori, Popruk, Roobthaisong, Sutthikornchai, Koompapong, Siri, Sukthana and Nacapunchai2015). Immunofluorescence and immunohistochemistry use specific antibodies to detect amoeba in biological samples. The success rate of treatment of PAM, if available, is very low.

In general, conventional amphotericin B is preferred over liposomal amphotericin B due to its greater efficacy against N. fowleri. Azithromycin (10 mg kg⁻¹ day⁻¹) and staurosporine have also shown promising. Azithromycin inhibits protein synthesis, while staurosporine induces apoptotic cell death in N. fowleri (Güémez and García, Reference Güémez and García2021). In PAM in particular, azithromycin alone or in combination with amphotericin B emerged as the most promising therapeutic options (Chaúque BJM et al., Reference Chaúque, Leal Dos Santos, Rodrigues, Fernandes, Moreira, Rott, Zanette and Goldim2026). Auranofin, an antirheumatic drug, at concentrations of 0.75–3.0 μg mL⁻¹ can increase membrane permeability, enhancing the efficacy of other drugs (Escrig et al., Reference Escrig, Hahn and Debnath2020, Chaúque BJM et al., 2026). The employment of loading auranofin into the nanoparticles may further improve the antiamebic effect and BBB permeability of this drug for the treatment of PAM (Escrig et al., Reference Escrig, Hahn and Debnath2020).

Miltefosine, a drug primarily used against leishmaniasis, has shown some efficacy in the treatment of N. fowleri infections despite its potential side effects, such as nausea and nephrotoxicity, which require careful monitoring (Mungroo et al., Reference Mungroo, Khan and Siddiqui2019; Siddiqui et al., Reference Siddiqui, Mungroo, Anuar, Alharbi, Alfahemi, Elmoselhi and Khan2022). Among antifungal drugs, posaconazole has shown potential when combined with other drugs to enhance their amoebicidal activity (Colon et al., Reference Colon, Rice, Guy and Kyle2019).

Recent studies have also explored the use of silver and gold nanoparticles combined with existing drugs, such as amphotericin B, to enhance their efficacy and reduce toxicity (Rajendran et al., Reference Rajendran, Anwar, Khan, Shah and Siddiqui2019).

Neurocysticercosis

NC is one of the most common parasitic diseases of the CNS. It is caused by the encysted larvae of the tapeworm Taenia solium. Humans are definitive hosts for T. solium, whereas pigs act as intermediate hosts. Taeniasis, i.e. intestinal infection with adult T. solium in the human host, occurs through ingestion of undercooked pork or insufficiently cooked pig meat with cysticerci infected with the larval stage (porcine cysticercosis). NC is found worldwide, particularly in Central and South America, India, Africa, East Asia and Eastern Europe. The estimated number of individuals with epilepsy due to NC is 0.45–1.35 million in Latin America, 1 million in India and 0.31–4.6 million in Africa (Coyle et al., Reference Coyle, Mahanty, Zunt, Wallin, Cantey, White, O’neal, Serpa, Southern, Wilkins, McCarthy, Higgs and Nash2008). Autochthonous cases of NC in Europe, especially in Eastern European countries, have been reported (Abraham et al., Reference Abraham, Schmidt, Kaminski, Stelzle, De Meijere, Bustos, Sahu, Garcia, Bobić, Cretu, Chiodini, Deksne, Dermauw, Devleesschauwer, Dorny, Fonseca, Gabriël, Gómez-morales, Kucsera, Laranjo-gonzález, Trevisan, Vilhena, Walker, Zammarchi and Winkler2020; Fabiani and Bruschi, Reference Fabiani and Bruschi2013; Zammarchi et al., Reference Zammarchi, Strohmeyer, Bartalesi, Bruno, Muñoz, Buonfrate, Nicoletti, García, Pozio and Bartoloni2013).

In general, the growing number of migrants from low-resource countries has led to an increase in cysticercosis in Europe. Most imported cases came from Latin America, where 44.0% of affected travellers and 69.8% of affected migrants had contracted the infection. The highest number of reported imported cases of cysticercosis is in Spain, likely because it hosts the largest number of Latin American migrants in Europe (Fabiani and Bruschi, Reference Fabiani and Bruschi2013). Generally, the majority of individuals with imported disease develop symptoms after 2– years after migration. NC is one of the leading causes of acquired epilepsy (30% of epilepsy cases) in endemic countries (Ndimubanzi et al., 2020).

Human cysticercosis occurs after humans ingest T. solium eggs, acting as accidental intermediate hosts. Migration of cysticerci to the human brain results in NC, manifesting in a variety of clinical non-patognomonic symptoms, most notably epilepsy, followed by focal deficits, headache and signs of increased intracranial pressure with vomiting, cerebral oedema and hydrocephalus (Carabin et al., Reference Carabin, Ndimubanzi, Budke, Nguyen, Qian, Demetry Cowan, Stoner, Rainwater and Dickey2011).

However, NC can present with almost any neurological sign or symptom (Zammarchi et al., Reference Zammarchi, Strohmeyer, Bartalesi, Bruno, Muñoz, Buonfrate, Nicoletti, García, Pozio and Bartoloni2013), including depression, difficulty concentrating, nausea, memory loss, drowsiness tremors and sometimes dizziness. These symptoms have earned NC the nickname of ‘the great imitator’ of other neurological diseases (Ratcliffe et al., Reference Ratcliffe, Adan, Marson, Solomon, Saini, Sinha and Keller2023b).

The diagnosis of NC is based principally on neuroimaging and is supported by immunodiagnostic tests (Hamamoto Filho et al., Reference Hamamoto Filho, Rodríguez-rivas and Fleury2022). Neuroimaging is central to the diagnosis and provides data on the number, size, location and stage of lesions as well as perilesional inflammation. Generally, CT visualizes living cysticerci as hypodense lesions not enhanced with intravenous contrast (Figure 4); live cysts may exhibit a small hyperdense scolex within them (Del Brutto et al., Reference Del Brutto, Wadia, Dumas, Cruz, Tsang and Schantz1996).

Figure 4.

Most radiological images (CT scan) of toxoplasmosis show single or multiple contrast enhancing lesions often with associated oedema.

Cysticerci are visualized in the CNS via MRI or CT, which provides information on the number of cysts, lesion morphology, stage of cyst evolution and degree of host inflammatory response to the parasite (Kusnoto Kusnoto et al., Reference Kusnoto Kusnoto, Sunarso, Suprihati, Aryaloka, Sawitri, Moses, Kurniasih, Wibowo, Wardhani, Wasito, Ahmad, Fauziah, Khaliim, Kusala, Yanestria, Julaeha, Fauzia and Ekawasti2025).

MRI is more sensitive than CT scans for the diagnosis of NC since it improves recognition of the perilesional oedema and degenerative changes of the parasite, as well as small cysts or those located inside the ventricles, brain stem, cerebellum and the racemose vesicles at the level of the posterior fossae and basal cisterns (Figure 5). However, CT scans are more sensitive in the detection of calcifications (Massaiti and Takayanagui, Reference Massaiti and Takayanagui2022). Recently, the development of 3-dimensional (3D) MRI sequences, such as Fast Imaging Employing Steady-State and 3D constructive interference in steady state, has improved the sensitivity and specificity of MRI, especially for subarachnoid and ventricular cysticerci (Massaiti and Takayanagui, Reference Massaiti and Takayanagui2022).

Degenerating cysticerci, which are more often symptomatic, are isodense or hyperdense, and oedematous inflammation around them usually causes ring or nodular enhancement by intravenous contrast (Kramer, Reference Kramer1995). However, neuroradiological images are pathognomonic only in a few cases and when the scolex is visible in the cyst (Kusnoto C et al., Reference Kusnoto Kusnoto, Sunarso, Suprihati, Aryaloka, Sawitri, Moses, Kurniasih, Wibowo, Wardhani, Wasito, Ahmad, Fauziah, Khaliim, Kusala, Yanestria, Julaeha, Fauzia and Ekawasti2025).

Guidelines published by the Infectious Disease Society of America and the American Society of Tropical Medicine and Hygiene (ASTMH) for the diagnosis of NC recommend that patients should be evaluated with both CT and MRI (ASTMH, Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017; White Al et al., Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017). When neurological imaging tests are often unsatisfying, specific serology could play an important role in confirming the diagnosis. Several serological assays to detect specific antibodies have been used for decades with different and somewhat conflicting results (Ramos-Kuri et al., Reference Ramos-Kuri, Montoya, Padilla, Govezensky, Díaz, Sciutto, Sotelo and Larralde1992). The Western Blot (WB) test using purified parasite antigens is one of the methods of choice to detect antibodies in serum, with a sensitivity of 98% in patients with more than 1 cerebral cyst and a specificity that can be as high as 100% (White et al., Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017). In patients with a single cerebral cyst, sensitivity decreases and can decrease to as low as 70%. The viability of the lesion is an important factor influencing antibody responses. If the cyst is old and calcified, sensitivity can be reduced by up to 30%. There is no advantage in detecting antibodies with WB on CSF.

EITB (enzyme-linked immunoelectron-transfer blot) with purified glycoprotein antigens is another test, which can be performed on serum samples or on CSF (Tsang and Wilkins, Reference Tsang and Wilkins1991). In any case, serological results must be carefully interpreted together with the other diagnostic criteria. The molecular biology techniques available today are only in-house. They can be performed on CSF and biopsy (Carpio et al., Reference Carpio, Romo, Parkhouse, Short and Dua2016).

Cysticercosis is a heterogeneous disease where treatment options largely depend on the location of the parasites. The clinical management of NC requires a multidisciplinary approach that includes drugs to control symptoms, including epilepsy, anti-inflammatories, antiparasitic treatment and sometimes surgery, which plays a role especially in obstructive hydrocephalus (White et al., Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017; Walton et al., Reference Walton, Castell, Collie, Wood, Sharma, Singh and Michael2021). Epilepsy can be controlled with appropriate symptomatic therapy with conventional anticonvulsant drugs, including levetiracetam, carbamazepine and valproate for the management of seizures associated with NC. Symptoms often result from self-limiting inflammation around degenerated cysticercus. The inflammation and concomitant local reaction lead to increased intracranial pressure, which can be counteracted by the administration of corticosteroids and mannitol or hypertonic solution (Carabin et al., Reference Carabin, Ndimubanzi, Budke, Nguyen, Qian, Demetry Cowan, Stoner, Rainwater and Dickey2011).

According to the last guidelines for the diagnosis and treatment of NC, surgical treatment is currently mainly reserved for intraventricular cysts (strength of recommendation strong) (Carpio et al., Reference Carpio, Romo, Parkhouse, Short and Dua2016; White et al., Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017). Neuroendoscopy is the treatment of first choice when cysticerci obstruct circulation (Hamamoto Filho et al., Reference Hamamoto Filho, Rodríguez-rivas and Fleury2022). Although recommendations cannot yet be definitive, available evidence suggests that viable, intact cysticerci that cause epilepsy or other symptoms can be treated with cestocidal therapy, especially if they cause mass effect.

Cestocidal therapy with praziquantel (PZQ) (50 mg kg⁻¹ day⁻¹ orally for 10–15 days) or albendazole (15 and 30 mg kg⁻¹ day⁻¹), administered in 2 doses daily for 8–10 days (15 mg kg⁻¹ day⁻¹ for parenchymal NC and 30 mg kg⁻¹ day⁻¹ for extraparenchymal disease), promotes the elimination of viable intracranial parasites. In some cases, the dose must be increased by reducing the number of days (De Carneri I, 2023; White et al., Reference AC, Coyle, Rajshekhar, Singh, Hauser, Mohanty, Garcia and Nash2017; Hamamoto Filho et al., Reference Hamamoto Filho, Rodríguez-rivas and Fleury2022). Treatment success rates vary from 60% to 85% and are related to the individual variability towards the active ingredient in plasma and CSF. Efficacy of treatment is assessed on the basis of the disappearance of clinical symptoms and brain scan results no earlier than 6 months after treatment. Parasitological anti-cysticercus treatment combined with dexamethasone is associated with a good clinical outcome, but may induce a reduction of PZQ plasma levels while increasing those of albendazole.

In patients with multiple viable intracranial cysticerci, steroids should always be administered before specific cestocidal therapy, as the sudden and simultaneous death of the parasites could cause uncontrollable inflammation that can be fatal. Conversely, when untreated patients show clinical and radiological signs of inflammation around a degenerating cysticerci, the parasite may already be dead, and therefore cestocidal therapy is unlikely to be effective. In these cases, it is reasonable to adopt a wait-and-see approach: symptomatic therapy only for 6–12 weeks, unless the patient’s condition worsens.

If there is no improvement, empiric cestocidal chemotherapy may be initiated, always keeping in mind alternative diagnoses such as other infections, including tuberculosis. Intracranial calcifications and lesions showing ring enhancement on neuroimaging are not viable parasites and probably do not warrant cestocidal therapy.

To prevent NC, it is recommended to cook pork or its derivatives, or to freeze the core of the meat product at −10°C for 48 h.

There are no vaccines for either pigs or humans.

Cerebral hydatidosis

Cystic echinococcosis (CE) is a zoonotic infection caused by the adult and larval stages of the tapeworm (cestode) belonging to the genus Echinococcus (family Taeniidae). E. multilocularis, E. vogeli and E. oligarthrus have been recognized but are less relevant in the context of human CNS infestation. The definitive hosts of Echinococcus are canids, such as dogs, wolves, foxes and jackals (Fennouh et al., Reference Fennouh, Yousfi, Saadet, Ouchetati, Salhi, Ouchene and Khelifi Touhami2026). Humans act as intermediate hosts and become infected through faecal–oral ingestion of contaminated water or food with the parasite’s eggs, which develop into oncospheres in the intestine and can migrate through the systemic circulation to various organs, including liver, lungs, spleen, bones and, rarely, in the heart, musculoskeletal system and the brain (De Carneri, Reference Bruschi and Pozio2023; Aung et al., Reference Aung, Nyein, Htut, Htet, Kyi, Anstey, Kyi, Hanson, Aziz, Seda, Aswani, Gosse, Krishnakumari and Pawlik2025).

CE is endemic in certain parts of Africa, Latin America, Australia, the Mediterranean basin, the Middle East and India, with prevalence rates ranging from 1.2 to 23 per 1000 inhabitants, particularly high where sheep, cattle and other animals are intensively reared (Arambulo, Reference Arambulo1997; Vaidya et al., Reference Vaidya, Zende, Paturkar, Gatne, Dighe, Waghmare, Moon, Bhave, Bengale and Nikale2018; Seimenis, Reference Seimenis2003). In Europe, in 2004, CE was the second leading cause of zoonoses among those considered to be of parasitic origin, with the greatest prevalence among populations in the Mediterranean area (Casulli et al., Reference Casulli, Antinori, Bartoloni, D’amelio, Gabrielli, Gazzoli, Rinaldi and Bruschi2023). In 2006, the incidence of human cases in the European Union was 0.1 per 100 000 inhabitants, with an increase in the number of cases mainly due to notifications received from Central and Eastern European countries (Moldovan et al., Reference Moldovan, Neghina, Calma, Marincu and Neghina2012).

Hydatid disease of the CNS (cerebral hydatidosis) is relatively rare and comprises about 2–3% of all hydatid cyst cases reported in the world. Although CE in adults reflects transmission occurring many years earlier, the disease in children and animal hosts is indicative of recent transmission (Elamour et al., Reference Elamour, Shimol and Melamed2022). The incidence of cerebral hydatidosis can reach up to 80% in paediatric age (Elamour et al., Reference Elamour, Shimol and Melamed2022), usually transmitted from dog saliva or uncooked contaminated vegetables (Padayachy and ozek, Reference Padayachy and ozek2023).

The most affected districts are above all the cerebral hemispheres (terminal branches of the middle cerebral artery, usually temporal–parietal–occipital), the cerebellum, the frontal hemisphere (Figure 5), the aqueduct of Sylvius, the subarachnoid space and the lateral ventricles (Padayachy and ozek, Reference Padayachy and ozek2023). Cerebral lesions occur in 1–4% of individuals with CE, with nonspecific clinical findings related to those of space-occupying lesions, increased intracranial pressure and seizure activity. Cysts may remain asymptomatic until they are large enough to cause a mass effect. Cyst rupture is rare but can occur spontaneously or secondary to trauma (Elamour et al., Reference Elamour, Shimol and Melamed2022).

Figure 5.

Neurocysticercosis. CT scan shows small, round cystic lesions (5−20 mm) with fluid density identical to that of cerebrospinal fluid (CSF). Inflammation is usually absent. There is no surrounding oedema, and the cyst wall does not pick up contrast.

The size and location of the mass cause headache, nausea and vomiting, seizures, weakness in extremities, cranial nerve involvement and sensory disturbances. In addition, the increased intracranial pressure can cause convulsions, ataxia, hemiparesis, diplopia and hemianopsia. If papilloedema is present, the risk of optic nerve atrophy and subsequent blindness is high (Can et al., Reference Can, Aldi, Sarikaya, Serin and Sakru2025).

In general, diagnosis of cerebral hydatidosis requires typical radiographic findings and specific serology tests, which have low sensitivity in extra-hepatic cases (McManus D, Reference McManus, Gray, Zhang and Yang2012). However, the predictive value of serological techniques depends on number, location, size and developmental stage of cysts. In the absence of image data, commercial tests with ELISA, WB, indirect hemagglutination, chemioluminescence assay and immunochromatographic test methods or in-house tests have proved useful (McManus et al., Reference McManus, Gray, Zhang and Yang2012). Even today, most of these tests use variously purified native antigens usually obtained from the cystic fluid of slaughtered animals (mainly sheep). The best known are antigen B and antigen 5. Usually, 2 tests are performed. In the case of a discrepancy, the WB is applied (Manzano-Román et al., Reference Manzano-Román, Sánchez-ovejero, Hernández-gonzález, Casulli and Siles-Lucas2015; Siles-Lucas et al., Reference Siles-Lucas, Casulli, Conraths and Müller2017). There are no tests available yet to detect parasite antigens.

The standard therapeutic approach for the patient with CE should be managed in accordance with the most up-to-date recommendations (WHO IWGE Expert Consensus) (Brunetti et al., Reference Brunetti, Kern and Vuitton2009). The currently available clinical approaches include pharmacological therapies (benzimidazoles, PZQ), percutaneous methods (PAIR (Percutaneous Aspiration Injection Reaspiration)), surgical approaches and follow-up in the absence of intervention (watch and wait). In general, for uncomplicated hepatic hydatid cysts, the WHO provides a stage-specific approach (Filice and Brunetti, Reference Filice and Brunetti1997; Brunetti et al., Reference Brunetti, Kern and Vuitton2009). Recently, some authors proposed and highlighted the anti-echinococcal effect of metformin in advanced experimental CE (Loos et al., Reference Loos, Negro, Ortega, Salinas, Arán, Pellizza, Salerno and Cumino2024).

More recently, a novel composite nanoparticle designated as dihydroartemisinin (DHA)–sodium taurocholate–polylactic-co-glycolic acid has been demonstrated to represent a promising liver-targeted nanoformulation that not only enhances DHA bioavailability but also offers a novel potent therapeutic strategy against CE (Moheteer et al., Reference Moheteer, Zhu, Pang, Rao, Aini, Aimulajiang, Zhang, Abula and Wusiman2025).

In cerebral hydatidosis, elective treatment may include albendazole (10–15 mg kg⁻¹ day⁻¹ divided twice daily). The addition of PZQ may be used in selected situations (complicated/recurrent/ruptured cases). Surgical approach represents the best for complete removal of cerebral cyst (Trueba-Argamasilla et al., Reference Trueba-Argamasilla, Iborra-bendicho, Simón-páez, Ros-de San Pedro and Segovia-hernández2023).

Cerebral hydatidosis must be differentiated from cerebral neoplasm, cysticercosis, malaria, schistosomiasis and amebiasis. Toxoplasmosis should always be excluded on the immunological status (CD4+ T lymphocyte count) of the patients, especially if immunocompromised (transplanted or AIDS).

Cerebral schistosomiasis

Cerebral schistosomiasis (CS) is a rare but serious neurological manifestation of schistosomiasis, a parasitic disease caused by trematodes of the genus Schistosoma, which is prevalent in Africa, the Middle East, South America and Asia. While the most common forms involve the intestines or urinary tract, in some cases, the parasite can affect the CNS, particularly the brain and spinal cord.

Schistosomes can reach the CNS through the venous plexuses once the worms have matured, mated and laid eggs, which can migrate or embolize to the brain.

An adult female of S. mansoni lays 100–300 eggs per day, compared to an S. haematobium female (20–200 eggs per day) and an S. japonicum female (500–3500 eggs per day) (Nascimento-Carvalho and Moreno-carvalho, Reference Nascimento-Carvalho and Moreno-carvalho2005). The shape of the eggs and the location of their excretion differentiate the various species. Eggs are deposited in the capillaries of the target organ that is parasitized by the breeding pair of worms (Shiff, Reference Shiff2000).

Eggs elicit a granulomatous inflammatory response, leading to pseudotumoral lesions, oedema and mass effect. Inflammation and immune response around trapped eggs can disrupt neuronal and cause consistent symptoms (Ross et al., Reference Ross, Bartley, Sleigh, Olds, Li, Williams and McManus2002).

Only 5% of patients develop CNS symptoms due to schistosomiasis, primarily caused by S. japonicum. Neurological symptoms usually appear within a few weeks of infection and progress acutely or subacutely, with signs progressively worsening (Allen et al., Reference Allen, McManus, Farrar, Hunstman, Darren and Yue-sheng2012).

The main neurological feature of CS caused by S. japonicum is diffuse encephalopathy and seizures (Ross et al., Reference Ross, Bartley, Sleigh, Olds, Li, Williams and McManus2002). Patients typically present with fever, headache, focal or generalized seizures, speech disturbances, nystagmus, motor weakness and cranial nerve abnormalities due to the formation of granulomatous mass lesions, increased intracranial pressure and papilloedema. Whereas S. japonicum usually causes encephalic disease, myelopathy, such as transverse myelitis, is the most common neurological manifestation of S. mansoni or S. haematobium infection (Gryseels et al., Reference Gryseels, Polman, Clerinx and Kestens2006).

Diagnosis of CS is made through microscopic examination of stool and urine (The Kato-Katz thick-smear technique) considered the standard diagnostic test as it is cost-effective and requires limited special resources, but it requires adult worms to produce eggs; serological tests can diagnose less advanced infections (Tsang and Wilkins, Reference Tsang and Wilkins1991; Pittella, Reference Pittella1997). The diagnostic evaluation of neuroschistosomiasis must include an imaging study, preferably an MRI. Neuro-schistosomiasis imaging findings are typically 1 or more grouped hyperintense lesions with punctate or nodular enhancement and a heterogeneous internal structure surrounded by oedema and mass effect (Figure 6) (Al Ameen et al., Reference Al Ameen, Faisal and Yacout2022).

Figure 6.

Neuroschistosomiasis. On CT, single or multiple hyperdense lesions with variable enhancement and surrounding hypodense oedema may be present, reflecting a focal granulomatous reaction.

A definitive diagnosis can only be ascertained with histopathological study at biopsy or at necropsy showing schistosome eggs and granulomas.

PZQ is the drug of choice. It increases the permeability of parasite membranes to calcium, leading to paralysis and death of the worms. It should be administered orally at a dose of 40 mg kg⁻¹ day⁻¹, divided into 2 doses for 1 day. Some physicians extend the dose to 3 days, especially in severe cases (Allen et al., Reference Allen, McManus, Farrar, Hunstman, Darren and Yue-sheng2012).

Anti-inflammatory drugs are essential to reduce inflammation due to egg-induced granuloma formation. These include corticosteroids (prednisone, 1–2 mg kg⁻¹ day⁻¹ tapered over 4–6 weeks or dexamethasone, 4–8 mg day⁻¹), adjusted based on severity and clinical response. Corticosteroids are started before or in conjunction with PZQ to reduce the worsening of symptoms due to antigen release from dying worms.

Symptomatic supportive treatment consists of antiepileptic drugs for seizure control (e.g. levetiracetam, phenytoin), muscle relaxants, physiotherapy for pain or spasticity management, and rehabilitation therapy, particularly for spinal cord injuries and deficits.

Preventive chemotherapy is with a single oral dose of PZQ, 40 mg kg⁻¹ (Nascimento-Carvalho and Moreno-carvalho, Reference Nascimento-Carvalho and Moreno-carvalho2005).

Cerebral toxocariasis

Toxocariasis of the human brain (also called neurotoxocariasis) is a rare but serious infection caused by larvae of the roundworms: Toxocara canis and Toxocara cati. Humans become accidental hosts when they ingest parasite eggs shed in dog or cat faeces. Eggs contaminate soil, sandboxes, unwashed vegetables or hands. A person (often a child) swallows the microscopic eggs. The larvae hatch in the intestine and migrate through the bloodstream, reaching the brain in rare cases, causing severe inflammation (Meliou et al., Reference Meliou, Mavridis, Pyrgelis and Agapiou2020).

Neurotoxocariasis is difficult to diagnose and usually involves blood tests (eosinophilia, antibodies to Toxocara), MRI or CT scan of the brain, sometimes CSF analysis. It may mimic tumours, multiple sclerosis or other infections. Neurotoxocariasis is treated by benzimidazole components, most frequently albendazole, corticosteroids or diethylcarbamazine. Early diagnosis and treatment could prevent long-term neurologic impairment and improve outcomes. Steroids can be useful to reduce brain inflammation.

Very rarely, the human brain may be affected by other parasites such as Trichinella spp. in neurotrichinellosis (Bruschi et al., Reference Bruschi, Brunetti and Pozio2013), Angiostrongylus cantonensis in eosinophilic meningoencephalitis (Lai, Reference Lai and Bruschi2014) and almost anecdotal Ophidascaris robertsi ascarid (Hossain et al., Reference Hossain, Kennedy, Wilson, Spratt, Koehler, Gasser, Šlapeta, Hawkins, Bandi and Senanayake2023) and Taenia multiceps in human coenurosis (Abbas et al., Reference Abbas, Tamponi, Madau, Cavallo, Varcasia and Scala2024).