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The infection of the nervous system by the cystic larvae of Taenia solium (neurocysticercosis) is a frequent cause of seizure disorders. Neurocysticercosis is endemic or presumed to be endemic in many low-income countries. The lifecycle of the worm and the clinical manifestations of neurocysticercosis are well established, and CT and MRI have substantially improved knowledge of the disease course. Improvements in immunodiagnosis have further advanced comprehension of the pathophysiology of this disease. This knowledge has led to individualised treatment approaches that account for the involvement of parenchymal or extraparenchymal spaces, the number and form of parasites, and the extent of degeneration and associated inflammation. Clinical investigations are focused on development of effective treatments and reduction of side-effects induced by treatment, such as seizures, hydrocephalus, infarcts, and neuroinjury.

Neurocysticercosis (caused by infection with the tapeworm Taenia solium ) is a major cause of acquired seizures and epilepsy worldwide. Nash and Garcia describe the different types of neurocysticercosis infection and discuss the role of the host inflammatory response in disease pathology. They also highlight recent advances in the diagnosis and treatment of the disease, including the limitations of current therapies. Neurocysticercosis is a parasitic disease caused by the larval (cystic) form of the pork cestode tapeworm, Taenia solium , and is a major cause of acquired seizures and epilepsy worldwide. Development of sensitive and specific diagnostic methods, particularly CT and MRI, has revolutionized our knowledge of the burden of cysticercosis infection and disease, and has led to the development of effective antihelminthic treatments for neurocysticercosis. The importance of calcified granulomas with perilesional edema as foci of seizures and epilepsy in populations where neurocysticercosis is endemic is newly recognized, and indicates that treatment with anti-inflammatory agents could have a role in controlling or preventing epilepsy in these patients. Importantly, neurocysticercosis is one of the few diseases that could potentially be controlled or eliminated—an accomplishment that would prevent millions of cases of epilepsy. This Review examines the rationale for treatment of neurocysticercosis and highlights the essential role of inflammation in the pathogenesis of disease, the exacerbation of symptoms that occurs as a result of antihelminthic treatment, and the limitations of current antihelminthic and anti-inflammatory treatments. Key Points Taenia solium neurocysticercosis is a common cause of seizure disorders worldwide Intraparenchymal neurocysticercosis is mostly associated with seizures; extraparenchymal neurocysticercosis can cause mass effects and hydrocephalus, and has a poor prognosis Management of patients with neurocysticercosis commonly involves antiepileptic drugs and steroids to treat the neurological and inflammatory symptoms, plus antihelminthic drugs to kill any viable parasites (in most cases) Most treatment recommendations for neurocysticercosis are based on expert opinion or anecdotal evidence; only a few controlled studies of antihelminthic drugs or steroids exist Neurocysticercosis could provide a useful model to study susceptibility to and pathogenesis of epilepsy Neurocysticercosis is a preventable, and probably eradicable, cause of seizures and epilepsy

Antigen tests for diagnosis and disease monitoring in some types of neurocysticercosis (NCC) are useful but access to testing has been limited by availability of proprietary reagents and/or kits. Three previously identified IgM-secreting hybridomas whose IgM products demonstrated specificity to Taenia solium underwent variable heavy and light chain sequencing and isotype conversion to mouse IgG. Screening of these recombinantly expressed IgG anti-Ts hybridomas, identified one (TsG10) with the highest affinity to crude Taenia antigen. TsG10 was then used as a capture antibody in a sandwich antigen detection immunoassay in combination with either a high titer polyclonal anti-Ts antibody or with biotinylated TsG10 (termed TsG10*bt). Using serum, plasma, and CSF samples from patients with active NCC and those from NCC-uninfected patients, ROC curve analyses demonstrated that the TsG10-TsG10-*bt assay achieved a 98% sensitivity and 100% specificity in detecting samples known to be antigen positive and outperformed the polyclonal based assay (sensitivity of 93% with 100% specificity). By comparing levels of Ts antigen (Ag) in paired CSF (n = 10) or plasma/serum (n = 19) samples from well-characterized patients with extra-parenchymal NCC early in infection and at the time of definitive cure, all but 2 (1 from CSF and 1 from plasma) became undetectable. There was a high degree of correlation (r = 0.98) between the Ag levels detected by this new assay and levels found by a commercial assay. Pilot studies indicate that this antigen can be detected in the urine of patients with active NCC. A newly developed recombinant monoclonal antibody-based Ts Ag detection immunoassay is extremely sensitive in the detection of extra-parenchymal NCC and can be used to monitor the success of treatment in the CSF, serum/plasma and urine. The ability to produce recombinant TsG10 at scale should enable use of this antigen detection immunoassay wherever NCC is endemic. ClinicalTrials.gov Identifiers: NCT00001205 - & NCT00001645.

Neurocysticercosis prevalence estimates often are based on serosurveys. However, assessments of Taenia solium seropositivity durability in patients with various neurocysticercosis types are lacking. We optimized a triplex serologic ELISA by using synthetic GP50, T24H, and Ts18var3 antigens for T. solium. We used that assay to test sequential serologic responses over several years after neurocysticercosis cure in 46 patients, 9 each with parenchymal or ventricular neurocysticercosis and 28 with subarachnoid disease. Triplex results were concordant with 98% of positive and 100% of negative enzyme-linked immunoelectrotransfer blots. Eight years after neurocysticercosis cure, 11.1% of patients with parenchymal, 47.3% with subarachnoid, and 41.7% with ventricular disease were still seropositive. Median time to seroreversion after cure in this cohort in a T. solium nonendemic area was 2 years for parenchymal disease, 4 years for ventricular disease, and 8 years for subarachnoid disease. Our findings can inform epidemiologic models that rely on serosurveys to estimate disease burden.

Neurocysticercosis (NCC), a parasitic brain infection caused by Taenia solium larvae, remains a leading cause of preventable epilepsy globally. Although calcified brain lesions were formerly considered as the quiescent end stage of NCC, they may act as epileptogenic foci. It has been suggested that parasitic antigens within calcified lesions may act as potential triggers of inflammation and subsequent seizure activity. In this study, we developed and optimized immunohistochemistry (IHC) assays employing anti-Taenia solium monoclonal antibodies (mAbs) to detect residual cyst antigens in calcified lesions in a porcine NCC model and assessed antigen persistence for up to 12 months after successful antiparasitic treatment. Six mAbs raised against T. solium whole cyst (TsW5, TsW8, and TsW12), vesicular fluid (TsV3 and TsV4), and excretory/secretory products (TsE1) were used for IHC assay development and tested in brain sections containing viable brain cysts from NCC pigs and uninfected tissue from controls to optimize assay conditions, blocking, primary and secondary antibody dilutions. Optimized assays were subsequently performed in selected calcified granulomas (n = 20) obtained from NCC-infected pigs sacrificed at 4, 8, and 12 months after antiparasitic treatment to identify residual cyst antigens as well as their localization and area of reactivity. We observed residual cyst antigens in 65-80% of calcified granulomas, with TsW8 and TsV3 showing the highest percentages of immunoreactivity. Antigen localization followed two patterns, one with antigens entirely located within the calcified lesions (TsW5, TsW8, TsW12, and Tsv4) and another with antigens located outside the cyst in the perilesional brain tissue (TsV3 and TsE1). Antigen detection and the extent of reactivity declined progressively after antiparasitic treatment but persisted at detectable immunoreactive areas in calcified granulomas up to month 12 months after treatment. T. solium antigens remain detectable in calcified granulomas and in the perilesional tissue for up to 12 months after antiparasitic treatment in the pig model.

Background and objectives Subarachnoid neurocysticercosis (SANCC) is the most severe manifestation of neurocysticercosis. Most complications (communicating hydrocephalus, ischemic stroke, aneurysm, and subarachnoid hemorrhage) are due to inflammation localized to the central nervous system (CNS). The role of eosinophils in the inflammation associated with SANCC has not been previously studied. Methods Cryopreserved CSF collected as part of a clinical trial for neurocysticercosis (NCC) were assessed for analytes associated with eosinophil activation and recruitment using multiplex bead assays in both subjects with SANCC ( n  = 28) and in NCC-negative controls ( n  = 26). The SANCC patients underwent chart review for extraction of clinical variables as well as grouping by disease severity to identify analytes that may be associated with the development of more severe symptoms of SANCC. Results Eosinophil granule proteins (EGPs – ECP, EDN, and EPO), markers of eosinophil activation, were elevated in the CSF of SANCC patients compared to controls. Moreover, the eosinophil-associated cytokines/chemokines IL-5, IL-13, IL-18, CCL24/eotaxin-2, and CCL26/eotaxin-3 were also significantly elevated in the CSF of SANCC patients compared to controls. In those for whom there were paired specimens ( n  = 13) from baseline and following cure, there was a significant reduction in these cytokines/chemokines (except CCL26/eotaxin-3). The percentage of CSF white blood cells that were eosinophils was positively correlated with EDN, EPO, IL-5, IL-13, CCL24, CCL26, CCL8, CCL13, and CCL5/RANTES, as well as the time it took to achieve biomarker cure. When SANCC patients were subdivided between those with severe disease and those with non-severe disease, the levels of eosinophil cationic protein (ECP), the CCR3 ligands (CCL7 and CCL5), CCL4, IL-18, and IL-1RA discriminated clearly between these 2 groups.  Discussion These data provide evidence for eosinophil recruitment and activation in the subarachnoid space in patients with SANCC, as well as for a potential role of eosinophils in driving inflammation-associated complications.

Racemose neurocysticercosis is an aggressive disease caused by the aberrant expansion of the cyst form of Taenia solium within the subarachnoid spaces of the human brain and spinal cord resulting in a mass effect and chronic inflammation. Although expansion is likely caused by the proliferation and growth of the parasite bladder wall, there is little direct evidence of the mechanisms that underlie these processes. Since the development and growth of cysts in related cestodes involves totipotential germinative cells, we hypothesized that the expansive growth of the racemose larvae is organized and maintained by germinative cells. Here, we identified proliferative cells expressing the serine/threonine-protein kinase plk1 by in situ hybridization. Proliferative cells were present within the bladder wall of racemose form and absent from the homologous tissue surrounding the vesicular form. Cyst proliferation in the related model species Taenia crassiceps (ORF strain) occurs normally by budding from the cyst bladder wall and proliferative cells were concentrated within the growth buds. Cells isolated from bladder wall of racemose larvae were established in primary cell culture and insulin stimulated their proliferation in a dose-dependent manner. These findings indicate that the growth of racemose larvae is likely due to abnormal cell proliferation. The different distribution of proliferative cells in the racemose larvae and their sensitivity to insulin may reflect significant changes at the cellular and molecular levels involved in their tumor-like growth. Parasite cell cultures offer a powerful tool to characterize the nature and formation of the racemose form, understand the developmental biology of T . solium , and to identify new effective drugs for treatment.

Subarachnoid neurocysticercosis (SANCC) is caused by an abnormally transformed form of the metacestode or larval form of the tapeworm  Taenia solium . In contrast to vesicular parenchymal and ventricular located cysts that contain a viable scolex and are anlage of the adult tapeworm, the subarachnoid cyst proliferates to form aberrant membranous cystic masses within the subarachnoid spaces that cause mass effects and acute and chronic arachnoiditis. How subarachnoid cyst proliferates and interacts with the human host is poorly understood, but parasite stem cells (germinative cells) likely participate. RNA-seq analysis of the subarachnoid cyst bladder wall compared to the bladder wall and scolex of the vesicular cyst revealed that the subarachnoid form exhibits activation of signaling pathways that promote proliferation and increased lipid metabolism. These adaptions allow growth in a nutrient-limited cerebral spinal fluid. In addition, we identified therapeutic drug targets that would inhibit growth of the parasite, potentially increase effectiveness of treatment, and shorten its duration.

Calcified neurocysticercosis (NCC), the end stage of brain cysts of the pork tapeworm Taenia solium is a common cause of epilepsy. Calcified NCC lesions are not inert and represent potential epileptogenic foci. Understanding the mechanisms of residual calcification in NCC is hindered by the difficulty of accessing human brain biopsies. Since cyst degeneration can be induced by antiparasitic treatment (APT) in NCC-infected pigs, this study assessed the residual calcification process in this model at three time points after APT. Fifteen naturally infected pigs with viable NCC confirmed by magnetic resonance imaging received APT with albendazole and praziquantel and were sacrificed after 4, 8, and 12 months (n = 5 each). The pigs' brains were removed and processed by ex vivo CT scan to assess the proportion of cysts that calcified by post-treatment time points using risk ratios (RR) from Poisson regression. Radiodensity levels (Hounsefield units) of calcified lesions were also measured and compared using linear coefficients from log-transformed values in generalized linear models. The overall proportion of residual calcification on CT scan was 63.9% (156 calcified lesions/244 viable cysts), being statistically higher in treated NCC pigs at 4 months (83.3% [50/60], RR = 2.61, P < 0.001) and 8 months (82.8% [77/93], RR = 2.59, P < 0.001) versus 12 months (31.9% [29/91]). At 8 months after APT, calcifications were more dense (100.6 ± 3.6 HU) compared to 12 months (74.4 ± 3.6 HU, β = 0.37, P = 0.010) and marginally higher compared to 4 months (85.2 ± 3.8 HU, β = 0.24, P = 0.096), and were also larger and more frequently found on histopathology. Calcification in NCC is a dynamic process that can be induced and monitored in naturally infected pigs. Eight months after treatment seems to be an optimal time point for assessing residual calcification.