Oxfendazole Nitazoxanide combination in experimental neurocysticercosis - Anti-inflammatory and cysticidal effects.

Neurocysticercosis (NCC) is a parasitic infection caused by the larval stage of the pork tapeworm, Taenia solium. The complications of NCC include seizures, headaches, cognitive impairment, and focal neurological deficits. In addition to antiparasitic drugs and surgery, the management of NCC includes the use of corticosteroids to reduce inflammation and control symptoms. The traditional treatment with albendazole and praziquantel has not been altered over 30 years and present several side effects. There are other anti-helminthic drugs such as oxfendazole and nitazoxanide that may show efficacy in NCC treatment. The aim of this study was to determine the histopathologic aspects of experimental NCC after in vivo treatment with the combination of oxfendazole and nitazoxanide. Balb/c mice were infected with T. crassiceps cysticerci and divided into groups of 10 animals each that received a single dose through gavage as follows: group treated with NaCl 0.9% (control group); group treated by monotherapy of the anti-helminthic drugs, 30 mg/kg in single dose of oxfendazole (OXF) or nitazoxanide (NTZ); and groups treated with the combination of the drugs (OXF/NTZ group). Macroscopic and microscopic analysis were performed. There was greater presence of final stage cysticerci after treatment. The microscopic analysis of the general pathological processes showed that the monotherapy with all treatment groups induced higher perivasculitis than what was observed in the control group. In contrast, the combination treatment showed a lower observation of PMN and MN inflammatory infiltration in comparison to the other treatments and to the control one. These results show that indeed the association of benzimidazole derivatives which present both anti-helminthic and anti-inflammatory properties with other cysticidal drugs are beneficial for the NCC treatment in which the aim is to destroy parasite without inducing inflammatory damage in the brain tissue.

Understanding the pathogenic mechanisms and therapeutic effects in neurocysticercosis.

Despite being a leading cause of acquired seizures in endemic regions, the pathological mechanisms of neurocysticercosis are still poorly understood. This study aims to investigate the impact of anthelmintic treatment on neuropathological features in a rat model of neurocysticercosis. Rats were intracranially infected with Taenia solium oncospheres and treated with albendazole + praziquantel (ABZ), oxfendazole + praziquantel (OXF), or untreated placebo (UT) for 7 days. Following the last dose of treatment, brain tissues were evaluated at 24 h and 2 months. We performed neuropathological assessment for cyst damage, perilesional brain inflammation, presence of axonal spheroids, and spongy changes. Both treatments showed comparable efficacy in cyst damage and inflammation. The presence of spongy change correlated with spheroids counts and were not affected by anthelmintic treatment. Compared to white matter, gray matter showed greater spongy change (91.7% vs. 21.4%, p < 0.0001), higher spheroids count (45.2 vs. 0.2, p = 0.0001), and increased inflammation (72.0% vs. 21.4%, p = 0.003). In this rat model, anthelmintic treatment destroyed brain parasitic cysts at the cost of local inflammation similar to what is described in human neurocysticercosis. Axonal spheroids and spongy changes as markers of damage were topographically correlated, and not affected by anthelmintic treatment.

Albendazole - Ivermectin combination decreases inflammation in experimental neurocysticercosis.

Neurocysticercosis (NCC) is a public health issue in endemic regions and is considered the main preventable cause of neurologic disease. It is caused by the presence of Taenia solium cysticercus in the central nervous system. The current treatment is performed with anthelminthic drugs - albendazole (ABZ) or praziquantel - associated with anti-inflammatory and corticosteroids in order to prevent the negative effects of the inflammatory reaction to the parasite's death. Ivermectin (IVM) is an anthelminthic drug that has been shown to present an anti-inflammatory effect. The aim of this study was to was to evaluate the histopathologic aspects of experimental NCC after in vivo treatment with a combination of ABZ-IVM. Balb/c mice were intracranially inoculated with T. crassiceps cysticerci and after 30 days of infection were treated with a single dose of NaCl 0.9% (control group), ABZ monotherapy (40 mg/kg), IVM monotherapy (0.2 mg/kg) or a combination of ABZ-IVM. 24h after the treatment the animals were euthanized and the brain was removed for histopathologic analysis. The IVM monotherapy and ABZ-IVM combination showed more degenerated cysticerci, less inflammatory infiltration, meningitis and hyperemia than the other groups. Therefore, it is possible to recommend the combination of albendazole and ivermectin as alternative chemotherapy for NCC due to its antiparasitic and anti-inflammatory effects, with potential to decrease the negative effects of the inflammatory burst when the parasite is killed within the CNS.

Update on the diagnosis and management of neurocysticercosis.

BACKGROUND: Neurocysticercosis (NCC) is a serious public health problem in several developing countries, including those in Latin America, Asia, and Africa. NCC is considered to be the main cause of late-onset epilepsy in endemic areas. OBJECTIVE: This review summarizes recent advances in diagnosis and therapy of NCC. Methods: Relevant articles and books were reviewed and used as a source of information for this review. RESULTS: The diagnosis of NCC is based upon neuroimaging studies (MRI and computed tomography) and laboratory analysis of the cerebrospinal fluid (CSF). Praziquantel and albendazole are considered parasiticidal drugs against NCC, but there is an intense debate over the value and safety of these drugs. CONCLUSION: Given the relative scarcity of clinical trials, more comparative interventional studies, especially randomized controlled trials in long-term clinical evolution, are required in order to clarify the controversy over the validity of parasitic therapy in patients with NCC.

Porcine model of neurocysticercosis by intracarotid injection of Taenia solium oncospheres: Dose assessment, infection outcomes and serological responses.

BACKGROUND: Neurocysticercosis (NCC) is the infection of the human central nervous system (CNS) by Taenia solium larvae that cause significant neurological morbidity. Studies on NCC pathophysiology, host-parasite interactions or therapeutic agents are limited by the lack of suitable animal models. We have previously reported that carotid injection of activated T. solium oncospheres directs parasites into the CNS and consistently reproduces NCC. This study assessed the minimal dose required to consistently obtain NCC by intracarotid oncosphere injection and compared antigen and antibody response profiles by dose-group. METHODS/PRINCIPAL FINDINGS: Three groups of pigs were infected with either 2500 (n = 10), 5000 (n = 11), or 10000 (n = 10) oncospheres. Two pigs died during the study. Necropsy exam at day 150 post-infection (PI) demonstrated viable NCC in 21/29 pigs (72.4%), with higher NCC rates with increasing oncosphere doses (4/9 [44.4%], 9/11 [81.8%] and 8/9 [88.9%] for 2500, 5000, and 10000 oncospheres respectively, P for trend = 0.035). CNS cyst burden was also higher in pigs with increasing doses (P for trend = 0.008). Viable and degenerated muscle cysticerci were also found in all pigs, with degenerated cysticerci more frequent in the 2500 oncosphere dose-group. All pigs were positive for circulating parasite antigens on ELISA (Ag-ELISA) from day 14 PI; circulating antigens markedly increased at day 30 PI and remained high with plateau levels in pigs infected with either 5000 or 10000 oncospheres, but not in pigs infected with 2500 oncospheres. Specific antibodies appeared at day 30 PI and were not different between dose-groups. CONCLUSION/SIGNIFICANCE: Intracarotid injection of 5000 or more oncospheres produces high NCC rates in pigs with CNS cyst burdens like those usually found in human NCC, making this model appropriate for studies on the pathogenesis of NCC and the effects of antiparasitic treatment.

Taenia solium Metacestode Factor as Probable Cause of Temporal Lobe Epilepsy.

This article analyzes data from scientific publications (mainly reviews) concerning the link between human neurocysticercosis and epilepsy. Along with data from our own studies on experimental hippocampal sclerosis induced by a Taenia crassiceps metacestode factor in mice, it explores the connection between mechanisms that likely favor the development of epilepsy in cases of human neurocysticercosis. The data from both sources suggest the idea that the T. solium metacestode factor causes hippocampal sclerosis and later epilepsy in humans with neurocysticercosis.

Subarachnoid racemose neurocysticercosis with cerebellar involvement: an old friend in an infrequent location?

Taenia solium is the most common parasitic infection of the central nervous system and it can cause parenchymal or extra-parenchymal lesions. Subarachnoid cysticercosis is a type of extra-parenchymal infection in which the prevalence is not known and racemose NC with cerebellar involvement has been rarely reported. The diagnosis is challenging because of its similarity to other infectious diseases or to subarachnoid involvement of systemic malignancies. Treatment usually requires cysticide drugs, however, there are no randomized studies concerning the anti-parasitic treatment in subarachnoid NC. We present a case of racemose NC in the cerebellar hemisphere to draw attention to this pathology, endemic in many parts of the world; and highlight all the current gaps in our understanding of this entity.

Inflammation in neurocysticercosis: clinical relevance and impact on treatment decisions.

INTRODUCTION: Neurocysticercosis is caused by the localization of Taenia solium larvae in the central nervous system. The disease remains endemic in most countries of Latin America, Asia and Africa. While major improvements have been made in its diagnosis and treatment, uncertainties persist regarding the clinical implications and treatment of the inflammatory reaction associated with the disease. AREAS COVERED: In this review, based on PubMed searches, the authors describe the characteristics of the immune-inflammatory response in patients with neurocysticercosis, its clinical implications and the treatment currently administered. The dual role of inflammation (participating in both, the death of the parasite, and the precipitation of serious complications) is discussed. New therapeutic strategies of potential interest are presented. EXPERT OPINION: Inflammatory reaction is the main pathogenic mechanism associated to neurocysticercosis. Its management is mainly based on corticosteroids administration. This strategy had improved prognostic of patients as it allows for the control of most of the inflammatory complications. On the other side, it might be involved in the persistence of parasites in some patients, despite cysticidal treatment, due to its immunosuppressive properties. New strategies are needed to improve therapeutical management, particularly in the severest presentations.

Taenia solium Cysticercosis and Its Impact in Neurological Disease.

Taenia solium neurocysticercosis (NCC) is endemic in most of the world and contributes significantly to the burden of epilepsy and other neurological morbidity. Also present in developed countries because of immigration and travel, NCC is one of few diseases targeted for eradication. This paper reviews all aspects of its life cycle (taeniasis, porcine cysticercosis, human cysticercosis), with a focus on recent advances in its diagnosis, management, and control. Diagnosis of taeniasis is limited by poor availability of immunological or molecular assays. Diagnosis of NCC rests on neuroimaging findings, supported by serological assays. The treatment of NCC should be approached in the context of the particular type of infection (intra- or extraparenchymal; number, location, and stage of lesions) and has evolved toward combined symptomatic and antiparasitic management, with particular attention to modulating inflammation. Research on NCC and particularly the use of recently available genome data and animal models of infection should help to elucidate mechanisms of brain inflammation, damage, and epileptogenesis.

Current approaches to cysticidal drug therapy for neurocysticercosis.

INTRODUCTION: Cysticidal drugs have improved the prognosis of thousands of patients with neurocysticercosis (NCC). However, conflicting studies have created controversies on the actual value of these drugs. Here, the reasons of these controversies, as well as evidence showing the beneficial role of cysticidal drugs are reviewed. AREAS COVERED: The present review (based on different databases searches up to March 2020), focuses on the evidence supporting the use of cysticidal drugs in patients with NCC. For parenchymal NCC, albendazole alone must be used for patients with one or two cysts, while the combination of albendazole plus praziquantel is advised for those with more than two lesions. Level I evidence on the optimal regimens of cysticidal drugs for treatment of extraparenchymal NCC is lacking, although there is growing evidence supporting the use of cysticidal drugs in these cases, providing that hydrocephalus and intracranial hypertension have previously been treated. EXPERT OPINION: With the exception of therapy of patients with viable parenchymal brain cysticerci, we are far from getting level I evidence on the best approach for each of the other forms of NCC, as most of our knowledge on therapy for extraparenchymal NCC is based on non-controlled studies or small series of patients.

Course and prognosis of adult-onset epilepsy in Brazil: A cohort study.

BACKGROUND: Most of the epilepsy longitudinal studies have analyzed children. However, in endemic regions, such as Brazil, neurocysticercosis accounts for many adult-onset epilepsy cases. So, the main objective of this study was to identify the clinical predictors associated with drug-resistant adult-onset epilepsy in Brazil during a long-term follow-up. METHODS: We followed 302 individuals with adult-onset epilepsy for 9.8 years in our University Hospital. Structured questionnaires about drug-resistant epilepsy were applied. The presence of drug-resistant epilepsy was the primary outcome. We used multilevel linear modeling in our data analysis. RESULTS: Overall 47 (15.6%) individuals presented drug-resistant epilepsy and the etiology was structural in 70.2% of them, while infectious etiology was present in 8.5% of this group. Infectious etiology occurred in 25.9% (n = 66) of the patients from the nondrug-resistant group. Those with developmental delay were two times more likely to present seizures. Structural epilepsy etiology was associated with an increased chance of relapsing. Poor school performance and abnormal electroencephalogram were also associated with an increased chance of seizures. CONCLUSION: The course of epilepsy was favorable in the majority of our patients, and drug-resistant epilepsy rates were similar to those found in other studies, although we evaluated older individuals with higher levels of infectious etiology. Also, we found that neurocysticercosis was associated with well-controlled epilepsy, while structural epilepsy was directly related to the occurrence of seizures. We also hypothesized that the smaller size of lesions found in neurocysticercosis could contribute to better treatment response.

In vitro nitazoxanide exposure affects energetic metabolism of Taenia crassiceps.

Nitazoxanide (NTZ) is a broad-spectrum drug used in intestinal infections, but still poorly explored in the treatment of parasitic tissular infections. This study aimed to evaluate the in vitro responses of the energetic metabolism of T. crassiceps cysticerci induced by NTZ. The organic acids of the tricarboxylic acid cycle, products derived from fatty acids oxidation and protein catabolism were analyzed. These acids were quantified after 24 h of in vitro exposure to different NTZ concentrations. A positive control group was performed with albendazole sulfoxide (ABZSO). The significant alterations in citrate, fumarate and malate concentrations showed the NTZ influence in the tricarboxylic acid (TCA) cycle. The non-detection of acetate confirmed that the main mode of action of NTZ is effective against T. crassiceps cysticerci. The statistical differences in fumarate, urea and beta-hydroxybutyrate concentrations showed the NTZ effect on protein catabolism and fatty acid oxidation. Therefore, the main energetic pathways such as the TCA cycle, protein catabolism and fatty acids oxidation were altered after in vitro NTZ exposure. In conclusion, NTZ induced a significant metabolic stress in the parasite indicating that it may be used as an alternative therapeutic choice for cysticercosis treatment. The use of metabolic approaches to establish comparisons between anti parasitic drugs mode of actions is proposed.

Parasitic Infections of the Nervous System.

Parasitic infections of the central nervous system are much more common than suspected, although most infections are asymptomatic. For example, parasites like the ubiquitous protozoa Toxoplasma gondii or the nematode larvae Toxocara canis infect significant proportions of the human population. Other parasitic infections such as malaria and neurocysticercosis are widespread in developing countries and become major causes of neurological morbidity in these regions as well in immigrants and travelers. This article reviews parasitic pathogens causing neurological morbidity and mortality, including an extensive list of less common parasitic infections of the human nervous system.

Partial inhibition of the main energetic pathways and its metabolic consequences after in vivo treatment with benzimidazole derivatives in experimental neurocysticercosis.

Benzimidazole derivatives such as albendazole (ABZ) and mebendazole are important molecules used in helminthic treatment. Neurocysticercosis is the main cause of acquired epilepsy throughout the world and is currently treated with ABZ. New molecules have been studied in order to aid in the treatment of this neglected tropical disease, among them RCB15 and RCB20. The aim of this study was to evaluate the metabolic impact of RCB15 and RCB20 on Taenia crassiceps cysticerci intracranially inoculated in Balb/c mice. Thirty days after the inoculation the mice were treated with 50 mg kg-1 of RCB15, RCB20, ABZ or NaCl 0.9%. The euthanasia and cysticerci removal were performed 24 h after the treatment. The cysticerci were analysed through high performance liquid chromatography. After the treatments, there was an impairment in the main energetic pathways such as glycolytic pathway, homolactic fermentation or in mitochondrion energy production detected through the decrease in pyruvate, lactate, oxaloacetate, malate and fumarate concentrations. This induced the parasite to resort to alternative energetic pathways such as proteins catabolism, propionate fermentation and fatty acids oxidation. Therefore, benzimidazole derivatives are a promising alternative to ABZ use as they also reach the brain tissue and induce a metabolic stress in the cysticerci.

Exploring the complex associations over time among albendazole treatment, cyst evolution, and seizure outcomes in neurocysticercosis.

OBJECTIVE: To develop a causal model for the occurrence of neurocysticercosis (NC)-related seizures and test hypotheses generated from the model. METHODS: We used data from a randomized controlled trial comparing albendazole with placebo among patients newly diagnosed with NC. Based on our causal model, we explored the associations among albendazole treatment, NC cyst evolution, and seizure outcomes over 24 months of follow-up using generalized linear mixed effect models. RESULTS: We included 153 participants, of whom 51% received albendazole. The association between seizure outcomes and treatment over time demonstrated lack of linearity and heterogeneity, requiring the inclusion of time-treatment interaction terms for valid modeling. Participants in the albendazole group had fewer seizures overall and of partial onset at all time points compared with the placebo group, but the difference increased over the first few months following treatment, then decreased over time. Generalized seizures exhibited a more complex association; those in the albendazole group had fewer seizures compared with those in the placebo group for the first few months after treatment, and then the association reversed and those in the placebo arm had fewer seizures. Adjusting for the number of NC cysts in each phase resulted in an attenuation of the strength of association between albendazole and seizure outcomes, consistent with mediation. Among participants in whom all cysts had disappeared (n = 21), none continued to have seizures. SIGNIFICANCE: Albendazole treatment is associated with a possible reduction in focal seizures in the short term (3-6 months), perhaps by hastening the resolution of the cysts. However, the effect is not discernible over the long term, because most cysts either calcify or resolve completely, regardless of whether treated with albendazole. The stage of evolution of the cysticercus is an important consideration in the evaluation of albendazole effect on seizure outcome.

Monitoring treatment of Taenia solium- neurocysticercosis by detection of circulating antigens: a case report.

BACKGROUND: Parenchymal neurocysticercosis is a frequent cause of seizures in areas endemic for Taenia solium. At present there is scarce data on the evolution of the levels of circulating metacestodal antigen before, during and after treatment with anthelmintic drugs. CASE PRESENTATION: A patient with paucisymptomatic neurocysticercosis (NCC) diagnosed by Ag-ELISA, and confirmed by MRI images, was treated with praziquantel, albendazole and dexamethasone. The level of circulating T. solium antigen was determined weekly. Circulating antigen disappeared from his blood within 14 days after the start of the treatment and correlated with the involution of the cysticerci in the brain shown by imaging. Seventeen years later, the patient has not shown any side effect nor symptoms related to the treatment or to NCC. CONCLUSIONS: If this encouraging finding is confirmed in a larger series of patients, this technique could be used to determine parasitological cure after treatment and might complement or sometimes replace sequential MRI-imaging of the brain.

A Personal Account Regarding the Origin and Evolution of Controversies in the Management of Neurocysticercosis.

A panel of experts from the Infectious Disease Society of America and The American Society of Tropical Medicine and Hygiene recently published guidelines for management of neurocysticercosis, showing that clinical manifestations as well as the stage of involution and the anatomical location of parasites must be taken into account before the start of a rational therapy. Soon thereafter, isolated opinions attempted to discredit these guidelines, arguing insufficient or inadequate evidence and suggesting that they should not be followed worldwide. In view of these conflicting reports, it is appropriate to review the origin and evolution of the controversy on the medical treatment of neurocysticercosis.