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In the past 50 years, enormous progress has been made in the diagnosis, treatment and control of taeniid cestode infections/diseases and in the scientific understanding thereof. Most interest in this group of parasites stems from the serious diseases that they cause in humans. It is through this lens that we summarize here the most important breakthroughs that have made a difference to the treatment of human diseases caused by these parasites, reduction in transmission of the taeniid species associated with human disease, or understanding of the parasites’ biology likely to impact diagnosis or treatment in the foreseeable future. Key topics discussed are the introduction of anti-cestode drugs, including benzimidazoles and praziquantel, and the development of new imaging modalities that have transformed the diagnosis and post-treatment monitoring of human echinococcoses and neurocysticercosis. The availability of new anti-cestode drugs for use in dogs and a detailed understanding of the transmission dynamics of Echinococcus granulosus sensu lato have underpinned successful programs that have eliminated cystic echinococcosis in some areas of the world and greatly reduced the incidence of infection in others. Despite these successes, cystic and alveolar echinococcosis and neurocysticercosis continue to be prevalent in many parts of the world, requiring new or renewed efforts to prevent the associated taeniid infections. Major advances made in the development of practical vaccines against E. granulosus and Taenia solium will hopefully assist in this endeavour, as might the understanding of the parasites’ biology that have come from an elucidation of the nuclear genomes of each of the most important taeniid species causing human diseases.

Antiparasitic agents against Taenia solium cysticercosis have been in use since 1979, although its use has been questioned on the basis that cysts would die naturally and thus treatment-induced inflammation is unnecessary. In addition, isolated reports have also questioned whether neurocysticercosis (NCC) is a cause of epilepsy. After more than three and a half decades, a large body of evidence is available. Little if any doubt exists about NCC as a cause of seizures - NCC is consistently associated with seizures when appropriate groups are compared, and in a large subset of cases, seizure semiology correlates with the anatomical location of lesions. Cyst degeneration and the subsequent inflammatory reaction increase seizure expression, although patients with non-inflamed cysts may have seizures, as do patients with long-standing, not inflamed calcified scars. Assessment of the evidence on cysticidal efficacy, safety, and the impact of cyst destruction in decreasing seizures leads to the conclusion that the benefits of antiparasitic treatment in parenchymal brain cysticercosis clearly outweigh the risks, and have provided substantive evidence of the role of NCC as a cause of seizures and epilepsy. Antiparasitic therapy should be considered a primary option in the management of patients with live or degenerating brain NCC cysts. This article is part of a Special Issue entitled "Neurocysticercosis and Epilepsy".

Stroke is a major cause of death and disability, with most of its burden now affecting low- and middle-income countries (LMIC). People in rural areas of LMIC who have a stroke receive very little acute stroke care and local healthcare workers and family caregivers in these regions lack the necessary knowledge to assist them. Intriguingly, a recent rapid growth in cell-phone use and digital technology in rural areas has not yet been appropriately exploited for health care training and delivery purposes. What should be done in rural areas, at the community setting-level, where access to healthcare is limited remains a challenge. We review the evidence on improving post-stroke outcomes including lowering the risks of functional disability, stroke recurrence, and mortality, and propose some approaches, to target post-stroke care and rehabilitation, noting key challenges in designing suitable interventions and emphasizing the advantages mHealth and communication technologies can offer. In the article, we present the prevailing stroke care situation and technological opportunities in rural Peru as a case study. As such, by addressing major limitations in rural healthcare systems, we investigate the potential of task-shifting complemented with technology to utilize and strengthen both community-based informal caregivers and community healthcare workers.

Background A unified set of criteria for neurocysticercosis (NCC) has helped to standardize its diagnosis in different settings. Methods Cysticercosis experts were convened to update current diagnostic criteria for NCC according to two principles: neuroimaging studies are essential for diagnosis, and all other information provides indirect evidence favoring the diagnosis. Recent diagnostic advances were incorporated to this revised set. Results This revised set is structured in absolute, neuroimaging and clinical/exposure criteria. Absolute criteria include: histological confirmation of parasites, evidence of subretinal cysts, and demonstration of the scolex within a cyst. Neuroimaging criteria are categorized as major (cystic lesions without scolex, enhancing lesions, multilobulated cysts, and calcifications), confirmative (resolution of cysts after cysticidal drug therapy, spontaneous resolution of single enhancing lesions, and migrating ventricular cysts on sequential neuroimaging studies) and minor (hydrocephalus and leptomeningeal enhancement). Clinical/exposure criteria include: detection of anticysticercal antibodies or cysticercal antigens by well-standardized tests, systemic cysticercosis, evidence of a household Taenia carrier, suggestive clinical manifestations, and residency in endemic areas. Besides patients having absolute criteria, definitive diagnosis can be made in those having two major neuroimaging criteria (or one major plus one confirmative criteria) plus exposure. For patients presenting with one major and one minor neuroimaging criteria plus exposure, definitive diagnosis of NCC requires the exclusion of confounding pathologies. Probable diagnosis is reserved for individuals presenting with one neuroimaging criteria plus strong evidence of exposure. Conclusions This revised set of diagnostic criteria provides simpler definitions and may facilitate its more uniform and widespread applicability in different scenarios.

Taenia solium (the pork tapeworm) is present in most developing countries, where it is a frequent cause of seizures and other neurological disease. Parasitic larvae invade the human brain, establish, and eventually resolve, leaving a calcified scar. While these lesions are common in endemic regions, and most of these are clinically silent, a proportion of individuals with calcified cysticerci develop seizures from these lesions, and 30-65% of these cases are associated with perilesional edema (PE), likely due to host inflammation. This manuscript summarizes the importance, characteristics, natural history, and potential prevention and treatments of symptomatic calcified neurocysticercosis (NCC).

Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety into of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected to 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood-brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120 h before the EB infusion, indicating a greater compromise of the blood-brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis.

Review of case reports and case series of patients with single cysticercus granulomas in non-endemic countries to determine the characteristics of this form of neurocysticercosis in these regions.MEDLINE and manual search of patients with single cysticercus granulomas diagnosed in non-endemic countries from 1991 to 2011. Abstracted data included: demographic profile, clinical manifestations, form of neurocysticercosis, and whether the disease occurred in immigrants, international travelers, or citizens from non-endemic countries who had never been abroad.A total of 77 patients were found. Of these, 61 (79%) were diagnosed since the year 2000. Thirty-four patients (44%) patients were immigrants from endemic countries, 18 (23%) were international travelers returning from disease-endemic areas, and the remaining 25 (33%) were citizens from non-endemic countries who had never been abroad. Most immigrants and international travelers became symptomatic two or more years after returning home. Countries with the most reported patients were Kuwait (n=18), UK (n=11), Australia (n=8), USA (n=7), Japan (n=6), and Israel (n=5).A single cerebral cysticercus granuloma in a non-endemic country is not a rare event. As seen in endemic regions, these cases have a good prognosis although more surgical procedures are performed in non-endemic countries, likely reflecting a decrease of diagnostic suspicion for cysticercosis and an increased availability of surgical options. The mean age of the reported cases was 25 years, and immigrants most often developed the disease greater than two years after arrival into a non-endemic area, suggesting a significant delay between infection and symptoms. However, some may have been infected and developed the disease while residing in non-endemic countries.

Modulation of host responses is an important strategy by which parasites ensure successful establishment and persistence. Host counteraction against this modulation may be required for the host to develop resistance to infection. In this pilot study, experimental infection of dogs with Echinococcus granulosus induced a strong polarization of the cytokine response towards a Th2 phenotype. Consecutive rounds of infection and cure induced resistance to infection resulting in a dramatically lower parasite burden. Repeatedly-infected resistant dogs also lost immune polarization and developed a balanced Th1/Th2 response. No major differences were observed in the production of regulatory cytokines (IL-10, TGF-β) between dogs with high parasite load and dogs with only few intestinal parasites. These results suggest that E. granulosus-driven immunomodulation contributes to successful infection in the definitive host. This information might be relevant for the development of more effective vaccines against this stage of the parasite.

Taenia solium cysticercosis is still a major cause of seizures around the world. Despite an extensive body of published literature on this topic, knowledge of the biology, immunology, pathophysiology, and treatment of this parasite remains largely incomplete. This review summarizes recent information on the biology, clinical manifestations, immunopathology treatment and control of this important and neglected zoonotic disease, with emphasis on areas where recent developments have changed traditional and established views.

Infections due to Taenia solium in humans (taeniasis/cysticercosis) remain a complex health problem, particularly in developing countries. We identified two oncosphere proteins that might protect the porcine intermediate host against cysticercosis and therefore help prevent disease in humans. One of these proteins was further identified by two-dimensional gel electrophoresis and micro-sequencing. The gene encoding this protective protein was also identified, cloned and characterized. The native 31.5 kDa protein Tso31 has four variants at the cDNA level. The longest sequence from which the others seem to derive, encodes a 253 amino acid peptide. The predicted protein has a molecular weight of 25.1 kDa, one putative N-glycosylation site, two fibronectin type III domains, and one C terminal transmembrane domain. The gene structure of the protein consists of four exons and three introns. The finding of one gene and four different cDNAs for Tso31 suggests the existence of a possible mechanism of differential splicing in this parasite. The Tso31 protein is exclusive to T. solium oncospheres with a putative protein structure of an extra-cellular receptor-like protein. The Tso31 protein was expressed as a recombinant protein fused to GST and tested in a vaccine to determine its effectiveness in protecting pigs against cysticercosis. Only two pigs out of eight vaccinated were protected and although the total median number of cyst decreased in vaccinated pigs compared to controls this decrease was not statistically significant (P = 0.09).

Compliance and acceptance for the finger-prick method of blood collection is generally better than for venipuncture. A finger-prick method of blood collection with quantitative antibody recovery is even more important for seroepidemiological surveys. Finger-prick blood collected and dried onto filter paper has been used; but, unfortunately, this method has several disadvantages, including loss of antibody activity, possible contact contamination from blood spots on adjacent filter papers, and difficulties in extracting antibodies, justifying the search for other methods of collecting and transporting blood samples. We report on a simple method of collecting a measured amount of finger-prick blood onto a sample pad, which is immediately transferred to storage/extraction buffer. The diluted blood sample is never dried, and because of the storage buffer, can be transported and stored without refrigeration. Furthermore, the diluted blood samples can then be tested directly without further preparation. We systematically compared several storage/extraction buffers and commercially available filter papers. We showed that antibody recovery was not significantly affected by the type of filter papers used but was significantly affected by the storage/extraction buffer used. The best such buffer is StabilZyme Select.

Neurocysticercosis, infection with larval Taenia solium, is a common, serious neuroparasitic infection. Larval degeneration results in inflammatory cell influx and granuloma formation which leads to clinical symptomatology. The role of chemokines in such cell influx is unknown. We demonstrate that monocyte stimulation by T. solium larval antigen (TsAg) results in a differential profile of CXCL8/IL-8 (146.5+/-8.5ng/ml after 24h), CCL2/MCP-1 (267+/-4 ng/ml after 48 h) and CCL3/MIP-1alpha (1.72+/-0.43 ng/ml after 8 h) secretion. There was coordinate mRNA accumulation reaching maximum at 1h for CCL3 and 2 h for CXCL8 and CCL2. TsAg induced maximal nuclear binding of p65, p50 and c-rel subunits of the transcriptional regulator NF-kappaB by 2 h. IkappaBalpha but not IkappaBbeta was degraded within 10 min before resynthesis by 2 h. Pre-treatment with the broad-spectrum NF-kappaB inhibitor pyrrolidine dithiocarbamate caused complete abrogation of TsAg-induced CCL2 secretion (p=0.005) and 91% reduction of CXCL8 secretion (p=0.0003). TsAg was unable to induce CXCL8 promoter activity in Toll-like receptor (TLR)-2 or TLR-4/MD-2 transfected HeLa cells in the absence of lectins or other adaptor molecules. In summary, our data demonstrate that TsAg induces chemokine secretion via specific pathways dependent on NF-kappaB but not TLR-4/TLR-2, and indicate a potential mechanism whereby larval degeneration results in brain inflammation.

The third and final diagnostic antigen of the lentil lectin purified glycoproteins (LLGP) extracted from the larval stage of Taenia solium has been characterized, cloned, and expressed. T24 is an integral membrane protein that belongs to the tetraspanin superfamily. It migrates at a position corresponding to 24-kDa and as a homodimer at 42-kDa. Antibodies from cysticercosis patients recognize secondary structure epitopes that are dependent upon correctly formed disulfide bonds. A portion of T24, the large, extracellular loop domain, was expressed in an immunologically reactive form in insect cells. When tested in a Western blot assay with a large battery of serum samples, this protein, T24H, has a sensitivity of 94% (101/107), for detecting cases of cysticercosis with two or more viable cysts, and a specificity of 98% (284/290). The identification and expression of T24H sets the stage for the development of an ELISA suitable for testing single samples and for large-scale serosurveys that is not dependent upon the isolation and purification of antigens from parasite materials.

The larval stage of the pork tapeworm (Taenia solium) infects the human nervous system, causing neurocysticercosis. This disease is one of the main causes of epileptic seizures in many less developed countries and is also increasingly seen in more developed countries because of immigration from endemic areas. Little information is available on the natural evolution of taeniasis or cysticercosis. Available therapeutic measures include steroids, treatments for symptoms, surgery, and, more controversially, antiparasitic drugs to kill brain parasites. Efforts to control and eliminate this disease are underway through antiparasitic treatment of endemic populations, development of pig vaccines, and other measures.

The diagnosis of neurocysticercosis was greatly improved by the introduction of computed tomography (CT) and magnetic resonance imaging (MRI). These techniques demonstrate the number and topography of lesions, their stage of involution, and the degree of inflammatory reaction of the host against the parasites and have largely replaced previous radiological procedures such as plain roentgenograms, pneumoencephalograms, cerebral angiography and myelography. In general, MRI provides better image detection and definition. The possibility of multiplanar reconstruction of images, its capability to visualize the posterior fossa without bone artifacts, and its high contrast resolution (far superior to that of CT) allow MRI to recognize many forms of cysticercosis not visualized on CT. However, the costs of MRI are high and the equipment is scarcely available in many endemic countries, and its sensitivity for the detection of calcified lesions is poor. CT remains the best screening neuroimaging procedure for patients with suspected neurocysticercosis, and MRI is the imaging modality of choice for the evaluation of patients with intraventricular cysticercosis, brainstem cysts and small cysts located over the convexity of cerebral hemispheres. Its better image definition also suggests that MRI is superior to CT in the follow-up of the patients after therapy.

Control or eradication of Taenia solium cysticercosis has been achieved to date only in Europe and North America. Significant improvements in sanitary conditions and developing functional slaughterhouse control systems were primarily responsible for control in these regions. Conversely, in endemic areas of developing countries control is limited by economic and sanitary conditions: the life cycle of T. solium is sustained because pigs have access to infected faeces, and cysticercosis-infested pork is available for consumption. Interventional trials with massive human cestocidal chemotherapy, treatment of both human and porcine populations with antihelminthic drugs and/or immunotherapy and health education have shown improvements in specific settings but not yet proven to be sustainable in the long-term. In order to ensure sustainability, any given control strategy towards elimination/eradication of porcine cysticercosis should incorporate economic incentives.

We performed repeated serological sampling of pigs in an endemic area of the Peruvian highlands (eight villages) to assess the feasibility of detecting incident cases of Taenia solium infection as indicators of ongoing transmission of the parasite. A total of 2245 samples corresponding to 1548 pigs were collected in three sampling rounds (n=716, 926, and 603, respectively). Village-period specific seroprevalences of antibodies by enzyme-linked immunoelectrotransfer blot (EITB) assay varied from 39% (95% CI: 34, 44) to 76% (95% CI: 72, 79). The prevalence of cysticercosis increased with the age of the pigs (similarly for both sexes). Around 40% of pigs were re-sampled at the end of each 4-month period. Crude incidence risks were 48% (57/120, 95% CI: 43–52) and 58% (111/192, 95% CI: 54–61) for each period. A proportion of seropositive animals became seronegative at the end of each period (23 and 15%). Incidence varied by the village, and the exposure period, and was higher in males than females (but did not differ by age).

We examined the genetic variability in the pig–human tapeworm, Taenia solium, by sequencing the genes for cytochrome oxidase I, internal transcribed spacer 1, and a diagnostic antigen, Ts14, from individual cysts isolated from Peru, Colombia, Mexico, India, China, and the Philippines. For these genes, the rate of nucleotide variation was minimal. Isolates from these countries can be distinguished based on one to eight nucleotide differences in the 396 nucleotide cytochrome oxidase I (COI) sequence. However, all of the 15 isolates from within Peru had identical COI sequences. The Ts14 sequences from India and China were identical and differed from the Peru sequence by three nucleotides in 333. These data indicate that there is minimal genetic variability within the species T. solium. Minimal variability was also seen in the ITS1 sequence, but this variation was observed within the individual. Twenty-two cloned sequences from six isolates sorted into 13 unique sequences. The variability observed within the sequences from individual cysts was as great as the variability between the isolates.

Twenty-six patients with single enhancing brain lesion (SEL) were openly assigned to receive single-day praziquantel therapy (n=14), or not (n=12). From 14 treated patients, complete resolution was found in 11, partial resolution in two, and the remaining case was later diagnosed as an arteriovenous malformation. Side effects presented in only one patient and remitted in the same day with symptomatic treatment. Conversely, the lesions persisted unchanged in six of 12 patients in the non-treatment group. Untreated patients with persisting lesions were prescribed praziquantel treatment. After this, SELs disappeared in three cases, other diagnoses (brain tuberculoma and arteriovenous malformation) were made in two, and one was not evaluated. When analyzed in regard to the baseline serology, resolution of lesions on computed tomography was found in 13 (complete=12, partial=1) of 14 seropositive patients, whereas it only happened in six (complete=5, partial=1) of 12 seronegative patients. Serological screening defines a subset of SEL patients with good prognosis. If antiparasitic therapy is to be used in patients with SEL, and we cannot find a strong argument against it, single-day praziquantel is the regimen of choice based on duration, costs, and minimal side effects.

A novel method for infecting pigs with Taenia solium using an intramuscular innoculum of oncospheres was investigated in a series of five experiments in 18 animals. The model is simple to perform, requires a minimal number of oncospheres, permits multiple infections per animal, and decreases the variation inherent in oral infection models. This intramuscular oncosphere assay (IMOA) may provide a valuable tool to evaluate therapeutic agents or potential vaccines for cysticercosis.

Sixteen individuals presenting with seizures in a rural village of Peru were screened for antibodies to Taenia solium, and those willing to attend were offered a complete neurological work-up including EEG and cerebral CT scan in a reference center. Seroprevalence using immunoblot was 35% (5/16). Eight individuals came for examination. CT scans were abnormal in all four seropositive cases (an enhancing lesion in one case, multiple live cysts and calcifications in one case, and multiple calcifications in two cases), and normal in the four seronegative individuals. Electroencephalographic tracings were normal in six cases, and abnormal in one seronegative and in one seropositive individual. Neurocysticercosis (NCC) is frequently found in epileptic individuals in most developing countries, and is probably the major cause of seizures in this zone.

We evaluated the presence and persistence of anticysticercal antibodies in piglets born to Taenia solium infected sows. Infected sows from a disease-endemic area of Peru were transported to a nondisease-endemic area and impregnated. Serum samples were collected from sows and piglets on Day 2 through Week 35 after birth. Using an immunoblot specific for cysticercosis, Ig isotypes to 7 cyst antigens were measured and quantified. Serum samples from the piglets contained detectable antibodies from Week 1 through Week 35 (27 weeks after weaning). The primary Ig isotype present in both sows and piglets was IgG. Antibodies did not appear in piglet serum samples until after suckling, demonstrating that anti-cysticercal antibodies are transferred solely via colostrum. Our data have shown that maternally transferred antibodies to cyst antigens may persist through much of a pig's life. Therefore, the presence of passively transferred antibodies must be considered in studies that examine the prevalence of cysticercosis in pigs. Furthermore, when designing control strategies for cysticercosis, careful evaluation and selection of sentinel pigs becomes a crucial component of sentinel selection.

A serological survey was performed using the enzyme-linked immunoelectrotransfer blot assay (EITB) in a village in the highlands of Peru where there are three distinct but close neighborhoods, to determine if there is a direct relationship between human and porcine Taenia solium infection. One hundred and eight out of 365 individuals were sampled, and 14 were seropositive (human seroprevalence 13%). Most seropositive individuals were neurologically asymptomatic. Thirty-eight out of 89 sampled pigs (43%) were seropositive. There was a clear geographical clustering of cases, and positive correlation between human and porcine seroprevalence was found when comparing the three neighborhoods. Cysticercosis is an important cause of neurological morbidity in most developing countries, and control/eradication trials are now being increasingly applied. Porcine serology provides an appropriate indicator of T. solium environmental contamination and should be used to estimate the risk of infection when evaluating control measures.

A recently described one-day regimen of praziquantel (PZQ) therapy for neurocysticercosis (NCC), three doses of 25 mg/k given at 2 h intervals, was applied in eight patients with viable NCC cysts without any evidence of inflammation. Resolution of lesions in computed tomography (CT) was observed in all five patients with a single cyst, whereas all cysts survived in three patients with multiple brain parasites. One-day praziquantel is a good regimen for patients with a single viable brain cysticercus but is poorly effective for multiple cysts.

Summary Identification of species of human tapeworms is crucial because the consequences of infection by Taenia solium and T saginata are very different. However, evacuation of species-identifiable tapeworms is uncommon and Taenia spp eggs are indistinguishable under the microscope. Treatment of taeniasis consists of niclosamide followed by a purgative. Recently, we adopted preniclosamide and postniclosamide electrolyte-polyethyleneglycol salt (EPS) purges to improve bowel cleaning. Retrospective comparison of traditional castor oil with EPS purge showed that recovery of the tapeworm scolex was significantly improved (20 of 68 vs none of 46, p=0·0001) in the EPS group. Furthermore, 42 of 68 (62%) individuals receiving EPS excreted identifiable gravid proglottids. EPS treatment helps the visual identification of Taenia spp.

Sir—Appropriate concern about the protection of research participants in low-income countries has led to changes in the ethics review process that have created a crisis for international medical research. The process of protocol approval may now be deemed an unethical barrier to international health research. Research projects increasingly benefit from multiple international partners that are frequently required by funding bodies. Internal review boards (IRBs) or ethics committees oversee only their own faculty members and the modifications required by each must be resubmitted to the others. Modifications are frequently required at annual reviews that must again be reconsidered by all. For example, a 4-year study involving a centre in a low-income country, two in the USA, and two in Europe, would require five initial applications, perhaps two revisions with subsequent resubmissions, and three annual reviews with perhaps two of these requiring modifications resubmitted to all. The result is 15 initial submissions and then, after approval, a further 25 applications in five formats. This method of review does not facilitate a high ethical standard. Rather, it represents a distortion of ethical review from a cooperative process to ensure high ethical standards into an unwieldy administrative task, which delays and discourages medical research in the areas of greatest need. We have several proposals that might resolve this crisis. The only effective manner for their enactment would be through the insistence of funding agencies. First, ethics review of multicentre international studies should be structured so that only one IRB in each participating country reviews the protocol. This should include the IRB at the principal investigator’s institution. Second, the documentation required for protocol review should be standardised, including a uniform format to eliminate needless reformatting. Finally, the informed consent process is best reviewed locally. Consent forms should be written in simple language to achieve maximum comprehension. However, distinctions between simple and complex terms do not correspond between languages and the local IRB has a better knowledge of the study site and population than does an IRB abroad. The local IRB should, therefore, have sole responsibility for the vocabulary of the consent documents, whereas the primary international IRB limits its review of the consent forms to issues of content. As researchers we share responsibility for the predictable consequences of our actions and inactions. Research addressing multidrug resistant tuberculosis, trypanosomiasis, malaria, and other diseases of poverty is needed. We are obliged to advance alternative solutions that ensure the protection of study participants without impeding research targeted at improving health in developing regions. We are not suggesting a process of ethical review that is any less stringent; only one that is less redundant and more appropriate to research in international settings.