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Keywords:

  • cysticercosis;
  • neurocysticercosis;
  • serology;
  • ELISA;
  • Western blot;
  • Taenia solium;
  • Peru
  • Cysticercose;
  • neurocysticercose;
  • sérologie;
  • ELISA;
  • Western Blot;
  • Taenia solium;
  • Pérou
  • Cisticercosis;
  • neurocisticercosis;
  • serología;
  • ELISA;
  • Western Blot;
  • Taenia solium;
  • Perú

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

Neurocysticercosis (NCC) is endemic in most parts of the world and is now recognised as an important contributor to neurological disease. Serological diagnosis of NCC improved greatly in the past two decades and contributed to demonstrating previously unsuspected regions of endemicity. Claims for an accurate serological screening tool for human cysticercosis are frequently raised. However, after symptomatic therapeutics are applied, management of NCC is driven by the characteristics of the central nervous system infection in terms of viability, number, location size and evolutionary stage of parasites, as well as by the resulting inflammation. It is unclear whether, in the absence of neuroimaging, serological confirmation of aetiology of suspected cases (neurologically symptomatic) or detection of asymptomatic cases in population screening would affect their management or prognosis.

La neurocysticercose est endémique dans la plupart des régions du monde et est maintenant reconnue comme un contributeur important dans la maladie neurologique. Le diagnostic sérologique de la neurocysticercose s’est fortement amélioré au cours des deux dernières décennies et a contribuéà révéler des régions d’endémicité préalablement insoupçonnées. Les réclamations pour un outil de dépistage sérologique précis pour la cysticercose humaine sont fréquentes. Cependant, après l’administration de la thérapeutique symptomatologique, la prise en charge de la neurocysticercose est guidée par les caractéristiques de l’infection du système nerveux central en termes de viabilité, de nombre, de taille de la localisation et du stade évolutif des parasites, ainsi que par l’inflammation résultante. Il est difficile de savoir si en l’absence d’imagerie neurologique, la confirmation sérologique de l’étiologie des cas suspects (symptomatologie neurologique), ou la détection des cas asymptomatiques par le dépistage de la population aurait une incidence sur leur prise en charge ou sur le pronostic.

La neurocisticercosis es endémica en la mayor parte del mundo y está reconocida como un contribuyente importante en la enfermedad neurológica. El diagnóstico serológico de la neurocisticercosis ha mejorado muchísimo en las últimas dos décadas y ha contribuido a demostrar su presencia en regiones endémicas previamente insospechadas. Es frecuente el reclamo de una herramienta de diagnóstico serológico preciso para la cisticercosis humana. Sin embargo, después de aplicar una terapia sintomática, el manejo de la neurocisticercosis se basa en las características de la infección del sistema nervioso central en términos de viabilidad, número, localización, tamaño y estadío de los parásitos, así como por la inflamación resultante. No está claro si, en la ausencia de imágenes cerebrales, la confirmación serológica de la etiología de casos bajo sospecha (con sintomatología neurológica), o la detección de casos asintomáticos en un rastreo poblacional, afectaría su manejo o prognosis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

Neurocysticercosis (NCC) is an important contributor to neurological disease in most of the world (Ndimubanzi et al. 2010). As a gross categorisation, cysticercosis of the nervous system can be divided into intraparenchymal brain cysticercosis or extraparenchymal NCC. Intraparenchymal NCC generally has a good prognosis, even without antiparasitic treatment: appropriate control of seizures is usually obtained with first-line antiepileptic drugs and brain cysts eventually degenerate and disappear or become a calcified scar, although this may take many years. Conversely, despite the almost complete lack of controlled studies of extraparenchymal NCC, most experts consider it a progressive and lethal disease. Intracranial hypertension and hydrocephalus develop and mortality is considerable (Garcia et al. 2005; Fleury et al. 2010).

Serological diagnosis of NCC performed poorly until the late 1980s, when ELISA assays were developed and applied to Taenia solium (Espinoza et al. 1986; Rosas et al. 1986). The introduction of the highly sensitive and specific immunoblot assay (enzyme-linked immunoelectrophoresis blot [EITB], Western blot) for the diagnosis of human cysticercosis provided a reliable immunodiagnostic tool (Tsang et al. 1989). It also improved the accuracy of seroprevalence studies, unveiling large proportions of infected or exposed individuals in many countries of Latin America, Asia (including the Indian subcontinent and wide parts of China) and Africa (Tsang & Wilson 1995; Bern et al. 1999). Perhaps due to raised awareness of the extent of the problem, the claim for an accurate serological screening tool for human cysticercosis is a frequent topic in the literature (Dorny et al. 2003; Esquivel-Velazquez et al. 2011). However, the benefits of isolated serological screening of populations or suspected cases are unclear. In the absence of brain imaging, serology alone may not modify the clinical management of most clinical cases, and serological demonstration of infection in a given asymptomatic individual may be of no practical use.

Thus, there are two scenarios in which a serological test for cysticercosis can be used: in suspected cases, which are individuals with neurological symptoms (mainly seizures, intracranial hypertension, focal symptoms or cognitive deficits) evaluated either as hospital patients or in community-based clinical studies; or in asymptomatic individuals, mostly screened as part of community-wide surveys. These scenarios are separately analysed, with focus on the expected spectrum of NCC in each of these two scenarios, and how serological diagnostic confirmation would affect the care of a given individual.

Serological diagnosis of cysticercosis in neurologically symptomatic patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

In hospitals dealing with symptomatic NCC, a major factor defining its diagnosis and management is the availability of brain imaging, either CT or MRI (Garcia et al. 2011; Nash & Garcia 2011). When available, imaging is the primary diagnostic tool and allows the attending clinician to know the presence, number, location, stage and volume of parasitic lesions in the central nervous system (CNS) (Dumas et al. 1997; Garcia & Del Brutto 2003). This information is crucial to define the need for surgical measures, and whether it would be unsafe to start antiparasitic therapy because of a higher risk of developing acute hydrocephalus, intracranial hypertension or inflammation in a cyst located in a sensitive area (e.g. the brainstem or the IV ventricle).

In all cases, however, the first line of treatment is the appropriate use of symptomatic measures such as antiepileptic drugs and managing intracranial hypertension, neither of which is dependent on serological confirmation of aetiology. From then on, patients with intraparenchymal NCC will likely benefit from receiving antiparasitic therapy by obtaining faster resolution of cysts and improved seizure control (Garcia et al. 2004; Del Brutto et al. 2006; Abba et al. 2010). A stronger need for specific antiparasitic management exists in extraparenchymal NCC, where surgery and antiparasitic drugs are key in the management and essential to avoid mortality and disability (Fleury et al. 2010).

In clinical centres of medium or high complexity, serology paired with neuroimaging is quite useful to define the most appropriate therapeutic approaches from both medical and surgical perspective (Garcia et al. 2011; Nash & Garcia 2011). In a hypothetical clinical scenario without available brain imaging, the situation is completely different, but initial case management remains the same: symptomatic measures including antiepileptic drugs and management of intracranial hypertension. If serological testing in the absence of neuroimaging were to be considered, the key question would be, after symptomatic management is well established, shall we consider using antiparasitic treatment without brain imaging?

On the basis of current information, initiating blind antiparasitic therapy without knowing the characteristics of the parasites in the CNS of a given individual would likely be ill-advised. In patients with only intraparenchymal NCC, the uncertain risks of blind antiparasitic therapy are only weighed against a low risk of poor seizure control, assuming that appropriate antiepileptic treatment is promptly installed and a presumed low risk of disease progression. In symptomatic extraparenchymal NCC (suspected because of hydrocephalus or intracranial hypertension), a much higher risk of destabilising intracranial hypertension if antiparasitic treatment is installed is likely and also increased likelihood of requiring surgical management. In such cases, where the disease may be lethal, the need to refer the patient to a centre where imaging or neurosurgery is available is more evident.

Would serological testing for cysticercosis serve to guide transfer and referral of NCC cases to a more equipped centre? Assuming that a specific serological tool was available to discriminate NCC-associated seizure cases, and the possibility of referring patients to a centre with imaging facilities existed (with the subsequent costs and disturbances for poor patients), it remains debatable whether seropositive, likely NCC patients should be referred to a distant centre for CT more or less urgently than other types of serologically negative patients with seizures, suspected hydrocephalus or surgery-requiring intracranial hypertension. Would the requirement for surgery in any of these conditions change according to whether they are secondary to NCC or another aetiology? Most likely not.

Serological testing for NCC in neurologically symptomatic patients, without neuroimaging, will thus neither change initial management nor the need for immediate referral. However, there is a role for serology in identifying individuals at higher risk of disease progression. NCC progression in terms of parasite growth and complicated disease is mostly restricted to patients with extraparenchymal infections (Bickerstaff et al. 1952, 1956; Estanol et al. 1986; Fleury et al. 2010). While advanced subarachnoid NCC will present with intracranial hypertension or hydrocephalus and thus warrant immediate surgery or referral, early stages (which most likely would only affect a small subgroup of all seropositive patients) may not be clinically evident. Another group to consider are patients with multiple viable cysts, who may not be at risk of disease progression, but will face multiple symptomatic periods over the years. When neuroimaging is not available, serological testing could thus focus on searching for the fraction of NCC patients with a higher likelihood of developing chronic, progressive or complicated disease. This is where a highly specific test would be useful to identify this small subgroup of cases (usually showing strongly positive reactions) for referral for neuroimaging and/or specific antiparasitic management. Such a screening test for extraparenchymal NCC or severe intraparenchymal NCC would, however, require a high positive predictive value to save individuals with low risk of disease progression from the costs and hassle of such a referral.

Parasite-specific antigen detection is an interesting alternative. Apparently, high levels of circulating antigen are associated with extraparenchymal disease or massive intraparenchymal infections (Zamora et al. 2005; Bobes et al. 2006), which correlates with the scarce literature on the performance of immunodiagnosis of subarachnoid NCC by serum antigen testing (Zamora et al. 2005; Bobes et al. 2006; Fleury et al. 2007; Rodriguez et al. 2011) or by antibody serology using EITB (Rodriguez et al. 2011), all of which demonstrates sensitivities much higher than those for parenchymal NCC. An unpublished analysis by our group shows a strong correlation between positive serum antigen and EITB reactions to four or more antibody bands (S. Rodriguez – Cysticercosis Working Group in Peru 2012, personal communication). Depending on their positive predictive value, high antigen levels or strong antibody reactions may provide a good filter to select patients with higher likelihood of developing complicate disease, for whom it transfer to a reference centre for imaging and treatment may be justified. Whether early extraparenchymal NCC can be safely treated in the absence of neuroimaging is yet unknown.

In some endemic settings, there is no chance of getting neuroimaging, ever. As in any other reality, symptomatic management for patients with seizures, intracranial hypertension or other neurological manifestations is warranted and should be properly set up and continued under medical supervision. Beyond symptomatic measures including antiepileptic drugs and management of inflammation and intracranial hypertension, surgery or antiparasitic drugs may benefit some patients with NCC, but the risks of surgery or antiparasitic therapies without knowing the characteristics of NCC invasion in a given patient seem to outweigh the advantages of aetiological confirmation by serology but without neuroimaging. It follows that initial case management does not depend on aetiological confirmation. At the current state of knowledge, serology for NCC in suspected clinical cases seems be primarily a complement to neuroimaging. One-time serological cysticercosis testing of clinical patients without associated neuroimaging may confirm the aetiological diagnosis but most likely would not alter their case management, nor their need for referral to a better-equipped health centre.

Beyond simple, cross-sectional seroprevalence studies, longitudinal serological follow-up could potentially produce valuable information for individualised case management even in the absence of neuroimaging (e.g. to try to withdraw antiepileptic drugs in clinically stable individuals who become seronegative) (Garcia et al. 1997, 2010) but this seems unlikely to happen for poor, rural populations.

Screening for cysticercosis in asymptomatic individuals

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

In community settings, specific antibodies to T. solium can be found in 10–25% of general population (Bern et al. 1999), most of which are mild reactions. The few available population-based imaging studies have all consistently shown a high prevalence of asymptomatic intraparenchymal brain calcifications (Cruz et al. 1999; Del Brutto et al. 2005; Medina et al. 2005; Montano et al. 2005). Asymptomatic infected individuals rarely harbour viable infections.

Serological screening for cysticercosis in asymptomatic populations could target any of a series of different groups: (i) all exposed individuals, (ii) all cysticercosis-infected individuals, (iii) individuals with NCC infection, (iv) individuals with viable NCC infections or (v) individuals with severe or potentially progressive NCC infections, such as those with extraparenchymal NCC or massive parenchymal NCC (the latter rarely found in asymptomatic individuals). Detecting groups (i) to (iv) will yield proportions of the population which may have been exposed or infected with T. solium cysts, most of whom will likely never develop symptoms. Detection of asymptomatic individuals with antibodies only or with resolved infections would be of no practical use since there is no evidence of a higher risk of developing de novo neurological symptoms in the future; even if this risk were eventually demonstrated, there is no preventive measure to avoid the development of symptoms.

From the perspective of the asymptomatic individual, the purpose of being screened should be to confirm a low risk of developing clinical disease or to warn of an increased risk of clinical disease which could be reduced with appropriate diagnostic or treatment interventions. As for symptomatic individuals, screening of asymptomatic populations could focus on subgroups with high risk for disease progression or complicated disease using high levels of antigen or strong antibody reactions as markers, in as much as these assays demonstrate a very high positive predictive value given the small fraction of the population expected to host asymptomatic, early extraparenchymal NCC (Garcia 2007). More data on the specificity of antigen detection in various populations are eagerly awaited.

Another different approach is to serologically screen the general population to have a population parameter to assess future control measures. Population statistics do not contribute to individual clinical management. But population prevalence surveys do help to understand the intensity of transmission in a given community at a given time and can serve to focus control activities. This may, however, not be the most efficient and cost-effective option and should be compared with other options such as serological screening of pigs (Gonzalez et al. 2003). Pigs have a much shorter lifespan than humans and their serology should thus reflect more accurately changes over time, pig sampling is less disturbing to the community, and it can provide appropriate sample sizes in a very short time (Gonzalez et al. 1994). Case detection of infected pigs or human taeniasis could provide more suitable options.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

In the absence of neuroimaging, serology for NCC is of no practical use for the patient – neither for suspected clinical cases with no access to neuroimaging nor for asymptomatic individuals in endemic regions – except for defining a baseline prevalence figure rather than an urgent clinical need. If a highly specific test for the early detection of extraparenchymal or massive NCC became available in endemic regions, it could identify NCC cases with higher risk of progressive disease and reduce severe morbidity and mortality. In the meantime, strengthening of local capacities for primary care of seizures, intracranial hypertension and other neurological disease manifestations will do more good than serology for neurological patients with and without NCC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References

Support from the Bill and Melinda Gates Foundation (Grant 23981) and the Fogarty International Center/NIH (Training grant # TW001140) is acknowledged. HG is now a Wellcome Trust Senior Research Fellow.

References

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  2. Abstract
  3. Introduction
  4. Serological diagnosis of cysticercosis in neurologically symptomatic patients
  5. Screening for cysticercosis in asymptomatic individuals
  6. Conclusion
  7. Acknowledgements
  8. References
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