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.

SUMMARY

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.

INTRODUCTION

The relation between human infection by the cystic larvae (cysticerci) of the pork tapeworm Taenia solium and neurological disease has been known since the 16th century, when Rumler in 1558 and Panarolus in 1652 described vesicles in the dura mater and corpus callosum of epileptic individuals (1). It was only 2 centuries later that Kuchenmeister demonstrated in Germany that ingestion of cysticerci resulted in intestinal taeniasis (demonstrated in the necropsy of an executed prisoner 72 h after feeding him cysts), closing the parasite life cycle (2). Taenia solium was widely endemic in most of Europe until the early 1900s and remains endemic in wide areas of the world, including most of Latin America, sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and parts of China (3–11) (Fig. 1). In these regions, infection of the human brain by cysticerci (neurocysticercosis [NCC]) accounts for approximately one-third of the cases of epilepsy (3, 5, 6, 8, 9, 11–15). Traveling and immigration make NCC a health burden even in regions of nonendemicity such as the United States and Europe/United Kingdom (10, 16–24).

FIG 1.

Geographic distribution of Taenia solium taeniasis/cysticercosis (WHO, 2015).

BIOLOGY OF THE PARASITE

Like most helminths, Taenia solium has a complex life cycle that involves a usual intermediate host (pig) that harbors the parasitic larvae in its tissues and a sole definitive host (human) that hosts the adult tapeworm in its intestines. In the usual cycle, the adult tapeworm expels eggs or proglottids with the feces of the human definitive host, each egg containing an infective hexacanth embryo or oncosphere protected by a thick keratin embryophore (25, 26). In areas with deficient sanitary conditions, free-roaming pigs have access to human feces and feed on them, ingesting the tapeworm eggs (27). The embryos are liberated from the eggshells and, activated by the action of gastric and intestinal juices, free themselves from the surrounding embryophoric membrane by using their three pairs of oncospheral hooks (28), attach to the intestinal epithelium, and actively cross the intestinal mucosa in a process facilitated by the secretion of parasite proteases (29, 30). After crossing the intestinal mucosa, the embryos reach the circulatory system of the pig. Infective embryos are then distributed by the bloodstream, become established, and develop into cystic, fluid-filled larvae or cysticerci, each containing an invaginated scolex with a double crown of hooks and four muscular suckers (Fig. 2). T. solium taeniasis occurs when humans ingest poorly cooked pork containing cysticerci. The scolex in the cyst evaginates following exposure to bile and intestinal juices, attaches to the intestinal mucosa by the action of its suckers and its double crown of hooks, and begins producing proglottids at its neck region, forming a strobila to develop into an adult tapeworm (25, 26).

FIG 2.

Life cycle of Taenia solium. (Adapted from reference 276.)

HUMAN TAENIASIS

The human carrier of an intestinal T. solium tapeworm is the sole source of infection for pigs and for other humans in its surroundings (31, 32). Despite its importance in establishing transmission and maintaining the endemicity of the disease, we know surprisingly little about human taeniasis. Yoshino published in the 1930s a seminal series of articles on the early stages of porcine cysticercosis, and to this purpose he infected himself with Taenia solium cysts (33, 34). From this published report and other series and anecdotal reports (35, 36), including another case of self-infection of a well-known British parasitologist, P. S. Craig (this time with the cysts of the harmless beef tapeworm Taenia saginata), we can conclude that in the human host, the tapeworm matures and begins expelling gravid proglottids approximately 3 to 4 months after infection with cysticerci. The adult T. solium tapeworm lives in the proximal small intestine and is reported to measure between 2 and 7 m (26), in our experience usually below 4 m. Attempts to establish the usual life span of the tapeworm are hampered by minimal or nil knowledge of the proportion of tapeworms who die before reaching patency (most sources of information refer to stool-positive cases). Even so, experts assume that the adult tapeworm lives approximately 3 years on average (37–39).

The genome of T. solium was initially published in 2013 (40), and now there is also available one genome from China (41), published in 2014, and two from Peru from 2015 (42). The size of the T. solium genome seems to be around 112 to 130 Mb, with 18 chromosomes and a GC content of 43%. Genome data have already been used to compare species evolution (40), as well as to identify and characterize host-parasite pathways (43, 44), microsatellite markers (42), and antigenic proteins (45, 46). The three human-infecting taenias, T. asiatica, T. saginata, and T. solium, share many common genomic features but differ from each other in evolution and diversification of certain specialized gene families. Comparison of homologous genes among these human tapeworms revealed that 90.3% of T. asiatica genes had homologues in T. saginata and T. solium (41), suggesting that these parasites share many proteins involved in host-parasite interactions, as well as molecular targets for diagnostics and treatment. Partial cysticercal transcriptomes have been produced using next-generation sequencing for expressed sequence tags or transcriptome sequencing (RNA-seq) (47–49). A few proteomic studies looking to characterize biological stages through protein profiles (50), explore host-parasite interactions (51), identify antigenic proteins (52, 53), and compare protein profiles according to the infected organ (brain versus muscle) have already been published (54, 55).

Besides T. solium, two other large tapeworms in the genus Taenia (Taenia saginata and Taenia asiatica) can infect humans as their definitive host. T. saginata, the beef tapeworm, is a much longer tapeworm and is endemic in wide regions of the world, including Europe and parts of the United States, and its cycle involves humans as tapeworm carriers and cysticercotic cattle. Proglottids of T. saginata are motile and can appear in the underwear of tapeworm carriers. T. asiatica, on the other hand, is geographically restricted to Korea, Japan, China, and Southeast Asia. It is closer to T. saginata, but its usual intermediate host is the pig, with the characteristic that cysts are found in the viscera and peritoneum of the pig (56, 57) rather than in the muscle tissues, as seen with porcine T. solium cysticercosis. Neither T. saginata nor T. asiatica causes human cysticercosis.

Diagnosis of Taeniasis

Finding the tapeworm scolex with its characteristic double crown of hooks is diagnostic, although rarely obtainable. Similarly, finding T. solium proglottids in stools allows species diagnosis by observation of the number of main uterine branches, or more recently by DNA tests (58, 59). However, proglottid excretion is intermittent and not reliable as a diagnostic approach. Historically, taeniasis has been diagnosed by microscopic examination of human stools. Direct examination of stool to detect T. solium eggs is poorly sensitive (26), although it is unclear whether T. solium does not release many eggs or whether they are released only intermittently. Concentration methods, particularly those using sedimentation, increase the diagnostic yield; however, the overall sensitivity of serial stool exams using concentration methods is still suboptimal. Antibodies stage specific to the adult tapeworm can be detected in serum (60, 61), and T. solium DNA can be detected in the stools of tapeworm carriers (62, 63), although these tests are not commercially available. The introduction of stool antigen (coproantigen) detection by ELISA greatly enhanced diagnostic sensitivity (64, 65) and provided a sensitive method to confirm treatment efficacy (66), although this assay is also poorly available outside academic research laboratories. In regions of endemicity, the prevalence of Taenia solium taeniasis by microscopy usually ranges around 1% (27, 67–69). The use of coproantigen detection increases the diagnostic yield by at least 60% (65). Caution should be exercised, however, when assessing putative population prevalence of taeniasis based solely on positive coproantigen ELISA results without parasitological confirmation (Fig. 3).

FIG 3.

Taenia solium. (A) Egg; (B) scolex; (C) gravid proglottid. (All images courtesy of Juan Jimenez, Lima, Peru.)

Treatment of Taeniasis

Two drugs are effective for the treatment of human taeniasis, niclosamide and praziquantel (PZQ). Niclosamide (2 g orally in a single dose for adults) is safe and well tolerated, with only mild and transient side effects. Its efficacy in treatment series has been reported to be above 80% (70). In a large-scale community-based deworming program, however, its efficacy was only 67% (71). Praziquantel seems to be effective at either 5 or 10 mg/kg (also a single oral dose) (72). If a person has taeniasis and simultaneously has latent, asymptomatic neurocysticercosis, praziquantel treatment for taeniasis may affect previously silent brain cysts and trigger seizures or other neurological symptoms (73–75). Judging by the numbers of doses of praziquantel used for schistosomiasis in regions of cysticercosis endemicity in Africa, this event seems to be extremely uncommon, but the impact of newly developed seizures or neurological symptoms in one or a few individuals could still be devastating for a community-based control program. On the other hand, only a few studies with mass chemotherapy for schistosomiasis were designed with sufficient follow-up to detect adverse central nervous system (CNS) events developing days after treatment. Niclosamide is not absorbed from the intestinal tract and thus it does not affect brain cysts. The reported efficacy of benzimidazoles such as mebendazole and albendazole (ABZ) to treat taeniasis in single-dose regimes is low (76, 77), requiring multiple doses and several days of treatment (78–81).

PORCINE CYSTICERCOSIS

In the porcine host (with a usual pig life span of 8 to 9 months), it is common to find muscular and subcutaneous cysts, as well as cysts in the nervous system. The few available studies of porcine cysticercosis using systematic thin-cut necropsy specimens demonstrate that most infected pigs have only a few (<10) cysts in the entire carcass (82). As expected, pigs with brain cysts are a subset of all infected pigs. Also, pigs with only degenerated cysts in the carcass (or with a majority of degenerating cysts) can be found, demonstrating that in some cases the infection can resolve by natural evolution. A minority of pigs host enormous numbers of cysts, in the range of thousands, and in these cases, the cysts are all viable (Fig. 4).

FIG 4.

Massive cysticercosis infection in a pig. (Courtesy of the Cysticercosis Elimination Program in Tumbes, Peru.)

Diagnosis of Porcine Cysticercosis

Traditional public health manuals advocate slaughterhouse pig inspection (83). Slaughterhouse inspection is limited to a few cuts to not damage the market value of the carcass and may only rarely find infections with low numbers of cysts (84). Similarly, villagers in areas of cysticercosis endemicity are familiar with examination of the tongue of the pig visually and by palpation (85). This method can identify most heavily infected pigs, although similarly to slaughterhouse inspection, its sensitivity drops markedly for mild infections (86). Seizures may occur in heavily infected pigs (87), but they are quite rare. Other methods have been proposed to diagnose and characterize porcine cysticercosis infection, including serology (antibody or antigen detection) (88, 89), DNA-based assays (90), or the gold standard of detailed dissection of the entire pig carcass (91). None of these has yet proven practical to be routinely used, outside specific research studies.

Treatment of Porcine Cysticercosis

Initial trials of drug treatment for porcine cysticercosis used flubendazole without much success. Praziquantel was the first drug to show promise, and it was initially used at 50 mg/kg/day for 15 days (92) and later in a single-day regime (93). Overall, the efficacy of praziquantel in porcine cysticercosis is partial and not consistent (91). An initial study using a 1-month regime of albendazole at 15 mg/kg, published in 1995, indicated significant efficacy, but the regime was not widely adopted due to its long duration, which made it impractical for use in the field (281). Three days of albendazole at 30 mg/kg/day destroys all cysts (94). The introduction of oxfendazole (OXF) provided a more efficacious agent, killing all cysts in the carcasses of pigs receiving a single dose of 30 mg/kg (95–97). Further reports confirmed this high efficacy for muscle cysts but also demonstrated that a proportion of brain cysts survive a single dose of oxfendazole (91, 98). Niclosamide, nitazoxanide, or triclabendazole does not show significant cysticidal efficacy (91).

HUMAN CYSTICERCOSIS AND NEUROCYSTICERCOSIS

In areas where T. solium is endemic, NCC is a common diagnosis in individuals with seizures and other neurological symptoms. Cases of human and porcine cysticercosis cluster around human tapeworm carriers, the source of infection (27, 31). In most regions of endemicity, the spectrum of symptomatic disease is varied and involves cases of single and multiple parenchymal NCC lesions as well as extraparenchymal NCC. Calcified lesions, usually single, often in patients with no recognized symptoms, are also frequently found (99–102). In the Indian subcontinent, however, the spectrum of disease seems to involve mostly young individuals with a single intraparenchymal cyst (103). The reason for this difference in clinical expression is unknown, although it could be related to less contact with tapeworm carriers, as similar patterns of disease are seen in people infected in regions where the disease is not endemic and in travelers (104).

Localization of Cysts in Human Tissues

In the human host (with a long life span), most infections are detected in the nervous system. This is partly due to the evident nature of seizures, intracranial hypertension, or other neurological symptoms in comparison to that of viable cysts in the muscles or other organs, where lesions may go unnoticed. It was initially believed that the establishing cysts localized preferentially in the brain, but evidence from the porcine host (105), old necropsy studies and radiological reports (106, 107), and radiological evidence of residual calcifications in other tissues (108) suggest that embryos are distributed to all tissues and are commonly destroyed by the immune response of the host, surviving preferentially in the brain and eye with the help of the blood-brain barrier (BBB) and the hemato-ocular barrier (109–111). In addition, viable cysticerci have been shown to use multiple active mechanisms of immune evasion, including the secretion of molecules able to block the complement system, affect the cellular response, increase regulatory T cells, degrade attacking immunoglobulins (including immunoglobulin-cleaving proteases, protease inhibitors and antioxidants, immunosuppressor factors, and other molecules like paramyosin, sulfated proteoglycans, prostaglandin E₂, taeniaestatin, and neuropeptides such as substance P and somatostatin) (112–114), or even cover itself with host immunoglobulins (110, 111, 115, 116). Eventually, intraparenchymal cysts degenerate and resolve, either by natural involution (117) or following treatment with antiparasitic agents (118), in a sequence well described decades ago and revisited in 2002 by Escobar and Weidenheim (119). Dead parasites resolve completely (in most cases) or leave a calcified scar (120).

Localization of Cysts in the Nervous System

Clinical manifestations of NCC differ according to the parasite location in the human CNS, inside or outside the brain parenchyma (intra- or extraparenchymal NCC). The presence of cysts or cyst clusters outside the brain parenchyma is a major driver of morbidity and mortality. Unlike parenchymal cysts that establish as small cysts, manifest with headache or seizures, and rarely grow beyond 2 cm in diameter, cysts in the ventricles or particularly those in the subarachnoid space tend to grow and spread into the surrounding spaces, causing clinical manifestations related to mass effects, hydrocephalus, chronic arachnoiditis, and vasculitis, with a much poorer prognosis.

TYPES OF NEUROCYSTICERCOSIS

The combination of lesion location and evolutionary stage of lesions results in a wide array of clinical presentations of NCC. A simplified, nonexclusive categorization is shown in Table 1.

TABLE 1.

Types of NCC^a

Location	Stage	Perilesional inflammation/edema
Parenchymal (single or multiple)	Viable	Variable
	Degenerating	Usually present and marked
	Calcified	May be present (associated with symptoms)
Extraparenchymal, intraventricular	Viable or in degeneration, rarely calcified	No
Extraparenchymal, subarachnoid	Viable or in degeneration, rarely calcified	Arachnoiditis or pachymeningitis, occasionally without a defined parasitic lesion

^aLess frequent locations include spinal (277), retinal (278), intrasellar (279), and subdural (280), among others.

Parenchymal NCC

As mentioned above, patients with parenchymal NCC usually present with seizures and chronic headache (3, 121–128), although patients with large cysts may present with focal deficits (129). Cognitive/memory deficits and psychiatric symptoms such as depression are frequently found (130–132), but these are usually not the reason why patients seek care. Overall, NCC, especially parenchymal brain cysticercosis, seems to account for one-third of all epilepsy cases in regions of endemicity, and as such, it represents the most important cause of acquired epilepsy worldwide.

Cysts go from a viable, quiescent state to complete resolution or calcification, passing through an involution process that involves focal inflammation, followed by cyst degeneration and then calcification. Cyst degeneration involves perilesional inflammation and is frequently associated with the onset or exacerbation of neurological symptoms (118). The boundaries between a viable cyst with inflammation and a degenerated parenchymal cyst are poorly defined. Cysts with perilesional contrast enhancement and edema are considered by some authors indistinctly as either cysts with inflammation or degenerating cysts, while other authors refer to changes in the density of cyst contents (133). Considering that in pigs, cysts may evaginate even after 2 weeks of antiparasitic treatment despite signs of inflammation and changes in the appearance of the cystic fluid (96), we have used in the past the absence of liquid content signal (hypodense on computed tomography [CT], hyperintense on T2 magnetic resonance imaging [MRI]) as the marker of parasite degeneration (134). In this view, cysts showing liquid contents are still considered cysts with inflammation and the absence of discernible liquid contents categorize the lesion as a degenerating cyst.

A subset of patients present with a single small parenchymal lesion, viable or in degeneration (9, 135). This type of NCC is particularly common on the Indian subcontinent, where it has been exhaustively described, affecting young individuals (8, 9, 135–140). It carries a much more benign prognosis, frequently with complete cure, low proportions of residual calcification, and low frequency of seizure relapses.

In rare cases, the patients with parenchymal NCC may show hundreds of small degenerating cysts, a particular and severe presentation named “cysticercotic encephalitis,” where diffuse brain inflammation places the patient at risk of death (141) (Fig. 5).

FIG 5.

Parenchymal neurocysticercosis. (A) Viable and degenerating cysts; (B) calcified lesions; (C) cysticercosis encephalitis.

Perilesional alterations, inflammation, and seizures.

Seizures in patients with NCC may occur in relation to cysts in any stage, most frequently with degenerating cysts but also with viable and calcified cysts (142, 143). Patients frequently seek neurological attention after months or years with seizures. In these patients, seizures are usually of the same type and are localization related to a parasitic lesion (142).

Although viable cysts show minimal signs of inflammation, gliosis, pericystic neuronal damage, and vascular alterations have been demonstrated (144–146). In symptomatic individuals, it is common to find perilesional edema and contrast enhancement around at least one of their cysts (118). While pericystic inflammation has been interpreted as marking the onset of parasite degeneration (119), some of these lesions may survive and continue to be apparently viable for months (120) or years (147, 148). Treatment with antiparasitic agents triggers a similar focal pericystic inflammatory response in temporal association with an exacerbation of seizures and other symptoms (149, 150).

Resolution of the parasitic lesions usually results in a decrease in symptoms. Individuals with calcified NCC cysts do not usually show perilesional inflammation, although perilesional edema is seen after a seizure in one-third to one-half of cases, a finding that may lead to the erroneous diagnosis of a degenerating cysticercus (151, 152). Most authors view pericalcification edema as an episodic immune response to parasite antigens remaining in the calcified matrix; however, the role of seizure activity as a cause of BBB disruption contributing to perilesional edema is yet unclear (153). Local inflammation around a cyst or a calcification has also been associated with an increased risk of later seizure relapses (154). Scarring also plays a role: perilesional gliosis around calcified cysts can be demonstrated by MRI, and it is also associated with an increased frequency of seizure relapses (155–157).

All of the above lead to the consideration that inflammation contributes to focal damage as well as to early and late seizure manifestations, and as such, seizures in NCC patients result from a combination of both focal damage and inflammation. Interestingly, chronic calcific NCC seems to be associated with hippocampal sclerosis, also suggesting distant damage (158–164).

Extraparenchymal NCC

Most cases of extraparenchymal NCC locate in the cerebral ventricles or in the subarachnoid spaces. Intraventricular cysts (particularly cysts in the third or fourth ventricle) can cause hydrocephalus or may cause symptoms due to direct compression of the brainstem (as in fourth ventricle cysts). More rarely, large cysts in the horns of the lateral ventricles can also cause mass effects. In the lateral ventricles, it is important to discern whether the cysts are attached to the wall or freely floating. Migration of cysts from one ventricle to another has been described with some frequency and seems to be unique to NCC (165–167). The degree of inflammation may be important for surgical (neuroendoscopical) resection, as cysts with surrounding inflammation may be adherent, difficult to remove, and prone to bleed.

The more frequent locations of subarachnoid NCC cysts are the Sylvian fissures, basal cisterns, and interhemispheric spaces, frequently affecting multiple sites. In these regions, and particularly in the Sylvian fissures, lesions tend to form large aggregates (“giant” cysts or cyst clusters). Lesions in the basal subarachnoid spaces or in the interhemispheric areas also tend to spread into the surrounding spaces. Conversely, small, well-defined cysts in the convexity of the cerebral hemispheres may behave similarly to parenchymal NCC (125) (Fig. 6).

FIG 6.

Extraparenchymal neurocysticercosis. (A) Intraventricular cyst; (B) basal subarachnoid cysticercosis; (C) Sylvian fissure and interhemispheric cysticercosis.

Subarachnoid NCC is, however, a very complex disease. Patients with basal subarachnoid NCC are on average 10 to 15 years older than patients with parenchymal NCC, and the few cases of long-term immigrants seen with subarachnoid NCC in the United States also had remained in the country for many years without further exposure, suggesting a very long incubation period (168–170). A second important characteristic is the proliferative nature of the subarachnoid NCC cyst membrane. Unlike the typical cyst membrane, subarachnoid cysts have a hypercellular epithelium with areas of exuberant membrane growth (that may involve internal areas of necrosis or fibrosis). This amount of parasite tissue is associated with high levels of circulating parasite antigens, strong antibody responses, and, in general, an inflammatory response reflected in abnormal cerebrospinal fluid (CSF) (hypercellular, with eosinophils, high protein, and occasionally low glucose) (17, 171). Mass effects and the chronic inflammatory response with resultant fibrosis frequently lead to hydrocephalus and the common presentation of intracranial hypertension. Inflammation may also result in vasculitis and associated ischemic events (172). The classic literature named subarachnoid cyst clusters “racemose” cysticercosis, in allusion to its resemblance to a bunch of grapes. The lack of a scolex structure in the pieces was noted, and multiple hypotheses tried to explain its disappearance. The most accepted hypothesis is that the uncontrolled growth of the membrane “incorporates” the scolex structures in its membranous expansion (173).

DIAGNOSTIC TOOLS

The diagnosis of NCC rests on neuroimaging tools and is supported by immunodiagnostic tests. Molecular tests are slowly being introduced, but so far these have not yet reached the required levels of sensitivity (174–177). Routine hematological tests are of poor use, and even eosinophilia has been found not to be frequent in newly diagnosed NCC patients (178).

Neuroimaging

The introduction of CT was one of the major advances in the knowledge of human NCC, providing clinicians with the capacity to visualize lesions in the brain parenchyma (up to that point, imaging was limited to the detection of calcifications [X-rays], distortions in the ventricular/cisternal anatomy [pneumoencephalography], or distortions in the vascular anatomy [arteriography]). The advent of CT changed the landscape of NCC by unveiling many cases with mild disease, much more benign than the severe cases seen before, which were limited to those that could be detected by old, less-sensitive techniques. The introduction of MRI a few years later further improved imaging definition and added the capacity to present images in different planes. In general, MRI is more sensitive than CT in detecting parenchymal and extraparenchymal disease, although its sensitivity to detect calcified lesions, particularly small ones, is quite limited (133, 179–181). Lesions in the ventricles and the cisterns are better visualized using volumetric balanced steady-state gradient echo sequences (FIESTA, BFFE, or CISS, depending on the company) (181–183). Current U.S. guidelines for the diagnosis of NCC suggest that whenever possible, patients should be assessed by both techniques (184).

Neuroimaging is more helpful than serology in the sense that it provides data on the number, size, location, and stage of lesions, as well as perilesional inflammation (133, 179, 180, 185). Therapeutic decisions beyond symptomatic therapy cannot be made in the absence of this information.

Immunodiagnosis

While neuroimages may be highly compatible with NCC (in fact, multiple cystic images with a scolex are pathognomonic of the disease, although care has to be taken to avoid confusion with other structures that may mimic a scolex) (180, 184, 186, 187), in many cases the diagnosis is not conclusive. In these cases, specific serology plays a major role in confirming the diagnosis. Antibody detection is most frequently used because of its higher sensitivity, while antigen detection provides additional information on the presence of living parasites (188).

Antibody detection.

The assay of choice for antibody detection is the enzyme-linked immunoelectrotransfer blot (EITB) assay using lentil lectin purified parasite glycoprotein antigens (LLGP) (189). This test has a sensitivity above 98% in patients with more than one live brain cyst, and its specificity is close to 100% (190, 191). EITB sensitivity drops in patients with a single viable brain cyst. Antibody detection ELISAs available in the market use less-purified antigens, resulting in lower sensitivity and, more importantly, frequent cross-reactions with related cestodes such as the ubiquitous Hymenolepis nana or Echinococcus sp. (hydatid disease) (192, 193).

The seven LLGP antigens used in the LLGP-EITB assay belong to three families, with low-molecular-weight antigens associated with viable disease and appearing after weeks or months of infection (190). Heavier-molecular-weight antigens appear first and are the latest to disappear after the patient is cured and all the parasites have died. Patients may be antibody positive for months or years after successful therapy (190). Drawbacks of the LLGP-EITB assay include its limited availability and complex processing, as well as the need for parasite material to produce the antigen mix. Efforts are under way to produce a simpler version based on recombinant or synthetic antigens (194).

Antigen detection.

Detecting circulating parasite antigen is a difficult task because unlike antibodies, antigen is limited in amount and not multiplied by the immune system (resulting in decreased sensitivity) and also because helminths share many diagnostic epitopes (resulting in frequent cross-reactions) (188). The production of monoclonal antibodies against Taenia saginata allowed the development of antigen-capture ELISAs with good specificity, although their sensitivity is still lower than that of the LLGP-EITB (195, 196). On the positive side, detecting parasite antigen confirms the presence of living parasites and as such it informs therapeutic decisions (197). Antigen levels also serve to monitor the efficacy of antiparasitic treatment (198, 199).

Molecular Tests

Taenia solium DNA has been detected by PCR or deep genomic sequencing using cerebrospinal fluid (CSF) of patients with subarachnoid NCC (175–177, 200, 201), although there are no reports of its use in parenchymal NCC cases, even less in patients with a single brain lesion where most diagnostic problems arise. Cell-free T. solium DNA has been demonstrated in the urine and serum of patients with NCC (174, 202), and recent data suggest that monocyte gene expression and serum mass spectrometry profiles could be used to identify NCC cases (203, 204). To date, however, molecular biology assays are not directly applied for routine case assessment.

Diagnostic Criteria

Diagnostic criteria for cysticercosis were developed more than 20 years ago by Del Brutto et al. (205), to homogenize the diagnostic approach and to reduce errors that occur when epidemiological data, clinical manifestations, and complementary tests are used by themselves to diagnose the disease. A second set of criteria, confined to the diagnosis of NCC, was reported in 2001 (206). This set used four categories of diagnostic criteria (absolute, major, minor, and epidemiologic), stratified according to their diagnostic strength, and two degrees of diagnostic certainty (definitive and probable). These criteria have been widely used for the diagnosis of NCC in both hospital and field settings and have proven useful in areas of endemicity and nonendemicity. The more recent version (187) emphasizes the importance of neuroimaging as the basis for a diagnosis of NCC, and as such, it is organized into absolute, neuroimaging, and clinical/exposure criteria. Likewise, proper interpretation of these criteria allows two degrees of diagnostic certainty, definitive and probable (Table 2). While this revised set permits a diagnosis of probable NCC in individuals presenting with suggestive clinical manifestations (mainly seizures) and evidence of exposure to cysticercosis, a definitive diagnosis of NCC cannot be established without the evidence provided by neuroimaging.

TABLE 2.

Revised Del Brutto’s diagnostic criteria and degrees of diagnostic certainty for neurocysticercosis^a

Category	Criterion or definitionb
Diagnostic criteria
Absolute criteria	Histological demonstration of the parasite from biopsy specimen of a brain or spinal cord lesion
	Visualization of subretinal cysticercus
	Conclusive demonstration of a scolex within a cystic lesion on neuroimaging studies
Neuroimaging criteria
Major	Cystic lesions without a discernible scolex
	Enhancing lesionsc
	Multilobulated cystic lesions in the subarachnoid space
	Typical parenchymal brain calcificationsc
Confirmative	Resolution of cystic lesions after cysticidal drug therapy
	Spontaneous resolution of single small enhancing lesionsd
	Migration of ventricular cysts documented on sequential neuroimaging studiesc
Minor	Obstructive hydrocephalus (symmetric or asymmetric) or abnormal enhancement of basal leptomeninges
Clinical/exposure criteria
Major	Detection of specific anticysticercal antibodies or cysticercal antigens by well-standardized immunodiagnostic testsc
	Cysticercosis outside the central nervous systemc
	Evidence of a household contact with T. solium infection
Minor	Clinical manifestations suggestive of neurocysticercosisc
	Individuals coming from or living in an area where cysticercosis is endemicc
Degrees of diagnostic certainty
Definitive diagnosis	One absolute criterion
	Two major neuroimaging criteria plus any clinical/exposure criteria
	One major and one confirmative neuroimaging criteria plus any clinical/exposure criteria
	One major neuroimaging criteria plus two clinical/exposure criteria (including at least one major clinical/exposure criterion), together with the exclusion of other pathologies producing similar neuroimaging findings
Probable diagnosis	One major neuroimaging criteria plus any two clinical/exposure criteria
	One minor neuroimaging criteria plus at least one major clinical/exposure criteria

^aAdapted from reference 187 with permission of Elsevier.

^bDefinitions: cystic lesions, rounded, well-defined lesions with liquid contents of signal similar to that of CSF on CT or MRI; enhancing lesions, single or multiple, ring- or nodule-enhancing lesions of 10 to 20 mm in diameter, with or without surrounding edema, but not displacing midline structures; typical parenchymal brain calcifications, single or multiple solid lesions, most usually of <10 mm in diameter; migration of ventricular cyst, demonstration of a different location of ventricular cystic lesions on sequential CTs or MRIs; well-standardized immunodiagnostic tests, to date, antibody detection by enzyme-linked immunoelectrotransfer blot assay using lentil lectin purified T. solium antigens and detection of cysticercal antigens by monoclonal antibody-based ELISA; cysticercosis outside the central nervous system, demonstration of cysticerci from biopsy of subcutaneous nodules, X-ray films, or CT showing cigar-shape calcifications in soft tissues, or visualization of the parasite in the anterior chamber of the eye; suggestive clinical manifestations, mainly seizures (often starting in individuals aged 20 to 49 years; the diagnosis of seizures in this context is not excluded if patients are outside the typical age range), but other manifestations include chronic headaches, focal neurologic deficits, intracranial hypertension, and cognitive decline; area of cysticercosis endemicity, a place where active transmission is documented.

^cOperational definition.

^dThe use of corticosteroids makes this criterion invalid.

MANAGEMENT OF NEUROCYSTICERCOSIS

Symptomatic NCC requires medical therapy with symptomatic medication and/or antiparasitic drugs and, less frequently, surgical interventions.

Medical Treatment

Symptomatic treatment.

Patients with symptomatic cysticercosis seek medical attention because of neurological symptoms. Symptomatic medication, including analgesics, antiepileptic drugs, mannitol, and steroids, are in general indicated as they would be administered for seizures, headache, or intracranial hypertension from any other etiology. Symptomatic management is important and should be well established before considering the onset of antiparasitic drug therapy (207).

Antiparasitic treatment.

Destroying live or degenerating cysticerci by using antiparasitic drugs is indicated in most cases (125). An interesting peculiarity of the use of antiparasitic drugs in NCC is that no immediate improvement is expected in the initial days or weeks. Conversely, its use triggers local perilesional inflammation that may cause or worsen neurological symptoms, and thus steroids or other agents are simultaneously administered to modulate this undesirable effect (208). In the long term, however, using antiparasitic drugs to destroy viable parenchymal NCC lesions results in fewer relapses of seizures with generalization (120, 209), and individuals who cure all their viable lesions also demonstrate fewer overall seizures (134). In addition, use of antiparasitic drugs to resolve subarachnoid NCC lesions reduces the significant mortality associated with this aggressive form of the disease (210).

The use of antiparasitic drugs in NCC has not been exempt from controversy (211). Praziquantel (PZQ) was first introduced in Mexico in 1979 (212). Clinicians in Latin America, treating mainly multicystic parenchymal disease and subarachnoid NCC, rapidly embraced the availability of antiparasitic therapy (213–215). In contrast, practitioners in the United States and India, treating mainly patients with single enhancing parenchymal NCC cysts, noted a relatively benign course with symptomatic therapy (216–218). The initial series of praziquantel and later albendazole reported significant neurological side effects occurring in the initial days of treatment, including death in some cases, rightly attributed to an exacerbated inflammatory reaction against the degenerating parasites (150). Simultaneous use of steroids helped to control treatment-associated symptoms (149). Some publications suggested that praziquantel and albendazole do not really result in cyst destruction and may even result in long-term sequelae (219) and also do not improve the prognosis of the underlying seizure disorder (220). Subsequent randomized controlled trials demonstrated beneficial effects of antiparasitic treatment to resolve viable cysts (with the associated reduction of mass effects), reduce the likelihood of disease progression, and improve the evolution of seizures due to parenchymal NCC, and it is accepted as the option of choice in most cases (120, 134, 184, 209, 221, 222). A proportion of patients, however, will continue having seizures despite the resolution of all of their brain cysts.

The regimen of choice for single parenchymal NCC is albendazole at 15 mg/kg/day for 7 to 15 days. Albendazole (at the same dose) combined with praziquantel at 50 mg/kg/day for 10 days demonstrated superior antiparasitic efficacy in cases with multiple viable cysts (134, 223). Longer regimens of albendazole are required in subarachnoid NCC. Some authors report continued use for several months until complete lesion resolution is seen in neuroimaging (169) or suggest the use of higher doses (224, 225). Yet there is no controlled comparative data on the safety and efficacy of combined albendazole and praziquantel in this type of disease. Higher plasma levels of albendazole sulfoxide (the active metabolite of albendazole) seem associated with higher parasiticidal efficacy (226). It should be kept in mind that antiparasitic therapy is contraindicated in the setting of uncontrolled elevated intracranial pressure, as seen with diffuse cerebral edema. Careful steroid management is important to modulate inflammation-related side effects and for the control of vasculitis and avoidance of vascular complications that can occur as the steroids are tapering (118, 227). More recently, methotrexate and etanercept have been used with this purpose (228–230).

Surgical Approaches

Surgery may be required in patients with NCC. The most frequent procedure is the insertion of a ventricle-peritoneal shunt to control hydrocephalus. Also, in the past 20 years, neuroendoscopy became the approach of choice for the management of intraventricular NCC. This procedure seems safe and effective, although caution is required when cysts are adhered to the ventricular wall, because of the risk of intraventricular bleeding (231). Open surgery is occasionally used to excise large cysts or cyst masses, most commonly in the Sylvian fissures or in the fourth ventricle (232).

CONTROL AND ELIMINATION

Development eliminates cysticercosis by canceling the conditions required to maintain the cycle (poor sanitation and noncommercial, domestic pig raising) (233–235). In poor localities, however, major changes in living conditions are unlikely to occur in the short term and active interventions are required to control or eliminate Taenia solium. Taeniasis/cysticercosis was recognized as potentially eradicable long ago (236), on the basis of availability of diagnostics and treatments, a life cycle that involves a domestic animal, and the lack of an invertebrate vector. Early efforts using mass human deworming with praziquantel in Ecuador (237) were followed by mass chemotherapy experiences in other Latin American countries (68, 238–241) and later in Asia and Africa (242–244). Addition of chemotherapy and vaccines to eliminate the pig reservoir increased the feasibility of interrupting transmission (37). Multiple control initiatives can be found in the literature. Early studies combining health education and human mass chemotherapy with praziquantel in Mexico gave inconclusive results (241, 245, 246). A study on pig confinement plus chemotherapy in Tanzania failed to control transmission (247), and assessment of mass praziquantel treatment for schistosomiasis showed a partial impact on the prevalence of taeniasis and porcine cysticercosis after three rounds of treatment but not in a village that received two rounds only (248). A study using daily doses of albendazole for 3 days in repeated campaigns, plus porcine vaccination in a small village in Lao People’s Democratic Republic, found a marked decrease in the prevalence of human taeniasis (78, 80), and a trial of porcine vaccine plus oxfendazole treatment protected pigs from cysticercosis in a population of approximately 200 pigs in Nepal (244). Health education interventions have resulted in very partial decreases in transmission indicators (249–251). In Peru, a large integrated program combining human and porcine mass chemotherapy, pig vaccination, and coproantigen detection-based case confirmation over 1 year has proven effective in achieving focal elimination of transmission in a wide area of the northern coast of the country (71). This program was able to interrupt T. solium transmission in 105 of 107 villages in a rural region comprising more than 80,000 individuals.

CURRENT RESEARCH IN TAENIA SOLIUM

There are many active fronts in Taenia solium research involving a very wide spectrum, from basic science (144, 202, 203) to mathematical modeling of transmission (252–255). Some of the most promising study fields include the following.

In Vitro and Animal Models

The lack of suitable in vitro and animal models has always been a drawback in cysticercosis research. The recent description of in vitro oncospheral development until early cyst stages (256, 257) now allows the systematic assessment of metabolic processes and antigen expression in these early stages of the parasite. Regarding animal models, infection had been reported in mice (258, 259), and more recently, reproducible brain infection in rats was obtained by intracranial oncosphere injection (144, 145, 256, 260). Oral infection of pigs is impractical because of variable rates of infection (261). Intracranial infection of piglets is feasible (262). Oncospheral injection in the pig carotid artery results in high rates of brain infection with small numbers of cysts, a model that resembles human NCC more closely than purchasing heavily infected pigs from villages where the disease is endemic, since the latter group has too many brain cysts, in the range of tens or hundreds (263).

Epileptogenesis

Despite claims that NCC might cause only acute, inflammation-related seizures and not epilepsy (264), there is much evidence that brain cysticerci result in the development of epileptogenic circuits (142). Moreover, recent studies demonstrate a consistent association between calcified NCC lesions and hippocampal sclerosis (158–161, 163), suggesting the possibility of distant formation of epileptogenic foci (158–160, 163, 265–268). Information to date suggests that development of a residual calcification (269) and lesion degeneration in the absence of antiparasitic treatment (270) are both associated with a poorer prognosis in terms of seizure relapses. Studies in animal models and in human cases may identify early markers of epileptogenesis and eventually serve to test interventions to prevent it. Studies in brain cysticercosis lesions in rodents have shown pro- and anti-inflammatory cytokine activity, disruption of the blood-brain barrier, angiogenesis, collagen deposition, and glial scarring (144, 271–273), and some authors suggest that substance P or other molecules produced early in the host granulomatous reaction to the dying parasite is capable of inducing seizure activity (274, 275). Local inflammatory damage and perilesional scarring may contribute to the presence and persistence of symptoms, particularly seizures. Along this line, since residual calcifications have consistently been associated with increased rates of seizure relapse, therapies that decrease the likelihood of residual calcification by modulating the inflammatory response or by directly influencing the deposit of calcium may result in improved clinical evolution.

FUTURE PERSPECTIVES

A better understanding of the mechanisms involved in parasite degeneration and clearance as well as the mechanisms of damage to the surrounding neural tissue should lead to improved clinical outcomes and perhaps even avoidance of epileptogenesis. Similarly, deciphering the dynamics of antigen and antibody reactions or assessing parasite DNA, as well as determining appropriate therapeutic serum levels of the most common antiparasitic drugs, could lead to improved monitoring of disease evolution and fine-tuning of therapy. Clearly, advanced tools such as genetic manipulation and omics studies should also lead to significant improvements in our understanding of the biology of T. solium and the pathogenesis of cysticercosis. On a higher level, however, the perspective for elimination and potential eradication of Taenia solium taeniasis/cysticercosis should be a major target for public health practitioners and decision makers.

Biographies

Hector H. Garcia, M.D., Ph.D., is the director of the Center for Global Health and professor at the Department of Microbiology at the Universidad Peruana Cayetano Heredia, as well as head of the Cysticercosis Unit at the Instituto Nacional de Ciencias Neurologicas in Lima, Peru. He earned his Ph.D. in 2002 from The Johns Hopkins University Bloomberg School of Public Health and his M.D. in 1989 from The Universidad Peruana Cayetano Heredia in Lima, Peru. Dr. Garcia is a coordinating member of the Cysticercosis Working Group in Peru, a multi-institutional network which is one of the foremost research groups worldwide in the study of neurocysticercosis, working in varied aspects of cysticercosis research that offers hands-on training in global health research to local scientists and health professionals.

Armando E. Gonzalez, D.V.M., Ph.D., a past Dean of the School of Veterinary Medicine at San Marcos University in Lima, Peru, and also a member of the Coordinating Board of the Cysticercosis Working Group in Peru, is an accomplished veterinary epidemiologist. He graduated from San Marcos University and obtained his M.S.C. degree in microbiology at the Universidad Peruana Cayetano Heredia and his Ph.D. in Veterinary Economics at the University of Reading in the United Kingdom. With over 200 publications in indexed journals on cysticercosis and other veterinary parasitoses, Prof. Gonzalez is one of the most productive scientists in Peru and also a mentor for many young veterinary researchers.

Robert H. Gilman, M.D., D.T.M.H., is a senior researcher based at the Department of International Health of the Johns Hopkins School of Public Health in Baltimore, MD. The long trajectory of Prof. Gilman has resulted in over 800 publications and important findings that include not only the work of the Cysticercosis Working Group in Peru but also seminal work in other infectious diseases, such as the discovery of Cyclospora cayetanensis and the development of the MODs test for tuberculosis. With more than 30 years of living in Peru, Prof. Gilman mentored not only Drs. Garcia and Gonzalez but also a large group of Peruvian researchers that have now returned to Peru and established their own research groups, building the critical mass for the future of biomedical research in the country.