Subarachnoid neurocysticercosis: emerging concepts and treatment.

PURPOSE OF REVIEW: Subarachnoid neurocysticercosis (SUBNCC) is caused by a morphologically unique proliferative form of Taenia solium involving the subarachnoid spaces. Prolonged therapy based upon the pathophysiology of SUBNCC and long-term follow-up have shed light on the course of disease and led to highly improved outcomes. RECENT FINDINGS: SUBNCC has a prolonged incubation period of between 10 and 25 years characterized by cyst proliferation and growth and invasion of contiguous spaces leading to mass effect (Stage 1). With induction of the host-immune responses, cysts degenerate leading to a predominately inflammatory arachnoiditis (Stage 2) causing hydrocephalus, infarcts, and other inflammatory based neurological manifestations. Inactive disease (Stage 3) may occur naturally but mostly is a result of successful treatment, which generally requires prolonged intensive anthelminthic and antiinflammatory treatments. Cerebral spinal fluid cestode antigen or cestode DNA falling to nondetectable levels predicts effective treatment. Prolonged treatment with extended follow-up has resulted in moderate disability and no mortality. Repeated short intensive 8-14-day courses of treatment are also used, but long-term outcomes and safety using this strategy are not reported. SUMMARY: SUBNCC gives rise to a chronic arachnoiditis. Its unique ability to proliferate and induce inflammatory responses requires long-term anthelmintic and antiinflammatory medications.

Angiostrongylus cantonensis in travelers: clinical manifestations, diagnosis, and treatment.

PURPOSE OF REVIEW: Angiostrongylus cantonensis eosinophilic meningitis is a neglected, yet important emerging disease, which has been increasingly recognized in travelers. In this review, we describe the occurrence of the disease in travelers, sources of infection, clinical manifestations, diagnosis, and currently recommended treatment. RECENT FINDINGS: Various intermediate hosts and/or paratenic hosts can be the source of infection in humans. Serological tests for antibody may be negative early in the course of the disease but PCR for antigen detection in the CSF has recently been developed and may help to make the diagnosis at an earlier stage. High-dose corticosteroids (e.g. prednisolone 60 mg per day for at least 1-2 weeks) are currently the recommended treatment. Efficacy and safety of antihelminthic drugs for treatment remains controversial because of theoretical concerns that they may worsen the inflammatory response to dead and dying worms. Previous clinical trials were conducted with small numbers of participants and were underpowered. Further well designed clinical trials are urgently needed. SUMMARY: Awareness about increasing numbers of A. cantonensis eosinophilic meningitis in travelers is very important. Travelers should be advised about possible sources of infection. Diagnosis should be confirmed by antigen or antibody detection in blood or CSF. High-dose corticosteroids are the recommended treatment. The efficacy of various antihelminthic drugs is unproven. A large-scale, double-blind, randomized, controlled trial of antihelminthic drug involving antihelminthic drugs such as albendazole is necessary to prove the efficacy before formally advocating their use on a regular basis.

Comparative profile of circulating antigenic peptides in CSF, serum & urine from patients with neurocysticercosis diagnosed by immunoblotting.

Traditionally serum and/or CSF specimens have been used for detection of either specific antibodies or antigens as a supportive diagnosis of NCC. However, in recent days, much interest has been shown employing noninvasive specimens such as urine. In our study, we identified and compared a profile of circulating antigenic peptides of parasite origin in three different body fluids (CSF, serum and urine) obtained from confirmed NCC cases and control subjects. The circulating antigenic peptides were resolved by SDS-PAGE and subjected to immunoblotting. For confirmation of their origin as parasite somatic or excretory secretory (ES) material, immunoreactivity was tested employing affinity purified polyclonal Taenia solium metacestode anti-somatic or ES antibodies, respectively. Only lower molecular weight antigenic peptides were found circulating in urine in contrast to serum and CSF specimens. Few somatic peptides were identified to be 100% specific for NCC (19·5 kDa in all three specimens; 131, 70 kDa in CSF and serum only; 128 kDa in CSF only). Similarly, the specific ES peptides detected were 32 kDa (in all three specimens), 16·5 kDa (in serum and CSF only), and 15 kDa (urine only). A test format detecting either one or more of these specific peptides would enhance the sensitivity in diagnosis of NCC.

Human neurocysticercosis: comparison of different diagnostic tests using cerebrospinal fluid.

Neurocysticercosis (NC), caused by the larval stage of Taenia solium, is one of the most common parasitic diseases of the central nervous system. The diagnosis of NC is mostly based on costly brain neuroimaging (computed tomography and/or nuclear magnetic resonance), which is rarely accessible in most affected areas. The most sensitive and specific tools for NC diagnosis are imagery techniques. The identification of specific antibodies and antigens is currently used only to support NC diagnosis due to their limited specificity and sensitivity. This study was performed to compare immunodiagnostic assays (antibody detection by enzyme-linked immunosorbent assay [ELISA] and enzyme-linked immunoelectrotransfer blotting [EITB] and HP10 antigen detection by ELISA) with the detection of parasite DNA by PCR amplification of a repetitive element of the parasite genome in the cerebrospinal fluid (CSF) of 121 radiologically and clinically characterized NC patients. Patients were divided into six groups according to the stage of the parasites and their localization. The CSF cellularity of each patient was also recorded. When all patients were considered, PCR exhibited the highest sensitivity (95.9%) and variable specificity (80% or 100%) depending on the controls used. The sensitivities of antibody detection by ELISA and EITB were not significantly different, and ELISA identified HP10 antigen mostly when vesicular cysticerci were located in the subarachnoideal basal cisterns. These results can help in the selection of different individual assays or combinations of assays to be used in NC diagnosis according to different requirements.

Reciprocal contribution of clinical studies and the HP10 antigen ELISA for the diagnosis of extraparenchymal neurocysticercosis.

To evaluate diagnosis of active neurocysticercosis, paired cerebral spinal fluid (CSF) and serum samples from 24 neurocysticercosis (NCC) patients and 17 control neurological patients were assayed in the HP10 Taenia antigen (Ag) ELISA. The CSF samples were also tested with an HP10 Lateral Flow Assay (LFA). The HP10 Ag was detected by ELISA in the CSF of 5/5 patients with Definitive extraparenchymal NCC, and in 4/5 of the corresponding sera. In the Definitive parenchymal group, on the other hand, the HP10 Ag was absent in 2/3 CSF (with a very low value in the one positive sample) and all the corresponding serum samples. Samples of CSF from 4/7 patients in the Probable parenchymal group, were also significantly HP10 Ag positive, suggesting the presence of extraparenchymal cysts not identified by the imaging studies. With the possible exception of one patient, the corresponding serum samples of the Probable parenchymal NCC group, were all HP10 Ag negative. Samples of CSF from 9 NCC patients diagnosed with Mixed parenchymal and extraparenchymal NCC were all significantly HP10 Ag positive, confirming the presence of extraparenchymal cysts, with only 7/9 of the corresponding serum samples being HP10 positive. Thus detection of the HP10 Ag indicates extraparenchymal and not parenchymal cyst localization and is more sensitive with CSF than serum. Three neurological patients clinically diagnosed as subarachnoid cyst, hydrocephalus and tuberculoma, respectively, were clearly positive for HP10 Ag. Of these, two were confirmed as NCC by subsequent imaging; the third died prior to further examination. Thus, a total of 8 patients had their clinical diagnosis questioned. Finally, there was good agreement between the HP10 Ag ELISA and LFA with CSF samples giving an optical density ≥0.4 in the ELISA assay. In conclusion, the HP10 Ag assay should provide a valuable and reciprocal tool in the clinical diagnosis and follow up of extraparenchymal NCC.

Detection of HP10 antigen in serum for diagnosis and follow-up of subarachnoidal and intraventricular human neurocysticercosis.

INTRODUCTION: Neurocysticercosis (NC), a parasitic disease caused by Taenia solium, may be either asymptomatic or show a mild to severe clinical picture with intracranial hypertension. The most severe form of the disease is caused when viable cysticerci are localised in the ventricles or in subarachnoidal cisterns at the base of the skull. Detection of the secreted metacestode antigen HP10 in cerebrospinal fluid is a sensitive and specific method for the diagnosis of these severe NC cases. OBJECTIVE AND METHODS: To evaluate the validity of HP10 antigen detection ELISA when applied to serum, using paired serum and cerebrospinal fluid samples from 116 radiologically and clinically characterised NC patients. RESULTS: The HP10 antigen assay exhibited a similarly high sensitivity in identifying severe NC cases from sera (84.8%) and CSF (91.3%). In contrast, HP10 antigen was rarely detected in asymptomatic or mild NC cases (3 of 57). Importantly, the HP10 antigen assay applied to serum showed high specificity (94%) when used in 126 serum samples of non-NC subjects from an endemic community with a confirmed coproparasitological diagnosis of intestinal parasitic infections. Finally, the HP10 assay also proved to be of value in the follow-up of treated patients. CONCLUSION: This study confirms that detection of the metacestode HP10 antigen in serum is a useful tool for diagnosis and follow-up of patients with severe forms of NC treated with cysticidal drugs.

Detection of Cysticercus antigens and antibodies in cerebrospinal fluid of patients with chronic meningitis.

Chronic meningitism is a less frequent manifestation of neurocysticercosis caused by Taenia solium cysticerci. In the present study we used Co-agglutination (Co-A), a simple and rapid slide agglutination test to detect specific Cysticercus antigen in the 67 cerebrospinal fluid (CSF) samples from patients with chronic meningitis of unknown etiology. The results were compared with that of ELISA for detection of antibodies. Among these samples four (5.97%) were positive for Cysticercus antigen by Co-A test and six (8.95%) were positive for antibodies by ELISA. Two samples were positive by both Co-A and ELISA, two were positive only by Co-A and four were positive only by ELISA. In the present study, although Cysticercus antigen and antibodies were present in CSF samples from eight (11.94%) patients, we cannot affirm that all the cases of chronic meningitis are due to cysticercosis, but for any case of chronic meningitis of unknown origin, it would be useful to consider the possibility of cysticercal meningitis.

Intrathecal synthesis of specific immunoglobulin G antibodies in neurocysticercosis: evaluation of antibody concentrations by enzyme-linked immunosorbent assay using a whole cysticercal extract and cyst vesicular fluid as antigens.

The demonstration of intrathecal antibody production has proven useful for showing the involvement of the central nervous system (CNS) in several diseases. In the present study, the intrathecal synthesis of cysticercus-specific immunoglobulin G (IgG) antibodies was investigated in 30 patients with neurocysticercosis based on calculation of the specific IgG antibody index (AI(IgG)). An AI(IgG) > or =1.5 was considered to be indicative of intrathecal antibody production. Antibody concentrations in serum and cerebrospinal fluid samples were evaluated using an enzyme-linked immunosorbent assay with 2 antigen preparations from Taenia solium cysticerci, namely, a whole cysticercal extract (TsoW) and the vesicular fluid of the parasite (TsoVF). Intrathecal, cysticercus-specific IgG antibody synthesis was observed in 21 (70%) and 23 (76.6%) patients using the TsoW and TsoVF antigens, respectively. The detection of the intrathecal synthesis of specific antibodies may be a potentially useful tool in establishing the involvement of CNS in cysticercosis.

Detection of Cysticercus cellulosae antigens in cerebrospinal fluid by dot enzyme-linked immunosorbent assay (Dot-ELISA) and standard ELISA.

The dot enzyme-linked immunoassay and standard enzyme-linked immunoassay were used to detect Cysticercus cellulosae antigens in cerebrospinal fluid of patients suffering with neurocysticercosis. Using the dot enzyme-linked immunoassay, 10 of 17 patients (59%) were positive at a reciprocal titer of 128 (range 128-1,024). In the standard assay, 13 of 17 (77%) were positive (range 128-512). Specificity was 100% in both assays using 48 cerebrospinal fluids from patients with various central nervous system infections. The quantification of antigens in cerebrospinal fluid using standard assay and photometric readings showed a range of 17 to 138 ng/ml. The results indicate that both assays are sensitive, specific, and economical for the diagnosis of neurocysticercosis.

Immunodiagnosis of human cysticercosis (Taenia solium): a field comparison of an antibody-enzyme-linked immunosorbent assay (ELISA), an antigen-ELISA, and an enzyme-linked immunoelectrotransfer blot (EITB) assay in Peru. The Cysticercosis Working Group in Peru (CWG).

We compared results of an enzyme-linked immunosorbent assay (ELISA) and an enzyme-linked immunoelectrotransfer blot (EITB) assay for the diagnosis of cysticercosis in sera and cerebrospinal fluid (CSF). Sera from 34 patients with confirmed cysticercosis were tested by both ELISA and EITB assays. Cerebrospinal fluid from some of these patients was also tested by ELISA for the presence of antibody (AB-ELISA) (n = 21) and antigen (AG-ELISA) (n = 15). Specificity in sera was examined by testing 51 serum samples from Bangladesh, where cysticercosis is not endemic. Cross-reactivity was evaluated in sera from patients with Echinococcus granulosus (hydatid) and Hymenolepis nana infections. Sensitivity in detecting cysticercosis in sera was 94% by EITB and 65% by AB-ELISA (P less than 0.01). Sensitivities in the CSF tested by EITB, AB-ELISA, and AG-ELISA were 86%, 62%, and 67%, respectively. The specificity of the EITB was 100%, while that of AB-ELISA was 63% (P less than 0.01). Cross-reactions occurred in the AB-ELISA with 11% and 20% of sera from hydatid and H. nana patients, respectively. Our results demonstrate that the EITB is the best assay available for the diagnosis of cysticercosis in both sera and CSF.

Detection of circulating antigen by monoclonal antibodies for immunodiagnosis of angiostrongyliasis.

Two monoclonal antibodies, which recognize the epitope on an antigen with a molecular weight of 204 kD from the fifth-stage worm of Angiostrongylus cantonensis, were previously prepared and used to detect circulating antigens in patients with eosinophilic meningitis or meningoencephalitis and in mice experimentally infected with this parasite by a double-antibody, sandwich enzyme-linked immunosorbent assay (ELISA). The levels of this circulating antigen in experimentally infected mice were significantly higher three weeks after infection. The ELISA values in the detection of circulating antigens in cerebrospinal fluid (CSF) from patients were markedly higher than those in serum. Immunodiagnosis of patients with angiostrongyliasis by this technique proved to be highly specific for circulating antigens in serum and CSF specimens; however, the sensitivity in CSF was significantly higher than in serum.

Identification of Taenia solium antigens in cerebrospinal fluid and larval antigens from patients with neurocysticercosis.

Two antigens (190 and 230 kDa) of the larvae of Taenia solium were detected in the cerebrospinal fluid (CSF) of 14 of 18 patients in which neurocysticercosis was suspected. Nine of these were confirmed by histopathology. Seven antigens were detected in cyst fluid of T. solium larvae removed from the brains of 6 infected patients. Two of these antigens had the same Mr as the T. solium antigens detected in the CSF. Polyacrylamide gel electrophoresis and electro-immunoblotting analyses were used for the identification and characterization. Antibodies in rabbit anti-larval antiserum and antibodies in sera of infected individuals recognized the same larval antigens in the larval cyst fluids and in the CSF of infected patients.

Immunochemical detection of antigens of larval Taenia solium and anti-larval antibodies in the cerebrospinal fluid of patients with neurocysticercosis.

A simple and quantitative enzyme-linked immunosorbent assay (ELISA) has been developed for the detection of antigens of larval Taenia solium in the cerebrospinal fluid (CSF) of patients with cerebral cysticercosis. Another ELISA was developed for detecting antibodies in CSF against larval antigens. The examination of sixteen patients with clinical diagnosis of cerebral cysticercosis revealed that eleven patients had both circulating larval antigens and anti-larval IgG (but not IgM) antibodies in their cerebrospinal fluids. Of these patients, those with surgically and histologically confirmed infections were all positive by the two tests. CSF samples from nine normal individuals and from six patients suffering from proven neurological disorders other than neurocysticercosis were negative for both tests. In development of these assays it was found that cross-linking of antigens to microtiter plates further improved the performance of the ELISA. The results of this study suggest that either or both of these tests may be useful in discriminating between neurocysticerosis and other clinically related diseases.

Detection of secreted cysticercal antigen: a useful tool in the diagnosis of inflammatory neurocysticercosis.

Neurocysticercosis is a common parasitic disease of the human central nervous system. It is particularly prevalent in developing countries, where it has a serious public health and economic impact. A major diagnostic problem with neurocysticercosis is its pleomorphic nature. Conventional diagnosis of neurocysticercosis still requires brain-computed tomography and/or magnetic resonance imaging, which are definitive but often prohibitively expensive and inaccessible in endemic areas. Herein, the monoclonal antibody HP10 antigen-trapping enzyme-linked immunosorbent assay, which has been used successfully to detect viable Taenia solium cysticercosis, was evaluated using cerebrospinal fluid (CSF) from Mexican neurocysticercosis patients with various defined pathologies. Sensitivity was higher in cases of inflammatory compared with non-inflammatory disease (94.1% vs. 33.3%) and in cases of multiple- compared with single-cyst cysticercosis (85% vs. 33.3%). Positivity was a strong indicator of active, inflammatory, multiple-cyst neurocysticercosis detecting 100% (15/15) of such cases. The overall specificity, as determined using CSF samples from patients with other neurological symptoms, was 97.7% (42/43). Since the assay only detects viable infection, it is of known value in the follow-up of treated patients to determine whether treatment has been successful. Thus, antigen detection may be of particular value in the assessment of symptomatic patients, who may potentially benefit from rapid treatment.

Estimation of the local synthesis of immunoglobulin G (IgG) in the central nervous system of patients with spinal cord schistosomiasis by the IgG index.

By analogy with other infections of the central nervous system (CNS), it is believed that schistosomal myeloradiculopathy (SMR) is an entity that may involve a mild-to-moderate degree of impairment of the blood-brain barrier along with intrathecal synthesis of antibodies. The first of these aspects is obvious but the second has not been clearly demonstrated. This study was undertaken in Brazil with the aim of investigating the production of immunoglobulin G (IgG) within the CNS in patients with SMR, by the determination of the cerebrospinal fluid (CSF) IgG index. The study population included 54 patients with SMR, evaluated prospectively. The CSF IgG index was increased in 43 of them (80%). Preliminary results from our laboratory suggest that these antibodies are reactive against Schistosoma mansoni antigens. Thus, this finding also suggests that this index may be useful in the differential diagnosis of SMR.

Antigenic analysis of Cysticercus cellulosae by crossed immunoelectrophoresis & its role in immune diagnosis of neurocysticercosis.

The antigenic composition of Cysticercus cellulosae cysts excised from infected pig and autopsied human brain was analysed by crossed immunoelectrophoresis with an intermediate gel technique using rabbit hyperimmune serum. Normal pork muscle and human brain antigen were used to differentiate parasite derived components from that of host. Attempts were made to look for the rich source of parasitic immunodominant antigens by analysing preparations of different parts of cyst namely scolex and fluid using rabbit hyperimmune serum. Twenty three antigenic components were identified in sonicate extract of porcine cyst, of which 15 were parasite derived. On comparison with antigens of whole cyst sonicate, scolex showed 10, cyst fluid 9 and human cyst sonicate 11 parasite derived antigens. Serum and cerebrospinal fluid (CSF) of neurocysticercotic patients reacted with 12 parasite derived antigens of porcine cyst sonicate (PCS) in a heterogenous manner. It was also noticed that human cyst sonicate (HCS) lacked 4 of the parasite derived antigens present in the PCS.

Host--parasite relationship in cysticercosis: immunologic study in different compartments of the host.

Cysticerci parasitize several mammalian species, including man, in which the parasitic disease shows unique characteristics since cysticerci are established mainly in immunologically privileged sites and can survive for many years. The study of the human immune response to cysticerci is helpful in diagnosis and could perhaps also aid in preventing or curing the disease. Anti-cysticercus IgG can be detected in serum and cerebrospinal fluid (CSF) of almost all patients with neurocysticercosis, by the enzyme-linked immunosorbent assay (ELISA); antibodies of the other classes are found less frequently. Antibodies react with up to eight Taenia solium cysticercus antigens, mainly with antigen B. This antigen has an affinity for collagen and is not commonly found in the CSF. It could therefore be participating in vasculitic processes spotted in the brain of neurocysticercotic patients. Immunoglobulins are also identified on the surface of the parasites: IgG is detected on parasites obtained from various tissues; IgM, IgA and IgE mostly on extracerebral cysticerci. We discuss the possibility of extraneural cysticerci being destroyed by the immune response of the host whereas natural aging may cause brain cysticerci death.

Detection of antigens of larval Taenia solium in the cerebrospinal fluid of patients with the use of HPLC and ELISA.

The cerebrospinal fluid (CSF) obtained from patients suspected of having neurocysticerosis (79 samples), as well as from control patients (without neurological symptoms), was separated using a high performance liquid chromatography gel filtration column. During the chromatographic separation, the eluted fractions were collected separately according to distinctive peaks. The elution characteristics of CSF components were identified by aligning more than 100 chromatograms and 6 distinctive peaks, eluting in consistent positions. Samples of each peak were tested in an enzyme-linked immunosorbent assay (ELISA) for the presence of larval antigens. Forty-four of the suspected 79 cases were found to have larval antigens in their CSF and these antigens were detected in peak no. 2, the mean of which is approximately 110,000 molecular weight. Also, in some cases, larval antigens were found in peak no. 1; however, we were able to detect them in only 23 CSF samples out of 44 CSF samples in which larval antigens were present in peak no. 2. Nine of these 23 CSF samples (derived from 79 patients in which neurocysticercosis was suspected) were later confirmed by histopathology. Values of ELISA readings of 5 CSF samples obtained from control patients (0.054 +/- 0.064) were considered negative. Thus, in 44 of 79 CSF samples from patients suspected of having neurocysticercosis, the ELISA values were highly positive (0.551 +/- 0.293). The remaining 35 CSF samples gave ELISA readings of 0.092 +/- 0.062, which were not significantly different from values obtained with CSF of control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A MAb-based ELISA for detecting circulating antigen in CSF of patients with neurocysticercosis.

A monoclonal antibody (MAb)-based enzyme-linked immunosorbent assay (ELISA) was evaluated for detecting circulating antigen (CAg) in the cerebrospinal fluid (CSF) of patients with neurocysticercosis. CAg of Cysticercus Cellulosae was detected in 95 out of 116 patients with neurocysticercosis. Of the 21 neurocysticercosis patients in whom CAg was not detected, 14 had only higher density spots, 3 had one or two lower density spots and 4 had no obvious damage in their brain Computed Tomography (CT) scans. CAg was also not detected in CSF samples of patients with other diseases of the central nervous system. These included cerebral tumor, encephalopyosis, brain trauma, viral meningitis and cerebral hemorrhage. Detecting CAg with MAb-based ELISA is better than any previously available methods for the diagnosis of active neurocysticercosis.

A case of neurocysticercosis-differential diagnostic aspects.

Neurocysticercosis is no medical rarity but in non-endemic countries especially, a high degree of physician awareness is necessary for diagnosis. The case of a German female patient who had focal seizures for the first time at the age of 23 caused by a cerebral cyst of cysticercus cellulosae is presented. Only surgical removal and subsequent histological examination allowed diagnosis while diagnostic investigation yielded no pathological findings.