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VIEWS & REVIEWS: O. H. Del Brutto, V. Rajshekhar, A. C. White, Jr., V. C. W. Tsang, T. E. Nash, O. M. Takayanagui, P. M. Schantz, C. A. W. Evans, A. Flisser, D. Correa, D. Botero, J. C. Allan, E. Sarti, A. E. Gonzalez, R. H. Gilman, and H.H. García Proposed diagnostic criteria for neurocysticercosis Neurology 2001; 57: 177-183 [Abstract] [Full text] [PDF]

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Reply to both Letters to the Editor

Oscar H Del Brutto   (14 November 2001)

Proposed diagnostic criteria for neurocysticercosis

Muralidhar K Katti   (14 November 2001)

cysticercus granuloma versus tuberculoma

Ravindra Kumar Garg   (17 September 2001)

Reply to both Letters to the Editor 14 November 2001
Oscar H Del Brutto Clinica Kennedy Guqyaqil Equador Send Correspondence to journal: Re: Reply to both Letters to the Editor sandi_moriarity{at}urmc.rochester.edu Oscar H Del Brutto	In contrast to that stated by Garg, our panel considered that it is just in Indian patients with spontaneously resolving small single enhancing lesions where the diagnosis of neurocysticercosis can be stablished with more confidence even in the absence of an absolute criterion. Those patients have two major plus one minor and one epidemiologic diagnostic criteria, which, according to our chart allow a definitive diagnosis of neurocysticercosis. We are not aware of any study showing that tuberculomas, fungal granulomas or brain tumors resolve without therapy, and the single reference quoted by Garg to support his statement that “Several studies have comprehensively demonstrated that, irrespective of etiology, single enhancing CT lesions resolve spontaneously”, probably refers to the non- specific areas of abnormal enhancement appearing on CT after a seizure that represent areas of rupture of the blood-brain barrier around the epileptogenic focus. On the other hand, Rajshekhar and Chandy [1] (in a large series of patients) demonstrated that for Indian patients with seizures and spontaneously resolving small single enhancing lesions, the diagnosis of neurocysticercosis could be accomplished with a 99.5% sensitivity and a 98.9% specificity. Needless to say, there are few conditions where the diagnosis can be stablished with such accuracy after the interpretation of clinical and imaging data. As noted by Katti, most tests used for the immunological diagnosis of neurocysticercosis have been faced with problems related to unsatisfactory reliability. We proposed diagnostic criteria to be useful worldwide, so we only included those tests from which enough experience is available. The serum EITB assay (as developed by the CDC, Atlanta, GA), has been extensively tested in several hospital- and population-based studies. [2] While a positive EITB assay predicts the diagnosis of cysticercosis with a specificity approaching 100%, such result reflects cysticerci infection in any tissue and not necessarily in the CNS. Unfortunately, the reliability of the EITB performed with CSF is lower than that performed using serum. That is why our panel considered a positive EITB only as a major diagnostic criteria for neurocysticercosis. According to our chart, we need positive neuroimaging findings in a proper clinical and epidemiological context, to make a definitive diagnosis of neurocysticercosis in patients with a positive serum EITB. The other immunological test considered in our diagnostic criteria was the ELISA performed with CSF (ELISA using serum is disappointing). However, the specificity of a positive ELISA for detection of anticysticercal antibodies is not as high as that of the EITB, since a number of patients with other infections of the CNS may test positive. [3] Since our criteria were stratified on the basis of their specificity (to avoid over diagnosis), the ELISA was included as a minor criteria, and its diagnostic strength should not be comparable with that of the EITB. In addition, while ELISA for detection of cysticercal antigens in CSF is a promising test, its specificity has not been properly evaluated in patients with other infections of the CNS. [4] Pending further results, we only considered a positive result on this test as minor diagnostic criteria. Katti has also raised some concern on the use of resolution of intracranial lesions after therapy with cysticidal drugs as a major diagnostic criteria for neurocysticercosis. Cysticercosis is such a complex disease that in some patients the diagnosis can not stablished even after proper interpretation of clinical, neuroimaging, and immunological data. In some of these cases, the use of cysticidal drugs as a diagnostic tool is justified to avoid the unnecessary practice of aggressive diagnostic approaches. [5] It is obvious that this criteria will not be available when the patients is first seen, but its proper use will facilitate the diagnosis in some cases. References: 1. Rajshekhar V, Chandy MJ. Validation of diagnostic criteria for solitary cysticercus granuloma in patients presenting with seizures. Acta Neurol Scand 1997;96:76-81. 2. García HH, Del Brutto OH. Taenia solium cysticercosis. Infect Dis Clin N Am 2000;14:97-119. 3. Del Brutto OH. Neurocysticercosis. Curr Op Neurol 1997;10:268-272. 4. García HH, Harrison LJS, Parkhouse RME, et al. A specific antigen-detection ELISA for the diagnosis of human neurocysticercosis. Trans R Soc Trop Med Hyg 1998;92:411-414. 5. Del Brutto OH. The use of albendazole in patients with single lesions enhanced on contrast CT. N Engl J Med 1993;328:356-357.
Proposed diagnostic criteria for neurocysticercosis 14 November 2001
Muralidhar K Katti SCTI for Medical Sciences and Technology Trivandrum India Send Correspondence to journal: Re: Proposed diagnostic criteria for neurocysticercosis sandi_moriarity{at}urmc.rochester.edu Muralidhar K Katti	The proposal of revised diagnostic criteria for neurocysticercosis (NCC) by Brutto et al. is very comprehensive, educative and highly useful, especially in endemic areas of the globe. [1] I wish to express my viewpoints on criteria 2 and 3 of the major category and 3 of the minor category (see Table 2 of text). [1] It would be more appropriate if criterion 3 of the major category were interchanged with that of criterion 2. This is because detection of anticysticercal antibody and/ cysticercal antigen is more useful in CSF or CSF and serum than in serum alone for immuno diagnosis of NCC [2, 3] as de novo synthesis of anticysticercal antibodies intrathecally is shown in cases of NCC. [4] Detection and quantification of cysticercal antigens released into CSF as a consequence of immune response, or excreted/secreted (ES) by live cysticerci would be more superior to antibody detection in differential diagnosis and prognosis of NCC. The relative merits of antigen detection versus antibody analysis have been reviewed. [5] In detection of antigens, false negative reactions can occur by ELISA or by any serological methods whereas an immunoblot test can be positive. This is because of complete masking of antigens by specific antibodies in immune complexes that would be unavailable for detection. In imunoblot tests, immune complexes are made to dissociate before they are resolved on poly acrylamide gel and subsequent transfer onto nitrocellulose (NC) membrane and thus antigens are detected. [3, 6] Previous studies have selectively demonstrated two cysticercal antigens circulating in human CSF from patients with NCC, with molecular mass of 24 -28 kDa and 64-68 kDa, of which 24-28 kDa antigen was highly specific. [3] On the contrary, detection of anticysticercal antibodies in CSF of chronic infections of the CNS and polyradiculopathy patients do show false positive reaction tested either by ELISA [7] or passive heamagglutination or immunoblot assay (data not shown). A positive enzyme-linked immuno electro transfer blot (EITB) assay for antibody to Taenia solium metacestode (and not T. solium as mentioned in Table 2 of the text) [1] antigens in serum alone would indicate systemic cysticercosis and under diagnose cases of NCC. In such cases, the degree of certainty would become only a possibility and not definitive of NCC for the reasons explained above. As far as performances of assays are concerned, sensitivity of any test per se depends on standardization and evaluation of the system whereas specificity, on the type of probe employed. [6] Therefore, current available immunological methods do not suffer from lack of sensitivity. However, variations in sensitivity and specificity of various immunoassays described for diagnosis of NCC are mainly because of – (i) hosts’ heterogeneous immune response, (ii) use of variety of cysticercal antigens from different sources namely, scolex, cyst fluid, membrane non-ruptured whole Cysticercus cellulosae from porcine and human sources by various investigators and (iii) antigenic variation or drift exhibited by the parasite. [8, 9] On comparative evaluation of various immunoassays no differences were observed qualitatively. [10] In my opinion, major criterion 2 may be modified and read as “Positive immunological tests (EITB, ELISA, DIA or PHA) for detection of anticysticercal antibodies and (EITB, tandem-ELISA, capture-DIA, RPHA) for cysticercal antigens in CSF or CSF and serum, and not serum alone." Regarding major criterion 3 of Table 2 cited in the text, [1] cysticercal drugs such as albedazole or praziquantal therapy is instituted only after a case is diagnosed as NCC based diagnostic criteria. Therefore, resolution of intra cranial cyst lesions after therapy would probably be a diagnostic criterion for retrospective studies and epidemiological purposes. References: 1. Del Brutto OH, Rajashekhar V, White Jr AC, et al. Proposed diagnostic criteria for neurocysticercosi. Neurol 2001;57:177-183. 2. Rosas N, Sotelo J, Neito D. ELISA in diagnosis of neurocysticercosis. Arch Neurol 1986;43:353-356. 3. Katti MK, Chandramuki A. Detection of cysticercal antigens in human cerebrospinal fluid. Serodiagn Immunother Infect Dis 1990;4:441-450. 4. Miller BL, Staugaitis SM, Tourtellotte WW, et al. Intra blood- brain-barrier IgG synthesis in cerebral cysticercosis. Arch Neurol 1985;4:782-784. 5. Richmann DD, Cleveland PH, Redfield DC, Oxman MN, Wahl GM. Rapid viral diagnosis. J Infect Dis 1984;149:298-310. 6. Katti MK. Are ELISA and immunoblot assay independent in immunodiagnosis of infectious diseases. Clin Infect Dis 2001;32:1114. 7. Katti MK, Acharya MT. Immunodiagnosis of tuberculous meningitis: detection of antibody response to antigens of Mycobacterium tuberculosis and Cysticercus cellulosae by enzyme-linked immunosorbent assay. J Immunoassay Immunochem 2001 (In press). 8. Yakoleff-Greenhouse V, Flisser A, Sierra A, Larralde C. Analysis of antigenic variation of Taenia solium. J Parasitol 1982;68:39-47. 9. Katti MK, Chandramuki A. Analysis of antigenic variation in Cysticercus cellulosae and partially purified cysticercal antigens by crossed immuno electrophoresis. Serodiagn Immunother Infect Dis 1993;5:97- 101. 10.Katti MK, Chandramuki A. Comparative evaluation of cysticercal antigens and immunoassays in the diagnosis of neurocysticercosis. Ann Trop Med Parasitol 1991;85(6):605-615.
cysticercus granuloma versus tuberculoma 17 September 2001
Ravindra Kumar Garg, assistant professor Department of Neurology, KGMC, Lucknow, India Send Correspondence to journal: Re: cysticercus granuloma versus tuberculoma garg50{at}yahoo.com Ravindra Kumar Garg	I read the article by Del Brutto et al [1] with great interest. I feel that very few Indian patients of neurocysticercosis will be able to satisfy absolute criteria. It is not possible to perform diagnostic brain biopsy in every suspected patient of neurocysticercosis. Direct visualization of the subretinal parasite is rare and hardly been reported from India, even patients with cystic lesions showing the scolex on CT or MR imaging are uncommon. In India, majority of patients of neurocysticercosis, have single enhancing CT lesions, multiple enhancing CT lesions are also not uncommon. Enhancing CT/MRI lesions have been grouped under major diagnostic criteria number–1. Another infective condition that is very common in India is CNS tuberculosis, and single or multiple tuberculoma of brain also present as single or multiple enhancing CT/MRI lesions. Imaging features of cysticercus granuloma and tuberculoma are exceedingly similar. These diagnostic criteria do not seem to be reliable in this important differentiation. Serum EITB assay is largely not available in India. Moreover, in patients with single enhancing CT lesions fewer than 50% specimens were positive for this test. [1] Authors considered the resolution of intracranial cystic lesions following therapy with albendazole or praziquantel as another criteria. In Indian randomized studies, involving multiple enhancing and single enhancing CT lesions, anticysticercal therapy has not demonstrated any efficacy, moreover, role of anticysticercal drugs on an already inflamed and dying cyst remains questionable. [2,3] Next major criterion is spontaneous resolution of single enhancing CT lesions. Single enhancing CT lesions are the most common imaging abnormality in Indian patients with new-onset of seizures. Histopathologically it has been observed that majority of these lesions are cysticercus granuloma (25 out of 51 brains biopsies), remaining 26 patients of this study did not show any definite evidence of cysticercus etiology. Six of these 26 patients were having tuberculoma. [4] Several studies have comprehensively demonstrated that, irrespective of etiology, single enhancing CT lesions resolve spontaneously. [5] These criteria are also not helpful even if the patient is showing multiple enhancing CT lesions. Again the list of differential diagnosis, along with multiple tuberculoma, includes fungal granuloma, primary or secondary malignancies and multiple pyogenic abscesses. No histopathological evidence is available from India to suggest that patients with multiple enhancing CT lesions have cysticercus granuloma. Even minor or epidemiologic criteria are not sufficiently specific to diagnose single or multiple enhancing CT/MRI lesions in Indian patients. I think that these diagnostic criteria are more suitable for the patients living in a geographical region where both neurocysticercosis as well as other CNS infections are uncommon. References 1. Del Brutto OH, Rajshekhar V, White Jr. AC et al. Proposed diagnostic criteria for neurocysticercosis. Neurology 2001; 57: 177-183. 2. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in single CT ring lesions in epilepsy. Neurology 1994; 44 : 1344-1346. 3. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in neurocysticercosis. Natl Med J India 1995 : 8 : 255-258 4.Rajshekhar V, Haran RP. Shankar Prakash G, Chandy MJ. Differentiating solitary small cysticercus granuloma and tuberculoma in patients with epilepsy. J Neurosurg 1993; 18: 402-407. 5.Chopra JS, Sawhney IMS, Suresh N, Prabhakar S, Dhand UK, Suri S. Vanishing CT lesions in epilepsy. J Neurol Sci 1992; 107: 40-49.