Demonstration of Scolex within Calcified Cysticercus Cyst: Its Possible Role in the Pathogenesis of Perilesional Edema

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1 Epilepsia, 43(12): , 2002 Blackwell Publishing, Inc International League Against Epilepsy Demonstration of Scolex within Calcified Cysticercus Cyst: Its Possible Role in the Pathogenesis of Perilesional Edema *Rakesh K. Gupta, *Rajesh Kumar, *Sanjeev Chawla, and Sunil Pradhan Departments of *Radiodiagnosis and Neurology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, U.P., India Summary: Purpose: This study was performed to understand the relation between the scolex as demonstrated on gradient echo (GRE) imaging in a calcified cysticercus cyst and the development of perilesional edema that may be of value in understanding the pathogenesis of this entity. Methods: Twenty-one patients with solitary calcified lesion on computed tomography (CT), with seizures of recent onset (within 15 days), were selected for this study. All the patients were subjected to magnetic resonance imaging (MRI) including GRE imaging. The patients were grouped on the basis of presence or absence of perilesional edema around the calcified lesion on MRI. Results: There were 14 patients with perilesional edema, and seven patients had no evidence of edema. Of these 14 patients with perilesional edema, rim enhancement was detected in 13 patients on postcontrast MRI, whereas no enhancement was observed in one patient. The scolex was seen in all these 14 patients on GRE images. Of the seven patients without evidence of edema, the scolex was not seen in any of these patients on GRE imaging. In addition, there was no evidence of any contrast enhancement on postcontrast study in any of the patients in this group. Conclusions: We conclude that the calcified cysts with scolex seen on GRE imaging are associated with perilesional edema. This is probably due to preservation of antigenic material in these calcified cysts, the release of which provokes an inflammatory response that may be responsible for the perilesional edema. Key Words: Calcified cysticercus cyst MRI Edema of brain Infection of brain Seizures. Accepted July 21, Address correspondence and reprint requests to Dr. R. K. Gupta at MR Section, Department of Radiodiagnosis, Sanjay Gandhi Post- Graduate Institute of Medical Sciences, Lucknow , India. rgupta@sgpgi.ac.in : rakeshree@hotmail.com Neurocysticercosis, presenting as single enhancing lesion on computed tomography (CT), or hyperintense lesion on magnetic resonance imaging (MRI), is a common finding in patients with seizures from developing countries (1). The lesion is usually <10 mm, well defined, nodular or ring contrast enhancing, cortical or subcortical, and usually associated with perilesional edema (1 3). The neurocysticercosis has been classified on the basis of imaging and pathologic features and grouped as vesicular, colloid, granulomatous, and calcified (4). The calcified stage is considered the healed stage of the disease and is thought to be quiescent (5,6). Lack of enhancement of this calcified lesion on CT further supports this concept (4,6). It also is reported that the previously treated patients with calcified cysts or the patients who initially have calcified cysts, not infrequently have seizures mimicking active disease (7). Recent reports have briefly mentioned the edema associated with the calcified cysticercus cysts; these also are associated with rim enhancement after contrast administration (7 9). A variety of explanations have been hypothesized for the recurrence of perilesional edema around these calcified cysts (7 9). Conventionally, CT is considered the gold standard for demonstration of calcified lesions (4). Recent studies have demonstrated the ability of phase-corrected GRE imaging in differentiation of the calcification from the chronic hemorrhage that appears similar on conventional MRI (10). By demonstrating the direction of phase shift of the T 2 hypointense lesion with bloom effect on GRE T 2* -weighted imaging, it is possible to have a definite conclusion whether it is a calcified (positive phase or bright signal) or hemorrhagic lesion (negative phase or hypointense signal) (10). In addition, it is known that calcified lesions are known to show enhancement, as lesions appearing calcified on CT are not completely calcified and show areas of noncalcified tissue that enhance on postcontrast MRI and appear partially calcified on histopathology (10,11). Recently it was shown that it is possible to demonstrate the scolex in a calcified cysticercus cyst by using GRE imaging (12). 1502

2 EDEMA AROUND CALCIFIED CYSTICERCUS CYST 1503 We studied patients with single calcified lesions showing perilesional edema with phase-corrected GRE imaging and compared these with the calcified lesions without edema within 15 days of seizure activity to look for the presence of scolex in these patients and to look for any relation between the presence of edema and demonstration of scolex that may help in better understanding the pathophysiology of this entity. METHODS Twenty-one patients with recent seizures and solitary calcified lesions on CT were selected for this study. There were 11 male and 10 female subjects with age ranging between 10 and 38 years. Informed consent was taken from all the patients and/or patient caregivers. The inclusion criteria for the selection of the candidates for this study were the presence of scolex on previous imaging studies, single calcified lesion on CT, and recent (within 15 days) history of seizures. The patients were divided into two groups on the basis of presence or absence of perilesional edema. All calcified lesions were screened for the presence of scolex within the cyst by using a fixed MRI protocol (defined later). Immunologic studies like serum enzyme-linked immunosorbent assay (ELISA) for cysticercus were available in 12 patients and were negative in all the cases, so they were not included in this study for the purpose of correlation. Seven of these patients had perifocal edema, and five had no perifocal edema. History of first episode of seizure, type of seizure, and duration of last seizure before the imaging study were recorded in every patient. Electroencephalography (EEG) was recorded as a part of the workup for seizure disorder by using standard technique. All patients were taking carbamazepine (CBZ), mg/kg/day, divided into three doses. In patients needing an additional antiepileptic drug (AED), clobazam (CLB), mg/kg/day, was given in two divided doses. MRI was performed on a 1.5-T superconducting unit (Magnetom, Siemens, Germany) with a circularly polarized head coil. The head of the individual was fixed with strap to avoid patient motion. Spin echo (SE) proton density (PD), T 2 (TR/TE 1, 2 /n 2,200/22, 80/1) and T 1 (TR/TE/n 1,000/15/2) weighted images were obtained with 5-mm slice thickness, 0.5 mm interslice gap, and matrix size of In addition, phase-corrected GRE images were also obtained with the following experimental parameters (TR/TE 1, 2 /n/flip angle 800/ 15, 35/2/15 ). Pre- and postcontrast magnetization transfer (MT) T 1 -weighted images were also obtained to ensure maximal enhancement after contrast administration. The imaging parameters for the MT T 1 -weighted images were the same as for the T 1 -weighted image, except for the off-resonance pulse applied 1.5 KHz away from the water resonance. Precontrast MT T 1 -weighted image was obtained to differentiate the MT effect from the actual contrast enhancement (13). Gadoliniumdiethylene triaminopentaacetic acid (Gd-DTPA) was injected intravenously in a dose of 0.1 mmol/kg body weight to obtain postcontrast MT T 1 -weighted images. The scolex was considered to be present in a calcified lesion when it was seen as hypointense eccentrically placed dot in a peripherally calcified hypointense rim on GRE T 2* -weighted images. In some cases, the scolex was seen as hypointense in bright (calcified) lesion on phase-corrected GRE images and was considered to be due to the scolex having a high content of paramagnetic substances (12). Statistical analysis The 2 test was used to determine the relation of the edema to the presence of scolex in these two groups of patients with SPSS statistical software, version 10. RESULTS The summary of the results is given in Table 1. The edema around the calcified lesion was present in 14 patients who had seizures within 15 days of its occurrence. Of these 14 patients, rim enhancement was detected in 13 (Fig. 1), whereas no enhancement was observed in one patient (Fig. 2). The scolex could be demonstrated in all the 14 patients on GRE T 2* -weighted images (Figs. 1 and 2) and in five patients on phase-corrected GRE imaging (Fig. 1). Of the seven patients with single calcified lesions and seizures, none showed any evidence of edema on T 2 -weighted images, and there was no evidence of any enhancement on postcontrast study. The scolex could not be demonstrated in all these patients, either on GRE T 2* -weighted images or on phase-corrected GRE imaging (Fig. 3). The difference between these two groups with respect to edema and the presence of a scolex showed a value of the 2 test (continuity correlation) of at p < All these patients were followed up with imaging from 3 to 6 months later while receiving treatment with AEDs to look for the status of edema in those who had edema on initial study and to look for development of edema or a break in blood brain barrier in patients who did not have edema in the initial study. The edema disappeared in all these patients on follow-up MRI with absence of contrast enhancement in all these patients, whereas no change in the initial status was seen in the patients with calcified lesions without edema. All 14 patients with demonstrable scolex had good control of seizures and disappearance of perifocal edema on a follow-up study. Two of these 14 patients had 1 year follow-up with good seizure control and no evidence of edema even on the third study. Four of the seven patients with calcification without scolex had poor control of seizures with a single drug and needed an additional drug for good control of

3 1504 R. K. GUPTA ET AL. Age/Sex Seizure date TABLE 1. Summary of the results MRI date Site Symptom Edema CE Scolex a 25/M 12/9/ /9/2000 RP SPS A N N 28/F 20/12/ /12/2000 RF SPS A N N 28/F 29/3/ /3/2001 LF SPS A N N 28/M 24/7/ /7/2001 LO SPS A N N 24/F 2/2/ /2/2001 LP SPS A N N 19/F 2/3/ /3/2000 LF GTCS A N N 14/M 27/8/2000 5/9/2000 RP SPS GTCS A N N 23/M 18/6/ /6/2001 RP SPS P Y Y 12/F 28/6/2000 7/7/2000 RP GTCS P Y Y 12/F 23/7/ /7/2000 LF GTCS P Y Y 12/F 23/7/2000 3/8/2000 LP GTCS P Y Y 38/F 28/7/2001 9/8/2001 LP SPS P Y Y 17/M 12/9/ /9/2000 RP SPS P Y Y 22/M 26/6/2000 4/7/2000 RP SPS P Y Y 24/F 30/10/2000 7/11/2000 LP SPS P Y Y 25/F 23/9/ /9/2001 RO SPS GTCS P Y Y 15/M 21/7/ /7/2001 RPO GTCS P Y Y 35/M 25/10/2000 3/11/2000 RP SPS P Y Y 23/M 1/5/2001 4/5/2001 LF SPS GTCS P N Y 28/M 18/7/ /7/2000 RP SPS P Y Y 10/M 12/11/ /11/2000 RO SPS P Y Y M, male; F, female; RP, right parietal; LP, left parietal; LO, left occipital; LF, left frontal; RF, right frontal; RO, right occipital; RPO, right parietooccipital; SPS, simple partial seizure; GTCS, generalized tonic clonic seizure; SPS GTCS, simple partial seizure to generalized tonic clonic seizure; A, absent; P, present; CE, contrast enhancement; N, no; Y, yes. a All these patients showed scolex in the initial vesicular/colloid stage of the disease, irrespective of its visibility at the time performance of this study. seizure activity. Topographic location of the calcified lesion correlated with the seizure type and is summarized in Table 2. DISCUSSION Calcification of the cysticercus cyst is considered the last stage of the disease and is considered innocuous (5,6). Recently edema associated with multiple calcified neurocysticercosis was described in a few individuals (7 9). The reports suggest that the calcified lesions are not dead parasites, as these incite perifocal inflammation and edema formation (8). All these cases showed rim enhancement after contrast administration, suggesting that these calcified cysts with edema are associated with a break in the blood brain barrier (8). In the present study, 13 of the 14 patients with perifocal edema showed rim enhancement when seen within 2 weeks of the last seizure, whereas none of the seven patients with calcified lesion with no edema had rim enhancement in the same time frame. This suggests that in addition to the seizure activity, perilesional inflammatory reactions also may contribute to the break in the blood brain barrier shown as enhancement on postcontrast MRI study. However, lack of enhancement in a case of calcified cyst with edema in one patient was surprising and may suggest that locally produced immunoallergic response and edema may not always be severe enough to demonstrate a break in the blood brain barrier on MRI. Pathological information on the lesion showing calcification on CT is very scanty in the English literature. Chung et al. (14) recently reported the histopathology in a CT-demonstrable calcified cysticercus cyst and found partial calcification of the scolex and the bladder wall of the parasite on microscopy. We also showed partial calcification in the bladder wall and the scolex on histopathology in a CT-demonstrable dense calcified cyst of the swine muscle (12). It also is known that the staging in the neurocysticercosis may not follow the protocol of sequential degeneration and then calcification and may bypass the stage of degeneration (1,15). Conversely, degenerating cyst may not undergo complete degradation and may undergo calcification from this early stage (1). In a calcified lesion, we may see calcified scolex or may see a degraded parasite with no clear definition of the scolex and the bladder wall of the cyst. Demonstration of the scolex in a calcified lesion suggests that parasite did not undergo complete degradation and preserved its antigenic components. We recently showed that it is possible to demonstrate scolex in a CT calcified cyst by using the phasecorrected GRE imaging technique (12). This is because the lesion, shown as calcified on CT, has protons present in it and can be separated with the help of MRI. Any lesion with Hounsfield value of >80 is considered calcification irrespective of the type of mineral present in the lesion (16). It is possible to separate the diamagnetic (calcification) material from paramagnetic material on

4 EDEMA AROUND CALCIFIED CYSTICERCUS CYST 1505 FIG. 1. Scolex in a calcified cyst with edema and rim enhancement. T 2 (a), T 1 (b), and precontrast MT T 1 (c) weighted images through the supraventricular region show a hypointense lesion with perifocal edema in the right frontal region on (a). It appears hypointense on T 1 (b) and MT T 1 -weighted images (c). Note the hyperintense rim around the hypointense lesion that shows enhancement after contrast administration (d). T 2* -weighted image (e) shows eccentrically placed scolex with a hypointense wall and shows bloom effect along with perifocal edema. The corresponding phase-corrected GRE image (f) shows the bright lesion (calcified) with eccentrically placed hypointense scolex. The repeated study 6 weeks later shows disappearance of edema on T 2 -weighted image (g) with no rim enhancement around the lesion (h). The plain computed tomography shows the lesion as calcified (i). the basis of the phase shift on phase imaging (12). We also showed that the CT calcified scolex initially contains a large amount of paramagnetic substance and gives a negative phase, and when it degenerates, it tends to demineralize and then calcifies again (12). This inflammation probably results in removal of the paramagnetic substances, and when this cyst recalcifies as a dystrophic calcification, it contains only diamagnetic substance and

5 1506 R. K. GUPTA ET AL. FIG. 2. Scolex containing calcified cyst with perifocal edema and no enhancement on postcontrast study. T 2 -weighted axial image (a) shows a hypointense lesion in the left frontal region with perifocal edema. Corresponding T 1 - (b) and MT T 1 -weighted (c) images show the lesion as merging with hypointense perifocal edema. Postcontrast MT T 1 -weighted image (d) does not show any enhancement. T 2* -weighted image (e) shows hypointense rim with eccentrically placed mural nodule consistent with scolex. Corresponding corrected phase image (f) shows bright signal consistent with the calcification. merges with the cyst wall calcification on phase images. It appears that the scolex with a negative phase in a calcified cyst suggests a vesicular cyst completely calcified without undergoing degeneration, whereas the scolex with a positive phase suggests that this cyst has undergone some degeneration with preservation of the scolex. In the present series, we observed that all the 14 patients showing perilesional edema demonstrated a scolex (phase negative five, and phase positive nine), whereas the calcified lesions without edema have not shown a scolex in any of the seven patients. It suggests that there is a relation between the development of edema and presence of a scolex in a calcified cyst. A number of reasons have been considered to explain the perilesional edema around the calcified lesion. One of the possible explanations considered by Nash and Patronas (8) is the host inflammatory response provoked by the antigen released by the calcified lesion. Conversely, they believe that all the calcified cysts do not produce edema, which is why some calcified cysts generate perilesional edema (8). The intensity of the host inflammatory reaction to the parasite is highly variable; some show remarkable tolerance to the parasite with minimal or no inflammation, but others develop an intense reaction and edema. What triggers this antigenic response is not well understood (1). The antigen recognized by the human immune system is maximally located on the external surface of tegument of the bladder wall and least on the scolex (17,18). It has also been shown that an adrenocorticotropic hormone (ACTH)-like substance is present on the interface of the host and the parasite and acts as the protector of the inflammatory response. The inflammatory response associated with disruption of this ACTH coating results in degeneration of the parasite. With the beginning of the cyst degeneration, the antigen is sequestered in the granulomatous reaction and becomes an antigenic reservoir. Subsequently there is a depletion of the antigenic reservoir, shown as a lack of immunostaining along the surface of the tegmentum (17). We believe that the calcified cysts containing a

6 EDEMA AROUND CALCIFIED CYSTICERCUS CYST 1507 FIG. 3. Calcified lesion without demonstrable perifocal edema, enhancement, and scolex. T 2 -weighted image (a) shows hypointense lesion in the left parietal region with no perifocal edema. Corresponding T 1 - (b) and MT T 1 (c) -weighted images show the lesion as hypointense compared with the white matter. Postcontrast MT T 1 -weighted image (d) does not show any enhancement. Corresponding T 2* (e) image shows bloom effect with no scolex. On corrected-phase GRE image (f), the lesion appears bright and is consistent with calcification. scolex are the ones that have their antigenicity intact and are able to release the antigen into the surrounding parenchyma, resulting in perilesional inflammation and edema. Those without a scolex, though, produce seizures but do not produce edema, as those are the real dead and innocuous parasite with respect to eliciting inflammatory response, as they are devoid of the scolex and the antigenic reserve. These lesions have been destroyed during the process of inflammation and are calcified as a part of the natural history of the disease. Immunologic tests like ELISA and immunoblot have been shown to be sensitive and specific for neurocysticercosis. However, the sensitivity is very low in a single small enhancing cysticercus lesion and varies from <10 to 28% (19,20). Rajshekhar et TABLE 2. Relation between type of seizure and localization of calcifications Types of seizures Parietal (n 12) Lobe involvement Frontal (n 5) Occipital (n 3) Parietooccipital (n 1) Simple partial seizures (n 12) Sensory 8 1 a Motor 1 2 Generalized seizure (n 6) Partial seizures, secondarily generalized (n 3) Partial sensory, GTCS 1 1 a Partial motor, GTCS 1 a These patients had complex visual phenomena at the onset. GTCS, generalized tonic clonic seizure.

7 1508 R. K. GUPTA ET AL. al. (21) performed immunoblot in 18 enhancing cysticercus granulomas and five healed lesions and found it to be positive in one in the former and none in the later group. One of the reasons reported for the low sensitivity of these tests in single enhancing lesion is the poor systemic immune response, resulting in the threshold required to detect these antibodies (21). We did not find positive serum ELISA cysticercus antibodies in any of the 12 patients with and without edema. It has been observed that the calcified lesions are the poor prognostic indicator of seizure recurrence after the discontinuation of AEDs (7,9). It also was mentioned that ring enhancement around the lesion is associated with increased seizure activity (4). We believe that a break in blood brain barrier, as suggested by the rim enhancement, is associated with perilesional inflammation and is not related to increased seizure activity. All the nonenhancing lesions in the present study showed seizure activity in patients with a single calcified lesion. We conclude that the calcified cysts that demonstrate scolex on GRE imaging are responsible for perilesional edema. This is due to the retention of complete antigenic reserve in these lesions, which cause the release of antigen and incite inflammatory response and are responsible for the development of edema. Acknowledgment: This work was supported by the grant from Department of Science and Technology, New Delhi, India (DST NO. SP/SO/B-45/97). Sanjeev Chawla acknowledges the financial assistance from Council of Scientific and Industrial Research, New Delhi, India. REFERENCES 1. Carpio A, Escobar A, Hauser WA. Cysticercosis and epilepsy: a critical review. Epilepsia 1998;39: Mervis B, Lotz JW. Computed tomography (CT) in parenchymatous cerebral cysticercosis. Clin Radiol 1980;31: Carpio A, Placencia M, Santillan F, et al. Proposal for a new classification of neurocysticercosis. Can J Neurol Sci 1994;21: Sheth TN, Pilon L, Keystone J, et al. Persistent MR contrast enhancement of calcified neurocysticercosis lesions. AJNR Am J Neuroradiol 1998;19: Kramer LD, Locke GE, Byrd SE, et al. Cerebral cysticercosis: documentation of natural history with CT. Radiology 1989;171: Park SY, Barkovich AJ, Weintrub PS. Clinical implications of calcified lesions of neurocysticercosis. Pediatr Infect Dis J 2000; 19: Del Brutto OH. Prognostic factors for seizure recurrence after withdrawal of antiepileptic drugs in patients with neurocysticercosis. Neurology 1994;44: Nash TE, Patronas NJ. Edema associated with calcified lesions in neurocysticercosis. Neurology 1999;53: Garg RK, Karak B, Kar AM. Neuroimaging abnormalities in Indian patients with uncontrolled partial seizures. Seizure 1998;7: Gupta RK, Rao SB, Jain R, et al. Differentiation of calcification from chronic hemorrhage with corrected gradient echo phase imaging. J Comput Assist Tomogr 2001;25: Tsuchiya K, Makita K, Furui S, et al. MRI appearances of calcified regions within intracranial tumors. Neuroradiology 1993;35: Chawla S, Gupta RK, Kumar R, et al. Demonstration of scolex in calcified cysticercus lesion using gradient echo with or without corrected phase imaging and its clinical implications. Clin Radiol 2002;57: Meyer JR, Androux RW, Salamon N, et al. Contrast-enhanced magnetization transfer imaging of the brain: importance of precontrast images. AJNR Am J Neuroradiol 1997;18: Chung CK, Lee SK, Chi JG. Temporal lobe epilepsy caused by intrahippocampal calcified cysticercus: a case report. J Korean Med Sci 1998;13: Pitella JEH. Neurocysticercosis. Brain Pathol 1997;7: Minguetti G, Ferreira MVC. Computed tomography in neurocysticercosis. J Neurol Neurosurg Psychiatry 1983;46: Shankar SK, Suryanarayana V, Vasantha S, et al. Biology of neurocysticercosis-parasite related factors modulating host response. Med J Armed Forces India 1994;50: Vasantha S, Ravi Kumar BV, Roopashree SD, et al. Neuroanatomy of cysticercus cellulosae (Cestoda) as revealed by acetylcholinesterase and nonspecific esterase histochemistry. Parasitol Res 1992; 78: Wilson M, Bryan RT, Fried JA, et al. Clinical evaluation of the cysticercosis enzyme-linked immunoelectrotransfer blot in patients with cysticercosis. J Infect Dis 1991;164: Garcia HH, Martinez M, Gilman R, et al. Diagnosis of cysticercosis in endemic regions; The Cysticercosis working group in Peru. Lancet 1991;338: Rajshekhar V, Wilson M, Schantz PM. Cysticercus immunoblot assay in Indian patients with single small enhancing CT lesions. J Neurol Neurosurg Psychiatry 1991;54:561 2.