- Email: [email protected]
Clinical and neuroimaging predictors of seizure recurrence in solitary calcified neurocysticercosis: A prospective observational study
Epilepsy Research 137 (2017) 78–83
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Clinical and neuroimaging predictors of seizure recurrence in solitary calcified neurocysticercosis: A prospective observational study
MARK
⁎
Alok Kumar Singha, Ravindra Kumar Garga, , Imran Rizvia, Hardeep Singh Malhotraa, Neeraj Kumara, Rakesh Kumar Guptab a b
Department of Neurology, King George Medical University, Uttar Pradesh, Lucknow, India Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, India
A R T I C L E I N F O
A B S T R A C T
Keywords: Solitary calcified neurocysticercosis Perilesional edema Scolex Seizure recurrence Antiepileptic drugs
Background: Solitary calcified neurocysticercosis is a common cause of seizures in the developing countries. Factors responsible for seizure recurrence in patients with solitary calcified neurocysticercosis are not known. We evaluated the clinical, neuroimaging and biochemical predictors of seizure recurrence. Methods: This was a prospective observational study. Patients with new-onset seizures and a solitary calcified neurocysticercosis were included. Patients were evaluated clinically; baseline electroencephalography and magnetic resonance imaging of brain were done for all patients.. The patients were followed for 1 year. Seizure recurrence was defined as the recurrence of an episode of seizure at least 1 week after the initiation of the antiepileptic drugs. Results: Fifty-four patients with a mean age of 20.43 ± 7.34 years were included. Thirteen patients developed seizure recurrence during the follow-up period. On univariate analysis, status epilepticus at presentation (p = 0.025), size of the lesion > 10 mm (p = 0.015), presence of perilesional edema (p < 0.001) and scolex (p = 0.033) were significantly associated with seizure recurrence. On multivariate analysis, only presence of perilesional edema (p = 0.018, odds ratio = 12.122, 95% confidence interval 1.521–96.639) was an independent predictor of seizure recurrence. Conclusion: Status epilepticus at presentation is associated with an increased risk of seizure recurrence. Neuroimaging features like presence of perilesional edema and scolex can similarly predict seizure recurrence. These neuroimaging features can serve as potential surrogate markers to define therapy in these patients. The findings of our study might be helpful in stratifying patients with a higher risk of seizure recurrence, especially those who may require a more aggressive management.
1. Introduction Neurocysticercosis is caused by the larval stage of the pork tapeworm Taenia solium. Neurocysticercosis is the major cause of seizures in most of the developing countries (Garcia et al., 2014). Calcified neurocysticercosis granuloma represents the final result of host immune response to the larval cysticercus of Taenia solium (Nash et al., 2004). Previously, calcified neurocysticercosis was considered to be inert but recent evidence suggests the role of calcified neurocysticercosis in the epileptogenesis (Nash et al., 2004). The role of calcified neurocysticercosis in epileptogenesis is further stressed by the presence of perilesional edema in about one-third of patients (Nash et al., 2001). Another evidence of activity of calcified neurocysticercosis is the demonstration of scolex in some of these lesions (Gupta et al., 2002). Patients of calcified neurocysticercosis who present with seizures are ⁎
treated using antiepileptic drugs which are arbitrarily withdrawn after 2 years if the patient remains seizure free. Recent studies have shown that calcified neurocysticercosis is a potential cause of antiepileptic drug resistant epilepsy (Rathore et al., 2013). A seizure recurrence rate of about 34% was seen during a 6 month follow up period in patients of solitary calcified neurocysticercosis (Sharma et al., 2013). The factors that can predict seizure recurrence in patients of calcified neurocysticercosis are not well understood. Previous studies have shown that the presence of perilesional edema around a calcified lesion is associated with seizure recurrence (Lachuriya et al., 2016; Nash et al., 2008). Blood-brain barrier disruption around the lesion leading to neuroinflammation might be involved in the seizure recurrence. Other features like presentation with status epilepticus or serial seizures and larger size of the lesion have also been implicated in seizure recurrence in these patients (Sharma et al., 2013; Lachuriya et al., 2016).
Corresponding author at: Department of Neurology, King George Medical University, Uttar Pradesh, Lucknow 226003, India. E-mail address: [email protected] (R.K. Garg).
http://dx.doi.org/10.1016/j.eplepsyres.2017.09.010 Received 17 March 2017; Received in revised form 31 May 2017; Accepted 16 September 2017 Available online 20 September 2017 0920-1211/ © 2017 Elsevier B.V. All rights reserved.
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 1. Flow diagram of the study.
In this study, we aimed to study the relevance of various clinical and neuroimaging features to predict the seizure recurrence in solitary calcified neurocysticercosis patients. The findings of this study might help in identifying patients with a higher risk of seizure recurrence who might require a more aggressive approach towards management.
resonance imaging, calcified neurocysticercosis appeared isointense or hypointense on T1 weighted images and hypointense on T2 weighted images. T2* star weighted angiography (SWAN) was used for confirming the presence of calcification; calcified lesion appeared hypointense on SWAN sequence.
2. Material and methods
2.3. Exclusion criteria
2.1. Study design and settings
Patients with neuroimaging suggestive of different stages of neurocysticercosis or patients with multiple lesions on neuroimaging were excluded from the study. Patients with clinical and neuroimaging features suggestive of an alternative diagnosis were also excluded from the study.
This was a prospective observational study conducted at a tertiary care centre; the institute is located in northern India and caters to a population of about 100 million. The study participants were enrolled between January 2013 to January 2015. A written informed consent was obtained from every subject before enrolling them for the study. The study was approved by the institutional ethical committee. The flow diagram of the study is shown in Fig. 1.
2.4. Evaluation All included patients underwent detailed clinical history, with general and neurological examination. History regarding semiology of seizure, duration of seizure, impairment of consciousness, post ictal focal deficits, dietary habits and residence was recorded from every patient. International League Against Epilepsy guidelines on the classification and terminology of ictal events was followed (Blume et al., 2001). Routine haematological and biochemical investigations including complete blood count, blood sugar, renal and liver function tests and serum electrolytes, were done in every patient. Serological evaluation for neurocysticercosis was not performed as it has a low sensitivity and specificity in the diagnosis of calcified neurocysticercosis and its utility in endemic zones is doubtful.
2.2. Inclusion criteria Diagnosis of neurocysticercosis was made on the basis of presence of punctate round calcified parenchymal lesions in patients belonging to endemic zone, presenting with seizures (Del Brutto et al., 2001). Patients of solitary calcified neurocysticercosis presenting with new onset seizure (within 15 days of first-ever seizure) were enrolled in the study. Diagnosis of solitary calcified neurocysticercosis was made on the basis of computed tomography scan of brain which was further confirmed by magnetic resonance imaging. On conventional magnetic 79
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
was used as an add-on drug in those with seizure recurrence. Drug compliance was ensured in each and every patient. Steroids or anticysticidal treatment was not given.
Table 1 Baseline clinical, demographic and neuroimaging characteristics of 54 solitary calcified neurocysticercosis patients. S.No
Variable
1.
Age in years Mean ± SD Males (%) Rural (%) Urban (%) Non-vegetarian (%) Seizure semiology Generalized (%) Focal (%) Status epilepticus at presentation (%) Todd's palsy (%) Headache (%) Location of lesion Frontal Parietal Temporal Occipital Size of the lesion > 10 mm (%) Perilesional edema Contrast enhancement Scolex EEG abnormal
Value
2.7. Follow up 2. 3. 4. 5.
6. 7. 8. 9.
10. 11. 12. 13. 14.
20.43 ± 7.342 26 (48.1%) 33 (61.1%) 21 (38.9%) 34 (63%)
All the study participants were followed for a period of 1 year for any seizure recurrence. Patients visited the neurology outpatient department for follow-up at 3 monthly intervals. Follow-up data was also recorded from visits resulting from breakthrough seizures. Seizure recurrence was defined as the recurrence of an episode of seizure at least 1 week after the initiation of the antiepileptic drugs.
33 (61.1%) 21 (38.9%) 6 (11.1%) 5 (9.3%) 23 (42.6%)
2.8. Statistical analysis Statistical analysis was done using SPSS version16.0 (Chicago, IL, USA). The categorical variables were expressed as percentages and the continuous variables were expressed as mean ± standard deviation. The categorical variables were compared using Chi-square test or Fisher exact test, as applicable. The means were compared using the independent sample t-test. Kaplan-Meyer survival analyses using the logrank test was used to estimate the event-free survival. Binary logistic regression was applied to look for the variables independently associated with the outcome. For the purpose of binary logistic regression seizure recurrence was taken as the dependent variable and all variables found to be significant on univariate analysis were taken as independent variables. All the p values < 0.05 were taken as significant.
26 (48.15%) 13 (24.07%) 5 (9.26%) 10 (18.53%) 8 (14.8%) 11 (20.4%) 23 (42.6%) 13 (24.1%) 4 (7.4%)
SD = Standard deviation, EEG = Electroencephalogram
Electroencephalography was also performed on all included patients. Electroencephalography was done on a 21-channel machine; the 10–20 system of electrode placement was followed. Electroencephalogram was classified as either “Normal” or “Abnormal”. Electroencephalogram was considered abnormal if an epileptiform activity was seen, which was defined as the presence of any of the following discharges: spikes, spike-wave, sharp waves, sharp-slow wave, and poly-spike waves. All patient underwent a plain computed tomography scan of the cranium which was followed by the magnetic resonance imaging of the brain. The neuroimaging protocol is described in the subsequent sections.
3. Results We initially included 59 consecutive patients with new onset seizure and a single calcified neurocysticercosis on the plain computed tomography of head; 5 were excluded after performing magnetic resonance imaging due to reasons provided in the Fig. 1. Hence, 54 patients were finally evaluated. 3.1. Baseline characteristics
2.5. Neuroimaging The baseline demographic, clinical and neuroimaging characteristics of 54 solitary calcified neurocysticercosis patients are shown in Table 1. The mean age of the patients was 20.43 ± 7.34 years (range 8–41 years). Twenty-six (48.1%) patients were males. Thirty-three (61.1%) patients were resident of rural areas. Thirty-four (63.0%) patients were non-vegetarian. On magnetic resonance imaging, perilesional edema was seen in 11 (20.4%) lesions; contrast enhancement was seen in 23 (42.6%) lesions and a scolex was demonstrable in 13 (24.1%) lesions. Four (7.4%) patients had an abnormal electroencephalogram at baseline (Table 1).
A Gadolinium-enhanced magnetic resonance imaging was performed in all cases. A 3 Tesla Signa HDxt magnetic resonance imaging scanner (GE Healthcare, Milwaukee, Wisconsin) using a 12-channel head coil was utilized for all imaging protocols. T1 weighted fast spin echo, T2 weighted fast spin echo, fluid attenuation inversion recovery (FLAIR), diffusion weighted imaging (DWI) and post contrast sequences were acquired in every patient. We also acquired images using the SWAN sequence (T2* weighted angiography; GE Healthcare) with a TE of 25 ms, a TR of 47 ms, flip angle of 15°, section thickness of 2.4 mm, acquisition matrix of 320 × 224, and a Field of view (FOV) of 240 × 240 mm2 to ensure that the lesion was calcified and solitary. Computed tomography and magnetic resonance imaging were interpreted by an expert radiologist. Location of lesion, size of lesion, presence of perilesional edema, contrast enhancement and presence of scolex were the various imaging features studied. The “scolex” was considered to be present in a calcified lesion if there was a hypointense eccentrically placed dot in a peripherally calcified hypointense rim on T2* weighted image (SWAN) (Gupta et al., 2002). “Perilesional edema” on magnetic resonance imaging was defined as the presence of a distinct perilesional hyperintensity on T2 and FLAIR images surrounding the calcified lesion.
3.2. Predictors of seizure recurrence on univariate analysis During the follow-up period of 1 year, 13 patients developed seizure recurrence. The mean time of seizure recurrence was 93.85 ± 58.67 days (range 30–240 days, median 90 days). On univariate analysis, status epilepticus at presentation (p = 0.025, odds ratio = 8.677, 95% confidence interval 1.369–54.879) was the only clinical variable that was associated with seizure recurrence. Amongst the neuroimaging variables size of the lesion > 10 mm (p = 0.015, odds ratio = 7.917, 95% confidence interval 1.564–40.073), presence of perilesional edema (p < 0.001, odds ratio 20.267, 95% confidence interval 4.004–102.588) and the presence of scolex (p = 0.033, odds ratio = 4.163, 95% confidence interval 1.068–16.228) were found to be significantly associated with seizure recurrence during follow-up. Contrast enhancement was seen more frequently in patients with seizure recurrence (61.5%) (p = 0.113).
2.6. Treatment Oxcarbazepine in a dose of 15 mg/kg body weight in two divided doses was used as the first line antiepileptic drug in all the study participants. Clobazam in a dose of 20–40 mg/day in two divided doses 80
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 2. (A & B) Images from a patient with seizure recurrence, showing perilesional edema around the calcified lesion in T2 image (A) SWAN image showing calcified granuloma, inset showing eccentric nodule suggestive of scolex within the lesion (B). (C & D) T2 and SWAN images from a patient with no recurrence of seizures, there is no evidence of edema or scolex in these images.
Kaplan–Meyer analysis revealed that there was a significant difference in the time to event (occurrence of seizure) when the patients were categorized according to the presence or absence of perilesional edema (Log rank test p < 0.001). There was a significantly higher seizure
Fig. 2. An abnormal electroencephalogram at baseline (p = 0.039, odds ratio = 12.00, 95% confidence interval 1.125–127.969) was also significantly associated with seizure recurrence during follow-up. Table 2
Table 2 Distribution of clinical, neuroimaging and biochemical parameters in patients with or without seizure recurrence (univariate analysis). Variables Age in years Mean ± SD Males (%) Rural (%) Non-vegetarian (%) Seizure semiology (generalized) Status epilepticus at presentation Todd's palsy Headache Location of lesion Frontal Parietal Temporal Occipital Size of the lesion > 10 mm Perilesional edema Contrast enhancement Scolex EEG abnormal
Seizure recurrence N = 13
No recurrence N = 41
P value
Odds ratio (95% CI)
22.92 ± 6.861 9 (69.2%) 6 (46.2%) 8 (61.5%) 9 (69.2%) 4 (30.8%) 3 (23.1%) 6 (46.2%)
19.63 ± 7.392 17 (41.5%) 27 (65.9%) 26 (63.4%) 24 (58.5%) 2 (4.9%) 2 (4.9) 17 (41.5%)
0.161 0.114 0.204 0.903 0.491 0.025 0.084 0.766
Mean difference 3.289 (−1.356 to 7.934) 3.176 (0.839–12.030) 0.444 (0.125–1.578) 0.923 (0.255–3.338) 1.594 (0.421–6.036) 8.667 (1.369–54.879) 5.850 (0.858–39.876) 1.210 (0.345–4.245)
6 4 1 2 5 8 8 6 3
20 (48.78%) 9 (21.95%) 4 (9.76%) 8 (19.51%) 3 (7.3%) 3 (7.3%) 15 (36.6%) 7 (17.1%) 1 (2.4%)
0.925
NA
0.015 < 0.001 0.113 0.033 0.039
7.917 (1.564–40.073) 20.267 (4.004–102.588) 2.773 (0.767–10.029) 4.163 (1.068–16.228) 12.00 (1.125–127.969)
(46.15%) (30.77%) (7.69%) (15.38%) (38.5%) (61.5%) (61.5%) (46.2%) (23.1%)
SD = Standard deviation, EEG = Electroencephalogram.
81
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 3. Kaplan-Meyer analysis of seizure recurrence (cumulative hazard) according to presence or absence of perilesional edema, depicting a significantly higher rate of seizure recurrence in patients with perilesional edema.
Leon et al., 2015). However, the factors responsible for seizure recurrence or the predictors of seizure recurrence in these patients have not been well described in the literature. We found that the occurrence of status epilepticus at presentation was a clinical variable significantly associated with seizure recurrence. Previous studies have also found that occurrence of serial seizures, status epilepticus and Todd's palsy are associated with seizure recurrence (Sharma et al., 2013; Lachuriya et al., 2016). An abnormal EEG at presentation was also one of the predictors of seizure recurrence in our study, this finding was also consistent with the previously reported findings (Sharma et al., 2013; Lachuriya et al., 2016). Neuroimaging findings like presence of perilesional edema, demonstration of scolex, and larger size of the lesion were found to be associated with seizure recurrence in our study. Edema surrounding a calcified lesion has been implicated as a cause of seizure recurrence in previous studies also (Nash et al., 2008). Demonstration of edema around calcified lesions is contrary to the previous belief that these lesions are inert. The perilesional edema most likely represents hosts response to newly released parasitic antigens (Nash, 2012). The occurrence of edema around the calcified lesions was first noticed by Del Brutto in as early as the year 1994 (Del Brutto, 1994). Nash and coworkers in the year 1999 described the possible role of perilesional edema in seizure recurrence (Nash and Patronas, 1999). Nash and coworkers further carried out a nested case control study and demonstrated that perilesional edema was significantly associated with seizure recurrence (Nash et al., 2008). These findings suggested that perilesional edema can be a potential target of treatment in these patients using anti-inflammatory agents like corticosteroids (Marin and Preux, 2008). Randomized controlled trials, however, are awaited in this regard. Gupta and co-workers have demonstrated the presence of scolex in calcified neurocysticercosis lesion using T2* weighted imaging. They
recurrence rate in patients with perilesional edema as shown in Fig. 3. 3.3. Predictors of seizure recurrence on multivariate analysis On binary logistic regression, presence of perilesional edema (p = 0.018, odds ratio = 12.122, 95% confidence interval 1.521–96.639) was the only factor found to be independently associated with seizure recurrence Table 3. 4. Discussion In this prospective observation study, we found that about 24.07% (13/54) patients with solitary calcified neurocysticercosis developed seizure recurrence during 1 year follow-up. The recurrence of seizures or poor seizure control was associated with several clinical, and imaging features. The frequency of recurrence of seizure or poor response to antiepileptic drugs have been reported previously in patients of calcified neurocysticercosis (Sharma et al., 2013; Lachuriya et al., 2016; Table 3 Multivariate analysis using binary logistic regression for independent predictors of seizure recurrence. Variable
Status epilepticus Size of lesion > 10 mm Perilesional edema Scolex Abnormal EEG
P value
0.654 0.219 0.018 0.104 0.077
Odds ratio
0.482 0.376 12.122 4.623 12.462
95% confidence interval Lower
Upper
0.020 0. 376 1.521 0. 729 0.760
11.695 71.249 96.639 29.304 204.397
EEG = electroencephalogram.
82
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Delhi, India for financial support (Grant No. 3/1/2/28/Neuro/2012NCD- I).
showed that the presence of scolex was also associated with presence of perilesional edema in these patients (Gupta et al., 2002). Gupta and coworkers therefore concluded that calcified cysts with scolex have antigenic material preserved within them which is responsible for the presence of perilesional edema (Gupta et al., 2002). We similarly found that lesions with demonstrable scolex were more commonly associated with seizure recurrences thus suggesting that these lesions might be more antigenic or active. We also found that lesions of size > 10 mm were associated with seizure recurrence on univariate analysis, however no such association was found on multivariate analysis. The calcifications of neurocysticercosis are commonly < 10 mm (Del Brutto et al., 2001). We found few lesions > 10 mm in our study; larger lesions were also reported in previous studies done in our setup (Lachuriya et al., 2016). Some older studies have classified calcified neurocysticercosis as an “inactive” stage (Sotelo et al., 1985; Bittencourt et al., 1990; Carpio et al., 1994), which can wrongly convey the message that these patients do not require active management. Our findings highlight the notion that calcified neurocysticercosis is not an inert or an inactive stage, rather it is an active stage with associated inflammation and an inherent risk to cause seizure recurrence. Our study had a limitation that we did not repeat the neuroimaging at the time of seizure recurrence, which might have defined the temporal course and possibly provided a further insight into the epileptogenesis of these lesions. An additional sequence in the form of magnetic transfer spin echo T1-weighted could have been performed to better the identification of patients with perilesional gliosis which can be an independent factor (Pradhan et al., 2000). Sample size of our study was not very large and repeating these observations in a larger population over a longer period may help to bring more clarity to issues associated with perilesional edema surrounding a calcified lesion. Thus, we conclude that clinical variables like status epilepticus, and neuroimaging variables like presence of surrounding edema and scolex can be useful in identifying patients with higher risk of seizure recurrence. These patients may require more close follow-up or more aggressive therapy in the form of anti-inflammatory agents to prevent the same.
References Bittencourt, P.R., Costa, A.J., Oliveira, T.V., Gracia, C.M., Gorz, A.M., Mazer, S., 1990. Clinical, radiological and cerebrospinal fluid presentation of neurocysticercosis: a prospective study. Arq. Neuropsiquiatr. 48, 286–295. Blume, W.T., Lüders, H.O., Mizrahi, E., et al., 2001. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 42, 1212–1218. Carpio, A., Placencia, M., Santillán, F., Escobar, A., 1994. A proposal for classification of neurocysticercosis. Can. J. Neurol. Sci. 21, 43–47. Del Brutto, O.H., Rajshekhar, V., White, A.C., et al., 2001. Proposed diagnostic criteria for neurocysticercosis. Neurology 57, 177–183. Del Brutto, O.H., 1994. Prognostic factors for seizure recurrence after withdrawal of antiepileptic drugs in patients with neurocysticercosis. Neurology 44, 1706–1709. Garcia, H.H., Nash, T.E., Del Brutto, O.H., 2014. Clinical symptoms, diagnosis, and treatment of neurocysticercosis. Lancet Neurol. 13, 1202–1215. Gupta, R.K., Kumar, R., Chawla, S., Pradhan, S., 2002. Demonstration of scolex within calcified cysticercus cyst: its possible role in the pathogenesis of perilesional edema. Epilepsia 43, 1502–1508. Lachuriya, G., Garg, R.K., Jain, A., et al., 2016. Toll-like receptor-4 polymorphisms and serum matrix metalloproteinase-9 in newly diagnosed patients with calcified neurocysticercosis and seizures. Medicine (Baltimore) 95, e3288. Leon, A., Saito, E.K., Mehta, B., McMurtray, A.M., 2015. Calcified parenchymal central nervous system cysticercosis and clinical outcomes in epilepsy. Epilepsy Behav. 43, 77–80. Marin, B., Preux, P.M., 2008. Perilesional brain oedema in calcific neurocysticercosis: a target to prevent seizure recurrence. Lancet Neurol. 7, 1075–1076. Nash, T.E., Patronas, N.J., 1999. Edema associated with calcified lesions in neurocysticercosis. Neurology 53, 777–781. Nash, T.E., Pretell, J., Garcia, H.H., 2001. Calcified cysticerci provoke perilesional edema and seizures. Clin. Infect. Dis. 33, 1649–1653. Nash, T.E., Del Brutto, O.H., Butman, J.A., et al., 2004. Calcific neurocysticercosis and epileptogenesis. Neurology 62, 1934–1938. Nash, T.E., Pretell, E.J., Lescano, A.G., et al., 2008. Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case–control study. Lancet Neurol. 7, 1099–1105. Nash, T., 2012. Edema surrounding calcified intracranial cysticerci: clinical manifestations, natural history, and treatment. Pathog. Glob. Health 106, 275–279. Pradhan, S., Kathuria, M.K., Gupta, R.K., 2000. Perilesional gliosis and seizure outcome: a study based on magnetization transfer magnetic resonance imaging in patients with neurocysticercosis. Ann. Neurol. 48, 181–187. Rathore, C., Thomas, B., Kesavadas, C., Abraham, M., Radhakrishnan, K., 2013. Calcified neurocysticercosis lesions and antiepileptic drug-resistant epilepsy: a surgically remediable syndrome? Epilepsia 54, 1815–1822. Sharma, L.N., Garg, R.K., Verma, R., Singh, M.K., Malhotra, H.S., 2013. Seizure recurrence in patients with solitary cystic granuloma or single parenchymal cerebral calcification: a comparative evaluation. Seizure 22, 840–845. Sotelo, J., Guerrero, V., Rubio, F., 1985. Neurocysticercosis: a new classification based on active and inactive forms. A study of 753 cases. Arch. Intern. Med. 145, 442–445.
Conflict of interest The authors declare that they have no conflict of interest. Acknowledgment We acknowledge the Indian Council of Medical Research, New
83
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Clinical and neuroimaging predictors of seizure recurrence in solitary calcified neurocysticercosis: A prospective observational study
MARK
⁎
Alok Kumar Singha, Ravindra Kumar Garga, , Imran Rizvia, Hardeep Singh Malhotraa, Neeraj Kumara, Rakesh Kumar Guptab a b
Department of Neurology, King George Medical University, Uttar Pradesh, Lucknow, India Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, India
A R T I C L E I N F O
A B S T R A C T
Keywords: Solitary calcified neurocysticercosis Perilesional edema Scolex Seizure recurrence Antiepileptic drugs
Background: Solitary calcified neurocysticercosis is a common cause of seizures in the developing countries. Factors responsible for seizure recurrence in patients with solitary calcified neurocysticercosis are not known. We evaluated the clinical, neuroimaging and biochemical predictors of seizure recurrence. Methods: This was a prospective observational study. Patients with new-onset seizures and a solitary calcified neurocysticercosis were included. Patients were evaluated clinically; baseline electroencephalography and magnetic resonance imaging of brain were done for all patients.. The patients were followed for 1 year. Seizure recurrence was defined as the recurrence of an episode of seizure at least 1 week after the initiation of the antiepileptic drugs. Results: Fifty-four patients with a mean age of 20.43 ± 7.34 years were included. Thirteen patients developed seizure recurrence during the follow-up period. On univariate analysis, status epilepticus at presentation (p = 0.025), size of the lesion > 10 mm (p = 0.015), presence of perilesional edema (p < 0.001) and scolex (p = 0.033) were significantly associated with seizure recurrence. On multivariate analysis, only presence of perilesional edema (p = 0.018, odds ratio = 12.122, 95% confidence interval 1.521–96.639) was an independent predictor of seizure recurrence. Conclusion: Status epilepticus at presentation is associated with an increased risk of seizure recurrence. Neuroimaging features like presence of perilesional edema and scolex can similarly predict seizure recurrence. These neuroimaging features can serve as potential surrogate markers to define therapy in these patients. The findings of our study might be helpful in stratifying patients with a higher risk of seizure recurrence, especially those who may require a more aggressive management.
1. Introduction Neurocysticercosis is caused by the larval stage of the pork tapeworm Taenia solium. Neurocysticercosis is the major cause of seizures in most of the developing countries (Garcia et al., 2014). Calcified neurocysticercosis granuloma represents the final result of host immune response to the larval cysticercus of Taenia solium (Nash et al., 2004). Previously, calcified neurocysticercosis was considered to be inert but recent evidence suggests the role of calcified neurocysticercosis in the epileptogenesis (Nash et al., 2004). The role of calcified neurocysticercosis in epileptogenesis is further stressed by the presence of perilesional edema in about one-third of patients (Nash et al., 2001). Another evidence of activity of calcified neurocysticercosis is the demonstration of scolex in some of these lesions (Gupta et al., 2002). Patients of calcified neurocysticercosis who present with seizures are ⁎
treated using antiepileptic drugs which are arbitrarily withdrawn after 2 years if the patient remains seizure free. Recent studies have shown that calcified neurocysticercosis is a potential cause of antiepileptic drug resistant epilepsy (Rathore et al., 2013). A seizure recurrence rate of about 34% was seen during a 6 month follow up period in patients of solitary calcified neurocysticercosis (Sharma et al., 2013). The factors that can predict seizure recurrence in patients of calcified neurocysticercosis are not well understood. Previous studies have shown that the presence of perilesional edema around a calcified lesion is associated with seizure recurrence (Lachuriya et al., 2016; Nash et al., 2008). Blood-brain barrier disruption around the lesion leading to neuroinflammation might be involved in the seizure recurrence. Other features like presentation with status epilepticus or serial seizures and larger size of the lesion have also been implicated in seizure recurrence in these patients (Sharma et al., 2013; Lachuriya et al., 2016).
Corresponding author at: Department of Neurology, King George Medical University, Uttar Pradesh, Lucknow 226003, India. E-mail address: [email protected] (R.K. Garg).
http://dx.doi.org/10.1016/j.eplepsyres.2017.09.010 Received 17 March 2017; Received in revised form 31 May 2017; Accepted 16 September 2017 Available online 20 September 2017 0920-1211/ © 2017 Elsevier B.V. All rights reserved.
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 1. Flow diagram of the study.
In this study, we aimed to study the relevance of various clinical and neuroimaging features to predict the seizure recurrence in solitary calcified neurocysticercosis patients. The findings of this study might help in identifying patients with a higher risk of seizure recurrence who might require a more aggressive approach towards management.
resonance imaging, calcified neurocysticercosis appeared isointense or hypointense on T1 weighted images and hypointense on T2 weighted images. T2* star weighted angiography (SWAN) was used for confirming the presence of calcification; calcified lesion appeared hypointense on SWAN sequence.
2. Material and methods
2.3. Exclusion criteria
2.1. Study design and settings
Patients with neuroimaging suggestive of different stages of neurocysticercosis or patients with multiple lesions on neuroimaging were excluded from the study. Patients with clinical and neuroimaging features suggestive of an alternative diagnosis were also excluded from the study.
This was a prospective observational study conducted at a tertiary care centre; the institute is located in northern India and caters to a population of about 100 million. The study participants were enrolled between January 2013 to January 2015. A written informed consent was obtained from every subject before enrolling them for the study. The study was approved by the institutional ethical committee. The flow diagram of the study is shown in Fig. 1.
2.4. Evaluation All included patients underwent detailed clinical history, with general and neurological examination. History regarding semiology of seizure, duration of seizure, impairment of consciousness, post ictal focal deficits, dietary habits and residence was recorded from every patient. International League Against Epilepsy guidelines on the classification and terminology of ictal events was followed (Blume et al., 2001). Routine haematological and biochemical investigations including complete blood count, blood sugar, renal and liver function tests and serum electrolytes, were done in every patient. Serological evaluation for neurocysticercosis was not performed as it has a low sensitivity and specificity in the diagnosis of calcified neurocysticercosis and its utility in endemic zones is doubtful.
2.2. Inclusion criteria Diagnosis of neurocysticercosis was made on the basis of presence of punctate round calcified parenchymal lesions in patients belonging to endemic zone, presenting with seizures (Del Brutto et al., 2001). Patients of solitary calcified neurocysticercosis presenting with new onset seizure (within 15 days of first-ever seizure) were enrolled in the study. Diagnosis of solitary calcified neurocysticercosis was made on the basis of computed tomography scan of brain which was further confirmed by magnetic resonance imaging. On conventional magnetic 79
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
was used as an add-on drug in those with seizure recurrence. Drug compliance was ensured in each and every patient. Steroids or anticysticidal treatment was not given.
Table 1 Baseline clinical, demographic and neuroimaging characteristics of 54 solitary calcified neurocysticercosis patients. S.No
Variable
1.
Age in years Mean ± SD Males (%) Rural (%) Urban (%) Non-vegetarian (%) Seizure semiology Generalized (%) Focal (%) Status epilepticus at presentation (%) Todd's palsy (%) Headache (%) Location of lesion Frontal Parietal Temporal Occipital Size of the lesion > 10 mm (%) Perilesional edema Contrast enhancement Scolex EEG abnormal
Value
2.7. Follow up 2. 3. 4. 5.
6. 7. 8. 9.
10. 11. 12. 13. 14.
20.43 ± 7.342 26 (48.1%) 33 (61.1%) 21 (38.9%) 34 (63%)
All the study participants were followed for a period of 1 year for any seizure recurrence. Patients visited the neurology outpatient department for follow-up at 3 monthly intervals. Follow-up data was also recorded from visits resulting from breakthrough seizures. Seizure recurrence was defined as the recurrence of an episode of seizure at least 1 week after the initiation of the antiepileptic drugs.
33 (61.1%) 21 (38.9%) 6 (11.1%) 5 (9.3%) 23 (42.6%)
2.8. Statistical analysis Statistical analysis was done using SPSS version16.0 (Chicago, IL, USA). The categorical variables were expressed as percentages and the continuous variables were expressed as mean ± standard deviation. The categorical variables were compared using Chi-square test or Fisher exact test, as applicable. The means were compared using the independent sample t-test. Kaplan-Meyer survival analyses using the logrank test was used to estimate the event-free survival. Binary logistic regression was applied to look for the variables independently associated with the outcome. For the purpose of binary logistic regression seizure recurrence was taken as the dependent variable and all variables found to be significant on univariate analysis were taken as independent variables. All the p values < 0.05 were taken as significant.
26 (48.15%) 13 (24.07%) 5 (9.26%) 10 (18.53%) 8 (14.8%) 11 (20.4%) 23 (42.6%) 13 (24.1%) 4 (7.4%)
SD = Standard deviation, EEG = Electroencephalogram
Electroencephalography was also performed on all included patients. Electroencephalography was done on a 21-channel machine; the 10–20 system of electrode placement was followed. Electroencephalogram was classified as either “Normal” or “Abnormal”. Electroencephalogram was considered abnormal if an epileptiform activity was seen, which was defined as the presence of any of the following discharges: spikes, spike-wave, sharp waves, sharp-slow wave, and poly-spike waves. All patient underwent a plain computed tomography scan of the cranium which was followed by the magnetic resonance imaging of the brain. The neuroimaging protocol is described in the subsequent sections.
3. Results We initially included 59 consecutive patients with new onset seizure and a single calcified neurocysticercosis on the plain computed tomography of head; 5 were excluded after performing magnetic resonance imaging due to reasons provided in the Fig. 1. Hence, 54 patients were finally evaluated. 3.1. Baseline characteristics
2.5. Neuroimaging The baseline demographic, clinical and neuroimaging characteristics of 54 solitary calcified neurocysticercosis patients are shown in Table 1. The mean age of the patients was 20.43 ± 7.34 years (range 8–41 years). Twenty-six (48.1%) patients were males. Thirty-three (61.1%) patients were resident of rural areas. Thirty-four (63.0%) patients were non-vegetarian. On magnetic resonance imaging, perilesional edema was seen in 11 (20.4%) lesions; contrast enhancement was seen in 23 (42.6%) lesions and a scolex was demonstrable in 13 (24.1%) lesions. Four (7.4%) patients had an abnormal electroencephalogram at baseline (Table 1).
A Gadolinium-enhanced magnetic resonance imaging was performed in all cases. A 3 Tesla Signa HDxt magnetic resonance imaging scanner (GE Healthcare, Milwaukee, Wisconsin) using a 12-channel head coil was utilized for all imaging protocols. T1 weighted fast spin echo, T2 weighted fast spin echo, fluid attenuation inversion recovery (FLAIR), diffusion weighted imaging (DWI) and post contrast sequences were acquired in every patient. We also acquired images using the SWAN sequence (T2* weighted angiography; GE Healthcare) with a TE of 25 ms, a TR of 47 ms, flip angle of 15°, section thickness of 2.4 mm, acquisition matrix of 320 × 224, and a Field of view (FOV) of 240 × 240 mm2 to ensure that the lesion was calcified and solitary. Computed tomography and magnetic resonance imaging were interpreted by an expert radiologist. Location of lesion, size of lesion, presence of perilesional edema, contrast enhancement and presence of scolex were the various imaging features studied. The “scolex” was considered to be present in a calcified lesion if there was a hypointense eccentrically placed dot in a peripherally calcified hypointense rim on T2* weighted image (SWAN) (Gupta et al., 2002). “Perilesional edema” on magnetic resonance imaging was defined as the presence of a distinct perilesional hyperintensity on T2 and FLAIR images surrounding the calcified lesion.
3.2. Predictors of seizure recurrence on univariate analysis During the follow-up period of 1 year, 13 patients developed seizure recurrence. The mean time of seizure recurrence was 93.85 ± 58.67 days (range 30–240 days, median 90 days). On univariate analysis, status epilepticus at presentation (p = 0.025, odds ratio = 8.677, 95% confidence interval 1.369–54.879) was the only clinical variable that was associated with seizure recurrence. Amongst the neuroimaging variables size of the lesion > 10 mm (p = 0.015, odds ratio = 7.917, 95% confidence interval 1.564–40.073), presence of perilesional edema (p < 0.001, odds ratio 20.267, 95% confidence interval 4.004–102.588) and the presence of scolex (p = 0.033, odds ratio = 4.163, 95% confidence interval 1.068–16.228) were found to be significantly associated with seizure recurrence during follow-up. Contrast enhancement was seen more frequently in patients with seizure recurrence (61.5%) (p = 0.113).
2.6. Treatment Oxcarbazepine in a dose of 15 mg/kg body weight in two divided doses was used as the first line antiepileptic drug in all the study participants. Clobazam in a dose of 20–40 mg/day in two divided doses 80
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 2. (A & B) Images from a patient with seizure recurrence, showing perilesional edema around the calcified lesion in T2 image (A) SWAN image showing calcified granuloma, inset showing eccentric nodule suggestive of scolex within the lesion (B). (C & D) T2 and SWAN images from a patient with no recurrence of seizures, there is no evidence of edema or scolex in these images.
Kaplan–Meyer analysis revealed that there was a significant difference in the time to event (occurrence of seizure) when the patients were categorized according to the presence or absence of perilesional edema (Log rank test p < 0.001). There was a significantly higher seizure
Fig. 2. An abnormal electroencephalogram at baseline (p = 0.039, odds ratio = 12.00, 95% confidence interval 1.125–127.969) was also significantly associated with seizure recurrence during follow-up. Table 2
Table 2 Distribution of clinical, neuroimaging and biochemical parameters in patients with or without seizure recurrence (univariate analysis). Variables Age in years Mean ± SD Males (%) Rural (%) Non-vegetarian (%) Seizure semiology (generalized) Status epilepticus at presentation Todd's palsy Headache Location of lesion Frontal Parietal Temporal Occipital Size of the lesion > 10 mm Perilesional edema Contrast enhancement Scolex EEG abnormal
Seizure recurrence N = 13
No recurrence N = 41
P value
Odds ratio (95% CI)
22.92 ± 6.861 9 (69.2%) 6 (46.2%) 8 (61.5%) 9 (69.2%) 4 (30.8%) 3 (23.1%) 6 (46.2%)
19.63 ± 7.392 17 (41.5%) 27 (65.9%) 26 (63.4%) 24 (58.5%) 2 (4.9%) 2 (4.9) 17 (41.5%)
0.161 0.114 0.204 0.903 0.491 0.025 0.084 0.766
Mean difference 3.289 (−1.356 to 7.934) 3.176 (0.839–12.030) 0.444 (0.125–1.578) 0.923 (0.255–3.338) 1.594 (0.421–6.036) 8.667 (1.369–54.879) 5.850 (0.858–39.876) 1.210 (0.345–4.245)
6 4 1 2 5 8 8 6 3
20 (48.78%) 9 (21.95%) 4 (9.76%) 8 (19.51%) 3 (7.3%) 3 (7.3%) 15 (36.6%) 7 (17.1%) 1 (2.4%)
0.925
NA
0.015 < 0.001 0.113 0.033 0.039
7.917 (1.564–40.073) 20.267 (4.004–102.588) 2.773 (0.767–10.029) 4.163 (1.068–16.228) 12.00 (1.125–127.969)
(46.15%) (30.77%) (7.69%) (15.38%) (38.5%) (61.5%) (61.5%) (46.2%) (23.1%)
SD = Standard deviation, EEG = Electroencephalogram.
81
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Fig. 3. Kaplan-Meyer analysis of seizure recurrence (cumulative hazard) according to presence or absence of perilesional edema, depicting a significantly higher rate of seizure recurrence in patients with perilesional edema.
Leon et al., 2015). However, the factors responsible for seizure recurrence or the predictors of seizure recurrence in these patients have not been well described in the literature. We found that the occurrence of status epilepticus at presentation was a clinical variable significantly associated with seizure recurrence. Previous studies have also found that occurrence of serial seizures, status epilepticus and Todd's palsy are associated with seizure recurrence (Sharma et al., 2013; Lachuriya et al., 2016). An abnormal EEG at presentation was also one of the predictors of seizure recurrence in our study, this finding was also consistent with the previously reported findings (Sharma et al., 2013; Lachuriya et al., 2016). Neuroimaging findings like presence of perilesional edema, demonstration of scolex, and larger size of the lesion were found to be associated with seizure recurrence in our study. Edema surrounding a calcified lesion has been implicated as a cause of seizure recurrence in previous studies also (Nash et al., 2008). Demonstration of edema around calcified lesions is contrary to the previous belief that these lesions are inert. The perilesional edema most likely represents hosts response to newly released parasitic antigens (Nash, 2012). The occurrence of edema around the calcified lesions was first noticed by Del Brutto in as early as the year 1994 (Del Brutto, 1994). Nash and coworkers in the year 1999 described the possible role of perilesional edema in seizure recurrence (Nash and Patronas, 1999). Nash and coworkers further carried out a nested case control study and demonstrated that perilesional edema was significantly associated with seizure recurrence (Nash et al., 2008). These findings suggested that perilesional edema can be a potential target of treatment in these patients using anti-inflammatory agents like corticosteroids (Marin and Preux, 2008). Randomized controlled trials, however, are awaited in this regard. Gupta and co-workers have demonstrated the presence of scolex in calcified neurocysticercosis lesion using T2* weighted imaging. They
recurrence rate in patients with perilesional edema as shown in Fig. 3. 3.3. Predictors of seizure recurrence on multivariate analysis On binary logistic regression, presence of perilesional edema (p = 0.018, odds ratio = 12.122, 95% confidence interval 1.521–96.639) was the only factor found to be independently associated with seizure recurrence Table 3. 4. Discussion In this prospective observation study, we found that about 24.07% (13/54) patients with solitary calcified neurocysticercosis developed seizure recurrence during 1 year follow-up. The recurrence of seizures or poor seizure control was associated with several clinical, and imaging features. The frequency of recurrence of seizure or poor response to antiepileptic drugs have been reported previously in patients of calcified neurocysticercosis (Sharma et al., 2013; Lachuriya et al., 2016; Table 3 Multivariate analysis using binary logistic regression for independent predictors of seizure recurrence. Variable
Status epilepticus Size of lesion > 10 mm Perilesional edema Scolex Abnormal EEG
P value
0.654 0.219 0.018 0.104 0.077
Odds ratio
0.482 0.376 12.122 4.623 12.462
95% confidence interval Lower
Upper
0.020 0. 376 1.521 0. 729 0.760
11.695 71.249 96.639 29.304 204.397
EEG = electroencephalogram.
82
Epilepsy Research 137 (2017) 78–83
A.K. Singh et al.
Delhi, India for financial support (Grant No. 3/1/2/28/Neuro/2012NCD- I).
showed that the presence of scolex was also associated with presence of perilesional edema in these patients (Gupta et al., 2002). Gupta and coworkers therefore concluded that calcified cysts with scolex have antigenic material preserved within them which is responsible for the presence of perilesional edema (Gupta et al., 2002). We similarly found that lesions with demonstrable scolex were more commonly associated with seizure recurrences thus suggesting that these lesions might be more antigenic or active. We also found that lesions of size > 10 mm were associated with seizure recurrence on univariate analysis, however no such association was found on multivariate analysis. The calcifications of neurocysticercosis are commonly < 10 mm (Del Brutto et al., 2001). We found few lesions > 10 mm in our study; larger lesions were also reported in previous studies done in our setup (Lachuriya et al., 2016). Some older studies have classified calcified neurocysticercosis as an “inactive” stage (Sotelo et al., 1985; Bittencourt et al., 1990; Carpio et al., 1994), which can wrongly convey the message that these patients do not require active management. Our findings highlight the notion that calcified neurocysticercosis is not an inert or an inactive stage, rather it is an active stage with associated inflammation and an inherent risk to cause seizure recurrence. Our study had a limitation that we did not repeat the neuroimaging at the time of seizure recurrence, which might have defined the temporal course and possibly provided a further insight into the epileptogenesis of these lesions. An additional sequence in the form of magnetic transfer spin echo T1-weighted could have been performed to better the identification of patients with perilesional gliosis which can be an independent factor (Pradhan et al., 2000). Sample size of our study was not very large and repeating these observations in a larger population over a longer period may help to bring more clarity to issues associated with perilesional edema surrounding a calcified lesion. Thus, we conclude that clinical variables like status epilepticus, and neuroimaging variables like presence of surrounding edema and scolex can be useful in identifying patients with higher risk of seizure recurrence. These patients may require more close follow-up or more aggressive therapy in the form of anti-inflammatory agents to prevent the same.
References Bittencourt, P.R., Costa, A.J., Oliveira, T.V., Gracia, C.M., Gorz, A.M., Mazer, S., 1990. Clinical, radiological and cerebrospinal fluid presentation of neurocysticercosis: a prospective study. Arq. Neuropsiquiatr. 48, 286–295. Blume, W.T., Lüders, H.O., Mizrahi, E., et al., 2001. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 42, 1212–1218. Carpio, A., Placencia, M., Santillán, F., Escobar, A., 1994. A proposal for classification of neurocysticercosis. Can. J. Neurol. Sci. 21, 43–47. Del Brutto, O.H., Rajshekhar, V., White, A.C., et al., 2001. Proposed diagnostic criteria for neurocysticercosis. Neurology 57, 177–183. Del Brutto, O.H., 1994. Prognostic factors for seizure recurrence after withdrawal of antiepileptic drugs in patients with neurocysticercosis. Neurology 44, 1706–1709. Garcia, H.H., Nash, T.E., Del Brutto, O.H., 2014. Clinical symptoms, diagnosis, and treatment of neurocysticercosis. Lancet Neurol. 13, 1202–1215. Gupta, R.K., Kumar, R., Chawla, S., Pradhan, S., 2002. Demonstration of scolex within calcified cysticercus cyst: its possible role in the pathogenesis of perilesional edema. Epilepsia 43, 1502–1508. Lachuriya, G., Garg, R.K., Jain, A., et al., 2016. Toll-like receptor-4 polymorphisms and serum matrix metalloproteinase-9 in newly diagnosed patients with calcified neurocysticercosis and seizures. Medicine (Baltimore) 95, e3288. Leon, A., Saito, E.K., Mehta, B., McMurtray, A.M., 2015. Calcified parenchymal central nervous system cysticercosis and clinical outcomes in epilepsy. Epilepsy Behav. 43, 77–80. Marin, B., Preux, P.M., 2008. Perilesional brain oedema in calcific neurocysticercosis: a target to prevent seizure recurrence. Lancet Neurol. 7, 1075–1076. Nash, T.E., Patronas, N.J., 1999. Edema associated with calcified lesions in neurocysticercosis. Neurology 53, 777–781. Nash, T.E., Pretell, J., Garcia, H.H., 2001. Calcified cysticerci provoke perilesional edema and seizures. Clin. Infect. Dis. 33, 1649–1653. Nash, T.E., Del Brutto, O.H., Butman, J.A., et al., 2004. Calcific neurocysticercosis and epileptogenesis. Neurology 62, 1934–1938. Nash, T.E., Pretell, E.J., Lescano, A.G., et al., 2008. Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case–control study. Lancet Neurol. 7, 1099–1105. Nash, T., 2012. Edema surrounding calcified intracranial cysticerci: clinical manifestations, natural history, and treatment. Pathog. Glob. Health 106, 275–279. Pradhan, S., Kathuria, M.K., Gupta, R.K., 2000. Perilesional gliosis and seizure outcome: a study based on magnetization transfer magnetic resonance imaging in patients with neurocysticercosis. Ann. Neurol. 48, 181–187. Rathore, C., Thomas, B., Kesavadas, C., Abraham, M., Radhakrishnan, K., 2013. Calcified neurocysticercosis lesions and antiepileptic drug-resistant epilepsy: a surgically remediable syndrome? Epilepsia 54, 1815–1822. Sharma, L.N., Garg, R.K., Verma, R., Singh, M.K., Malhotra, H.S., 2013. Seizure recurrence in patients with solitary cystic granuloma or single parenchymal cerebral calcification: a comparative evaluation. Seizure 22, 840–845. Sotelo, J., Guerrero, V., Rubio, F., 1985. Neurocysticercosis: a new classification based on active and inactive forms. A study of 753 cases. Arch. Intern. Med. 145, 442–445.
Conflict of interest The authors declare that they have no conflict of interest. Acknowledgment We acknowledge the Indian Council of Medical Research, New
83