Epilepsy Research (2014) 108, 1889—1895
journal homepage: www.elsevier.com/locate/epilepsyres
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis Marino M. Bianchin a,b,∗, Tonicarlo R. Velasco a,c, Lauro Wichert-Ana a,c, Veriano Alexandre Jr. a,c, David Araujo Jr. a,d, Antonio Carlos dos Santos a,d, Carlos G. Carlotti Jr. a,e, Osvaldo M. Takayanagui c, Américo C. Sakamoto a,c a
Center for Epilepsy Surgery (CIREP), Hospital das Clínicas de Ribeirão Preto, Department of Neurology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil b Basic Research and Advanced Investigations in Neurology (B.R.A.I.N.), Hospital de Clínicas de Porto Alegre, UFRGS,Porto Alegre, Brazil c Department of Neurosciences and Behavior, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirao Preto, Brazil d Department of Radiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil e Neurosurgery Division, Department of Surgery and Anatomy, Ribeirão Preto School of Medicine, University of São Paulo at Ribeirão Preto, Ribeirão Preto, Brazil Received 20 June 2014; received in revised form 11 September 2014; accepted 13 September 2014 Available online 11 October 2014
KEYWORDS Hippocampal sclerosis; Focal epilepsy; Epileptogenesis; Cysticercosis; Initial precipitating injury
Summary Recent observations suggest that neurocysticercosis (NCC) might act as an initial precipitating injury (IPI) causing mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS). A total of 191 patients from Brazil, a country in which NCC is endemic, were surgically treated for MTLE-HS, and subsequent findings for patients with MTLE-HS were compared with those of patients with MTLE-HS plus NCC. Seventy-one patients (37,2%) presented chronic findings of NCC (cNCC). MTLE-HS plus cNCC was significantly more common in women (O.R. = 2.45; 95%CI = 1.30—4.60; p = 0.005), in patients with no history of classical forms of IPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in those with bi-temporal interictal spikes on video-EEG (O.R. = 2.00; 95%CI = 1.07—3.73; p = 0.03). Single cNCC lesions were observed to occur significantly more often on the same side as hippocampal sclerosis, a finding suggesting
∗ Corresponding author at: CIREP, Hospital das Clínicas de Ribeirão Preto, Campus Universitário, Bairro Monte Alegre, Ribeirão Preto CEP 14048-900, SP, Brazil. Tel.: +55 51 96 37 69 69. E-mail address: [email protected] (M.M. Bianchin).
http://dx.doi.org/10.1016/j.eplepsyres.2014.09.018 0920-1211/© 2014 Elsevier B.V. All rights reserved.
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M.M. Bianchin et al. an anatomical relationship between NCC and MTLE-HS. Taken together, our results suggest that NCC may be a marker, or contributes to or even causes MTLE-HS. Based on our findings, we propose two distinct, non-excluding, and potentially synergistic mechanisms involved in the development of MTLE-HS in NCC, one of them being inflammatory-mediated, while the other is electrogenicmediated. Taken together, our observations may provide further evidence suggesting a role of NCC in the genesis or development of MTLE-HS. © 2014 Elsevier B.V. All rights reserved.
Introduction Neurocysticercosis (NCC) is caused by Taenia solium, an infestation which is endemic in Latin America, Asia, India, and Africa, and affects millions of individuals. It is one of the most common causes of CNS infection and acquired epilepsy worldwide. In developed countries, NCC is less common but is still a public health problem (Nash and Garcia, 2011; Del Brutto, 2012; Croker et al., 2012; Singh et al., 2013; Carpio et al., 2013; Bruno et al., 2013; Cantey et al., 2014). Recent observations suggest that NCC might act as an initial precipitating injury (IPI), causing mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLEHS) in some patients. First described in single case reports (Kobayashi et al., 2001; Wichert-Ana et al., 2004; da Silva et al., 2006; Singla et al., 2007), this association was later found to be much more common (Bianchin et al., 2006, 2012, 2013; Velasco et al., 2006; Rathore et al., 2012, 2013). Considering the high prevalence of NCC and MTLE-HS worldwide, this becomes an important issue which deserves further investigation. In Brazil, NCC is endemic and we have pointed previously a possible association between NCC and MTLE-HS (Bianchin et al., 2006, 2012, 2013; Velasco et al., 2006). Here, we evaluated further differences in demographic, clinical neuroimaging and surgical outcome of 191 consecutive MTLE-HS patients in order to better understand how an interplay between two of the most common causes of human focal epilepsy may occur.
Methods Patients After approval by the Ethics Committee of our institution, we selected a series of 200 consecutive patients surgically treated for MTLE-HS at CIREP (Center for Epilepsy Surgery at Ribeirao Preto) from 1995 to 2000. Nine patients were excluded because of incomplete data. The remaining 191 patients were eligible and were included in the study. The variables studied included gender, age at surgery, age at epilepsy onset (recurrent seizures), epilepsy duration, positive history for an initial precipitating insult (IPI), monthly seizure frequency, video-EEG interictal recordings, and neuroimaging. A positive history of IPI was considered if patients had a history of birth injury, febrile convulsion, meningitis or meningoencephalitis (other than neurocysticercosis), status epilepticus, or traumatic brain injury. Traumatic brain injury was based on a history of head concussion severe enough to require hospitalized observation. Patients were
categorized as seizure-free if they experienced no complex partial seizures or generalized tonic—clonic seizures after surgery. All patients included in this study received care at a public governmental university hospital and were from lowincome households, which qualified them for public health assistance. Socio-economic background and years of study did not differ between patients with MTLE-HS alone and patients with MTLE-HS plus cNCC. The study was approved the Research Ethics Committee of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and was conducted according with The Code of Ethics of the World Medical Association (Declaration of Helsinki). All patients gave written informed consent to participate. Our study is in accordance with the STROBE requirements.
Diagnosis of neurocysticercosis Definitive neurocysticercosis was diagnosed if the following criteria were met (i) an absolute criterion, such as histological demonstration of the parasite or cystic lesions showing the scolex on CT or MRI; (ii) two major criteria, such as lesions highly suggestive of neurocysticercosis on neuroimaging studies, spontaneously resolving small single enhancing lesions, or resolution of intracranial cystic lesions after therapy with albendazole or praziquantel; or (iii) one major and two minor criteria, such as lesions compatible with neurocysticercosis on neuroimaging studies, clinical manifestations suggestive of neurocysticercosis, and positive CSF ELISA for the detection of anticysticercal antibodies, plus epidemiological evidence. According to the above criteria, the presence of solid, dense, supratentorial calcifications, 1—10 mm in diameter, in the absence of other illnesses should be considered to be highly suggestive of neurocysticercosis (Del Brutto et al., 2001; Velasco et al., 2006).
Neuroimaging Neuroimaging included a CT-scan and MRI with special protocols for MTLE-HS. Based on MRI analysis, MTLE-HS was classified as unilateral or bilateral. Based on neuroradiologic findings, the patients were divided into two groups and compared: patients with MTLE-HS without radiological evidence of NCC (MTLE-only) and patients with MTLE plus radiological evidence of chronic NCC (MTLE-cNCC). Exams of patients with a single chronic calcified cNCC were carefully evaluated and the cerebral hemisphere of the cNCC lesions and side of hippocampal sclerosis were recorded for analysis.
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis
Presurgical evaluation of patients Presurgical evaluation was performed by an experienced multidisciplinary team and included a detailed clinical history and neurological examination, interictal and ictal video-EEG analysis, structural and functional imaging, psychiatric evaluation, neuropsychological testing, and, when appropriate, the intracarotid amobarbital test (Wada’s test) for memory and speech representation. As part of the presurgical evaluation, all patients were submitted to prolonged video-EEG recording (Vangard System, Cleveland, OH, USA) using scalp electrodes and sphenoidal electrodes. Interictal spikes were assessed by visual analysis as previously described and classified as (1) unilateral interictal spikes, if 100% or more of all spikes occurred in one temporal lobe, (2) no spikes, if no spikes were observed during videoEEG, or (3) bilateral, in all other cases. At least four seizures were recorded for each patient. In all cases, the epileptogenic zone (EZ) was inferred on the basis of the clinical, neuroimaging, neuropsychological and electrophysiological results. When the EZ could not be estimated noninvasively, patients underwent intracranial EEG recordings.
Surgical procedure and postoperative follow-up The surgical approach was similar for all patients. Surgery was resection of a maximum of 4.0 to 5.0 cm of the anterior lateral temporal lobe. The mesial resection included 2/3 of the amygdala and the anterior 2.0 to 3.0 cm of the hippocampus. All patients had anathomopathological confirmation of mesial temporal sclerosis. Surgical outcome was defined by seizure status determined during outpatient clinical interviews. For seizure outcome, we used Engels’ classification. Seizure outcome was assessed during routine follow-up by experienced epileptologists who were blind to the presurgical parameters or the design of this study. Most patients included in this cohort were available for the evaluation of surgical outcome and continued to be followed up in our service at the end of the present study.
Statistics Continuous variables were analyzed using the Student t-test. Categorical variables were analyzed by the Chi-square test or Fisher’s exact test. The chance of finding a chronic calcified lesion at the same side of the hippocampal sclerosis was further evaluated using Binominal Test. Binary logistic regression using SPSS Statistics v.17.0 established independence of variables and odds-ratio adjustments. In this study, all pre-surgical variables listed in Table 2, except age at IPI, were included in a backward stepwise selection model, using likelihood ratio elimination. In this model, removal testing is based on the probability of the likelihood-ratio statistic, which in turn is based on the maximum partial likelihood estimates. Results were considered significant if p < 0.05.
Results Clinical characteristics of patients, electrophysiological and neuroradiological findings and comparisons between
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patients with MTLE-HS alone and with MTEL-HS plus chronic calcified neurocysticercosis are presented in Table 1 In this cohort of 191 patients, 71 (37.2%) evaluated and surgically treated for MTLE-HS presented neuroradiological findings compatible with cNCC. Of these 71 patients, 39 (54.9%) had a single cNCC lesion and 32 (45.1%) had more than one cNCC lesion. All NCC lesions of these patients were old, chronic and calcified lesions. Considering only these 71 patients with cNCC, 45 (63.4%) were women and only 26 (36.6%) were men, a significant difference (p = 0.01). When compared with pure MTLE-HS, patients with MTLE-HS plus cNCC were found to have fewer years of schooling, a lower frequency of febrile seizures or classic forms of IPI, and a trend to show interictal video-EEG bi-temporal spikes more often. After eight steps, logistic regression showed that cNCC in MTLE was observed more frequently in women (O.R. = 2.45; 95%CI = 1.30—4.60; p = 0.005), in patients with no history of classical forms of IPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in those with bi-temporal interictal spikes on video-EEG (O.R. = 2.00; 95%CI = 1.07—3.73; p = 0.03) (Table 2). After backward stepwise selection logistic regression, no differences were observed between MTLE-HS and MTLE-HS plus cNCC patients regarding years of education or history of febrile seizures. Additionally, 73 (60.8%) patients without cNCC and 24 (60.0%) patients with a single cNCC lesion presented 100% unilateral temporal spikes. Among the patients with more than one cNCC lesion, only 9 (28.1%) presented 100% unilateral temporal spikes, a significant difference (p = 0.004). Thirty-nine patients presented a single cNCC lesion. The single cNCC lesion was located in the temporal lobes in 13 of them (33%), in the occipital lobes in 12 (31%), in the parietal lobes in 7 (18%), in the frontal lobes in 5 (13%) and in other regions in 2 (5%). In patients with a single calcification, this calcification occurred more frequently in the same brain hemisphere as the one with hippocampal sclerosis. More specifically, among these 39 patients, 21 single cNCC were observed in the left hemisphere and 17 (81%) of these patients presented left MTLE-HS. Only 4 (19%) of these patients presented right MTLE-HS. On the other hand, 18 patients presented a right hemisphere single cNCC and 10 of these (56%) presented right MTLE-HS, while 8 (44%) presented left MTLE-HS. In other words, 27 (69.2%) from 39 patients had the single cNCC lesion located in the same brain hemisphere of the hippocampal sclerosis while 12 (29.8%) of patients had the single cNCC lesion located in the opposite hemisphere of the hippocampal sclerosis. Thus, the distribution of single cNCC in MTLE-HS patients was more frequently co-localized in the same brain hemisphere. Fisher’s test confirmed that this distribution pattern had a lower probability to occur by chance (p = 0.024). Binominal test showed that the chance to observe a cNCC lesion in the same brain hemisphere of the hippocampal sclerosis had a low probability to occur by the chance (p = 0.0237). This suggests that hippocampal sclerosis was significantly more likely to occur in the same hemisphere as cNCC. In our view, this finding may suggest an anatomical relationship between cNCC lesions and hippocampal sclerosis. Due to the lobar distributions of single cNCC, which in our patients were observed to occur predominantly in the temporal or occipital lobes, we suggest that lesions in the temporal or occipital lobes might be particularly responsible for the observation of a
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Table 1 Clinical, neurophysiological, and neuroradiological findings in MTLE-HS patients with cNCC (HS-NCC) or MTLE-HS without cNCC (HS-only). Variable
All patients
p
Groups HS-NCC (n = 71)
HS-only (n = 120)
Gender Male Female
93 (48.7%) 98 (51.3%)
26 (36.6%) 45 (63.4%)
67 (55.8%) 53 (44.2%)
0.01*
Years of education Mean SD
6.62 4.47
5.79 4.26
7.12 4.53
0.047*
10.32 7.64
9.96 6.49
10.53 8.27
0.61
59 (30.9%) 132 (69.1%)
30 (42.3%) 38 (57.7%)
29 (24.2%) 94 (75.8%)
0.009*
1.95 1.34
2.08 1.42
1.89 1.31
0.46
128 (67.0%) 63 (33.0%)
54 (76.1%) 17 (23.9%)
74 (61.7%) 46 (38.3%)
0.041*
Disease duration (y) Mean SD
24.60 9.42
25.37 8.90
24.11 9.72
0.37
Age at surgery (y) Mean SD
34.91 8.72
35.32 7.80
34.67 9.25
0.62
Seizures/month Mean SD
3.57 0.72
3.58 0.69
3.56 0.74
0.86
Side MTS Right Left
75 (39.3%) 116 (60.7%)
28 (39.4%) 43 (60.6%)
47 (39.2%) 73 (60.8%)
0.971
106 (55.5%) 85 (44.5%)
33 (46.5%) 38 (53.5%)
73 (60.8%) 47 (39.2%)
0.054
141 (73.8%) 50 (26.2%)
52 (73.2%) 19 (26.8%)
92 (76.7) 28 (23.3)
Age at epilepsy onset (y) Mean SD History of IPI No Yes Age at IPI (y) n = 132 Mean SD Febrile seizures No Yes
Interictal EEG 100% Unilateral spikes Bilateral Surgical outcome Engel I Other *
0.595
Significant in univariate analysis.
congruent hemispherical relationship between MTLE-HS and cNCC, although we could not test this possibility or specific neuronal pathways in this study because we would need a much larger number of patients. Other authors have suggested a similar possibility (Rathore et al., 2012). This might be an interesting aspect for future researches. Nevertheless, taken together these findings might suggest an anatomical connection between NCC and MTLE-HS, perhaps
further supporting the hypothesis of a cause-effect relationship between NCC and MTLE-HS.
Discussion Seventy one (37.2%) of 191 patients with MTLE-HS refractory epilepsy presented chronic NCC, a prevalence far higher
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis
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Table 2 Final step of a backward stepwise logistic regression model showing the variables independently associated with MTLE-HS plus cNCC. Variables
Female gender No classical IPI history Bilateral interictal EEG *
Univariate analysis
Adjusted p
Logistic regression
Crude O.R.
95%CI
Adjusted O.R.
95%CI
2.19 2.29 1.79
1.20—4.00 1.22—4.31 0.99—3.24
2.45 2.67 2.00
1.30—4.60 1.37—5.18 1.07—3.73
0.005* 0.004* 0.03*
Remained significant after logistic regression. IPI—–initial precipitating injury.
than expected for our population (Velasco et al., 2006; Bianchin et al., 2012, 2013). In this study, cNCC lesions in MTLE-HS patients was independently and significantly more common in women, in patients without a history of classical forms of IPIs and in patients with bi-temporal spikes during interictal video-EEG. Single cNCC lesions seemed to occur more often on the same side as MTLE-HS. This last finding is important because if its confirmed it might suggests a plausible anatomical connection between NCC and MTLE-HS. At this point, we may also suggest that the presence of cNCC in some MTLE-HS patients may not be simply a coincidence. Considering that central nervous infections might be a risk factor for MTLE-HS development, it is plausible to propose that NCC, similarly to other inflammatory or infectious diseases (Mathern et al., 1995, 2002; Bando et al., 2011; Rathore et al., 2012), could act as an IPI and lead to MTLE-HS. Among our MTLE-HS patients, cNCC was more commonly observed in women. The prevalence of NCC is higher in Brazilian males, but females present more frequently with severe forms of NCC (Agapejev, 1996). Severe forms of neurocysticercosis are characterized by an intense inflammatory response and are more common in female patients (Rangel et al., 1987). This is in line with the concept that inflammatory processes seem to be related to the pathogenesis of MTLE-HS and suggests that inflammatory mechanisms might be important in the development of MTLE-HS associated with NCC (Bianchin et al., 2012). Electroencephalographic spikes are a hallmark of epilepsy. Our observation that bilateral temporal interictal spikes were more common in MTLE-HS plus cNCC patients or in patients with multiple cNCC lesions might suggest a more diffuse epileptic process in patients with MTLE-HS plus cNCC. Seizures are frequent neurological manifestations of neurocysticercosis. Several lines of evidence suggest that status epileptics or recurrent seizures might lead to hippocampal damage and temporal lobe epilepsy (Bertram, 2007; Mathern et al., 2002). In this venue, it is possible that some individuals in our series might have developed seizureinduced hippocampal damage and, eventually, MTLE-HS due to NCC. If this is the case, hippocampal damage and mesial temporal lobe epileptogenicity may be caused by phenomena similar to those observed during kindling models of temporal epilepsy (Bertram, 2007; Lévesque and Avoli, 2013). Based on the above discussion, we suggest that two distinct, non-excluding and potentially synergistic mechanisms might be involved in the development of MTLE-HS in NCC, one being inflammatory-mediated, and the other
being electrogenic-mediated. Further studies are necessary to confirm our hypothesis. A history of IPI is frequently associated with MTLE-HS (Mathern et al., 1995, 2002; Bando et al., 2011). Our finding that patients with MTLE-HS plus NCC present a significantly lower incidence of classical IPI histories further suggests that NCC per se might be associated with the genesis of MTLE-HS in some patients, especially in those without other explanations for MTLE-HS. Because NCC might be initially a silent infection for most patients, it is possible that several patients who acquire NCC earlier in life might lack a clear history of classical forms of IPI. In these patients, hippocampal damage could occur or be facilitated by NCC through repetitive seizures and/or inflammatory mediated mechanisms. Because seizures associated with NCC might vanish with time, only the epileptic symptoms caused by MTLE-HS might be evident later in life. When such patients go for more detailed medical investigation because of epilepsy, many of them may display non-active, old, calcified NCC lesions located in extra-mesial regions, but may present refractory seizures initiating in the mesial temporal lobe. After surgery, patients became seizure free as long as they remained medicated, making it difficult, although possible, to establish an association between these two pathologies. Our study has some limitations that need to be acknowledged. It is a retrospective study, carried out on surgical patients. We did not explore all the clinical impact that cNCC might have on MTLE-HS, like for example cognitive or neuropsychiatric aspects (Terra-Bustamante et al., 2005). Moreover, as previously discussed by our group, the presence of calcified cysticercotic lesions in MTLH-HS patients does not necessarily imply that there is a causal relationship between both disorders (Velasco et al., 2006). A missing variable or factor could be responsible for the association of MTLE-HS and cNCC. A possible alternative explanation would be that cysticercosis and hippocampal sclerosis may be associated with a third variable, such as low socio-economic status, or a genetic or immunological predisposition that could explain this association. Although efforts were undertaken to control the socio-economic variables in this work, our study is retrospective. Perhaps only a prospective cohort study could establish a causal relationship between neurocysticercosis and MTLE-HS, although this type of study is hardly feasible, for obvious reasons. Nevertheless, our findings present strong points which need to be considered. It analyzed a large cohort of MTLE-HS patients from a region in which neurocysticercosis is endemic, and all patients were extensively evaluated by a team specialized
1894 in the treatment of NCC or epilepsy. Logistic regression was used for establishing the independence of variable studied. More importantly, we determined that in patients with a single cNCC, there is a possible association between the hemisphere of cNCC and the hemisphere of MTLE-HS. This is an anatomical relationship that could hardly be explained by low socio-economic status, or other genetic or immunological predispositions. Moreover, our observations have biological plausibility because they are supported by previous studies suggesting that infectious or inflammatory disorders could lead to MTLE-HS; neurocysticercosis might as well be one of these disorders. Thus, we believe that these results are interesting and may contribute to a better understanding of the spectrum of neurocysticercosis and epilepsy.
Conclusions In this study we present evidence implying a role of NCC in MTLE-HS, a possibility that might be important if one consider the worldwide prevalence of neurocysticercosis (Bianchin et al., 2010). Also, we suggest that NCC might be a marker for MTLE-HS or provide plausible mechanisms for how NCC may contribute or even cause MTLE-HS. Our observations may improve the current knowledge about the pathogenesis of MTLE-HS and about epilepsy associated with NCC. In our view, these aspects are important because they open new opportunities for epilepsy research and may contribute to further elucidating the pathogenesis of epilepsy worldwide.
Acknowledgements This study was fully supported by Brazilian Government research grant agencies CNPq (http://www.cnpq.br), grants no. 306644/2010-0 and no. 485423/2012-0, and FAPERGS/CNPq/PRONEM (11.2043.0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors has any conflict of interest to disclose. We thanks Prof. Patrícia Klarmann Ziegelmann and Nucleo de Assessoria Estatística (NAE) UFRGS for statistical help and Elettra Greene for review of the English language.
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Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis Singla, M., Singh, P., Kaushal, S., Bansal, R., Singh, G., 2007. Hippocampal sclerosis in association with neurocysticercosis. Epileptic Disord. 9, 292—299. Singh, G., Burneo, J.G., Sander, J.W., 2013. From seizures to epilepsy and its substrates: neurocysticercosis. Epilepsia 54, 783—792. Terra-Bustamante, V.C., Coimbra, E.R., Rezek, K.O., Escorsi-Rosset, S.R., Guarnieri, R., Dalmagro, C.L., Inuzuka, L.M., Bianchin, M.M., Wichert-Ana, L., Alexandre, V., Takayanagui, O.M., Araújo, D., dos Santos, A.C., Carlotti, C.G., Walz, R., Markowitsch, H.J., Sakamoto, A.C., 2005. Cognitive performance of patients with mesial temporal lobe epilepsy and incidental calcified neurocysticercosis. J. Neurol. Neurosurg. Psychiatry 76 (8), 1080—1083.
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Velasco, T.R., Zanello, P.A., Dalmagro, C.L., Araújo Jr., D., Santos, A.C., Bianchin, M.M., Alexandre Jr., V., Walz, R., Assirati, J.A., Carlotti Jr., C.G., Takayanagui, O.M., Sakamoto, A.C., Leite, J.P., 2006. Calcified cysticercotic lesions and intractable epilepsy: a cross sectional study of 512 patients. J. Neurol. Neurosurg. Psychiatry 77 (4), 485—488. Wichert-Ana, L., Velasco, T.R., Terra-Bustamante, V.C., Alexandre Jr., V., Walz, R., Bianchin, M.M., Leite, J.P., Assirati, J.A., Carlotti, C.G., Araújo, D., Santos, A.C., Takayanagui, O.M., Sakamoto, A.C., 2004. Surgical treatment for mesial temporal lobe epilepsy in the presence of massive calcified neurocysticercosis. Arch. Neurol. 61, 1117—1119.
journal homepage: www.elsevier.com/locate/epilepsyres
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis Marino M. Bianchin a,b,∗, Tonicarlo R. Velasco a,c, Lauro Wichert-Ana a,c, Veriano Alexandre Jr. a,c, David Araujo Jr. a,d, Antonio Carlos dos Santos a,d, Carlos G. Carlotti Jr. a,e, Osvaldo M. Takayanagui c, Américo C. Sakamoto a,c a
Center for Epilepsy Surgery (CIREP), Hospital das Clínicas de Ribeirão Preto, Department of Neurology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil b Basic Research and Advanced Investigations in Neurology (B.R.A.I.N.), Hospital de Clínicas de Porto Alegre, UFRGS,Porto Alegre, Brazil c Department of Neurosciences and Behavior, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirao Preto, Brazil d Department of Radiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil e Neurosurgery Division, Department of Surgery and Anatomy, Ribeirão Preto School of Medicine, University of São Paulo at Ribeirão Preto, Ribeirão Preto, Brazil Received 20 June 2014; received in revised form 11 September 2014; accepted 13 September 2014 Available online 11 October 2014
KEYWORDS Hippocampal sclerosis; Focal epilepsy; Epileptogenesis; Cysticercosis; Initial precipitating injury
Summary Recent observations suggest that neurocysticercosis (NCC) might act as an initial precipitating injury (IPI) causing mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS). A total of 191 patients from Brazil, a country in which NCC is endemic, were surgically treated for MTLE-HS, and subsequent findings for patients with MTLE-HS were compared with those of patients with MTLE-HS plus NCC. Seventy-one patients (37,2%) presented chronic findings of NCC (cNCC). MTLE-HS plus cNCC was significantly more common in women (O.R. = 2.45; 95%CI = 1.30—4.60; p = 0.005), in patients with no history of classical forms of IPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in those with bi-temporal interictal spikes on video-EEG (O.R. = 2.00; 95%CI = 1.07—3.73; p = 0.03). Single cNCC lesions were observed to occur significantly more often on the same side as hippocampal sclerosis, a finding suggesting
∗ Corresponding author at: CIREP, Hospital das Clínicas de Ribeirão Preto, Campus Universitário, Bairro Monte Alegre, Ribeirão Preto CEP 14048-900, SP, Brazil. Tel.: +55 51 96 37 69 69. E-mail address: [email protected] (M.M. Bianchin).
http://dx.doi.org/10.1016/j.eplepsyres.2014.09.018 0920-1211/© 2014 Elsevier B.V. All rights reserved.
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M.M. Bianchin et al. an anatomical relationship between NCC and MTLE-HS. Taken together, our results suggest that NCC may be a marker, or contributes to or even causes MTLE-HS. Based on our findings, we propose two distinct, non-excluding, and potentially synergistic mechanisms involved in the development of MTLE-HS in NCC, one of them being inflammatory-mediated, while the other is electrogenicmediated. Taken together, our observations may provide further evidence suggesting a role of NCC in the genesis or development of MTLE-HS. © 2014 Elsevier B.V. All rights reserved.
Introduction Neurocysticercosis (NCC) is caused by Taenia solium, an infestation which is endemic in Latin America, Asia, India, and Africa, and affects millions of individuals. It is one of the most common causes of CNS infection and acquired epilepsy worldwide. In developed countries, NCC is less common but is still a public health problem (Nash and Garcia, 2011; Del Brutto, 2012; Croker et al., 2012; Singh et al., 2013; Carpio et al., 2013; Bruno et al., 2013; Cantey et al., 2014). Recent observations suggest that NCC might act as an initial precipitating injury (IPI), causing mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLEHS) in some patients. First described in single case reports (Kobayashi et al., 2001; Wichert-Ana et al., 2004; da Silva et al., 2006; Singla et al., 2007), this association was later found to be much more common (Bianchin et al., 2006, 2012, 2013; Velasco et al., 2006; Rathore et al., 2012, 2013). Considering the high prevalence of NCC and MTLE-HS worldwide, this becomes an important issue which deserves further investigation. In Brazil, NCC is endemic and we have pointed previously a possible association between NCC and MTLE-HS (Bianchin et al., 2006, 2012, 2013; Velasco et al., 2006). Here, we evaluated further differences in demographic, clinical neuroimaging and surgical outcome of 191 consecutive MTLE-HS patients in order to better understand how an interplay between two of the most common causes of human focal epilepsy may occur.
Methods Patients After approval by the Ethics Committee of our institution, we selected a series of 200 consecutive patients surgically treated for MTLE-HS at CIREP (Center for Epilepsy Surgery at Ribeirao Preto) from 1995 to 2000. Nine patients were excluded because of incomplete data. The remaining 191 patients were eligible and were included in the study. The variables studied included gender, age at surgery, age at epilepsy onset (recurrent seizures), epilepsy duration, positive history for an initial precipitating insult (IPI), monthly seizure frequency, video-EEG interictal recordings, and neuroimaging. A positive history of IPI was considered if patients had a history of birth injury, febrile convulsion, meningitis or meningoencephalitis (other than neurocysticercosis), status epilepticus, or traumatic brain injury. Traumatic brain injury was based on a history of head concussion severe enough to require hospitalized observation. Patients were
categorized as seizure-free if they experienced no complex partial seizures or generalized tonic—clonic seizures after surgery. All patients included in this study received care at a public governmental university hospital and were from lowincome households, which qualified them for public health assistance. Socio-economic background and years of study did not differ between patients with MTLE-HS alone and patients with MTLE-HS plus cNCC. The study was approved the Research Ethics Committee of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and was conducted according with The Code of Ethics of the World Medical Association (Declaration of Helsinki). All patients gave written informed consent to participate. Our study is in accordance with the STROBE requirements.
Diagnosis of neurocysticercosis Definitive neurocysticercosis was diagnosed if the following criteria were met (i) an absolute criterion, such as histological demonstration of the parasite or cystic lesions showing the scolex on CT or MRI; (ii) two major criteria, such as lesions highly suggestive of neurocysticercosis on neuroimaging studies, spontaneously resolving small single enhancing lesions, or resolution of intracranial cystic lesions after therapy with albendazole or praziquantel; or (iii) one major and two minor criteria, such as lesions compatible with neurocysticercosis on neuroimaging studies, clinical manifestations suggestive of neurocysticercosis, and positive CSF ELISA for the detection of anticysticercal antibodies, plus epidemiological evidence. According to the above criteria, the presence of solid, dense, supratentorial calcifications, 1—10 mm in diameter, in the absence of other illnesses should be considered to be highly suggestive of neurocysticercosis (Del Brutto et al., 2001; Velasco et al., 2006).
Neuroimaging Neuroimaging included a CT-scan and MRI with special protocols for MTLE-HS. Based on MRI analysis, MTLE-HS was classified as unilateral or bilateral. Based on neuroradiologic findings, the patients were divided into two groups and compared: patients with MTLE-HS without radiological evidence of NCC (MTLE-only) and patients with MTLE plus radiological evidence of chronic NCC (MTLE-cNCC). Exams of patients with a single chronic calcified cNCC were carefully evaluated and the cerebral hemisphere of the cNCC lesions and side of hippocampal sclerosis were recorded for analysis.
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis
Presurgical evaluation of patients Presurgical evaluation was performed by an experienced multidisciplinary team and included a detailed clinical history and neurological examination, interictal and ictal video-EEG analysis, structural and functional imaging, psychiatric evaluation, neuropsychological testing, and, when appropriate, the intracarotid amobarbital test (Wada’s test) for memory and speech representation. As part of the presurgical evaluation, all patients were submitted to prolonged video-EEG recording (Vangard System, Cleveland, OH, USA) using scalp electrodes and sphenoidal electrodes. Interictal spikes were assessed by visual analysis as previously described and classified as (1) unilateral interictal spikes, if 100% or more of all spikes occurred in one temporal lobe, (2) no spikes, if no spikes were observed during videoEEG, or (3) bilateral, in all other cases. At least four seizures were recorded for each patient. In all cases, the epileptogenic zone (EZ) was inferred on the basis of the clinical, neuroimaging, neuropsychological and electrophysiological results. When the EZ could not be estimated noninvasively, patients underwent intracranial EEG recordings.
Surgical procedure and postoperative follow-up The surgical approach was similar for all patients. Surgery was resection of a maximum of 4.0 to 5.0 cm of the anterior lateral temporal lobe. The mesial resection included 2/3 of the amygdala and the anterior 2.0 to 3.0 cm of the hippocampus. All patients had anathomopathological confirmation of mesial temporal sclerosis. Surgical outcome was defined by seizure status determined during outpatient clinical interviews. For seizure outcome, we used Engels’ classification. Seizure outcome was assessed during routine follow-up by experienced epileptologists who were blind to the presurgical parameters or the design of this study. Most patients included in this cohort were available for the evaluation of surgical outcome and continued to be followed up in our service at the end of the present study.
Statistics Continuous variables were analyzed using the Student t-test. Categorical variables were analyzed by the Chi-square test or Fisher’s exact test. The chance of finding a chronic calcified lesion at the same side of the hippocampal sclerosis was further evaluated using Binominal Test. Binary logistic regression using SPSS Statistics v.17.0 established independence of variables and odds-ratio adjustments. In this study, all pre-surgical variables listed in Table 2, except age at IPI, were included in a backward stepwise selection model, using likelihood ratio elimination. In this model, removal testing is based on the probability of the likelihood-ratio statistic, which in turn is based on the maximum partial likelihood estimates. Results were considered significant if p < 0.05.
Results Clinical characteristics of patients, electrophysiological and neuroradiological findings and comparisons between
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patients with MTLE-HS alone and with MTEL-HS plus chronic calcified neurocysticercosis are presented in Table 1 In this cohort of 191 patients, 71 (37.2%) evaluated and surgically treated for MTLE-HS presented neuroradiological findings compatible with cNCC. Of these 71 patients, 39 (54.9%) had a single cNCC lesion and 32 (45.1%) had more than one cNCC lesion. All NCC lesions of these patients were old, chronic and calcified lesions. Considering only these 71 patients with cNCC, 45 (63.4%) were women and only 26 (36.6%) were men, a significant difference (p = 0.01). When compared with pure MTLE-HS, patients with MTLE-HS plus cNCC were found to have fewer years of schooling, a lower frequency of febrile seizures or classic forms of IPI, and a trend to show interictal video-EEG bi-temporal spikes more often. After eight steps, logistic regression showed that cNCC in MTLE was observed more frequently in women (O.R. = 2.45; 95%CI = 1.30—4.60; p = 0.005), in patients with no history of classical forms of IPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in those with bi-temporal interictal spikes on video-EEG (O.R. = 2.00; 95%CI = 1.07—3.73; p = 0.03) (Table 2). After backward stepwise selection logistic regression, no differences were observed between MTLE-HS and MTLE-HS plus cNCC patients regarding years of education or history of febrile seizures. Additionally, 73 (60.8%) patients without cNCC and 24 (60.0%) patients with a single cNCC lesion presented 100% unilateral temporal spikes. Among the patients with more than one cNCC lesion, only 9 (28.1%) presented 100% unilateral temporal spikes, a significant difference (p = 0.004). Thirty-nine patients presented a single cNCC lesion. The single cNCC lesion was located in the temporal lobes in 13 of them (33%), in the occipital lobes in 12 (31%), in the parietal lobes in 7 (18%), in the frontal lobes in 5 (13%) and in other regions in 2 (5%). In patients with a single calcification, this calcification occurred more frequently in the same brain hemisphere as the one with hippocampal sclerosis. More specifically, among these 39 patients, 21 single cNCC were observed in the left hemisphere and 17 (81%) of these patients presented left MTLE-HS. Only 4 (19%) of these patients presented right MTLE-HS. On the other hand, 18 patients presented a right hemisphere single cNCC and 10 of these (56%) presented right MTLE-HS, while 8 (44%) presented left MTLE-HS. In other words, 27 (69.2%) from 39 patients had the single cNCC lesion located in the same brain hemisphere of the hippocampal sclerosis while 12 (29.8%) of patients had the single cNCC lesion located in the opposite hemisphere of the hippocampal sclerosis. Thus, the distribution of single cNCC in MTLE-HS patients was more frequently co-localized in the same brain hemisphere. Fisher’s test confirmed that this distribution pattern had a lower probability to occur by chance (p = 0.024). Binominal test showed that the chance to observe a cNCC lesion in the same brain hemisphere of the hippocampal sclerosis had a low probability to occur by the chance (p = 0.0237). This suggests that hippocampal sclerosis was significantly more likely to occur in the same hemisphere as cNCC. In our view, this finding may suggest an anatomical relationship between cNCC lesions and hippocampal sclerosis. Due to the lobar distributions of single cNCC, which in our patients were observed to occur predominantly in the temporal or occipital lobes, we suggest that lesions in the temporal or occipital lobes might be particularly responsible for the observation of a
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Table 1 Clinical, neurophysiological, and neuroradiological findings in MTLE-HS patients with cNCC (HS-NCC) or MTLE-HS without cNCC (HS-only). Variable
All patients
p
Groups HS-NCC (n = 71)
HS-only (n = 120)
Gender Male Female
93 (48.7%) 98 (51.3%)
26 (36.6%) 45 (63.4%)
67 (55.8%) 53 (44.2%)
0.01*
Years of education Mean SD
6.62 4.47
5.79 4.26
7.12 4.53
0.047*
10.32 7.64
9.96 6.49
10.53 8.27
0.61
59 (30.9%) 132 (69.1%)
30 (42.3%) 38 (57.7%)
29 (24.2%) 94 (75.8%)
0.009*
1.95 1.34
2.08 1.42
1.89 1.31
0.46
128 (67.0%) 63 (33.0%)
54 (76.1%) 17 (23.9%)
74 (61.7%) 46 (38.3%)
0.041*
Disease duration (y) Mean SD
24.60 9.42
25.37 8.90
24.11 9.72
0.37
Age at surgery (y) Mean SD
34.91 8.72
35.32 7.80
34.67 9.25
0.62
Seizures/month Mean SD
3.57 0.72
3.58 0.69
3.56 0.74
0.86
Side MTS Right Left
75 (39.3%) 116 (60.7%)
28 (39.4%) 43 (60.6%)
47 (39.2%) 73 (60.8%)
0.971
106 (55.5%) 85 (44.5%)
33 (46.5%) 38 (53.5%)
73 (60.8%) 47 (39.2%)
0.054
141 (73.8%) 50 (26.2%)
52 (73.2%) 19 (26.8%)
92 (76.7) 28 (23.3)
Age at epilepsy onset (y) Mean SD History of IPI No Yes Age at IPI (y) n = 132 Mean SD Febrile seizures No Yes
Interictal EEG 100% Unilateral spikes Bilateral Surgical outcome Engel I Other *
0.595
Significant in univariate analysis.
congruent hemispherical relationship between MTLE-HS and cNCC, although we could not test this possibility or specific neuronal pathways in this study because we would need a much larger number of patients. Other authors have suggested a similar possibility (Rathore et al., 2012). This might be an interesting aspect for future researches. Nevertheless, taken together these findings might suggest an anatomical connection between NCC and MTLE-HS, perhaps
further supporting the hypothesis of a cause-effect relationship between NCC and MTLE-HS.
Discussion Seventy one (37.2%) of 191 patients with MTLE-HS refractory epilepsy presented chronic NCC, a prevalence far higher
Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis
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Table 2 Final step of a backward stepwise logistic regression model showing the variables independently associated with MTLE-HS plus cNCC. Variables
Female gender No classical IPI history Bilateral interictal EEG *
Univariate analysis
Adjusted p
Logistic regression
Crude O.R.
95%CI
Adjusted O.R.
95%CI
2.19 2.29 1.79
1.20—4.00 1.22—4.31 0.99—3.24
2.45 2.67 2.00
1.30—4.60 1.37—5.18 1.07—3.73
0.005* 0.004* 0.03*
Remained significant after logistic regression. IPI—–initial precipitating injury.
than expected for our population (Velasco et al., 2006; Bianchin et al., 2012, 2013). In this study, cNCC lesions in MTLE-HS patients was independently and significantly more common in women, in patients without a history of classical forms of IPIs and in patients with bi-temporal spikes during interictal video-EEG. Single cNCC lesions seemed to occur more often on the same side as MTLE-HS. This last finding is important because if its confirmed it might suggests a plausible anatomical connection between NCC and MTLE-HS. At this point, we may also suggest that the presence of cNCC in some MTLE-HS patients may not be simply a coincidence. Considering that central nervous infections might be a risk factor for MTLE-HS development, it is plausible to propose that NCC, similarly to other inflammatory or infectious diseases (Mathern et al., 1995, 2002; Bando et al., 2011; Rathore et al., 2012), could act as an IPI and lead to MTLE-HS. Among our MTLE-HS patients, cNCC was more commonly observed in women. The prevalence of NCC is higher in Brazilian males, but females present more frequently with severe forms of NCC (Agapejev, 1996). Severe forms of neurocysticercosis are characterized by an intense inflammatory response and are more common in female patients (Rangel et al., 1987). This is in line with the concept that inflammatory processes seem to be related to the pathogenesis of MTLE-HS and suggests that inflammatory mechanisms might be important in the development of MTLE-HS associated with NCC (Bianchin et al., 2012). Electroencephalographic spikes are a hallmark of epilepsy. Our observation that bilateral temporal interictal spikes were more common in MTLE-HS plus cNCC patients or in patients with multiple cNCC lesions might suggest a more diffuse epileptic process in patients with MTLE-HS plus cNCC. Seizures are frequent neurological manifestations of neurocysticercosis. Several lines of evidence suggest that status epileptics or recurrent seizures might lead to hippocampal damage and temporal lobe epilepsy (Bertram, 2007; Mathern et al., 2002). In this venue, it is possible that some individuals in our series might have developed seizureinduced hippocampal damage and, eventually, MTLE-HS due to NCC. If this is the case, hippocampal damage and mesial temporal lobe epileptogenicity may be caused by phenomena similar to those observed during kindling models of temporal epilepsy (Bertram, 2007; Lévesque and Avoli, 2013). Based on the above discussion, we suggest that two distinct, non-excluding and potentially synergistic mechanisms might be involved in the development of MTLE-HS in NCC, one being inflammatory-mediated, and the other
being electrogenic-mediated. Further studies are necessary to confirm our hypothesis. A history of IPI is frequently associated with MTLE-HS (Mathern et al., 1995, 2002; Bando et al., 2011). Our finding that patients with MTLE-HS plus NCC present a significantly lower incidence of classical IPI histories further suggests that NCC per se might be associated with the genesis of MTLE-HS in some patients, especially in those without other explanations for MTLE-HS. Because NCC might be initially a silent infection for most patients, it is possible that several patients who acquire NCC earlier in life might lack a clear history of classical forms of IPI. In these patients, hippocampal damage could occur or be facilitated by NCC through repetitive seizures and/or inflammatory mediated mechanisms. Because seizures associated with NCC might vanish with time, only the epileptic symptoms caused by MTLE-HS might be evident later in life. When such patients go for more detailed medical investigation because of epilepsy, many of them may display non-active, old, calcified NCC lesions located in extra-mesial regions, but may present refractory seizures initiating in the mesial temporal lobe. After surgery, patients became seizure free as long as they remained medicated, making it difficult, although possible, to establish an association between these two pathologies. Our study has some limitations that need to be acknowledged. It is a retrospective study, carried out on surgical patients. We did not explore all the clinical impact that cNCC might have on MTLE-HS, like for example cognitive or neuropsychiatric aspects (Terra-Bustamante et al., 2005). Moreover, as previously discussed by our group, the presence of calcified cysticercotic lesions in MTLH-HS patients does not necessarily imply that there is a causal relationship between both disorders (Velasco et al., 2006). A missing variable or factor could be responsible for the association of MTLE-HS and cNCC. A possible alternative explanation would be that cysticercosis and hippocampal sclerosis may be associated with a third variable, such as low socio-economic status, or a genetic or immunological predisposition that could explain this association. Although efforts were undertaken to control the socio-economic variables in this work, our study is retrospective. Perhaps only a prospective cohort study could establish a causal relationship between neurocysticercosis and MTLE-HS, although this type of study is hardly feasible, for obvious reasons. Nevertheless, our findings present strong points which need to be considered. It analyzed a large cohort of MTLE-HS patients from a region in which neurocysticercosis is endemic, and all patients were extensively evaluated by a team specialized
1894 in the treatment of NCC or epilepsy. Logistic regression was used for establishing the independence of variable studied. More importantly, we determined that in patients with a single cNCC, there is a possible association between the hemisphere of cNCC and the hemisphere of MTLE-HS. This is an anatomical relationship that could hardly be explained by low socio-economic status, or other genetic or immunological predispositions. Moreover, our observations have biological plausibility because they are supported by previous studies suggesting that infectious or inflammatory disorders could lead to MTLE-HS; neurocysticercosis might as well be one of these disorders. Thus, we believe that these results are interesting and may contribute to a better understanding of the spectrum of neurocysticercosis and epilepsy.
Conclusions In this study we present evidence implying a role of NCC in MTLE-HS, a possibility that might be important if one consider the worldwide prevalence of neurocysticercosis (Bianchin et al., 2010). Also, we suggest that NCC might be a marker for MTLE-HS or provide plausible mechanisms for how NCC may contribute or even cause MTLE-HS. Our observations may improve the current knowledge about the pathogenesis of MTLE-HS and about epilepsy associated with NCC. In our view, these aspects are important because they open new opportunities for epilepsy research and may contribute to further elucidating the pathogenesis of epilepsy worldwide.
Acknowledgements This study was fully supported by Brazilian Government research grant agencies CNPq (http://www.cnpq.br), grants no. 306644/2010-0 and no. 485423/2012-0, and FAPERGS/CNPq/PRONEM (11.2043.0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors has any conflict of interest to disclose. We thanks Prof. Patrícia Klarmann Ziegelmann and Nucleo de Assessoria Estatística (NAE) UFRGS for statistical help and Elettra Greene for review of the English language.
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