Epilepsy Research (2014) 108, 1889—1895

jo ur nal ho me p ag e: www.elsev ier .com/ locate /ep i lepsyres

Characteristics of mesial temporal lobeepilepsy associated with hippocampalsclerosis plus neurocysticercosis

Marino M. Bianchina,b,∗, Tonicarlo R. Velascoa,c,Lauro Wichert-Anaa,c, Veriano Alexandre Jr.a,c,David Araujo Jr.a,d, Antonio Carlos dos Santosa,d,Carlos G. Carlotti Jr.a,e, Osvaldo M. Takayanaguic,Américo C. Sakamotoa,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, Brazilb Basic Research and Advanced Investigations in Neurology (B.R.A.I.N.), Hospital de Clínicas de PortoAlegre, UFRGS,Porto Alegre, Brazilc Department of Neurosciences and Behavior, Ribeirão Preto School of Medicine, University of São Paulo,Ribeirao Preto, Brazild Department of Radiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto,Brazile Neurosurgery Division, Department of Surgery and Anatomy, Ribeirão Preto School of Medicine, Universityof São Paulo at Ribeirão Preto, Ribeirão Preto, Brazil

Received 20 June 2014; received in revised form 11 September 2014; accepted 13 September 2014Available online 11 October 2014

KEYWORDSHippocampalsclerosis;Focal epilepsy;

Summary Recent observations suggest that neurocysticercosis (NCC) might act as an initialprecipitating injury (IPI) causing mesial temporal lobe epilepsy associated with hippocampalsclerosis (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

Epileptogenesis;Cysticercosis;Initial precipitatinginjury

compared with those of patients with MTLE-HS plus NCC. Seventy-one patients (37,2%) pre-sented chronic findings of NCC (cNCC). MTLE-HS plus cNCC was significantly more common inwomen (O.R. = 2.45; 95%CI = 1.30—4.60; p = 0.005), in patients with no history of classical formsof IPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in those with bi-temporal interictal spikeson video-EEG (O.R. = 2.00; 95%CI = 1.07—3.73; p = 0.03). Single cNCC lesions were observed tooccur 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 CEP14048-900, SP, Brazil. Tel.: +55 51 96 37 69 69.

E-mail address: mmbianchin@hotmail.com (M.M. Bianchin).

http://dx.doi.org/10.1016/j.eplepsyres.2014.09.0180920-1211/© 2014 Elsevier B.V. All rights reserved.

1890 M.M. Bianchin et al.

an anatomical relationship between NCC and MTLE-HS. Taken together, our results suggest thatNCC may be a marker, or contributes to or even causes MTLE-HS. Based on our findings, we proposetwo distinct, non-excluding, and potentially synergistic mechanisms involved in the developmentof MTLE-HS in NCC, one of them being inflammatory-mediated, while the other is electrogenic-mediated. Taken together, our observations may provide further evidence suggesting a role ofNCC in the genesis or development of MTLE-HS.© 2014 Elsevier B.V. All rights reserved.

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ntroduction

eurocysticercosis (NCC) is caused by Taenia solium, annfestation which is endemic in Latin America, Asia, India,nd Africa, and affects millions of individuals. It is one of theost common causes of CNS infection and acquired epilepsyorldwide. In developed countries, NCC is less common but

s still a public health problem (Nash and Garcia, 2011; Delrutto, 2012; Croker et al., 2012; Singh et al., 2013; Carpiot al., 2013; Bruno et al., 2013; Cantey et al., 2014).

Recent observations suggest that NCC might act as annitial precipitating injury (IPI), causing mesial temporalobe epilepsy associated with hippocampal sclerosis (MTLE-S) in some patients. First described in single case reports

Kobayashi et al., 2001; Wichert-Ana et al., 2004; da Silvat al., 2006; Singla et al., 2007), this association was lateround to be much more common (Bianchin et al., 2006,012, 2013; Velasco et al., 2006; Rathore et al., 2012,013). Considering the high prevalence of NCC and MTLE-HSorldwide, this becomes an important issue which deserves

urther investigation.In Brazil, NCC is endemic and we have pointed previously

possible association between NCC and MTLE-HS (Bianchint al., 2006, 2012, 2013; Velasco et al., 2006). Here, wevaluated further differences in demographic, clinical neu-oimaging and surgical outcome of 191 consecutive MTLE-HSatients in order to better understand how an interplayetween two of the most common causes of human focalpilepsy may occur.

ethods

atients

fter approval by the Ethics Committee of our institution,e selected a series of 200 consecutive patients surgically

reated for MTLE-HS at CIREP (Center for Epilepsy Surgeryt Ribeirao Preto) from 1995 to 2000. Nine patients werexcluded because of incomplete data. The remaining 191atients were eligible and were included in the study. Theariables studied included gender, age at surgery, age atpilepsy onset (recurrent seizures), epilepsy duration, pos-tive history for an initial precipitating insult (IPI), monthlyeizure frequency, video-EEG interictal recordings, and neu-oimaging. A positive history of IPI was considered if patientsad a history of birth injury, febrile convulsion, meningitis

r meningoencephalitis (other than neurocysticercosis), sta-us epilepticus, or traumatic brain injury. Traumatic brainnjury was based on a history of head concussion severenough to require hospitalized observation. Patients were

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ategorized as seizure-free if they experienced no complexartial seizures or generalized tonic—clonic seizures afterurgery. All patients included in this study received care at aublic governmental university hospital and were from low-ncome households, which qualified them for public healthssistance. Socio-economic background and years of studyid not differ between patients with MTLE-HS alone andatients with MTLE-HS plus cNCC.

The study was approved the Research Ethics Committeef the University Hospital, Faculty of Medicine of Ribeirãoreto, University of São Paulo, and was conducted accordingith The Code of Ethics of the World Medical Association

Declaration of Helsinki). All patients gave written informedonsent to participate. Our study is in accordance with theTROBE requirements.

iagnosis of neurocysticercosis

efinitive neurocysticercosis was diagnosed if the followingriteria were met (i) an absolute criterion, such as his-ological demonstration of the parasite or cystic lesionshowing the scolex on CT or MRI; (ii) two major crite-ia, such as lesions highly suggestive of neurocysticercosisn neuroimaging studies, spontaneously resolving small sin-le enhancing lesions, or resolution of intracranial cysticesions after therapy with albendazole or praziquantel; oriii) one major and two minor criteria, such as lesions com-atible with neurocysticercosis on neuroimaging studies,linical manifestations suggestive of neurocysticercosis, andositive CSF ELISA for the detection of anticysticercal anti-odies, plus epidemiological evidence. According to thebove criteria, the presence of solid, dense, supratento-ial calcifications, 1—10 mm in diameter, in the absence ofther illnesses should be considered to be highly suggestivef neurocysticercosis (Del Brutto et al., 2001; Velasco et al.,006).

euroimaging

euroimaging included a CT-scan and MRI with special pro-ocols for MTLE-HS. Based on MRI analysis, MTLE-HS waslassified as unilateral or bilateral. Based on neuroradiologic

vidence of chronic NCC (MTLE-cNCC). Exams of patientsith a single chronic calcified cNCC were carefully evalu-ted and the cerebral hemisphere of the cNCC lesions andide of hippocampal sclerosis were recorded for analysis.

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Characteristics of mesial temporal lobe epilepsy associated

Presurgical evaluation of patients

Presurgical evaluation was performed by an experiencedmultidisciplinary team and included a detailed clinicalhistory and neurological examination, interictal and ictalvideo-EEG analysis, structural and functional imaging, psy-chiatric evaluation, neuropsychological testing, and, whenappropriate, the intracarotid amobarbital test (Wada’s test)for memory and speech representation. As part of thepresurgical evaluation, all patients were submitted to pro-longed video-EEG recording (Vangard System, Cleveland,OH, USA) using scalp electrodes and sphenoidal electrodes.Interictal spikes were assessed by visual analysis as pre-viously described and classified as (1) unilateral interictalspikes, if 100% or more of all spikes occurred in one temporallobe, (2) no spikes, if no spikes were observed during video-EEG, or (3) bilateral, in all other cases. At least four seizureswere recorded for each patient. In all cases, the epilepto-genic zone (EZ) was inferred on the basis of the clinical,neuroimaging, neuropsychological and electrophysiologicalresults. 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. Surgerywas resection of a maximum of 4.0 to 5.0 cm of the ante-rior lateral temporal lobe. The mesial resection included2/3 of the amygdala and the anterior 2.0 to 3.0 cm of thehippocampus. All patients had anathomopathological con-firmation of mesial temporal sclerosis. Surgical outcomewas defined by seizure status determined during outpatientclinical interviews. For seizure outcome, we used Engels’classification. Seizure outcome was assessed during routinefollow-up by experienced epileptologists who were blind tothe presurgical parameters or the design of this study. Mostpatients included in this cohort were available for the eval-uation of surgical outcome and continued to be followed upin 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 testor Fisher’s exact test. The chance of finding a chronic cal-cified lesion at the same side of the hippocampal sclerosiswas further evaluated using Binominal Test. Binary logisticregression using SPSS Statistics v.17.0 established indepen-dence 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, usinglikelihood ratio elimination. In this model, removal testingis based on the probability of the likelihood-ratio statistic,which in turn is based on the maximum partial likelihoodestimates. Results were considered significant if p < 0.05.

Results

Clinical characteristics of patients, electrophysiologicaland neuroradiological findings and comparisons between

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hippocampal sclerosis plus neurocysticercosis 1891

atients with MTLE-HS alone and with MTEL-HS plus chronicalcified neurocysticercosis are presented in Table 1 Inhis cohort of 191 patients, 71 (37.2%) evaluated and sur-ically treated for MTLE-HS presented neuroradiologicalndings compatible with cNCC. Of these 71 patients, 3954.9%) had a single cNCC lesion and 32 (45.1%) had morehan one cNCC lesion. All NCC lesions of these patientsere old, chronic and calcified lesions. Considering only

hese 71 patients with cNCC, 45 (63.4%) were womennd only 26 (36.6%) were men, a significant differencep = 0.01). When compared with pure MTLE-HS, patientsith MTLE-HS plus cNCC were found to have fewer yearsf schooling, a lower frequency of febrile seizures or clas-ic forms of IPI, and a trend to show interictal video-EEGi-temporal spikes more often. After eight steps, logis-ic regression showed that cNCC in MTLE was observedore frequently in women (O.R. = 2.45; 95%CI = 1.30—4.60;

= 0.005), in patients with no history of classical forms ofPI (O.R. = 2.67; 95%CI = 1.37—5.18; p = 0.004), and in thoseith bi-temporal interictal spikes on video-EEG (O.R. = 2.00;5%CI = 1.07—3.73; p = 0.03) (Table 2). After backward step-ise selection logistic regression, no differences werebserved between MTLE-HS and MTLE-HS plus cNCC patientsegarding years of education or history of febrile seizures.dditionally, 73 (60.8%) patients without cNCC and 2460.0%) patients with a single cNCC lesion presented 100%nilateral temporal spikes. Among the patients with morehan one cNCC lesion, only 9 (28.1%) presented 100% unilat-ral temporal spikes, a significant difference (p = 0.004).

Thirty-nine patients presented a single cNCC lesion. Theingle cNCC lesion was located in the temporal lobes in 13f them (33%), in the occipital lobes in 12 (31%), in the pari-tal lobes in 7 (18%), in the frontal lobes in 5 (13%) andn other regions in 2 (5%). In patients with a single calci-cation, this calcification occurred more frequently in theame brain hemisphere as the one with hippocampal scle-osis. More specifically, among these 39 patients, 21 singleNCC were observed in the left hemisphere and 17 (81%)f these patients presented left MTLE-HS. Only 4 (19%) ofhese patients presented right MTLE-HS. On the other hand,8 patients presented a right hemisphere single cNCC and0 of these (56%) presented right MTLE-HS, while 8 (44%)resented left MTLE-HS. In other words, 27 (69.2%) from 39atients had the single cNCC lesion located in the same brainemisphere of the hippocampal sclerosis while 12 (29.8%) ofatients had the single cNCC lesion located in the oppositeemisphere of the hippocampal sclerosis. Thus, the distribu-ion of single cNCC in MTLE-HS patients was more frequentlyo-localized in the same brain hemisphere. Fisher’s test con-rmed that this distribution pattern had a lower probabilityo occur by chance (p = 0.024). Binominal test showed thathe chance to observe a cNCC lesion in the same brain hemi-phere of the hippocampal sclerosis had a low probabilityo occur by the chance (p = 0.0237). This suggests that hip-ocampal sclerosis was significantly more likely to occurn the same hemisphere as cNCC. In our view, this find-ng may suggest an anatomical relationship between cNCCesions and hippocampal sclerosis. Due to the lobar distri-

utions of single cNCC, which in our patients were observedo occur predominantly in the temporal or occipital lobes,e suggest that lesions in the temporal or occipital lobesight be particularly responsible for the observation of a

1892 M.M. Bianchin et al.

Table 1 Clinical, neurophysiological, and neuroradiological findings in MTLE-HS patients with cNCC (HS-NCC) or MTLE-HSwithout cNCC (HS-only).

Variable All patients Groups p

HS-NCC (n = 71) HS-only (n = 120)

GenderMale 93 (48.7%) 26 (36.6%) 67 (55.8%) 0.01*

Female 98 (51.3%) 45 (63.4%) 53 (44.2%)

Years of educationMean 6.62 5.79 7.12 0.047*

SD 4.47 4.26 4.53

Age at epilepsy onset (y)Mean 10.32 9.96 10.53 0.61SD 7.64 6.49 8.27

History of IPINo 59 (30.9%) 30 (42.3%) 29 (24.2%) 0.009*

Yes 132 (69.1%) 38 (57.7%) 94 (75.8%)

Age at IPI (y) n = 132Mean 1.95 2.08 1.89 0.46SD 1.34 1.42 1.31

Febrile seizuresNo 128 (67.0%) 54 (76.1%) 74 (61.7%) 0.041*

Yes 63 (33.0%) 17 (23.9%) 46 (38.3%)

Disease duration (y)Mean 24.60 25.37 24.11 0.37SD 9.42 8.90 9.72

Age at surgery (y)Mean 34.91 35.32 34.67 0.62SD 8.72 7.80 9.25

Seizures/monthMean 3.57 3.58 3.56 0.86SD 0.72 0.69 0.74

Side MTSRight 75 (39.3%) 28 (39.4%) 47 (39.2%) 0.971Left 116 (60.7%) 43 (60.6%) 73 (60.8%)

Interictal EEG100% Unilateral spikes 106 (55.5%) 33 (46.5%) 73 (60.8%) 0.054Bilateral 85 (44.5%) 38 (53.5%) 47 (39.2%)

Surgical outcomeEngel I 141 (73.8%) 52 (73.2%) 92 (76.7) 0.595Other 50 (26.2%) 19 (26.8%) 28 (23.3)

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* Significant in univariate analysis.

ongruent hemispherical relationship between MTLE-HS andNCC, although we could not test this possibility or spe-ific neuronal pathways in this study because we wouldeed a much larger number of patients. Other authors have

uggested a similar possibility (Rathore et al., 2012). Thisight be an interesting aspect for future researches. Nev-

rtheless, taken together these findings might suggest annatomical connection between NCC and MTLE-HS, perhaps

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iscussion

eventy one (37.2%) of 191 patients with MTLE-HS refrac-ory epilepsy presented chronic NCC, a prevalence far higher

Characteristics of mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis 1893

Table 2 Final step of a backward stepwise logistic regression model showing the variables independently associated withMTLE-HS plus cNCC.

Variables Univariate analysis Logistic regression Adjusted p

Crude O.R. 95%CI Adjusted O.R. 95%CI

Female gender 2.19 1.20—4.00 2.45 1.30—4.60 0.005*

No classical IPI history 2.29 1.22—4.31 2.67 1.37—5.18 0.004*

Bilateral interictal EEG 1.79 0.99—3.24 2.00 1.07—3.73 0.03*

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than expected for our population (Velasco et al., 2006;Bianchin et al., 2012, 2013).

In this study, cNCC lesions in MTLE-HS patients was inde-pendently and significantly more common in women, inpatients without a history of classical forms of IPIs and inpatients with bi-temporal spikes during interictal video-EEG.Single cNCC lesions seemed to occur more often on the sameside as MTLE-HS. This last finding is important because ifits confirmed it might suggests a plausible anatomical con-nection between NCC and MTLE-HS. At this point, we mayalso suggest that the presence of cNCC in some MTLE-HSpatients may not be simply a coincidence. Considering thatcentral nervous infections might be a risk factor for MTLE-HSdevelopment, it is plausible to propose that NCC, similarlyto other inflammatory or infectious diseases (Mathern et al.,1995, 2002; Bando et al., 2011; Rathore et al., 2012), couldact as an IPI and lead to MTLE-HS.

Among our MTLE-HS patients, cNCC was more commonlyobserved in women. The prevalence of NCC is higher inBrazilian males, but females present more frequently withsevere forms of NCC (Agapejev, 1996). Severe forms ofneurocysticercosis are characterized by an intense inflam-matory response and are more common in female patients(Rangel et al., 1987). This is in line with the concept thatinflammatory processes seem to be related to the pathogen-esis of MTLE-HS and suggests that inflammatory mechanismsmight be important in the development of MTLE-HS associ-ated with NCC (Bianchin et al., 2012).

Electroencephalographic spikes are a hallmark ofepilepsy. Our observation that bilateral temporal interictalspikes were more common in MTLE-HS plus cNCC patientsor in patients with multiple cNCC lesions might suggest amore diffuse epileptic process in patients with MTLE-HS pluscNCC. Seizures are frequent neurological manifestations ofneurocysticercosis. Several lines of evidence suggest thatstatus epileptics or recurrent seizures might lead to hip-pocampal damage and temporal lobe epilepsy (Bertram,2007; Mathern et al., 2002). In this venue, it is possible thatsome individuals in our series might have developed seizure-induced hippocampal damage and, eventually, MTLE-HSdue to NCC. If this is the case, hippocampal damage andmesial temporal lobe epileptogenicity may be caused byphenomena similar to those observed during kindling mod-els of temporal epilepsy (Bertram, 2007; Lévesque and Avoli,

2013). Based on the above discussion, we suggest that twodistinct, non-excluding and potentially synergistic mecha-nisms might be involved in the development of MTLE-HSin NCC, one being inflammatory-mediated, and the other

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eing electrogenic-mediated. Further studies are necessaryo confirm our hypothesis.

A history of IPI is frequently associated with MTLE-HSMathern et al., 1995, 2002; Bando et al., 2011). Our findinghat patients with MTLE-HS plus NCC present a significantlyower incidence of classical IPI histories further suggestshat NCC per se might be associated with the genesis ofTLE-HS in some patients, especially in those without otherxplanations for MTLE-HS. Because NCC might be initially ailent infection for most patients, it is possible that severalatients who acquire NCC earlier in life might lack a clearistory of classical forms of IPI. In these patients, hippocam-al damage could occur or be facilitated by NCC throughepetitive seizures and/or inflammatory mediated mecha-isms. Because seizures associated with NCC might vanishith time, only the epileptic symptoms caused by MTLE-HSight be evident later in life. When such patients go forore detailed medical investigation because of epilepsy,any of them may display non-active, old, calcified NCC

esions located in extra-mesial regions, but may presentefractory seizures initiating in the mesial temporal lobe.fter surgery, patients became seizure free as long as theyemained medicated, making it difficult, although possible,o establish an association between these two pathologies.

Our study has some limitations that need to be acknowl-dged. It is a retrospective study, carried out on surgicalatients. We did not explore all the clinical impact thatNCC might have on MTLE-HS, like for example cognitive oreuropsychiatric aspects (Terra-Bustamante et al., 2005).oreover, as previously discussed by our group, the pres-nce of calcified cysticercotic lesions in MTLH-HS patientsoes not necessarily imply that there is a causal relation-hip between both disorders (Velasco et al., 2006). A missingariable or factor could be responsible for the association ofTLE-HS and cNCC. A possible alternative explanation woulde that cysticercosis and hippocampal sclerosis may be asso-iated with a third variable, such as low socio-economictatus, or a genetic or immunological predisposition thatould explain this association. Although efforts were under-aken to control the socio-economic variables in this work,ur study is retrospective. Perhaps only a prospective cohorttudy could establish a causal relationship between neu-ocysticercosis and MTLE-HS, although this type of studys hardly feasible, for obvious reasons. Nevertheless, our

ndings present strong points which need to be consid-red. It analyzed a large cohort of MTLE-HS patients from

region in which neurocysticercosis is endemic, and allatients were extensively evaluated by a team specialized

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n the treatment of NCC or epilepsy. Logistic regressionas used for establishing the independence of variable

tudied. More importantly, we determined that in patientsith a single cNCC, there is a possible association between

he hemisphere of cNCC and the hemisphere of MTLE-HS.his is an anatomical relationship that could hardly bexplained by low socio-economic status, or other genetic ormmunological predispositions. Moreover, our observationsave biological plausibility because they are supported byrevious studies suggesting that infectious or inflammatoryisorders could lead to MTLE-HS; neurocysticercosis mights well be one of these disorders. Thus, we believe thathese results are interesting and may contribute to a bet-er understanding of the spectrum of neurocysticercosis andpilepsy.

onclusions

n this study we present evidence implying a role of NCCn MTLE-HS, a possibility that might be important if oneonsider the worldwide prevalence of neurocysticercosisBianchin et al., 2010). Also, we suggest that NCC mighte a marker for MTLE-HS or provide plausible mechanismsor how NCC may contribute or even cause MTLE-HS. Ourbservations may improve the current knowledge about theathogenesis of MTLE-HS and about epilepsy associated withCC. In our view, these aspects are important because theypen new opportunities for epilepsy research and may con-ribute to further elucidating the pathogenesis of epilepsyorldwide.

cknowledgements

his study was fully supported by Brazilian Govern-ent research grant agencies CNPq (http://www.cnpq.br),

rants no. 306644/2010-0 and no. 485423/2012-0, andAPERGS/CNPq/PRONEM (11.2043.0). The funders had noole in study design, data collection and analysis, decisiono publish, or preparation of the manuscript. None of theuthors has any conflict of interest to disclose. We thanksrof. Patrícia Klarmann Ziegelmann and Nucleo de Assesso-ia Estatística (NAE) UFRGS for statistical help and Elettrareene for review of the English language.

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