Epilepsy Research (2015) 110, 221—227

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

Hyperventilation induces sympatheticoveractivation in mesial temporal epilepsy

Giovanni Assenzaa,∗, Oriano Mecarelli b, Mario Tombinia,Patrizia Pulitanob, Giovanni Pellegrinoa, Antonella Benvengaa,Federica Assenzaa, Chiara Campanaa, Giovanni Di Pinoa,Vincenzo Di Lazzaroa

a Clinical Neurology, Campus Biomedico, University of Rome, Rome, Italyb Department of Neurology and Psychiatry, Sapienza University, Policlinico Umberto 1 Hospital, Rome, Italy

Received 12 June 2014; received in revised form 2 December 2014; accepted 3 December 2014Available online 13 December 2014

KEYWORDSHyperventilation;Heart rate variability;Mesial temporal lobeepilepsy;Sympathetic nervoussystem

SummaryObjective: Hyperventilation (HV) during electroencephalography (EEG) is a standard clinicalprocedure to trigger seizures in patients affected by mesial temporal lobe epilepsy (MTLE).Despite the pathophysiology of this susceptibility to HV is not definitively understood, it may behypothesized to be related to ictal and interictal sympathetic nervous system abnormalities,the presence of which is well known in MTLE patients. In order to test this hypothesis weinvestigated the HV effect on heart rate variability (HRV) in a group of MTLE patients, comparedto a matched group of healthy controls.Material and methods: Forty patients affected by MTLE and 40 age- and sex-matched controlswere enrolled in the study. In those subjects, a standard electroencephalographic recording hasbeen acquired and the high and the low frequency components (HF, LF) of heart rate variability(HRV) and their ratio (LF/HF) have been analyzed at rest and during the HV. Indeed, LF/HF is areliable index of sympathetic tone modulation.

Results: HRV did not differ between MTLE and healthy subjects at rest, whereas HV induced asignificant LF/HF increase only in MTLE. Within the MTLE group, males showed higher LF/HFincrease during HV respect to females, while no differences related to the side of the epilepticfocus were found.Discussion: MTLE patients showed an increased sympathetic response to HV compared to healthysubjects. HRV analysis points towards an autonomic overactivation as a pathophysiological

Abbreviations: HV, hyperventilation; MTLE, mesial temporal lobe epilepsy; HRV, heart rate variability; HF, high frequency componentsof heart rate variability; LF, low frequency components of heart rate variability.

∗ Corresponding author. Giovanni Assenza, MD, Campus Biomedico University of Rome, Tel.: +39 06 225411220; fax: +39 06 225411955.E-mail address: gianni.assenza@gmail.com (G. Assenza).

http://dx.doi.org/10.1016/j.eplepsyres.2014.12.0030920-1211/© 2014 Elsevier B.V. All rights reserved.

222 G. Assenza et al.

pathway subtending seizure triggered by hyperventilation in MTLE. Autonomic susceptibility inMTLE may help to explain the increased prevalence of arrhythmic events in these patients,potentially predisposing to Sudden Unexpected Death in Epilepsy (SUDEP).© 2014 Elsevier B.V. All rights reserved.

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yperventilation (HV) is a standard procedure of electroen-ephalogram (EEG) recordings that, in normal individuals,rovokes a physiological slowing of brain rhythms (Gibbst al., 1943). In epileptic patients, HV can also triggernterictal epileptiform discharges and seizures. HV boostspileptiform discharges in a vast majority of patientsffected by idiopathic generalized epilepsies (Drury, 2000)nd in a smaller percentage of focal epilepsies (Morgannd Scott, 1970). Within the focal patient group, tem-oral lobe epilepsy show higher susceptibility (Guaranhat al., 2005). Data on putative pathophysiological pathwaysnducing this EEG ‘‘activation’’ during HV are not conclu-ive. One hypothesis points towards the role played by HVn haemodynamic changes: it decreases arterial pCO2 andeads to vasoconstriction of precapillary arterioles which,s a consequence, reduces cerebral blood flow (Kety andchmidt, 1948; Wasserman and Patterson, 1961) and sustainsEG slow activity (Berger, 1934; Davis and Wallace, 1942;ibbs et al., 1942). Such changes resemble those observed inerebral hypoxia and ischaemia (Kraaier et al., 1988a; Meyernd Gotoh, 1960). On the other hand, specific EEG stud-es performed during progressive hypocarbia and hypoxiauggested that EEG changes due to HV are largely indepen-ent from cerebral hypoxia (Kraaier et al., 1988b) and maye determined by HV effects on autonomic nervous systemalance. In particular, prolonged inspiration induces acti-ation of lung stretch receptors, and a consecutive vagalesponse (Robertson et al., 2012). It is known that epilep-ic patients, in particular those with mesial temporal lobepilepsy (MTLE), suffer ictal and interictal autonomic unbal-nce (Ansakorpi et al., 2000; Tinuper et al., 2001), becausef the direct effect on heart rate of an abnormal activitynvolving the insular cortex (Oppenheimer et al., 1992). Inhis light, in the present study we aimed at studying HVffects on autonomic balance in patients affected by MTLEespect to healthy subjects.

aterial and methods

atients

e retrospectively analyzed ECG of 40 patients (47 ± 14ears, 24 females) affected by MTLE (24 patients witheft epileptic focus—–LEF -, and 16 with right epilepticocus—–REF-; demographical and clinical data in Table 1)cquired during standard EEG performed at the ‘‘Epilepsyutpatient clinic’’ of Campus Bio-Medico University ofome and at ‘‘Epilepsy outpatient clinic’’ of La Sapienza

niversity of Rome. MTLE was diagnosed by the conver-ence of clinical, EEG and MRI examinations, according tohe recommendations of the International League Againstpilepsy (Commission on Classification and Terminology of

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he International League Against Epilepsy, 1981, 1989).atients were also grouped according to their seizurerequency (SF) in 4 classes (Class 1: SF < 1/month; Class: 1/week < SF ≥1/month; Class 3: 1/day <SF ≥ 1/week;lass 4: SF ≥ 1/day). Forty age and sex-matched healthy

ndividuals (51 ± 21 years, 24 females) were also col-ected for the study (unpaired t-test for the variablege: t = −970, df 78, p = 0.335). The study protocol waspproved by the Local Ethic Committee. Patients did notrovide their written consent to participate to the studyecause it was a retrospective study executed analysinglinical outpatient standard electroencephalographicecordings.

CG recordings

lectrocardiographic (ECG) signal was recorded from twolectrodes placed over the chest simultaneously to atandard EEG recording (256 Hz sampling rate) performedith eyes-closed, at rest (4 min) and during HV (4 min). EEGas acquired using 19 scalp electrodes positioned accord-

ng to the International 10—20 System (0.3—50 Hz bandpass,inked ear reference, impedances of all electrodes below

k�).

eart rate variability (HRV)

RV was analyzed in the frequency domain using dedicatedRV Analysis Software 2.0 for Windows (Biomedical Signalnalysis Group, Department of Applied Physics, University ofuopio, Finland). HRV analysis was performed on the follow-ng RR-interval epochs: (i) the last 2 min at the end of restingtate; (ii) the last 2 min at the end of HV. We only considered

high frequency component, reflecting mostly vagal activitycentred at 0.1 Hz, range: 0.04—0.15 Hz), and a low fre-uency component (range 0.15—0.4 Hz), which origins from

mixed contribution of sympathetic and vagal activities.he very low frequency oscillatory components (<0.04 Hz,LF) were not assessed because they are usually largely con-aminated by DC noise. For both the components of interest,e computed Normalized units of power (respectively, LFnd HF) dividing each component power by the differencef the total power minus the DC component. The LF/HFatio (LF/HF) was exploited as an index of sympatho-vagalalance (Task Force of the European Society of Cardiologynd North American Society of Pacing and Electrophysiology,996) (Fig. 1).

ata are reported as mean ± standard deviation. HRV vari-bles were normally distributed (Kolgmorow—Smirnov test

> 0.5). A generalized linear model was created to checkor a possible condition effect (Basal vs. Hyperventilation)

Hyperventilation induces sympathetic overactivation in mesial temporal epilepsy 223

Table 1 Clinical data of mesial temporal lobe epileptic patients and healthy subjects.

Group N Gender Age Epilepticfocus side

Aetiology Drugs (N) Seizurefrequencyclass (N)

MTLE 40 24F/16M 47 ± 14 yy 24L/16R 26 crypto14 sympt(5 HS)

Monotherapy = 24Poly = 16Na-blockers = 16

Class 1 = 7Class 2 = 18Class 3 = 10Class 4 = 5

Healthy 40 24F/16M 51 ± 21 yy

MTLE: mesial temporal lobe epileptic patients; F: female; M: male; yy: years; L: left; R: right; crypto: cryptogenic; sympt: symptomatic;ncy; y

HS: hippocampal sclerosis; poly: poly-therapy; SF: seizure freque

Class 3: 1/day < SF ≥ 1/week; Class 4: SF ≥ 1/day.

on HRV variables (LF, HF and LF/HF ratio) between healthysubjects and epileptic patients (between-subject factor,group). Within epileptic patients group, a generalized linermodel was built to test whether lateralization of epileptic

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Fig. 1 (A) 2 min of EEG at rest (basal) and 2 min of EEG during hyperin healthy subjects (left) and in patients with mesial temporal loperformed on electrocardiogram trace of these epochs. (B) Distributioanalyzed via fast-fourier transformation and the power spectrum deof very low frequency (VLF), low frequency (LF) and high frequency (a condition (basal vs. hyperventilation) significant effect and a comLF, HF and LF/HF HRV variables. * LF, HF and LF/FH were different(p = 0.0001, p = 0.0001 and p = 0.002, respectively).MTLE: mesial temporal lobe epileptic patients; LF: low frequencyfrequency component; LF/HF: low frequency to high frequency comunits (mean ± standard deviation).

y: years; Class 1: SF < 1/month; Class 2: 1/week < SF ≥ 1/month;

ocus (side effect, left vs. right), gender (male vs. female),EG hyperventilation-sensitivity (i.e. the increase ofpileptic EEG waves induced by hyperventilation; positives. negative), aetiology (cryptogenic vs. symptomatic),

ventilation were selected in standard outpatient EEG recordingsbe epilepsy (MTLE). An analysis of heart rate variability wasn of R—R waves was plotted over time. (C) R—R distribution was

nsity (PSD) was calculated according to the 3 frequency rangesHF) bands. (D) Generalized linear model analysis demonstratedbined condition × group (MTLE vs. healthy subjects) effect for

between hyperventilation and basal condition in MTLE group

component; HF: High frequency component; VLF: very lowponent ratio. Data in the table are expressed in normalized

224 G. Assenza et al.

Fig. 2 b: basal condition; h: hyperventilation condition; HV: EEG hyperventilation-sensitivity; R: right side mesial temporal lobeepilepsy; L: left side mesial temporal lobe epilepsy; M: male; F: female; HV+: EEG epileptic ‘‘activation’’ induced by hyperven-tilation; HV− no EEG epileptic ‘‘activation’’ induced by hyperventilation; Et+: symptomatic epilepsy; Et−: cryptogenic epilepsy;Hs+: hippocampal sclerosis; Hs−: no hippocampal sclerosis; Na+: assumption of sodium blocker drugs; Na−: no assumption of sodiumblocker drugs. MTLE: Mesial temporal lobe epilepsy. hv: hyperventilation condition; HS: sclerosis of hippocampus; Na blockers: useof Na channels blocker antiepileptic drugs; * Generalized linear model analysis demonstrated, in MTLE patients, a condition × gendereffect on LF/HF (F = 4.323; p = .044). ** Generalized linear model analysis demonstrated, in MTLE patients, a condition × aetiologyeffect on LF and HF (F = 4.639; p = 0.038; F = 4.842, p = 0.034, respectively). Generalized linear model analysis did not demonstrateds tilato

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ignificant effects for condition × side, condition × EEG hypervenn LF, HF and LF/HF.

clerosis of hippocampus (positive vs. negative), sodium-hannel blockers drug therapy (positive vs. negative)nfluenced the response to HV (condition effect). Compar-son between groups was also performed with independentamples t-test. One-way ANOVA tested the differencesmong different seizure frequency groups and HRV vari-bles. Pearson’s correlation coefficients were employed toheck a possible relationship among HRV variables and age.

esults

V induced a specific modulation of HRV in MTLE patientsespect to healthy subjects (Fig. 1). Generalized linearodel analysis demonstrated a significant condition effect,ut also a combined condition × group effect for LF, HFnd LF/HF HRV variables (condition effect: LF, F = 17.818,

= 0.0001; HF, F = 16.620, p = 0.0001; LF/HF, F = 12.044, = 0.001; condition × group effect: LF, F = 10.366, p = 0.002;F, F = 10.501, p = 0.002; LF/HF, F = 9.217, p = 0.003). Meanalues analysis (univariate analysis) revealed that the effectf HV was evident only for the group of epileptic patients.n particular, during HV, LF increased (t = −4.995, p = 0.0001)nd HF decreased in MTLE (t = 4.972, p = 0.0001) respect toasal condition. This does not happen in healthy subjectsrespectively, t = −0.751, p = 0.618 and t = 0.617, p = 0.541).onsequently LF/HF ratio was increased during HV only inTLE (t = −3.396, p = 0.002). When building a generalized

inear model only in MTLE to verify a possible conditionffect on LEF respect to REF patients we did not find anyondition × side effect (Fig. 2). When checking for a possibleondition effect dependent on gender, we found that the HV

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ion-sensitivity, condition × HS, condition × Na blockers effects

ffect on LF/HF was more pronounced in male than in femaleTLE (LF, F = 0.353, p = 0.556; HF, F = 0.399, p = 0.531; LF/HF,

= 4.323, p = 0.044). t-Test analysis did not revealed differ-nces in basal values between males and females (p > 0.05).o effects of gender on HRV variables were found when MTLEnd healthy subjects were grouped together (p > 0.05). InTLE, the condition effect on HRV parameters was inde-endent at all from EEG hyperventilation-sensitivity (LF,

= 0.004, p = 0.947; HF, F = 0.014, p = 0.908; LF/HF, F = 0.049, = 0.826). MTLE assuming therapy with Na-blockers demon-trated a higher basal level of LF/HF ratio (p = 0.034),ut condition effect was not influenced by Na-Blockersssumption (LF, F = 1.082, p = 0.305; HF, F = 1.068, p = 0.308;F/HF, F = 0.788, p = 0.380). Hippocampal sclerosis did notnfluence the condition effect (LF, F = 1.169, p = 0.287; HF,

= 1.341, p = 0.254; LF/HF, F = 1.229, p = 0.275). A combinedffect of aetiology with condition demonstrated that symp-omatic patients showed smaller variations of LF and HFalues in HV condition respect to the cryptogenic group (LF,

= 0.049, p = 0.038; HF, F = 4.842, p = 0.034; LF/HF, F = 0.004, = 0.950). No differences in HRV values distribution wereound among seizure frequency groups. No correlation wereound among HRV variables and age in epileptic and healthyroups (p > 0.4).

iscussion

ur data are in favour of an overactivation of sympatheticervous system induced by HV, as expressed by HRV param-ters, in patients affected by MTLE respect to healthyontrols. In particular, during a standard EEG recording, HV

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Hyperventilation induces sympathetic overactivation in mes

increased the ratio between LF and HF band power, which isconsidered as a reliable ECG-derived index of sympatheticactivation (Vernieri et al., 2010).

These results provide new hints on the physiologicalpathways mediating seizure susceptibility to HV in MTLEpatients. Studies during progressive hypocarbia and hypoxiaand during drug-induced hypoperfusion (Kraaier et al., 1992)demonstrated that the EEG epileptic activation observedduring HV should be mainly or totally attributed to fac-tors other than cerebral hypoxia or hypoperfusion. In thislight, our data offer the sympathetic overactivation as apotential seizure precipitant caused by hyperventilation.This theory is strengthened by the converging evidencethat several well-established seizure precipitants sharesympathetic overactivation as common neurophysiologicalsubstrate (e.g. stress, sleep deprivation, fever, recreationaldrug assumption; Frucht et al., 2000) and that differenttherapeutic strategies rely on counteracting sympatheticactivation by means of vagal stimulation (Chadwick, 2001;Assenza et al., 2014; Capone et al., 2014). Furthermore,elegant studies provided a potential anatomic substrate link-ing the hyperventilation manoeuvre with autonomic nervoussystem overactivation in MTLE patients. In facts, in animals,air insufflation into the nasal cavities triggers discharges inexperimentally created foci of forebrain structures (Servitand Strejckovà, 1973). In MTLE patients, nasal instead of oralHV is much more effective in activating epileptic discharges.Conversely, local anaesthesia of the mucosal membraneof the superior nasal meatus led to temporary suppres-sion of this activation (Servit and Strejckovà, 1976; Servitet al., 1977). This evidence, together with the very shortlatency for the activating effect to take place (30—60 safter the start of deep breathing), facilitates the possibilityof a reflex mesial-temporal cortical activation triggered bymechanical stimulation of the olfactory epithelium throughHV in MTLE (Servit et al., 1981). Servit and colleagues alsodemonstrated that this mechanical activation is mediatedby the stimulation of subcortical limbic structure, as hip-pocampus and amygdale, which can, in turn, influence theautonomic visceral balance and, in particular, the heart rate(Oppenheimer et al., 1992). Hippocampus is also the brainstructure mainly affected in MTLE (Mathern et al., 1997).In this neuronal network linking olfactory epithelium withlimbic structures, our results of a sympathetic overactiva-tion caused by HV may find an anatomic and physiologicalexplanation.

Autonomic cardiac modifications induced by epilepticactivity were largely demonstrated by means of the wide useof polygraphic recordings in standard EEG. Cardiac rhythmchanges occur during the majority of epileptic seizures.The most common cardiac arrhythmia seen during epilep-tic seizures is sinus tachycardia, which occurs in >90% ofseizures, usually without consequences (Blumhardt et al.,1986; Opherk et al., 2002). Dangerous arrhythmias have alsobeen described (Della Marca et al., 2008; Assenza et al.,2012), in particular in MTLE patients (Tinuper et al., 2001;Rugg-Gunn et al., 2004), and they are major candidates toprovoke the Sudden Unexpected Death in Epilepsy (SUDEP),

which affects between 0.1 and 2 per 1000 patient-years(Duncan and Brodie, 2011). SUDEP has been ascribed to theinvolvement of cortical limbic structures modulating cardiacautonomic balance during seizures (Oppenheimer et al.,

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mporal epilepsy 225

992). In this light, chronic, repeated activation of the auto-omic nervous system can lead a sympathovagal imbalance,ltimately triggering fatal arrhythmias. Even if we did notnclude patients with SUDEP in our cohort, our results canrovide a potential tool to test sympathovagal reactivitynduced by a testing procedure (hyperventilation) — easilynd routinely performed in epileptic patients — to recog-ize those patients exposed to higher risk of sympathovagaltress. HRV is a reliable approach allowing an easy and quickvaluation of sympathovagal tone through the analysis ofery short period of electrocardiographic signals (Task Forcef the European Society of Cardiology and North Americanociety of Pacing and Electrophysiology, 1996). A recenteta-analysis on the value of HRV in epileptic patients con-

luded for a reduced vagal tone at rest in epileptic patientsespect to healthy controls, as expressed by a lower HFomponent (Lotufo et al., 2012). Despite we did not findignificant changes in basal condition between healthy andTLE groups, the significantly different variation from basal

o HV condition that we described in MTLE may own a similarignificance: an unbalance of sympathetic/parasympatheticone with a disadvantage for the vagal system. The lack ofn exact formal replication of the results of Lotufo’s meta-nalysis may arise from the duration of our basal conditionvaluation (2 min) which is dissimilar from that reported inhe most of meta-analysis studies, but which was neces-ary to suite our analysis to the approved procedures forecording standard EEG in outpatient subjects (Mecarelli,010). However, the guidelines for HRV analysis (Task Forcef the European Society of Cardiology and North Americanociety of Pacing and Electrophysiology, 1996) confirm theeliability of these very short recordings and suggest to con-ider, as clinically relevant variations, only those occurringetween two dynamic conditions (e.g. clinostatic and ortho-tatic condition in tilt testing), as we did analysing changesetween the resting state and the hyperventilation condi-ions. This dynamic comparison was not reported in anyf the experiments cited by Lotufo and coworkers’ meta-nalysis. Furthermore even if they provided an excellentork of synthesis of a huge number of manuscripts aboutRV in epilepsy, their meta-analysis suffers from a veryigh heterogeneity of epileptic conditions, age, aetiologiesnd types of HRV analysis. This heterogeneity of patientsnalyzed, in our opinion, does not allow a reliable general-zation of their results and in particular a comparison withur results. For instance, we studied adult patients, whileotufo’s result of a HF reduction in epileptic patients wased by several experiments in paediatric patients, and auto-omic function is strictly age-dependent (Collins, 1991).

In our MTLE patient cohorts, men showed a higheresponse to HV than women, while gender was not relevantn basal conditions as in the cohort reported in the meta-nalysis by Lotufo et al. (2012). To date, there is no finalonclusive proof about any relationship between gendernd hyperventilation-induced autonomic or EEG response inpileptic patients (Holmes et al., 2004; Kraaier et al., 1988a;an der Worp et al., 1991). We can speculate that, as inealthy subjects, during autonomic activation females own

more efficient vagal response to baroreflex activity pertur-ation compared to males (Fisher et al., 2012). All our MTLEatients were on therapy with antiepileptic drugs. Whennalysing HRV variables in patients taking Na-blockers, they

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emonstrated an increased basal level of sympathetic toneLF/HF ratio) compared to non-Na-blocker MTLE patients.his result is not surprising because of the well-established

nfluence of these drugs on cardiac nerve conduction, in lineith the previous evidence on the role of Na-blocker drugs

n favouring arrhythmic events in epileptic patients (Surgest al., 2009). Finally, symptomatic MTLE patients showedinor HF and LF fluctuations induced by HV respect to the

ryptogenic group. This result may find an explanation inhe functional impairment of temporal-insular brain regionsaused by lesions themselves.

The major limitation of the present study is the lackf homogeneity of the patients group for the type and theumber of assumed drugs and for the aetiology. These weak-esses do not allow a subgroup analysis to discern singlerug influence and lesional topography influences on HRVhanges induced by the HV. A highly focused experimentr a higher number of subjects might solve these openeduestions.

onclusion

resent data demonstrated that MTLE patients exhibitn increased sympathetic response to HV compared toealthy subjects. HRV analysis performed in this study pointsowards an autonomic hypersensitivity of MTLE patients as

possible pathophysiological pathway contributing to theeizure precipitating effect of HV in this epileptic con-ition. The autonomic susceptibility to hyperventilationay favour arrhythmic events, potentially correlated with

UDEP. Future studies with larger cohorts are needed tonvestigate the relevance of the topographical specificity ofpileptic focus on HV susceptibility.

cknowledgments

uthors thank the neurophysiopathology technicians Ritaini and Emma Fabrizio for their valuable support in recor-ing EEG data.

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