Cardiovascular autonomic functions in

Epilepsy Research(2009)85,

261—269

j o u r n a l h o m e p a g e:w w w.e l s e v i e r.c o m/l o c a t e/e p i l e p s y r e

s

Cardiovascular autonomic functions in

well-controlled and intractable partial epilepsies Shalini Mukherjee a,Manjari Tripathi b,Poodipedi S.Chandra c,

Rajeev Yadav d,Navita Choudhary e,Rajesh Sagar f,Ra?a Bhore g,

Ravindra Mohan Pandey h,K.K.Deepak e,?

a Dept.of Neurology,UT Southwestern Medical Center at Dallas,5323Harry Hines Blvd,Dallas,TX,United States

b Dept.of Neurology,All India Institute of Medical Sciences,New Delhi110608,India

c Dept.of Neurosurgery,All India Institute of Medical Sciences,New Delhi110608,India

d Department of Electrical and Computer Engineering,Concordia University,Montreal,Canada

e Dept.o

f Physiology,All India Institute of Medical Sciences,New Delhi110608,India

f Dept.of Psychiatry,All India Institute of Medical Sciences,New Delhi110608,India

g Department of Clinical Sciences,UT Southwestern Medical Center at Dallas,5323Harry Hines Blvd,Dallas,TX,United States

h Dept.of Biostatistics,All India Institute of Medical Sciences,New Delhi110608,India

Received6March2008;received in revised form20March2009;accepted27March2009

Available online5May2009

KEYWORDS SUDEP

well-controlled epilepsy; Intractable; Autonomic tone; Inter-ictal; Dysautonomia Summary

Background:Epilepsy is associated with imbalance of sympathetic and parasympathetic activity which may lead to sudden unexplained death in epilepsy(SUDEP).Well-controlled(WcE)and intractable epilepsy(IE)subjects may present different autonomic pro?les,which can be helpful in explaining the predisposition of the latter to SUDEP.

Purpose:T o compare inter-ictal cardiovascular autonomic function in subjects with partial WcE and IE.

Methods:Thirty WcE and31IE subjects underwent a battery of autonomic function tests:deep breathing,Valsalva maneuver,isometric exercise,cold pressor and tilt-table.Autonomic tone was assessed by heart rate variability(HRV).Their autonomic severity score and anxiety status was also assessed.

?Corresponding author.T el.:+9101126593583/26594801/26594971(o)/01126164342(r);fax:+9126588663/26588789.

E-mail addresses:shalini mukherjee@https://www.360docs.net/doc/0611674472.html,(S.Mukherjee),manjari.tripathi@https://www.360docs.net/doc/0611674472.html,(M.Tripathi),saratpchandra@https://www.360docs.net/doc/0611674472.html, (P.S.Chandra),rajeevyadav@https://www.360docs.net/doc/0611674472.html,(R.Yadav),navitachoudhary@https://www.360docs.net/doc/0611674472.html,(N.Choudhary),rajeshsagar@https://www.360docs.net/doc/0611674472.html,(R.Sagar), ra?a.bhore@https://www.360docs.net/doc/0611674472.html,(R.Bhore),rmpandey@https://www.360docs.net/doc/0611674472.html,(R.M.Pandey),kkdeepak@https://www.360docs.net/doc/0611674472.html,(K.K.Deepak).

0920-1211/$—see front matter?2009Elsevier B.V.All rights reserved.

doi:10.1016/j.eplepsyres.2009.03.021

262S.Mukherjee et

al.

Results:IE subjects had elevated low frequency component(52.0vs.37.6,p=0.047)and decremented high frequency component(114vs.397,p=0.013)of HRV and higher diastolic BP(75.62±9.77vs.68.64±0.43,p=0.036).In deep breathing test,they had lesser HR changes (20±10.18vs.29.68±11.23,p=0.007)and lower E:I(1.29±0.16vs.1.43±0.21,p=0.008).IE subjects had higher dysautonomia(chi square165.0,p<0.0001).

Conclusions:We observed a higher vasomotor tone,higher sympathetic tone,lower parasympa-thetic tone,lower parasympathetic reactivity and more severe dysautonomia in the IE subjects. Refractoriness may lead to an alteration in cardiovascular autonomic regulation,which might be a predisposing factor for SUDEP.

?2009Elsevier B.V.All rights reserved.

Introduction

Seizures are frequently associated with autonomic symp-toms,which occur either during the seizure prodrome(aura) or as a predominant part of the seizure manifestation.The abnormal cortical activity underlying a seizure can involve central regions that regulate autonomic activity and present with autonomic symptoms,either initially or during its prop-agation.Seizure related hypo or hyperactivity modi?es the cardiovascular system.In many instances,there is tachy-cardia and pressor responses preceding or accompanying the seizure discharge,while bradyarrythmias and arterial hypotension are rare(Nashef et al.,1996;Devinsky et al., 1997;Leutmezer et al.,2003).Around a third of simple par-tial seizures and all generalized seizures are accompanied by autonomic symptoms(Nouri and Marshall,2006),although in partial seizures,autonomic symptoms often go undetected (Devinsky,2004).

Studies also suggest interictal autonomic disturbances, mostly showing enhanced sympathetic cardiovascular tone (Frysinger et al.,1993;Devinsky et al.,1994;Faustmann and Ganz,1994).Changes in parasympathetic heart rate modulation resulting in lower heart rate variability(HRV) have been noticed in temporal lobe epilepsies(Ansakorpi et al.,2000,2002,2004;Ronkainen et al.,2006)and general-ized epilepsies(Harnod et al.,2007;El-Sayed et al.,2007). Anti-epileptic drug therapy,speci?cally carbamezapine may also in?uence cardiovascular autonomic functions(T omson et al.,1998;Ansakorpi et al.,2000).

The mortality rate among people with epilepsy is2—3 times higher and the risk of sudden death is24times greater than in the general population(Ficker et al.,1998). Sudden unexplained death in epilepsy subjects(SUDEP) accounts for deaths in about2%of population based cohorts with epilepsy and in18—25%subjects with more severe intractable epilepsy(Walczak,2003).

The prevailing hypothesis regarding SUDEP involves seizure-induced cardio-respiratory disturbances mediated by the autonomic nervous system(Nashef et al.,1996; Rocamora et al.,2003).It has been proposed that imbalance of sympathetic and parasympathetic cardiovascular activity is a potential cause of SUDEP.It has also been postulated that reduced controls in autonomic nervous system in refrac-tory seizure disorders may be the likely cause for SUDEP (Massetani et al.,1997;Ansakorpi et al.,2000).Among the other causes,some studies have identi?ed anti-epileptic drug(AED)therapy,especially polytherapy as a risk factor independent of seizure control(Nilsson et al.,1999;Walczak et al.,2001;Walczak,2003),along with frequent dose changes and high serum concentrations of carbamazepine (Nilsson et al.,2001).Other studies have however,not been able to?nd any speci?c association between SUDEP and par-ticular AED therapy and hypothesized that SUDEP was linked more to the severity of epilepsy rather than AEDs(Leestma et al.,1997).

Keeping in mind the strong association between cardiovascular autonomic dysfunction and SUDEP and how the latter was linked to seizure severity, we wanted to study autonomic functions in sub-jects with intractable and well-controlled partial epilepsies.There is only one previous study,in which autonomic functions were compared between well con-trolled and intractable subjects with temporal lobe epilepsies(Ansakorpi et al.,2000).We hypothesized that the autonomic functions in subjects with intractable epilepsy would be different from those with well-controlled partial epilepsies,irrespective of localization of seizure foci.This is the?rst study in which heart rate variability, a complete battery of autonomic functions tests and neuropsychological questionnaires are used to compare autonomic and psychological status in subjects with refractory and well-controlled partial epilepsy.

Materials and methods

Subjects

The study was carried out in the Autonomic Function Lab in the Department of Physiology,All India Institute of Medical Sciences. Subjects were referred from the Out-Patient Departments of Neu-rology and Neurosurgery.All consecutive subjects who were treated by these departments in the age group between5and50years and con?rmed as having partial seizures,either wellcontrolled or intractable,were included in this observational study.Subjects were diagnosed as having medically intractable partial epilepsy if he has2or more disabling seizures per month,for2or more years,which is not controlled by2or more anti-epileptic drugs in their maximum tolerated doses(Radhakrishnan,1999).For the well-controlled group,only those subjects who were seizure-free for at least6months prior to the study were included.The study was approved by the Institutional Ethics committee and informed con-sent was obtained from subjects(or guardians in case of minors). Subjects with signs or symptoms other than epilepsy and suffering from diseases that are known to affect the autonomic nervous sys-tem(i.e.diabetes mellitus,cardiopulmonary disease,renal failure) were excluded from the study.Subjects with diagnosed psychiatric illness and with chronic alcoholism or smoking were also excluded.

Cardiovascular autonomic functions263

Their AED regimen was kept unchanged during the course of the study.Pregnant women were not included.

Study conditions

Subjects underwent a battery of tests to assess autonomic reac-tivity.The IE subjects were tested,in almost all cases,during hospitalization prior to epilepsy surgery.Considering the possibility that the results may be affected by anxiety of surgery and hospital-ization,we carried out detailed neuropsychological questionnaires in both groups.

Subjects were advised to refrain from food and beverages(other than water)for2h before the test and to only take their regular dose of AEDs before the test.All the tests were carried out in an air-conditioned laboratory environment(22±2?C)in supine positions for head up tilt and HRV and sitting positions for the other reactivity tests.They were carried out between9a.m.and4p.m.and the total duration of the tests was2.5—3h.Cardiovascular autonomic reactivity was tested using a standard battery of tests,as described previously(Ewing and Clarke,1982;Deepak et al.,1996).Heart rate responses during deep breathing test,Valsalva maneuver and head up tilt were noted as markers of parasympathetic reactivity,while blood pressure responses during cold pressor test,isometric hand-grip test and head up tilt were studied as markers of sympathetic reactivity.We also measured cardiovascular autonomic tone in the two groups,by means of5min supine electrocardiograph(ECG)to analyze HRV.

Baseline measurements

We used a standard polyrite(Recorders and Medicare,India)to trace heart rate and respiration.ECG recordings were taken using the Lead II con?guration and respiration was recorded using a chest stethograph.Resting BP(by standard mercury sphygmomanometer), heart rate and respiratory rate were estimated after the patient was rested for at least15min.Continuous ECG and respiratory tracings were obtained during the reactivity tests.Adequate time was given between each test for the blood pressure and heart rate to come back to normal levels.The following tests were performed in the order described.

Deep breathing test

Subjects were asked to breathe at6breath/min with equal inspi-ratory/expiratory cycles,each of5s.E:I ratio was calculated by dividing the average of the maximum RR interval(RRI)and aver-age of the minimum RRI;the difference between the maximum and minimum heart rate(HR)gave the HR.

Valsalva maneuver

Subjects were trained to blow into a mouthpiece with a tubing to a mercury manometer and maintain a pressure of40mm Hg,for 15s.Care was taken to see that this was a forced expiration from the chest,with an open glottis and the procedure was repeated if necessary.We calculated the Valsalva ratio(VR)from the maximum RRI in stage IV divided by the minimum RRI in stage II.T achycar-dia ratio(TR)and bradycardia ratio was calculated by dividing the maximum HR in stage II and minimum HR in stage IV by basal HR respectively.The maximum and minimum HR during the procedure was calculated.

Sustained hand grip test

Subjects were asked to maximally contract a handgrip dynamome-ter(Jetter and Scheerer,Germany)using their dominant hand and the maximum voluntary contraction(MVC)was calculated.He/she was then asked to press the dynamometer at30%MVC for up to 4min or as long as sustainable(in children).BP was measured before,and after contraction at1,2and4min,in the contra-lateral arm.

Cold pressor test

Subjects were asked to dip their hand into ice cold water(10?C) for1min.Changes in BP and HR were monitored as baseline,and at1min,before retracting the hand.The maximum increases in systolic and diastolic pressure were noted.

Head up tilt test

Subjects were rested on a mechanical tilt table and tilted to70?in 15s.An ECG was recorded continuously while BP was recorded inter-mittently during a5min tilt.BP was measured at baseline,0.5min, 1min,and2.5min and at5min during the tilting procedure.The ratio between the longest RRI at around30th beat to the shortest RRI at around15th beat was calculated as the30:15ratio.

Test for cardiovascular tone

The patient was rested comfortably for at least15min in a silent, dimly lit,electromagnetically shielded room—after which res-piration and ECG waveforms were recorded for5min.HRV was assessed following established guidelines(CCTILAE,1989).Signals were acquired using BIOPAC MP150(BIOPAC,USA)system and Acqknowledge3.5software.ECG was recorded in the Lead II con?g-uration and collected via the ECG ampli?er module.The signal was sampled at1000Hz,using a50Hz notch?lter and35Hz(low pass) and0.05Hz(high pass)?lters.Analysis was carried out using MAT-LAB v6.5(MathWorks Inc.,Japan).Raw digital signal from Biopac was pruned to ASCII.After acquisition,the ECG was?ltered using 5th order Butterworth IIR?lter with a cutoff frequency of3Hz and 20Hz.

We developed a novel R-peak detection algorithm using the nonlinear frequency-weighted energy(FWE)operator,to?nd the R-peaks of the QRS complex(Plotkin and Swamy,1992;Agarwal et al.,1996;Yadav et al.,2007).Quantitative time domain analysis was performed on normal—normal(NN or RR)interval,and mean, SDNN(standard deviation of NN intervals),SDSD(standard devia-tion of successive NN differences),RMSSD(square root of the mean squared difference of the consecutive NN intervals),NN50(num-ber of pairs of adjacent NN intervals differing by more than50ms), and pNN50(proportion of NN intervals differing more than50ms to the total number of NN intervals)were computed.Both parametric and nonparametric spectral analysis were performed to estimate the power of the contributing frequencies in the R—R wave.Prior to spectral analysis,R—R wave was cubic spline interpolated at4Hz, a Welch power spectral density(PSD)was calculated,and the val-ues were normalized.The PSD was estimated in three frequency bands of very low frequency(VLF,0.001—0.04Hz),low frequency (LF,0.040—0.15Hz)and high frequency(HF,0.15—0.4Hz)(Akselrod et al.,1981).The spectral estimates of respiration were also car-ried out using Welch FFT and autoregressive(AR)power spectral density;the latter gave the best results with an order of10. Neuropsychological evaluation

At the end of the study,we administered three different investigator-rated questionnaires to assess the anxiety of the patient.The Hamilton Anxiety Scale(Hamilton,1959),covering the whole range of anxiety neurosis,has14test items,each having a maximum score of4;yielding a total maximum score of56points. The Clinical Anxiety Scale(Snaith et al.,1982),derived from the Hamilton anxiety scale is mostly con?ned to psychic anxiety and tension in the somatic musculature.There are7items,each hav-ing a maximum score of4and total maximum score of24points. The Brief Scale of Anxiety(Tyrer et al.,1984)is a subdivision of the comprehensive Psychopathophysiological Rating Scale and is help-ful in assessing mixed states of anxiety.There are10items with a

264S.Mukherjee et al.

Table1Demographics of the study groups.

No.of patients Age Seizure free since Refractory since Well controlled

Male1818.67±9.09 2.12—

Female1219.83±8.12 2.24—

T otal3019.13±8.72 2.18—

Intractable

Male2221.95±11.54—13.09

Female922.44±6.25—11.55

T otal3122.11±10.18—12.64

maximum score of6given to any one item;total maximum score is 24.

Autonomic symptom score

A detailed history of autonomic symptoms were taken and the subjects were scored on presence/absence of the following symptoms:nasal stuf?ness/dryness;excessive/loss of sweating response;postural fall/dizziness;gastrointestinal disturbances like diarrhea/constipation/pain in the abdomen;vascular headache (heaviness in head/throbbing headache/migraine);micturition dis-turbances,occasional attack of bronchospasm,i.e.after exercise, laughter or emotion;abnormal sensation of warmth/cold all over the body and abnormal warm/cold sensation in the extremities.A total of9items were scored as either1(presence)or0(absence) of symptoms.

We also devised an autonomic severity score,in which7indices of autonomic function(E:I. HR,VR,30:15ratio, rise in diastolic BP in cold pressor test, rise in diastolic BP in hand grip test and fall in systolic BP in head up tilt)were considered.A normal score was counted as0,borderline as1and abnormal scores as 2.Normal autonomic functions were designated a total score of0; mild autonomic neuropathy:1—4;moderate autonomic neuropathy: 5—8and severe autonomic neuropathy:9—14points(Deepak et al., 1996).

Data processing and statistical analysis

Descriptive statistics for all analyzed factors were computed as mean±standard deviation,except for HRV,which are expressed as median and range.The distribution of the data was deter-mined using the Kolmogorov—Smirnov and Shapiro—Wilk tests for normality.In the case of those parameters where normality assump-tion was met,two-way analysis of variance(ANOVA)models were used to compare autonomic parameters,anxiety scores and auto-nomic symptom scores.This was done between the group of well-controlled epilepsy(WcE)subjects vs.intractable epilepsy(IE) subjects after adjusting for the second factor of AED use(with vs. without carbamazepine or CBZ therapy).Gender and age were not included as factors in these models,since the small sample size in each category did not afford enough statistical power to do so.A test for interaction(if any)between group and drug use was also included in the two-way ANOVA model.In those parameters like HRV where normality assumptions were not met,a Friedman’s two-way test(nonparametric analog to ANOVA)was used.Autonomic severity scores were analyzed by Pearson’s chi square test of independence. The data was analyzed by using the SAS version9.1.3.A two-sided p-value,p<0.05,was considered signi?cant for all statistical tests.Results

The demographics of the subjects are shown in T able1and the list of AEDs taken are shown in T able2.In the WcE group, 26subjects were stable on1AED,while4were on2AEDs. Seventeen subjects were on CBZ either alone(16)or in com-bination(1)with another AED.In the IE group,25subjects were on2AEDs while5were on3AEDs;24subjects were on CBZ in combination with other drugs.

T wo-way ANOVA models(or the nonparametric analog of ANOVA,namely,Friedman’s test)comparing the vari-ous parameters studied(resting autonomic variables,tests for sympathetic and parasympathetic reactivity,HRV,auto-nomic and neuropsychological scores)between the two disease groups(WcE and IE),after adjusting for the main effect of anti-epileptic drug use(with or without CBZ)and group by drug-use interaction effect showed that there was no statistically signi?cant two-way interaction between groups and drug use.The p values for the group by drug inter-Table2Anti-epileptic medications taken by the study groups.

Anti-epileptic drugs(AEDs)Well controlled Intractable

CBZ16—

CBZ+CLO—6

CBZ+DPH11

CBZ+LRE—4

CBZ+PB—1

CBZ+TPA—1

CBZ+VPA—6

CBZ+VPA+DPH—1

CBZ+VPA+LRE—3

CBZ+VPA+TPA—1

DBH+CLO1—

DPH2—

VPA81

VPA+CLO—1

VPA+LRE23

VPA+TPA—2 Abbreviations:CBZ,carbamezapine;CLO,clobazam;DPH, phenytoin;LRE,lamotrigine;PB,phenobarbital;TPA,topira-mate;VPA,valproate.

Cardiovascular autonomic functions265

Table3Resting autonomic parameters in the study groups.

Parameters Well controlled(N=30)(mean±SD)Intractable(N=31)(mean±SD)p-Value SBP(mm Hg)110.07±11.86115.79±10.380.145 DBP(mm Hg)68.64±.4375.62±9.770.036 HR(bpm)85.36±16.9581.43±12.650.560 RR(cpm)17.5±3.5519.43±3.530.054 Results were obtained by a two-way ANOVA model for the two groups,adjusting for AED use(with/without CBZ).As there was no evidence of interaction due to AED,the group differences alone are shown.Abbreviations:SBP,systolic blood pressure;DBP,diastolic blood pressure;HR,heart rate;RR,respiratory rate.

action effect ranged from minimum p=0.06(for NN50)to maximum p=0.91(for VR).In other words,in this study the magnitude of difference in autonomic parameters between WcE and IE subjects was the same regardless of whether they used CBZ or not.Hence,the results described below are those obtained from ANOVA model examining the main effect of groups and the main effect of drug use.The p val-ues for drug use(CBZ vs.no CBZ)ranged from minimum p=0.11(for HR)to maximum p=0.96(for rise in SYSTOLIC BP with hand grip test).Thus,there was no signi?cant dif-ference in the parameters studied between subjects using CBZ or no CBZ therapy.

Resting parameters

The WcE subjects had a signi?cantly lower diastolic BP during resting conditions without concurrent change in HR (p=0.036;T able3);this was also observed in the resting conditions at multiple testing levels.

Sympathetic reactivity tests

T wenty-eight subjects in the WcE group and27subjects in IE group performed all the reactivity tests.In response to the hand grip test and cold pressor test,there was no signi?cant rise in diastolic BP(p=0.604;T able4);similarly the fall in systolic BP was not different in the two groups in response to head up tilt test(p=0.682;T able4). Parasympathetic reactivity tests

Five subjects(3of IE and2of WcE)were unable to follow the instructions and the deep breathing test was repeated. In the deep breathing test,the rise in HR and the

Table4T ests to measure autonomic reactivity in the study groups.

Variable Well controlled(N=28)(mean±SD)Intractable(N=27)(mean±SD)p-Value T ests for sympathetic reactivity

Hand grip test

Basal DBP75.79±8.8581.29±10.070.026 Rise in DBP20.85±7.7819.85±8.280.604 Cold pressor test

Basal DBP78±8.1380.93±9.620.678 Rise in DBP15.70±8.4315.46±8.860.934 Head up tilt

Basal SBP109.79±12.57115.04±9.740.275 Fall in SBP 3.71±3.99 4.37±4.190.682 T ests for parasympathetic reactivity

Deep breathing

HR29.68±11.2320±10.180.007 E:I 1.43±0.21 1.29±0.160.008 Valsalva maneuver

VR 1.93±0.43 1.87±0.460.890 TR 1.42±0.3 1.30±0.150.241 BR0.75±0.140.74±0.140.5841 Head up tilt

30:15ratio 1.22±0.36 1.11±0.080.686 Results were obtained by a two-way ANOVA model for the two groups,adjusting for AED use(with/without CBZ).As there was no evidence of interaction due to AED,the group differences alone are shown.Abbreviations:SBP,systolic blood pressure;DBP,diastolic blood pressure;E:I,expiratory/inspiratory ratio;VR,valsalva ratio;TR,tachycardia ratio;BR,bradycardia ratio;30:15,ratio of the RRI of the30th beat to the15th beat after tilt at70?.

266S.Mukherjee et al.

Table5Comparison of heart rate variability-frequency and time domain measures.

Variable Well controlled(N=30)median and range Intractable(N=31)median and range p-Value Frequency domain measures

VLF(ms2)275.14(33.99—2073.32)307.01(28.88—1769.06)0.529 LF(ms2)141.5(19—1496)297(6—3623)0.078 LF(nu)37.6(8.1—74)51.15(20—83.2)0.048 HF(ms2)397(3—1793)114(10—999)0.013 HF(nu)36.3(4.6—80.5)33.15(12.5—75.1)0.308 LF/HF 1.15(0.21—4.04) 1.92(0.27—6.64)0.075 Time domain measures

SDNN26.71(4.34—68.61)22.11(3.26—78.44)0.435 SDSD35.62(6.35—132.86)29.95(3.87—148.06)0.423 RMSSD35.58(6.34—132.69)29.91(3.87—147.88)0.423 NN5015.95(3.9—23.4)11.0(1.5—22.1)0.033 pNN50 3.89(0.75—5.9) 2.69(0.31—5.3)0.034 Results were obtained by a two-way ANOVA model for the two groups,adjusting for AED use(with/without CBZ).As there was no evidence of interaction due to AED,the group differences alone are shown.Frequency domain measures:VLF,very low frequency; LF,low frequency;HF,high frequency,frequencies described in ms2or normalized units(nu).Time domain measures:SDNN,standard deviation of NN intervals;SDSD,standard deviation of successive NN differences;RMSSD,square root of the mean squared difference of the consecutive NN intervals;NN50,number of pairs of adjacent NN intervals differing by more than50ms;pNN50,proportion of NN intervals differing more than50ms to the total number of NN intervals.

Table6Comparison of autonomic symptoms and neuropsychological scores.

Variable Well controlled(N=30)(mean±SD)Intractable(N=20)(mean±SD)p-Value Autonomic symptom score 2.38±1.89 2.31±1.490.885 Hamilton’s anxiety score9.25±5.979.33±3.00.95 Clinical scale of anxiety4±2.837.44±5.830.061 Brief Scale of anxiety 2.75±1.5 6.67±3.580.018 Results were obtained by a two-way ANOVA model for the two groups,adjusting for AED use(with/without CBZ).As there was no evidence of interaction due to AED,the group differences alone are shown.

E:I ratio was signi?cantly lower in IE than WcE subjects (p=0.007for HR and p=0.008for E:I ratio;T able4). The other measures from Valsalva maneuver and the30:15 ratios were not signi?cantly different between the two groups.

Heart rate variability(HRV)measures

Low frequency(LFnu)component was signi?cantly higher (p=0.078and p=0.048),and HF was signi?cantly lower (p=0.013and p=0.308)in the IE than the WcE group. This means that IE subjects had a higher sympathetic drive to the myocardium.However,in time domain measures,IE subjects exhibited a trend towards lower values,of which only NN50and pNN50were reached signi?cance. This shows that the parasympathetic drive to the heart was lower in IE than WcE subjects(T ask Force,1996) (T able5).

There were no signi?cant differences in anxiety ques-tionnaires(T able6)except in the brief anxiety scores (WcE2.75±1.5vs.IE6.67±3.58,p=0.018).Subjects were not different in terms of reported autonomic symptoms. However,autonomic dysfunctions were more severe in IE subjects,as was evident from their autonomic severity scores(T able7).In the WcE group,9/28(32.48%)had mild, 3/28(10.71%)had moderate and1/28(3.57%)had severe autonomic neuropathy.In comparison,the IE subjects,14/27

Table7Chi square distribution of autonomic severity.

Normal Mild Moderate Severe T otal Chi square p-Value Well controlled1494128165.0<0.0001 Intractable7146027

T otal212310155

Pearson’s chi square test of independence,p<0.001.

Cardiovascular autonomic functions267

(51.85%)had mild and6/27(22.23%)had moderate auto-nomic neuropathy(p<0.0001).

Discussion

We found a higher sympathetic and a lower parasympathetic tone in HRV,along with lower parasympathetic reactivity in subjects with intractable epilepsy,when compared to subjects whose epilepsy was controlled with medication.

A difference was also noted in the baseline sympathovagal tone,which was higher in those refractory to treatment. Overall,the degree of autonomic severity was signi?cantly higher in the IE subjects.On the basis of our?ndings,we conclude that subjects with recurrent seizures have a dif-ferent autonomic pro?le from those who are seizure free for a considerable amount of time.

Previously,there has been only one study which com-pared the autonomic pro?les in subjects with well controlled and intractable epilepsies of the temporal lobe(Ansakorpi et al.,2000).Our results are similar in that we found no differences in sympathetic reactivity in the two groups. We had,however,also incorporated an additional test for sympathetic reactivity(cold pressor test),which makes our study more robust.A recent study(Sathyaprabha et al., 2006)observed a severe loss of sympathetic as well as parasympathetic reactivity in73chronic intractable epilep-tic subjects,when compared to age and sex matched healthy controls.The main difference between our study and the former is the comparison with healthy controls vis-à-vis with well-controlled epilepsy subjects(our case),whose auto-nomic functions are already compromised.Also,subjects with generalized epilepsies have more severe autonomic dysfunctions and a heterogeneous group of partial and gen-eralized refractory epilepsies would re?ect more severe dysautonomia when compared to healthy controls.Many previous studies have shown that epilepsy subjects have signi?cant autonomic dysfunctions when compared to con-trols and the dysfunction is correlated to seizure severity (Faustmann and Ganz,1994;T omson et al.,1998;Devinsky et al.,1994).

Many factors may contribute to explain the differences that we observed between the two groups:they could arise from differences in seizure severity,different anatomical localizations of the seizure foci,as well as the effect of anti-epileptic drugs(AEDs).Several studies indicate that AEDs like CBZ are signi?cantly associated with autonomic dysfunc-tion in epileptic subjects(Devinsky et al.,1994;Isojarvi et al.,1998;Persson et al.,2003).In our study,56.67%of sub-jects in the WcE group and77.42%of those in the IE group were on CBZ—either alone or in combination with other AEDs.However in our study,when we analyzed the data with respect to CBZ use in the two groups,no signi?cant interac-tion was evident.Hence,the dysautonomia in the IE group was present irrespective of CBZ regimen.Localization of the seizure foci may also be directly associated with autonomic dysfunction,since structures like the amygdala and the insu-lar cortex plays an important role in modulating heart rate (Cechetto,2000;King et al.,1997).Furthermore,severity of autonomic dysfunction is also seen to depend on the volume of cerebral structures recruited in a seizure(Epstein et al., 1992).

We observed higher baseline BP in IE subjects at multiple testing levels without any concomitant changes in HR,signifying a higher vasomotor tone.This may be due to either baroreceptor abnormalities or inter-ference of seizure activity on central neurons involved in baroreceptor modulation,resulting in a continuous baseline activation of vasomotor neurons.In a seizure model using pentylenetetrazole-treated rats,Kanter et al. (1995)observed seizure-induced neuronal activation and demonstrated that central neurons involved in barore?ex modulation are activated directly by seizure discharge,and not in response to seizure associated hypertension.Barore-?ex sensitivity was seen to be lower in refractory TLE subjects and improve after resective surgery(Hilz et al., 2002).

We compared IE subjects who were hospitalized for resective surgery,with WcE subjects.In order to?nd out whether anxiety could be a factor in in?uencing our results, we carried out detailed neuropsychological questionnaires in both groups.Our data did not show any differences between the groups,except a rise in scores in the Brief Scale of anxiety questionnaire.It is important to remember that this scale can also rate pathological anxiety in the setting of a concomitant medical or neurological disorder.The IE sub-jects are more severely affected by epilepsy than the WC group,which may explain the increased scores.However, the actual scores(6.67±3.58out of24)show only a mild anxiety response.

This study brings to light some important?ndings.Our results corroborate previous studies which concluded that degree of autonomic abnormalities may be related to seizure severity(Nashef et al.,1998;Nilsson et al.,1999;Walczak et al.,2001;Ansakorpi et al.,2002;Persson et al.,2005).We also found IE subjects to have higher sympathetic activation, lower parasympathetic function and higher sympathovagal tone when compared to WcE subjects,which has not previ-ously been reported.Higher sympathetic function and lower parasympathetic function has been demonstrated to be sig-ni?cant risk factors for SUDEP.We also report this study in a young cohort of intractable epilepsy subjects,where the average age was21.24years.This is especially important in the context of altered cardiovascular autonomic functions, which may predispose them to SUDEP.When we compare the dysautonomic symptoms,we do not see marked differences in the severity of symptoms in the two groups.However,the total number of patients with some sort of autonomic dys-function(mild,moderate and severe)was higher in the IE subjects(20/27or75%)than in the WcE subjects(14/28or 50%).

As in any observational study with a small sample size, this study too has certain limitations.We were unable to consider the effects of factors such as age,gender and multidrug therapy in our analysis,due to sample size constraints.The IE group had more male subjects when com-pared to those in the WcE group,and the effect of these gender differences on the results cannot be accounted for in this study.This was also a heterogeneous sample with respect to localization of the seizure foci and AED regimen. In the future,a prospective,randomized trial in subjects with homogenous foci followed over time may help further elucidate the role of dysautonomia in epilepsy and the com-plex association with SUDEP.

268S.Mukherjee et al.

We conclude that WcE and IE subjects have differ-ent autonomic pro?les.The decrease in parasympathetic reactivity,increase in vasomotor tone and sympathetic acti-vation and overall higher degree of dysautonomia in IE subjects may increase their risk of cardiovascular emergen-cies and SUDEP.

Acknowledgment

The author was funded by a doctoral fellowship from the Council of Scienti?c and Industrial Research(CSIR)to carry out this work,while in India.

References

Agarwal,R.,Gotman,J.,Flanagan,D.,Rosenblat,B.,1996.Auto-matic EEG analysis during long term monitoring in the ICU.Clin.

Electroencephalogr.Neurophysiol.107,44—58.

Akselrod,S.,Gordon,D.,Ubel,F.A.,Shannon,D.C.,Berger,A.C., Cohen,R.J.,1981.Power spectrum analysis of heart rate?uc-tuation:a quantitative probe of beat-to-beat cardiovascular control.Science213(4504),220—222.

Ansakorpi,H.,Korpelainen,J.T.,Huikuri,H.V.,T olonen,U.,Myl-lyla,V.,Isojarvi,J.I.T.,2002.Heart rate dynamics in refractory and well controlled temporal epilepsy.J.Neurol.Neurosurg.

Psychiatry72,26—30.

Ansakorpi,H.,Korpelainen,J.T.,Huikuri,H.V.,T olonen,U.,Myllyla, V.V.,Isojarvi,J.I.,2000.Interictal cardiovascular autonomic responses in patients with temporal lobe Epilepsy.Epilepsia41, 42—47.

Ansakorpi,H.,Korpelainen,J.T.,T anskanen,P.,2004.Cardiovas-cular regulation and hippocampal sclerosis.Epilepsia45(8), 933—939.

Cechetto,D.F.,2000.Neuropathology and cardiovascular regula-tion.In:Horst,G.J.T.(Ed.),The Nervous System and the Heart.

Humana Press,New Jersey,pp.159—179.

Commission on Classi?cation and T erminology of the International League Against Epilepsy,1989.Proposal for revised classi?cation of epilepsies and epileptic syndromes.Epilepsia30,389—399. Deepak,K.K.,Godbole,S.A.,Kochhar,K.P.,Shah,P.,Kochupillai, N.,1996.Autonomic dysfunction and peripheral vasodilatory response in diabetes.Indian J.Physiol.Pharmacol.40(4), 325—329.

Devinsky,O.,2004.Effects of seizures on autonomic and cardiovas-cular function.Epilepsy Curr.4(2),43—46.

Devinsky,O.,Pacia,S.,T atambhotla,G.,1997.Bradycardia and asystole induced by partial seizures:a case report and literature review.Neurology48(6),1712—1714.

Devinsky,O.,Perrine,K.,Theodore,W.H.,1994.Interictal auto-nomic nervous systems function in patients with epilepsy.

Epilepsia35,199—204.

El-Sayed,H.L.,Kotby,A.A.,T omoum,H.Y.,El-Hadidi,E.S.,Behery, S.E.,El-Ganzory,A.M.,2007.Non-invasive assessment of car-dioregulatory autonomic functions in children with epilepsy.

Acta Neurol.Scand.115(6),377—384.

Epstein,M.A.,Michael,R.,Connor,M.,1992.Cardiac rhythm during temporal lobe seizures.Neurology42,50—53.

Ewing,D.J.,Clarke,B.F.,1982.Diagnosis and management of dia-betic autonomic neuropathy.Br.Med.J.285,916—918. Faustmann,P.M.,Ganz,R.E.,1994.Central cardio-autonomic dis-organization in interictal states of epilepsy detected by phase space analysis.Int.J.Neurosci.78(1—2),43—47.

Ficker,D.M.,So,E.L.,Shen,W.K.,1998.Population-based study of the incidence of sudden unexplained death in epilepsy.Neurol-ogy51(5),1270—1274.Frysinger,R.C.,Engel,J.,Harper,R.M.,1993.Interictal heart rate patterns in partial seizure disorders.Neurology43(10), 2136—2139.

Hamilton,M.,1959.The assessment of anxiety states by rating.Br.

J.Med.Psychol.32,50—55.

Harnod,T.,Yang,C.C.,Hsin,Y.L.,Shieh,K.R.,Wang,P.J.,Kuo,T.B., 2007.Heart rate variability in children with refractory general-ized epilepsy.Seizure,October29[epub ahead of print]. Hilz,M.J.,Devinsky,O.,Doyle,W.,Mauerer,A.,Dütsch,M.,2002.

Decrease of sympathetic cardiovascular modulation after tem-poral lobe epilepsy surgery.Brain125(5),985—995.

Isojarvi,J.I.,Ansakorpi,H.,Suominen,K.,et al.,1998.Interictal cardiovascular autonomic responses in patients with epilepsy.

Epilepsia39(4),420—426.

Kanter,R.K.,Strauss,J.A.,Sauro,M.D.,1995.Seizure-induced c-fos expression in rat medulla oblongata is not dependent on associ-ated elevation of blood pressure.Neurosci.Lett.194,201—204. King,D.,Bronen,R.A.,Spencer,D.D.,Spencer,S.S.,1997.T opo-graphic distribution of seizure onset and hippocampal atrophy: relationship between MRI and depth EEG.Electroencephalogr.

Clin Neurophysiol.103(6),692—697.

Leestma,J.E.,Annegers,J.F.,Brodie,M.J.,et al.,1997.Sudden un-explained death in epilepsy:observations from a large clinical development program.Epilepsia38,47—55.

Leutmezer,F.,Schernthaner,C.,Lurger,S.,2003.Electrocardio-graphic changes at the onset of epileptic seizures.Epilepsia44

(3),348—354.

Massetani,R.,Strata,G.,Galli,R.,Gori,S.,Gneri,C.,Limbruno, U.,1997.Alteration of cardiac function in patients with temporal lobe epilepsy:different role of EEG-ECG monitoring and spectral analysis of RR variability.Epilepsia38,363—369.

Nashef,L.,Walker,F.,Allen,P.,Sander,J.W.,Shorvon,S.D.,Fish,

D.R.,1996.Apnoea and bradycardia during epileptic seizures:

relation to sudden death in epilepsy.J.Neurol.Neurosurg.Psy-chiatry60(3),297—300.

Nashef,L.,Garner,S.,Sander,J.W.A.S.,Fish,D.R.,Shorovan,S.D., 1998.Circumsances of death in sudden unexplained death in epilepsy:interviews of beraved relatives.J.Neurol.Neurosurg.

Psychiatry64,349—352.

Nilsson,L.,Bergman,U.,Diwan,V.,Farahmand,B.Y.,Persson,P.G., T omson,T.,2001.Antiepileptic drug therapy and its manage-ment in sudden unexpected death in epilepsy:a case—control study.Epilepsia42(5),667—673.

Nilsson,L.,Farahmand,B.,Persson,Y.,Thiblin,P.G.,T omsan,T., 1999.Risk factor of sudden unexpected death in epilepsy:a case control https://www.360docs.net/doc/0611674472.html,ncet353,888—893.

Nouri,S.,Marshall, B.,2006.Sudden unexpected death in epilepsy.(Online)(access2008February).Available from url address https://www.360docs.net/doc/0611674472.html,/neuro/topic659.

htm#section～References.

Persson,H.,Ericson,M.,T omson,T.,2003.Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy.Epilepsy Res.57,69—75.

Persson,H.,Kumlien,E.,Ericson,M.,T omson,T.,et al.,2005.Pre-operative heart rate variability in relation to surgery outcome in refractory epilepsy.Neurology65,1021—1025.

Plotkin, E.I.,Swamy,M.N.S.,1992.Nonlinear signal processing based-on parameter invariant moving average modeling.In: https://www.360docs.net/doc/0611674472.html,ECE21,pp.TM3.11.1—TM3.11.4.

Radhakrishnan,K.,1999.Medically refractory epilepsy.In:Rad-hakrishnan,K.(Ed.),Sree Chitra Tirunal Institute for Medical Sciences and T echnology.Trivandrum,pp.8—9.

Rocamora,R.,Kurthen,M.,Lickfett,L.,Von Oertzen,J.,Elger,C.E., 2003.Cardiac asystole in epilepsy:clinical and neurophysiologic features.Epilepsia44(2),179.

Ronkainen, E.,Korpelainen,J.T.,Heikkinen, E.,Myllyl?,V.V., Huikuri,H.V.,Isoj?rvi,J.I.,2006.Cardiac autonomic control in patients with refractory epilepsy before and during vagus nerve

Cardiovascular autonomic functions269

stimulation treatment:a one-year follow-up study.Epilepsia47 (March(3)),556—562.

Sathyaprabha,T.N.,Satishchandra,P.,Netravathi,K.,Sinha,S., Thennarasu,K.,Raju,T.R.,2006.Cardiac autonomic dysfunction in chronic refractory epilepsy.Epilepsy Res.72(1),49—56. Snaith,R.P.,Baugh,S.J.,Clayden,A.D.,Husain,A.,Sipple,M.A., 1982.The Clinical Anxiety Scale:an instrument derived from the Hamilton Anxiety Scale.Br.J.Psychiatry141,518—523.

T ask Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology,1996.Heart rate variability:standards of measurement,physiological inter-pretation,and clinical use.Circulation93,1043—1065.

T omson,T.,Ericson,M.,Iihrman,C.,Lindblad,L.E.,1998.Heart rate variability in patients with epilepsy.Epilepsy Res.30(1), 77—83.Tyrer,P.,Owen,R.T.,Cicchetti,D.,1984.Brief Scale for Anxiety:

a subdivision of the Comprehensive Psychopathological Rating

Scale.J.Neurol.Psychiatry47,970—975.

Walczak,T.,2003.Do antiepileptic drugs play a role in sudden unex-pected death in epilepsy?Drug Saf.26(10),673—683(review). Walczak,T.S.,Leppik,I.E.,D’Amelio,M.,Ruggles,K.,Cascino,G.D., Annegers,J.F.,Hauser,W.A.,2001.Incidence and Risk factors in sudden unexpected death in epilepsy:a prospective cohort study.Neurology56,519—525.

Yadav,R.,Agarwal,R.,Swamy,M.N.S.,2007.STFT-based segmenta-tion in model-based seizure detection.Electrical and Computer Engineering,CCECE Canadian Conference on April22—26,pp.

729—732.