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Lateralization in autononic dysfunction in ischemicstroke involving the insular cortex

S. Meyer, M. Strittmatter,1,CA C. Fischer,1 T. Georg2 and B. Schmitz3,4

Department of Neurology and Pediatrics; 2Institute for Medical Biometrics, Epidemiology, and Medical Informatics; 3Department of Neuroradiology,

University of the Saarland; 1Department of Neurology and Stroke Unit, SHG Kliniken Merzig, von-Fellenberg Stift,Trierer Strasse148, 66663 Merzig;4Department of Diagnostic Radiology, University Hospitals Ulm, Germany

CACorresponding Author: [email protected]

Received 9 October 2003; accepted14 October 2003

DOI: 10.1097/01.wnr.0000103755.04757.52

Autonomic nervous system dysfunction is a common complication

of ischemic stroke. Clinical and experimental data indicate hemi-spheric lateralizationin the control of autonomic activity.The insu-lar cortex has also been shown to play a crucial role in the centralautonomic network. The aim of this study was to assess cardio-autonomic dysfunction in patients with ischemic insular versusnon-insular cortex infarction, and to demonstrate a possible later-alization in autonomic activity mediated by the insular cor tex.Sympathetic function was prospectively assessed by determiningplasma norepinephrine and epinephrine in 15 patients with left-hemisphere (LH; four insular infarction), and 14 with right-hemi-sphere (RH) middle cerebral artery (MCA) stroke (¢ve insular

infarction). Systolic and diastolic blood pressure and heart rate

were recorded during the ¢rst 5 days after stroke. Sympatheticactivity was signi¢cantlyhigher ininsular thanin non-insularinfarc-

tion (po0.05) with concomitantly elevated cardiovascularparameters in insular stroke patients.The pathological activationof the sympathetic nervous system was most excessive inRH-stroke involving theinsular cortex (po0.05).Ourdata indicatea hemispheric lateralization in autonomic activity which ismediatedby theright-sidedinsular cortex.Patients with RH strokeinvolving theinsular cortex aremost susceptible to develop cardio-autonomic dysfunction. NeuroReport 15:357^361 c 2004 Lippin-cott Williams & Wilkins.

Key words: Autonomic nervous system; Hemispheric lateralization; Insular cortex; Plasma catecholamines; Stroke

INTRODUCTION

There is a growing body of evidence from animal andclinical studies that cerebrovascular disease alters cardio-vascular and autonomic function [1]. Early mortality instroke patients is associated with a high incidence of cardiacarrhythmias and myocardial damage [2,3]. Distinct cerebralregions have been implicated in the genesis of thepathological activation of the sympathetic nervous system[4,5]. Evidence exists for cortical lateralization in theregulation of cardiovascular functions, indicating that righthemisphere (RH) ischemia has sympathetic consequences

greater than left hemisphere (LH) ischemia [6]. Unilateralcerebral inactivation and stimulation causes hemispheric-dependent changes in cardiovascular parameters suggestinga suprabulbar right–left asymmetry in autonomic control[7,8]. The location, i.e. insular infarction, and to a lesserextent the size of stroke, may cause different autonomicabnormalities in stroke patients [9]. Experimental data alsoindicate that the insula, the amygdala, and lateral hypothal-amus play a crucial role in the autonomic control of theheart [10]. Of these, the insular cortex within the middlecerebral artery (MCA) territory is the most importantcortical area engaged in cardiovascular regulation [11].

However, there are few data on the different effects of LH vs RH insular cortex infarction on cardio-autonomic

function. The aim of this study was to demonstrate thedifferential effects of the stroke localization (insular (I) vsnon-insular (NI) infarction in LH and RH stroke) on theautonomic nervous system, and on cardiovascular para-meters in the acute post-ischemic phase.

SUBJECTS AND METHODSStudy population and entry criteria: This prospectivestudy was conducted according to the principles establishedin the Helsinki declaration and after approval by our

institutional review board (IRB). After informed consent, 29patients with ischemic stroke were included within 24 h of the onset of symptoms. Fifteen patients (age 60.97 10.8years) suffered from territorial LH stroke, 14 patients (age64.07 10.8 years) from territorial RH stroke affecting theMCA. In the LH and RH stroke patients, four and fivepatients, respectively, suffered complete insular cortexinfarction. Cerebral infarction and localization were verified

by MRI (Siemens, Vision, 1.5 T, Erlangen, Germany) includ-ing diffusion-weighted sequences or cerebral computedtomography (Twin Flash, Elscint, Haifa, Israel) including afollow-up cerebral CT within 1 week. All brain scans werereviewed by an experienced neuroradiologist blinded to theother data.

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Patients with transient ischemic attacks, intracranialhemorrhage or symptoms of increased intracranial pressure,patients with regular use of medications that alter auto-nomic function, with a past medical history of endocrinedisease, severe ischemic heart disease, or congestive heartfailure (NYHA III-IV) were excluded. No significantdifferences existed in the number of patients with knownhypertension and/or hypertensive medication between

non-insular and insular stroke patients prior to admission.The median time interval from symptom onset untilinclusion into our study was comparable between the studygroups (non-insular stroke 8.0 h, range 2.4–22.1h; insular-stroke 8.3 h, range 2.5–21.9 h). No significant differences inneurologic deficit according to the Scandinavian StrokeScale Score (SSSS) existed between patients with non-insular(median SSSS 42) vs insular stroke (median SSSS 41) onadmission.

Methods: Venous blood samples were drawn from anindwelling catheter for the determination of norepinephrine

(NE) and epinephrine (E) on admission to the hospital, 4 hafter admission, and on days 2–5 at 07.00 h. Since environ-mental conditions such as light, noise, position, pain, fearand hunger can raise plasma catecholamine levels rapidly,

blood sampling for the catecholamine assay was done understrictly standardized conditions with patients in bed in thesupine position 30 min prior to blood sampling. All studypatients were synchronized to the same day- and night-timeschedule (meals at 07.30, 11.30 and 17.30h; sleep fromapprox. 22.00 h until 06.00 h) thus further minimizingextraneous factors that might influence autonomic function.Plasma NE and E concentrations were measured using highperformance liquid chromatography (HPLC) with electro-chemical detection as described previously [6]. NE and E

concentrations are given in ng/l.Simultaneously to plasma catecholamine measurements,

cardiovascular parameters were recorded at 07.00 h. Systolicand diastolic blood pressures (BPsys/BPdia) were deter-mined with an automatic non-invasive BP meter (Sirecust401; Siemens, Erlangen, Germany). BP cuffs were positioned

on the unaffected arm ipsilateral to the infarct. Patients wereinstructed to keep their arm as motionless as possible.

The results are summarized in Table 1, Table 2, Fig. 1, andFig. 2. Data are given as means7 s.e.m. Due to the size of the study population, autonomic and cardiovascular par-ameters within each group were compared with the non-parametric Wilcoxon signed rank test. Statistical comparison

between the study groups was performed using the

Kruskal–Wallis test with post-hoc Bonferroni testing;po0.05 was considered significant.

RESULTS Autonomic parameters: NE and E: Plasma NE concentra-tions were significantly higher in patients with strokeinvolving the insular cortex compared to NI-cortex stroke(Fig. 1). In NI infarction, NE declined significantly(po0.05), in I-cortex infarction a sustained pathologicalaugmentation in NE was seen. In non-insular stroke, NEconcentration was comparable between RH and LH stroke(Table 2). The most excessive sympathetic activation was

seen in patients with RH stroke involving the insular cortex.Plasma NE concentration was significantly higher in RH-insular stroke compared to LH-insular stroke and non-insular stroke patients (po0.05; Table 2).

Compared with non-insular cortex stroke, plasma E levelswere also significantly higher in insular cortex stroke(Fig. 2), with the most prominent pathological activationin RH stroke with involvement of the insular cortex(po0.05; Table 2). No significant differences were seen inE concentration in non-insular stroke affecting RH or LH.

Cardiovascular parameters: Systolic (BPsys) and diastolic(BPdia) blood pressure were initially elevated in all study

groups. Only in patients with non-insular cortex infarctionthere was a substantial drop in both BPsys and BPdia(po0.05; Table 1). The highest BPsys and BPdia were seenin patients with RH-I stroke (Table 1). Differences in BPsysand BPdia at the different time points, however, did notreach the level of significance.

Table 1. Systolic/diastolic bloodpressure, andheart ratein patientswith non-insular (NI) vs insular (I) cortex stroke (mean7s.e.m.) and right-hemisphericinsular (RH-I) cortex stroke.

Admission Admission + 4 h Day 2 Day 3 Day 4 Day 5

NIBPsys 163.276.2 159.975.0 151.274.9 145.674.9 149.175.7 146.775.1a

BPdia 87.172.7 81.472.9 79.772.3 79.072.7 79.972.3 79.172.9a

HR 79.672.8 78.072.7 71.772.7 71.772.7 72.172.3 71.872.3

IBPsys 170.479.9 157.879.0 164.179.1 153.179.5 155.776.8 152.2711.4BPdia 84.174.7 74.273.3 78.475.0 77.474.7 85.872.6 78.174.1HR 80.074.4 77.473.6 77.174.0 80.075.8 76.774.2 82.976.3

RH-IBPsys 171.0713.5 167.6727.3 176.0723.8 162.0712.8 163.279.7 169.0737.4BPdia 83.0713.5 73.2711.2 74.6718.4 81.5717.9 85.479.8 80.6712.4HR 82.0715.6 79.679.3 80.2713.7 91.2714.6 80.0711.2 93.6717.2b

BPsys/BPdia: Blood pressure systolic/diastolic (mm Hg); HR: Heart rate.aDi¡erences between BPsys and BPdia on admissionvs BPsys and BPdia on day 5,po0.05,bsigni¢cantly elevated heart rate in right-hemispheric insular stroke compared to left-hemispheric insular stroke, and non-insular cortex stroke,po0.05.

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In patients with non-insular stroke a decrease in HR wasseen (po0.01), while HR moderately increased during the5-day study period in patients with insular stroke (Table 1).Heart rate was significantly higher in RH-I stroke than inLH-I stroke and patients with non-insular infarction

(po0.05; Table 1).

DISCUSSIONSeveral investigations in humans have shown that strokeinduces changes in cardiac autonomic control which mightcause hypertension, arrhythmias, myocardial necrosis andeven sudden death [1–3]. These complications are attributedto damage of the central autonomic network. Clinical trialshave demonstrated that insular infarction, and to a lesserextent the hemispheric laterality (right vs left) and size of stroke, may cause autonomic abnormalities [9,13]. Stimula-tion of the left and right insular cortices elicits specificcardiovascular responses in epileptic patients; phasic

stimulation of the insula entrained to the cardiac cycle iscapable of inducing severe arrhythmias in rats [8,14].Cerebral inactivation in patients with epilepsy also suggestslateralization in control of cardiac and autonomic functionwith a right-sided cerebral predominance for sympathetic

function [7].We demonstrated distinct alterations in plasma catechol-

amine levels following cerebral ischemic infarction, with apronounced increase in sympathetic autonomic function instroke patients with involvment of the insular cortex (Fig. 1,Fig. 2). Contrary to the results from Sander and Klingelhofer[13], severe and excessive disturbances in autonomicfunction were seen in RH insular cortex infarction while inLH insular cortex infarction only a moderate elevation insympathetic autonomic function was noted in our studypopulation. In addition to the data presented by Sander andKlingelhofer [9,13], our study demonstrates a sustainedautonomic dysfunction which prevailed over the first 5 daysafter stroke, most strikingly in RH insular cortex stroke.

Table 2. Plasma norepinephrine (NE) and epinephrine (E) in non-insular (NI) and insular (I) stroke dependent on left-hemispheric (LH) and right-hemi-spheric (RH) localization (mean7s.e.m.).

Admission Admission + 4 h Day 2 Day 3 Day 4 Day 5

NI-LHNE 467.5727.1 318.6720.3 284.0733.6 324.7747.2 262.6732.1 361.87106.4E 47.9711.6 40.477.1 45.4711.1 47.5713.4 38.2711.5 41.8710.7

NI-RH

NE 422.8746.7 278.7754.7 355.2796.9 285.6745.0 306.8749.1 255.0770.1E 42.576.8 27.576.1 42.978.8 32.776.0 38.5712.6 32.3712.6

I-LHNE 498.77209.8 322.7788.2 368.77116.2 585.57180.1 418.3798.4 425.17138.6E 74.8724.6 36.179.0 37.0717.5 55.0720.3 37.075.7 40.676.6

I-RHNE 1295.57491.4 951.97318.5 890.67313.3 120 6.97382.6* 943.77210.3* 997.27223.1E 171.7759.3* 110.9738.6 132.3747.6 99.9729.4 94.9726.8 175.7757.7

*Signi¢cantly elevatedplasma NE and E levels in right-hemispheric insular stroke compared to left-hemispheric insular stroke, and non insular cortex stroke,po0.05.

00.00

200.00

400.00

600.00

800.00

1000.00

1200.00

1400.00

Adm. Adm.+4h Day 2 Day 3 Day 4 Day 5

N E ( n g / l )

Non-insular stroke

Insular stroke

†††

††

*

Fig.1. Plasma norepinephrine concentration (NE) in non-insular vs insu-lar cortex s troke. Adm.: Admission to the hospital; Adm + 4 h: 4 h afteradmissionto thehospital.Di¡erences between the twogroups;wpo 0.05,wwpo 0.01. *Di¡erences between NE on admissionvs NE onday 5 in non-insular stroke, po 0.05.

0.0

20.0

40.0

60.0

80.0

100.0

120.0

140.0

160.0

180.0

Adm. Adm.+4h Day 2

E ( n g / l )

Non-insular stroke

Insular stroke

††

†

Day 3 Day 4 Day 5

Fig. 2. Plasma epinephrine concentration (E) in non-insular vs. insularcortex stroke. Adm.: Admission to the hospital; Adm. + 4 h: 4 h after ad-mission to the hospital. Di¡erences between the two groups: wpo 0.05,wwpo 0.01.

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Thus, despite the relatively small number of patientsincluded in this study, the consistent data over a 5-dayperiod with six measurements of autonomic functionstrongly indicate that the right insular cortex plays a crucialrole in the initiation and promotion of sympatheticdysfunction in ischemic stroke. The vital role of the right-sided insular cortex in autonomic control is furthercorroborated by the fact that very similar physiological

patterns in both NE and E concentration were seen in non-insular RH and LH stroke. The differential activation of theautonomic nervous system cannot be attributed to differentinsular stroke size since both in RH and LH insular strokepatients the complete insular cortex was involved.

Up-regulation in autonomic function was paralleled by sustained elevation of cardiovascular parameters ininsular cortex stroke patients, most notably in RH-I stroke(Table 1). Up-regulation of cardio-autonomic function iseither mediated directly via modulation of the sympatheticactivity or by reduced parasympathetic activity with areciprocal shift in sympathetic function. Experimentalstudies have so far yielded contradictory data. Oppenhei-mer and Cechetto showed that the increase in HR in cerebral

ischemia was abolished by the b1-antagonist atenolol,while atropine did not increase HR in bradycardia [15].In a second study, Oppenheimer and co-workers demon-strated that bradycardia elicited from stimulation of thecaudo-posterior area of the insula was abolished byatropine [16]. Our data are not conclusive as to whetherdisturbances in cardio-autonomic tone are caused by adirect activation of the sympathetic nervous system or byreduced parasympathetic function. Two possible patho-physiological models could explain our results: RHinsular cortex primarily controls and inhibits sympatheticfunction. Thus ischemic damage to this region wouldresult in unleashing sympathetic autonomic tone with aconcomitant increase in cardiovascular parameters.

Alternatively, RH could have a greater role in cerebralregulation of cardiac function by virtue of the modificationof parasympathetic effects as suggested by Ahern andco-workers [17]. This hypothesis is corroborated by thefact that RH stroke in humans is associated with areduced respiratory HR variability, a reflex mainly underparasympathetic control; a corresponding asymmetry withrespect to sympathetic cardiovascular reflexes could not befound [18].

Since cerebrovascular autoregulation is impaired instroke, cerebral perfusion in acute ischemic states largelydepends on systemic BP [19]. An endogenous up-regulationshould have a positive effect on the clinical course of stroke,since initially high BP can prevent the early progresssion of

stroke, whereas the lowering of BP to normal valuesworsens the clinical outcome [20,21]. We showed differentpatterns in BPsys and BPdia and heart rate with sustainedhypertensive values in insular cortex infarction compared tonon-insular infarction, most apparently in RH insularstroke. This might be of prognostic significance sincepositron emission tomography studies have shown areduced hemodynamic reserve in hypertensive patientswhich renders the penumbra vulnerable even to a smallreduction in BP [22]. Thus the possible adverse effects of sympathovagal shifts as a possible progenitor of cardiacarrhythmogenesis reported by many observers [2] may beoffset by an increase in penumbra viability. Recent data,however, indicate that elevated plasma norepinephrine

concentration is an independent predictor of poor long-term outcome in thromboembolic stroke [23].

CONCLUSIONOur investigation shows that RH insular cortex strokecauses an excessive and sustained increase in cardio-

sympathetic tone. This is indicative of hemispheric lat-eralization of the central autonomic nervous systemmediated by the right insular cortex. The precise underlyingpathophysiological mechanism, either a direct increase insympathetic drive or a decrease in parasympathetic functionwith a reciprocal rise in sympathetic tone, remains to beelucidated. The rise in sympathetic function, via augmentedcardiovascular parameters, might increase penumbra via-

bility. However, the role of plasma catecholamines onneurological outcome in stroke remains controversial[24,25]. We conclude that right-sided involvement of theinsular cortex should be taken into account in the manage-ment of stroke because of an excessive pathologicalactivation of the sympathetic nervous system.

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