Neurological Research A Journal of Progress in Neurosurgery, Neurology and Neurosciences
ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20
Compensatory mechanisms in patients with asymptomatic carotid artery occlusion Torsten Kuwert, Michael Hennerici, Karl-J. Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich, Wolfgang Rautenberg & Ludwig E. Feinendegen To cite this article: Torsten Kuwert, Michael Hennerici, Karl-J. Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich, Wolfgang Rautenberg & Ludwig E. Feinendegen (1990) Compensatory mechanisms in patients with asymptomatic carotid artery occlusion, Neurological Research, 12:2, 89-93, DOI: 10.1080/01616412.1990.11739923 To link to this article: http://dx.doi.org/10.1080/01616412.1990.11739923
Published online: 20 Jul 2016.
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Date: 17 July 2017, At: 00:11
Compensatory mechanisms in patients with asymp tomat ic caroti d artery occlusion Torsten Kuwert, Michael Hennerici* , Karl-). Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich *, Wolfgang Rautenber g* and Ludwig E. Feinendeg en Institute of Medicine, Nuclear Researth Center jiilich, W Germany ahd *Department of Neurology, HeinrichHeine University of Dusseldorf, W Germany
Twelve patients with asymptomat ic occlusion of one (n = 8) or both (n = 4) internal carotid arteries were examined by positron emission tomography (PET) and transcranial Doppler ultrasound. PET measuremen ts included the determination of the regional cerebral blood flow (rCBFYt oxygen extraction ratio (rOER), cerebral metabolic rate of oxygen (rCMRO~, and cerebral metabolic rate of glucose consumption (rCMRGic). Transcranial Doppler ultrasound (TCD) was used to determine the pathways and efficacy of collateralization via the circle of Willis and included spectrum analysis of flow velocities within the middle and anterior cerebral arteries as well as vasoreattivity tests. In corresponde nce with ultrasound evidence of a haemodynamically effective intracranial collateral circulation no significant differences between patients and controls were observed for rOER, rCMR02 and rCMRGic, but rCBF was globally reduced. Furthermore, in all patients with unilateral carotid occlusion PET excluded side asymmetries of any parameter studied. In contrast, flow velocity parameters measured by TCD were significantly reduced ipsilateral and significantly increased contralateral to the carotid obstruction. Vasodilative capacities, however, remained preserved even in the territory of the occluded carotid system. These data indicate that patients with asymptomat ic carotid occlusion compensate by haemodynam ic and not by metabolic mechanisms in contrast to symptomatic patients. Keywords: Arteries, asymptomat ic carotid disease, positron emission tomography, Doppler ultrasound The improvemen t of noninvasive methods for the evaluation of carotid artery disease (CAD) has led to the detection of many neurologica lly asymptomat ic patients with haemodynam ically significant obstructive lesions. Several studies have been designed to investigate prospectivel y the risk of cerebral infarction in such patients 1 - 3• Despite some differences in study design a striking similarity in the results was the very low incidence of stroke ranging from 0.5 % to 1.4% annually. Furthermore , for patients with occlusion, a slightly worse prognosis has been suggested 4, comparable with th e prognosis of patients with symptomatic CAD5 • No reliable diagnostic criteria have yet been established to predict the individual patient's prognosis. Ameng many possibilities at least three parameters should be considered: firstly the rate of progression 6, secondly the embolic capacity of the process, and thirdly the intracranial tissue perfusion and m etabolism. Positron emission tomography (PET) addressing the latter7 ' 8 and transcranial Doppler ultrasound (TCD) considering cerebral circulation 9 - 11 are noninvasive methods for the evaluation which, by their complemen tary character, may be used to pred ict the individual patient's prognosis already in the neurologica lly asymptomat ic stage.
PATIENTS The patients recruited and then selected for our prospective trial on the natural history of asymptomat ic extracranial arterial disease1 were 12 men aged between 53 Correspondence to: Professor M. Hennerici, Department of Neurology, Univers ity Heidelberg, Theodor Kutzer-Ufer, D6800 Mannheim 1, FRG.
and 76 years (mean 69 years). Occlusion of one (n = 8) or both (n = 4) carotid arteries was known, for more than 3 years, in each from repeat extracranial Doppler ultra" sound and duplex system examin ations 10•1·1 • The vertebra-ba silar arteries were normal in all subjects as determi ned by extracranial and transcranial Doppler examination s. Selective intra-arterial digital subtraction angiograms performed in four men (three with unilateral, one with bilateral occlusio n) confirmed the ultrasound results. None of them had any signs or symptoms of cerebrovascular disease, being admitted because of coronary or peripheral artery diseases, cervical bruits, or for routine check-up because of prevailing risk factors for atherosclerosis. Cranial computed tomography before PET excluded focal silent lesions. METHODS
Positron emission tomography PET measuremen ts were performed using the ECAT-11 scanner in a transaxial resolution of 16 mm and an axial resolution of 20 mm. The images were reconstru cted by filtered back-project ion. The attenuation correction was made using Ge68/Ga68 transmission scans. All stud ies were performed with subd ued light with the subject's eyes open and his ears unplugged. Intravenous and intraarterial cannulation permitted radiotracer injection and collection of blood samples. The position of the head was carefully set using a laser beam. Two or three scans parallel to the orbito-meata l plane were performed at OM-levels + 4.5, +6.0 and +7.5 em. The regional cerebral metabolic rate of glucose consumption (rCMRGic) was m easured accord ing to the standard procedure f irst
© 1990 Butterworth - Heinemann 0161-6412/90/0200 89-05
Neurological Research, 1990, Volume 12, june 89
TCD and PET in carotid occlusion: T. Kuwert et a/
Figure 1: Semi-automatically placed regions of interest.
described by Reivich et a/. 12 using the Sokoloff et a/. model equation 13, the kinetic constants published by Phelps et a/. 14, and a lumped constant of 0.48 obtained by Gjedde (personal communication). Regional cerebral blood flow (rCBF) and oxygen extraction ratio (rOER) were measured using the steady-state inhalation technique developed by the Hammersmith group15• Regional cerebral rate of oxygen consumption (rCMR02) was calculated from the product of rCBF, rOER and the arterial oxygen content. The PET data were analysed using an interactive mapping program identifying the cortical rim by a border finding algorithm and subdividing the cortical ribbon automatically as shown in Figure 1. Eight cortical regions of interest (ROI) were defined on each slice corresponding to the vascular territories of the anterior (ACA), middle (MCA) and posterior (PCA) cerebral arteries. The ROis were defined on the rCBF images and then transferred to the images of rOER, rCMR0 2 and rCMRGic. The arithmetic means of the ROI values weighted by their cross-sectional areas were calculated in each arterial territory for an estimate of each param·eter selectively. The arithmetic mean of all ROI values were then calculated in each patient to obtain individual global cortical values for each parameter measured. In patients with unilateral occlusions bilateral differences were calculated by subtracting the ipsilateral value from the contralateral one. Selective measurements of rCMRGlc, rCBF, rOER, and rCMR0 2 were performed among a control group of 15 normal volunteers (11 men and 4 women; mean age: 44.5 years; range: 23-66 years). The continuous inhalation technique was applied in six cases, the FOG technique in nine. Written and informed consent was obtained before PET scanning in all subjects. Transcranial Doppler ultrasound A two-dimensional directional pulsed wave Doppler scanning system operating at 2 MHz (EME -trans - scan, Uberlingen) was used. Details of th e examination procedure and of normal valu es are described elsewhere9 • Recordings of flow velocity within th e circle of Willis were taken from a trans-temporal approach to evaluate 90 Neuroiogical Research, 1990, Volume 12, june
the existing collateral flow pathways. Identification of each vessel was based on the interpretation of peak systolic, diastolic and the averaged weighted mean flow velocities, depth control of the range-gated Doppler volume and the flow direction recorded instantaneously and during compression tests of the contralateral common carotid artery (CCA). Active collateral circulation was determined in unilateral carotid ocClusion by: (1) raised Doppler frequency values in the contralateral ACA, the anterior communicating artery and inverse ipsilateral ACA flow direction with decrease following contralateral CCA compression and/or (2) raised Doppler frequency values in the P1 segment of the PCA and the posterior communicating artery with increase following contralateral CCA compression. In patients With bilateral carotid occlusion 1, raised Doppler frequency values in both PCAs and posterior communicating arte·ries 2 with decrease following compression of either vertebral arteries characterized this condition. Although an estimate of potential collateral flow is difficult in patients with evidence of collateral flow, vasoreactivity tests were used for that purpose. MCA peak and mean velocities were recorded before and after inhalation of 7% carbon dioxide as well as end exspiratory C0 2• The reactivity index Rl 16 was calculated as percentage change in MCA peak velocity per absolute change of end exspiratory C0 2 and compared with a series of sex- and agematched controls. Fast Fourier transform (FFT) flow velocity spectra from the ACA and MCA were used for an estimate of the efficacy of these mechanisms. Systolic peak, average weighted mean flow velocities and the pulsatility index9 were used for a comparison of the recorded Doppler values between either side. Data analysis Statistical analysis was performed using the Student's two-tailed t-test to compare group means and the twotailed paired t-test to compare mean bilateral differences. In cases of unequal variance (F-test) Welch's t-test and the Wilcoxon rank-test were used to compare group · means. The significance level was set at 0.01.
Figure 2: rCBF (upper left), rCMR02 (upper right), rOER (lower left), and rCMR.Giu (lower right) in a patient with unilateral occlusion of the internal carotid artery (ICA): no significant bilateral difference.
TCO and PET in carotid occlusion: T. Kuwert et a/
table 1: Arithmetic mean difference (±standard deviation) of corresponding contralateral and ipsilateral regions of interest in unilateral carotid occlusion for rCBF, rOER, rCMR0 2 and rCMRGic ~rCBF'
MOER•
(ml 10og- 1 min- 1)
(%)
MCMR02• (ml 10og- 1 min- 1)
ilrCMRGJc• (mg 10og- 1 min- 1)
-0.016 1.86
-1.43 2.37
-0.01 0.23
-0.06 0.26
,0.8 1.15
-0.29 2.06
-0.03 0.13
0.17 0.3
-0.8 0.86
1 2.31
-0.02 0.15
0.07 0.15
0.82 4.77
-1.43 6.21
-0.11 0.54
-0.14 0.9
-0.87 1.73
0.9 1.87
0.02 0.2
0.08 0.2
Region
Frontalb
x• SD
Fronto-temporalb
x SD
Temporo-occipitalb
x SD
Occipitalb
x SD
Hemisphericalb
x SD
•AIJ differences obtained by s"ubtracting the contralateral value from the ipsilateral one; bNo significance (paired t-test).
RESULTS Neither in the patients with unilateral nor in those with bilateral carotid occlusion could any focal disturbance of rCBF, rOER, rCMR0 2 and rCMRGic be detected (Table 1). PET results of a typical case are shown in Figure 2; despite unilateral left-s ided occlusion of the ICA, no difference between both hemispheres in any of the investigated parameters was visualized. Global rCBF, however, was significantly reduced in patients versus controls (Table 2); rOER tended to be increased . and rCMR0 2 to be decreased, but this did not reach statistical significance (P > 0.01). No difference was observed for rCMRGic. TCD showed active pathways of collateralization in all patients with unilateral ICA occlusion from the contralateral carotid system via the anterior circle of Willis. In patients with bilateral occlusion the posterior comTable 2: Arithmetic mean values (±standard deviation) of global rCBF, rOER; rCMR0 2 and rCMRGlc in patients with occlusion of the internal carotid artery and also controls Patients rCBF• (ml 100 g- 1 min- 1 ) rOERb (%) rCMR0 2 b (ml 100 g- 1 min- 1) rCMRGJcb (ml 100 g - 1 min- 1)
31 .8 ± 48.5" ± 2.77 ± 6.33 ±
8.74 10.4 0.95 1.98
Controls 48.6 38.04 3.86 6.56
± ± ± ±
8.42 3.13 0.89 1.4
•p < 0.01 (Student's t-test). bNo significance (P >0.01).
x = mean
difference, so
= standard
deviat ion.
municating arteries formed the major collateral. A retrograde perfusion of at least one ophthalmic artery was observed in all cases with bilateral occlusion, but in only three of eight patients with unilateral occlusion. In patients with unilateral occlusion peak and mean flow velocities, as well as the pulsatility index, were within normal limits but a marked reduction of these values occurred ipsilateral to the occluded ICA in contrast to the compensatory increase on the contralateral side (Table 3). If both carotid arteries were occluded, an asymmetry would still persist at slightly reduced peak and mean flow velocity levels but with markedly decreased P1 values. In addition the vasoreactivity tests showed a preserved vasodilative potential: the reactivity index was within normal limits (>8) in all MCAs.
DISCUSSION PET has been used to measure cerebral tissue perfusion and metabolism in patients with transient ischaemic attacks and stroke7' 8' 17' 18• Gibbs et af.l reported an increased volume/flow ratio in symptomatic patients with ICA occlusion and conclucjed that vasodilation acts as the first compensatory mechanism in order to maintain constant tissue perfusion distal to a haemodynamically significant obstruction. If tissue perfusion further decreases, an increase of rOER acts as a sequel compensatory mechanism to maintain rCM R0 2 at a constant level. Cerebral autoregulation was then suspected to be exhausted due to maximal vasodilation, although this was not investigated.
Table 3: Arithmetic mean values of Doppler spectrum parameters (± standard deviation) from the middle cerebral arteries (MCA) in patients with occlusion of the internal carotid artery (ICA) versus controls FFT parameter
Peak systole (em s- 1) Mean velocity (em s- 1) Pulsatility ind ex
Unilateral ICA occlusion MCA Ipsilateral
Contralateral
70 ± 7.31 43 ± 4.21 0.87 ± 0.071
100 ± 6.6 64 ± 7.5 1.1 ± 0.08
Bilateral ICA occlusion Both MCAs
Age-matched controls
69 ± 12.92 47 ± 8.12 0.76 ± 0.053
78.2 ± 12.4 50.4 ± 9.3 1.0 ± 0.02
Wilcoxon-test: 1 1psilateral versus contralateral P < 0.01; 2 ipsilateral versus bilateral no sign ificance P > 0.01; 3 ipsilateral versus bilate ral P < 0.01. N eurological Research, 1990, Volume 12, june 91
TCD and PET in carotid occlusion: T. Kuwert et a/
These mechanisms may also be important in patients who are increasingly being diagnosed at an early, still neurologically asymptomatic stage. Apart from the observation of sequential deterio~ation of CAD as a common indicator of an increased stroke risk1' 3, we are still missing any valid parameter to predict the individual patient's prognosis. The group of 12 carefully selected patients with uni- or bi-laterally occluded ICAs was therefore suspected to be at high-risk for stroke1' 4' 5 • The data presented do not favour a haemodynamic interpretation of this high stroke risk: PET studies excluded the typical combination of low rCBF, low rCMR02 and high rOER, which is termed the 'misery perfusion syndrome' 18 • Only low rCBF values of symmetric distribution between both hemispheres were observed in patients with unilateral ICA occlusion, which is suspected to resu It mainly from the age difference of approximately 20 years in the younger control groups19 • In addition, the presence of multiple risk factors in patients with atherosclerosis may have contributed to this difference, since some of them have been shown to reduce grey matter flow measured by the Xenon-133 inhalation method if groups of normal volunteers with risk factors versus those without risk factors were compared 20 - 22 • rOER and both rCMR0 2 and rCMRGic levels, which characterize cerebral metabolism, did not differ between patients and controls and in particular did not reveal any significant asymmetry. This is a striking difference between our group of asymptomatic patients with ICA occlusion and symptomatic patients reported in the literature, who showed an increase of rOER at lower rCMR0 2 levels in association with lower rCBF values 7' 8 ipsilateral to the occluded ICA. Whil e PET studies excluded definite territorial abnormalities in these asymptomatic patients with ICA occlusion, TCD documents the influence of several compensatory mechanisms to maintain tissue perfusion and cerebral circulation: patency of collateral pathways and preserved C"apacity of vasoreactivity are the major haemodynamic parameters indicating efficient active and potential haemodynamic reserves. Furthermore, cerebral circulation was not exhausted - despite the tendency of symmetrically increased rOER values, vasodilation as revealed by bilateral vasoreactivity tests16 was not exhausted on either hemisphere as might have been suspected from the model of successive haemodynamic and metabolic compensatory mechanisms proposed by Gibbs et aJ.l. Our interpretation of overlapping, independent mechanisms is further supported by recent studies which have failed to demonstrate a significant improvement in oxygen metabolism after successful EC -IC arterial bypass performed in patients with the typical'misery perfusion syndrome' despite restoration of the haemodynamic situation 23 • It is also in agreement with a recent study of Powers et a/.8 who reported 19 symptomatic patients with ICA occlusion: only those with angiographically demonstrated sufficient collateralization via the circle of Willis have normal haemodynamic and metabolic findings, whereas patients with collateralization via leptomeningeal vessels had asymmetric findings with either an increase of the CBF/CBV ratio or an increas e of rO ER ipsilateral to the occlusion as com pared with the co ntralateral site.
CONCLUSION Patients with asymptomatic CAD share a smaller risk of stroke than patients with similar vascular processes but 92 Neurological Research, 1990, Volume 12, june
a history of TIA: tissue perfusion and cerebral metabol ism (rCBF, rOER, rCMR0 2 and rCMRGlc) are likely to be normal, if noninvasive TCD reveals efficacy of active collateral pathways with preservation of normal intra-arterial flow velocity values within the territory of the occluded carotid artery. Demonstration of a vasodilative reserve potential further favours the interpretation of a haemodynamically safe situation. In the future those patients should be elaborated who failed to show efficient compensatory mechanism as measured by TCD . Supplementary PET studies may then be able to disclose focal areas of 'misery perfusion' and contribute to the selection of further high-risk patients who may represent potential candidates for carotid surgery before occlusion even at an asymptomatic stage.
ACKNOWlEDGEMENTS This work was supported in part by grants from the Deutsche Forschungsgemeinschaft SFB 200/D2. The authors thank Prof. G. Sti:icklin and his staff from the Institute of Nuclear Chemistry for providing the radiopharmaceuticals, and Doris Beaujean and Barbara Kosemetzky for her valuable· secretarial help.
REFERENCES 1 Hennerici M, Hi.ilsbome r HB, Hefter H, Lammerts D, Rautenberg W. Natu ral history of asymptomatic extracranial arterial d isease. Brain 1987; 110: 777-791 . 2 Roederer GO, Langlois YE, Jager KA, Primozich jF, Beach KW, 'Phillips DJ, Strand ness DE. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984; 15: 605-613. 3 Chambers BR, Norris JW. Outcome in patients with asym ptomatic neck bruits. N Engl J Med 1986; 315: 880-865. 4 He nnerici M, Hi.ilsbo mer HB, Rautenberg W, Hefter H. Spontaneous history of asymptomatic inte rnal carotid occlusion. Stroke 1986; 17: 718-722. 5 Cote R, Barnett HjM, Tayor DW. Internal carotid occlusion: a prospective study. Stroke 1983; 14: 898-902. 6 Hennerici M, Rautenberg W, Trockel U, Kladetzky RG. Spon. taneous progression and regression of small carotid atheroma. Lancet 1985; i: 1415-1419. 7 Gibbs JM, Leenders KL, Wise RJS, jones T. Evaluation of cerebral perfusion reserve in patients with carotid artery occlusion. Lancet 1984; i: 310-314. 8 Powers WJ, Press GA, Grubb RL, Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987; 106: 27 -35."' 9 Hennerici M, Rautenberg W, Sitzer G, SchwartzA. Transc ranial Doppler ultrasound for the assessment of intracranial arterial flow velocity - parts I and II. Surg Ne uro/1987; 27: 439 - 448 and 523 - 532. 10 Hennerici M, Freund H.-j. Efficacy of CW-Doppler and duplex system examinations for the evaluation of extracranial carotid disease. j Clin Ultrasound 1984; 12: 155-161. 11 Trockel U, Hennerici M, Aulich A, Sandmann W. The superiority of combined continous wave Doppler examination over periorbital Doppler for the detection of extracranial carotid d isease. j Neural Neurosurg Psychiatr 1984; 47: 43-,50. 12 Reivich M, Kuhl D, Wolf A, Greenberg j, Phelps M, ldo T, Casella V, Fowler j, Hoffman j, Alavi A, So P, Sokoloff L. The 8 F) fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res 1979; 44: 127-137. 13 Sokoloff L, Reivich M, Kennedy C, desRosiers MH, Patlak CS, Pettigrew KD, Sakurada 0 , Shinohara M. The (14C) deoxyglucose method for the measurement of local cerebral gl ucose utilization: Theory, procedure, and normal valu es in the conscious and anesthetized albino rat. j Neurochem 1977; 28: 897- 916. ' 14 Phelps ME, Huang SC, Hoffman EJ, Selin MS, Sokoloff L, Kuhl DE. Tomographic measure ment of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-o-glucose: Validation of method. Ann Neuro/1979; 6: 371-388.
e
TCD and PET in carotid occlusion: T. Kuwerr er a1
15 Frackowiak RSJ, Le nzi GL, jones T, Heather J.D. Quantitative measurement of regional cereb ral blood flow and oxygen metabolism in man using 15 0 and positron e mis sio n tomography: Theory, procedure, and normal values.} Comput Ass Tomogr 1980; 4: 727-736. 16 BishopCCR, Powell S, lnsall M, Rutt D, Browse NL. Effect of internal carotid artery occlusion on middle cerebral artery blood flow at rest and in respon se to hypercapnea. Lancet 1986; i: 710-712. 17 ltoh M, Hatazawa j, Pozilli C, Fukuda H, Abe Y, Fujiwara T, Kubota K, Yamaguchi K, Sato T, Watanabe H, Ida T, Matsuzawa T. Hemodynamic s and oxygen metabolis m in patie nts after reversible isc hemic attack or minor ischemic stroke assessed with positron emission tomography. Neuroradiolog y 1987; 29: 416 - 421 . 18 Baron JC, Bousse r MG, Rey·A, Giullard A, Comar D, Castaigne P. Reversal of focal 'misery-perfus ion syndrome' by extra- intracranial arterial bypass in hemodynamic cerebral ischemia: A case
19
20 21 22 23
study with 15 0 pos itron emission tomography. Stroke 1981; 12: 454-459. Frackowiak RSL Wise RJS, Gibbs JM, jones T. Positron emission tomography of abnormal and diseased states. I. Stud ies in aging and cerebrovascula r disease at Hammersmith Hospital. Ann Neurol1984; Suppl 15: S112-S118. Rogers RL, MeyerS, Shaw TG, Martel KF, Hardenbe rg JP, Zaid RR. Cigarette smoking d ecreases cereb"ral blood flow suggesting increased risk for stroke. }AMA 1983; 20(250): 2796-2800. Meyer JS, Rogers RL, Martel KF. Prospective analysis of long-term control of mild hypertension on cerebral blood flow. Stroke 1985; 16: 985-990. Meyer JS, Rogers RL, Martel KF, judd BW. Hyperlipide mia is a risk factor for decreased cerebral perfusion and stroke. Arch Neurol1987; 44: 418-422. Powers WL Raichle ME. Positron emission tomography in cerebrovascula r disease. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke, New York: Churchiii-Livingstone, 1986: pp. 127- 137.
Neurological Research, 1990, Volume 12, june
93
ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20
Compensatory mechanisms in patients with asymptomatic carotid artery occlusion Torsten Kuwert, Michael Hennerici, Karl-J. Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich, Wolfgang Rautenberg & Ludwig E. Feinendegen To cite this article: Torsten Kuwert, Michael Hennerici, Karl-J. Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich, Wolfgang Rautenberg & Ludwig E. Feinendegen (1990) Compensatory mechanisms in patients with asymptomatic carotid artery occlusion, Neurological Research, 12:2, 89-93, DOI: 10.1080/01616412.1990.11739923 To link to this article: http://dx.doi.org/10.1080/01616412.1990.11739923
Published online: 20 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 11 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yner20 Download by: [Cornell University Library]
Date: 17 July 2017, At: 00:11
Compensatory mechanisms in patients with asymp tomat ic caroti d artery occlusion Torsten Kuwert, Michael Hennerici* , Karl-). Langen, Hans Herzog, Elena Rota Kops, Albrecht Aulich *, Wolfgang Rautenber g* and Ludwig E. Feinendeg en Institute of Medicine, Nuclear Researth Center jiilich, W Germany ahd *Department of Neurology, HeinrichHeine University of Dusseldorf, W Germany
Twelve patients with asymptomat ic occlusion of one (n = 8) or both (n = 4) internal carotid arteries were examined by positron emission tomography (PET) and transcranial Doppler ultrasound. PET measuremen ts included the determination of the regional cerebral blood flow (rCBFYt oxygen extraction ratio (rOER), cerebral metabolic rate of oxygen (rCMRO~, and cerebral metabolic rate of glucose consumption (rCMRGic). Transcranial Doppler ultrasound (TCD) was used to determine the pathways and efficacy of collateralization via the circle of Willis and included spectrum analysis of flow velocities within the middle and anterior cerebral arteries as well as vasoreattivity tests. In corresponde nce with ultrasound evidence of a haemodynamically effective intracranial collateral circulation no significant differences between patients and controls were observed for rOER, rCMR02 and rCMRGic, but rCBF was globally reduced. Furthermore, in all patients with unilateral carotid occlusion PET excluded side asymmetries of any parameter studied. In contrast, flow velocity parameters measured by TCD were significantly reduced ipsilateral and significantly increased contralateral to the carotid obstruction. Vasodilative capacities, however, remained preserved even in the territory of the occluded carotid system. These data indicate that patients with asymptomat ic carotid occlusion compensate by haemodynam ic and not by metabolic mechanisms in contrast to symptomatic patients. Keywords: Arteries, asymptomat ic carotid disease, positron emission tomography, Doppler ultrasound The improvemen t of noninvasive methods for the evaluation of carotid artery disease (CAD) has led to the detection of many neurologica lly asymptomat ic patients with haemodynam ically significant obstructive lesions. Several studies have been designed to investigate prospectivel y the risk of cerebral infarction in such patients 1 - 3• Despite some differences in study design a striking similarity in the results was the very low incidence of stroke ranging from 0.5 % to 1.4% annually. Furthermore , for patients with occlusion, a slightly worse prognosis has been suggested 4, comparable with th e prognosis of patients with symptomatic CAD5 • No reliable diagnostic criteria have yet been established to predict the individual patient's prognosis. Ameng many possibilities at least three parameters should be considered: firstly the rate of progression 6, secondly the embolic capacity of the process, and thirdly the intracranial tissue perfusion and m etabolism. Positron emission tomography (PET) addressing the latter7 ' 8 and transcranial Doppler ultrasound (TCD) considering cerebral circulation 9 - 11 are noninvasive methods for the evaluation which, by their complemen tary character, may be used to pred ict the individual patient's prognosis already in the neurologica lly asymptomat ic stage.
PATIENTS The patients recruited and then selected for our prospective trial on the natural history of asymptomat ic extracranial arterial disease1 were 12 men aged between 53 Correspondence to: Professor M. Hennerici, Department of Neurology, Univers ity Heidelberg, Theodor Kutzer-Ufer, D6800 Mannheim 1, FRG.
and 76 years (mean 69 years). Occlusion of one (n = 8) or both (n = 4) carotid arteries was known, for more than 3 years, in each from repeat extracranial Doppler ultra" sound and duplex system examin ations 10•1·1 • The vertebra-ba silar arteries were normal in all subjects as determi ned by extracranial and transcranial Doppler examination s. Selective intra-arterial digital subtraction angiograms performed in four men (three with unilateral, one with bilateral occlusio n) confirmed the ultrasound results. None of them had any signs or symptoms of cerebrovascular disease, being admitted because of coronary or peripheral artery diseases, cervical bruits, or for routine check-up because of prevailing risk factors for atherosclerosis. Cranial computed tomography before PET excluded focal silent lesions. METHODS
Positron emission tomography PET measuremen ts were performed using the ECAT-11 scanner in a transaxial resolution of 16 mm and an axial resolution of 20 mm. The images were reconstru cted by filtered back-project ion. The attenuation correction was made using Ge68/Ga68 transmission scans. All stud ies were performed with subd ued light with the subject's eyes open and his ears unplugged. Intravenous and intraarterial cannulation permitted radiotracer injection and collection of blood samples. The position of the head was carefully set using a laser beam. Two or three scans parallel to the orbito-meata l plane were performed at OM-levels + 4.5, +6.0 and +7.5 em. The regional cerebral metabolic rate of glucose consumption (rCMRGic) was m easured accord ing to the standard procedure f irst
© 1990 Butterworth - Heinemann 0161-6412/90/0200 89-05
Neurological Research, 1990, Volume 12, june 89
TCD and PET in carotid occlusion: T. Kuwert et a/
Figure 1: Semi-automatically placed regions of interest.
described by Reivich et a/. 12 using the Sokoloff et a/. model equation 13, the kinetic constants published by Phelps et a/. 14, and a lumped constant of 0.48 obtained by Gjedde (personal communication). Regional cerebral blood flow (rCBF) and oxygen extraction ratio (rOER) were measured using the steady-state inhalation technique developed by the Hammersmith group15• Regional cerebral rate of oxygen consumption (rCMR02) was calculated from the product of rCBF, rOER and the arterial oxygen content. The PET data were analysed using an interactive mapping program identifying the cortical rim by a border finding algorithm and subdividing the cortical ribbon automatically as shown in Figure 1. Eight cortical regions of interest (ROI) were defined on each slice corresponding to the vascular territories of the anterior (ACA), middle (MCA) and posterior (PCA) cerebral arteries. The ROis were defined on the rCBF images and then transferred to the images of rOER, rCMR0 2 and rCMRGic. The arithmetic means of the ROI values weighted by their cross-sectional areas were calculated in each arterial territory for an estimate of each param·eter selectively. The arithmetic mean of all ROI values were then calculated in each patient to obtain individual global cortical values for each parameter measured. In patients with unilateral occlusions bilateral differences were calculated by subtracting the ipsilateral value from the contralateral one. Selective measurements of rCMRGlc, rCBF, rOER, and rCMR0 2 were performed among a control group of 15 normal volunteers (11 men and 4 women; mean age: 44.5 years; range: 23-66 years). The continuous inhalation technique was applied in six cases, the FOG technique in nine. Written and informed consent was obtained before PET scanning in all subjects. Transcranial Doppler ultrasound A two-dimensional directional pulsed wave Doppler scanning system operating at 2 MHz (EME -trans - scan, Uberlingen) was used. Details of th e examination procedure and of normal valu es are described elsewhere9 • Recordings of flow velocity within th e circle of Willis were taken from a trans-temporal approach to evaluate 90 Neuroiogical Research, 1990, Volume 12, june
the existing collateral flow pathways. Identification of each vessel was based on the interpretation of peak systolic, diastolic and the averaged weighted mean flow velocities, depth control of the range-gated Doppler volume and the flow direction recorded instantaneously and during compression tests of the contralateral common carotid artery (CCA). Active collateral circulation was determined in unilateral carotid ocClusion by: (1) raised Doppler frequency values in the contralateral ACA, the anterior communicating artery and inverse ipsilateral ACA flow direction with decrease following contralateral CCA compression and/or (2) raised Doppler frequency values in the P1 segment of the PCA and the posterior communicating artery with increase following contralateral CCA compression. In patients With bilateral carotid occlusion 1, raised Doppler frequency values in both PCAs and posterior communicating arte·ries 2 with decrease following compression of either vertebral arteries characterized this condition. Although an estimate of potential collateral flow is difficult in patients with evidence of collateral flow, vasoreactivity tests were used for that purpose. MCA peak and mean velocities were recorded before and after inhalation of 7% carbon dioxide as well as end exspiratory C0 2• The reactivity index Rl 16 was calculated as percentage change in MCA peak velocity per absolute change of end exspiratory C0 2 and compared with a series of sex- and agematched controls. Fast Fourier transform (FFT) flow velocity spectra from the ACA and MCA were used for an estimate of the efficacy of these mechanisms. Systolic peak, average weighted mean flow velocities and the pulsatility index9 were used for a comparison of the recorded Doppler values between either side. Data analysis Statistical analysis was performed using the Student's two-tailed t-test to compare group means and the twotailed paired t-test to compare mean bilateral differences. In cases of unequal variance (F-test) Welch's t-test and the Wilcoxon rank-test were used to compare group · means. The significance level was set at 0.01.
Figure 2: rCBF (upper left), rCMR02 (upper right), rOER (lower left), and rCMR.Giu (lower right) in a patient with unilateral occlusion of the internal carotid artery (ICA): no significant bilateral difference.
TCO and PET in carotid occlusion: T. Kuwert et a/
table 1: Arithmetic mean difference (±standard deviation) of corresponding contralateral and ipsilateral regions of interest in unilateral carotid occlusion for rCBF, rOER, rCMR0 2 and rCMRGic ~rCBF'
MOER•
(ml 10og- 1 min- 1)
(%)
MCMR02• (ml 10og- 1 min- 1)
ilrCMRGJc• (mg 10og- 1 min- 1)
-0.016 1.86
-1.43 2.37
-0.01 0.23
-0.06 0.26
,0.8 1.15
-0.29 2.06
-0.03 0.13
0.17 0.3
-0.8 0.86
1 2.31
-0.02 0.15
0.07 0.15
0.82 4.77
-1.43 6.21
-0.11 0.54
-0.14 0.9
-0.87 1.73
0.9 1.87
0.02 0.2
0.08 0.2
Region
Frontalb
x• SD
Fronto-temporalb
x SD
Temporo-occipitalb
x SD
Occipitalb
x SD
Hemisphericalb
x SD
•AIJ differences obtained by s"ubtracting the contralateral value from the ipsilateral one; bNo significance (paired t-test).
RESULTS Neither in the patients with unilateral nor in those with bilateral carotid occlusion could any focal disturbance of rCBF, rOER, rCMR0 2 and rCMRGic be detected (Table 1). PET results of a typical case are shown in Figure 2; despite unilateral left-s ided occlusion of the ICA, no difference between both hemispheres in any of the investigated parameters was visualized. Global rCBF, however, was significantly reduced in patients versus controls (Table 2); rOER tended to be increased . and rCMR0 2 to be decreased, but this did not reach statistical significance (P > 0.01). No difference was observed for rCMRGic. TCD showed active pathways of collateralization in all patients with unilateral ICA occlusion from the contralateral carotid system via the anterior circle of Willis. In patients with bilateral occlusion the posterior comTable 2: Arithmetic mean values (±standard deviation) of global rCBF, rOER; rCMR0 2 and rCMRGlc in patients with occlusion of the internal carotid artery and also controls Patients rCBF• (ml 100 g- 1 min- 1 ) rOERb (%) rCMR0 2 b (ml 100 g- 1 min- 1) rCMRGJcb (ml 100 g - 1 min- 1)
31 .8 ± 48.5" ± 2.77 ± 6.33 ±
8.74 10.4 0.95 1.98
Controls 48.6 38.04 3.86 6.56
± ± ± ±
8.42 3.13 0.89 1.4
•p < 0.01 (Student's t-test). bNo significance (P >0.01).
x = mean
difference, so
= standard
deviat ion.
municating arteries formed the major collateral. A retrograde perfusion of at least one ophthalmic artery was observed in all cases with bilateral occlusion, but in only three of eight patients with unilateral occlusion. In patients with unilateral occlusion peak and mean flow velocities, as well as the pulsatility index, were within normal limits but a marked reduction of these values occurred ipsilateral to the occluded ICA in contrast to the compensatory increase on the contralateral side (Table 3). If both carotid arteries were occluded, an asymmetry would still persist at slightly reduced peak and mean flow velocity levels but with markedly decreased P1 values. In addition the vasoreactivity tests showed a preserved vasodilative potential: the reactivity index was within normal limits (>8) in all MCAs.
DISCUSSION PET has been used to measure cerebral tissue perfusion and metabolism in patients with transient ischaemic attacks and stroke7' 8' 17' 18• Gibbs et af.l reported an increased volume/flow ratio in symptomatic patients with ICA occlusion and conclucjed that vasodilation acts as the first compensatory mechanism in order to maintain constant tissue perfusion distal to a haemodynamically significant obstruction. If tissue perfusion further decreases, an increase of rOER acts as a sequel compensatory mechanism to maintain rCM R0 2 at a constant level. Cerebral autoregulation was then suspected to be exhausted due to maximal vasodilation, although this was not investigated.
Table 3: Arithmetic mean values of Doppler spectrum parameters (± standard deviation) from the middle cerebral arteries (MCA) in patients with occlusion of the internal carotid artery (ICA) versus controls FFT parameter
Peak systole (em s- 1) Mean velocity (em s- 1) Pulsatility ind ex
Unilateral ICA occlusion MCA Ipsilateral
Contralateral
70 ± 7.31 43 ± 4.21 0.87 ± 0.071
100 ± 6.6 64 ± 7.5 1.1 ± 0.08
Bilateral ICA occlusion Both MCAs
Age-matched controls
69 ± 12.92 47 ± 8.12 0.76 ± 0.053
78.2 ± 12.4 50.4 ± 9.3 1.0 ± 0.02
Wilcoxon-test: 1 1psilateral versus contralateral P < 0.01; 2 ipsilateral versus bilateral no sign ificance P > 0.01; 3 ipsilateral versus bilate ral P < 0.01. N eurological Research, 1990, Volume 12, june 91
TCD and PET in carotid occlusion: T. Kuwert et a/
These mechanisms may also be important in patients who are increasingly being diagnosed at an early, still neurologically asymptomatic stage. Apart from the observation of sequential deterio~ation of CAD as a common indicator of an increased stroke risk1' 3, we are still missing any valid parameter to predict the individual patient's prognosis. The group of 12 carefully selected patients with uni- or bi-laterally occluded ICAs was therefore suspected to be at high-risk for stroke1' 4' 5 • The data presented do not favour a haemodynamic interpretation of this high stroke risk: PET studies excluded the typical combination of low rCBF, low rCMR02 and high rOER, which is termed the 'misery perfusion syndrome' 18 • Only low rCBF values of symmetric distribution between both hemispheres were observed in patients with unilateral ICA occlusion, which is suspected to resu It mainly from the age difference of approximately 20 years in the younger control groups19 • In addition, the presence of multiple risk factors in patients with atherosclerosis may have contributed to this difference, since some of them have been shown to reduce grey matter flow measured by the Xenon-133 inhalation method if groups of normal volunteers with risk factors versus those without risk factors were compared 20 - 22 • rOER and both rCMR0 2 and rCMRGic levels, which characterize cerebral metabolism, did not differ between patients and controls and in particular did not reveal any significant asymmetry. This is a striking difference between our group of asymptomatic patients with ICA occlusion and symptomatic patients reported in the literature, who showed an increase of rOER at lower rCMR0 2 levels in association with lower rCBF values 7' 8 ipsilateral to the occluded ICA. Whil e PET studies excluded definite territorial abnormalities in these asymptomatic patients with ICA occlusion, TCD documents the influence of several compensatory mechanisms to maintain tissue perfusion and cerebral circulation: patency of collateral pathways and preserved C"apacity of vasoreactivity are the major haemodynamic parameters indicating efficient active and potential haemodynamic reserves. Furthermore, cerebral circulation was not exhausted - despite the tendency of symmetrically increased rOER values, vasodilation as revealed by bilateral vasoreactivity tests16 was not exhausted on either hemisphere as might have been suspected from the model of successive haemodynamic and metabolic compensatory mechanisms proposed by Gibbs et aJ.l. Our interpretation of overlapping, independent mechanisms is further supported by recent studies which have failed to demonstrate a significant improvement in oxygen metabolism after successful EC -IC arterial bypass performed in patients with the typical'misery perfusion syndrome' despite restoration of the haemodynamic situation 23 • It is also in agreement with a recent study of Powers et a/.8 who reported 19 symptomatic patients with ICA occlusion: only those with angiographically demonstrated sufficient collateralization via the circle of Willis have normal haemodynamic and metabolic findings, whereas patients with collateralization via leptomeningeal vessels had asymmetric findings with either an increase of the CBF/CBV ratio or an increas e of rO ER ipsilateral to the occlusion as com pared with the co ntralateral site.
CONCLUSION Patients with asymptomatic CAD share a smaller risk of stroke than patients with similar vascular processes but 92 Neurological Research, 1990, Volume 12, june
a history of TIA: tissue perfusion and cerebral metabol ism (rCBF, rOER, rCMR0 2 and rCMRGlc) are likely to be normal, if noninvasive TCD reveals efficacy of active collateral pathways with preservation of normal intra-arterial flow velocity values within the territory of the occluded carotid artery. Demonstration of a vasodilative reserve potential further favours the interpretation of a haemodynamically safe situation. In the future those patients should be elaborated who failed to show efficient compensatory mechanism as measured by TCD . Supplementary PET studies may then be able to disclose focal areas of 'misery perfusion' and contribute to the selection of further high-risk patients who may represent potential candidates for carotid surgery before occlusion even at an asymptomatic stage.
ACKNOWlEDGEMENTS This work was supported in part by grants from the Deutsche Forschungsgemeinschaft SFB 200/D2. The authors thank Prof. G. Sti:icklin and his staff from the Institute of Nuclear Chemistry for providing the radiopharmaceuticals, and Doris Beaujean and Barbara Kosemetzky for her valuable· secretarial help.
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