(Stroke. 2001;32:1154.)
© 2001 American Heart Association, Inc.
Original Contributions |
Neurological Deterioration in Acute Lacunar Infarctions
The Role of Excitatory and Inhibitory Neurotransmitters
From the Section of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain (J.S., M.C., A.D.), and Service of Neurology (J.C., R.L.) and Neuroradiology (J.M.P.), Hospital Clínico Universitario, Santiago de Compostela, Spain.
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Abstract |
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Background and Purpose—The mechanisms involved in the neurological deterioration of acute lacunar strokes are unknown. Although accumulating evidence suggests that glutamate release plays a role in the progression of territorial infarctions, it remains to be established whether excitotoxicity also participates in lacunar stroke progression. We investigated whether excitatory and inhibitory amino acid concentrations in blood predict subsequent progressive motor deficits in lacunar infarctions.
Methods—We studied 113
consecutive patients with lacunar infarct, defined by clinical and
computed tomography/magnetic resonance imaging criteria, within the
first 24 hours after stroke onset. Neurological deterioration was
defined as a decrease of 
1 points in the motor items of the Canadian
Stroke Scale in the first 48 hours after admission. Glutamate, glycine,
and GABA were determined by high-performance liquid
chromatography in plasma samples obtained on admission.
Predictive values, sensitivity, specificity, and accuracy of specific
glutamate and GABA concentrations and glutamatexglycine/GABA
index for progression of lacunar stroke were
calculated.
Results—Twenty-seven patients (23.9%) had neurological worsening. Plasma concentrations of glutamate (253±70 versus 123±73 µmol/L, mean±SD) were higher and those of GABA (140±63 versus 411±97 nmol/L) were lower in the progressing group than in the nonprogressing group (both P<0.001). Glutamate concentrations >200 µmol/L and GABA levels <240 nmol/L had a positive predictive value for neurological deterioration of 67% and 84%, respectively. A excitotoxic index >106 had a positive predictive value of 85%.
Conclusions—These findings suggest that an imbalance between the glutamate and GABA concentrations may play a role in the pathophysiology of progressing lacunar infarctions.
Key Words: excitotoxicity • GABA • glutamates • lacunar infarction • stroke, acute
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Introduction |
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Lacunar infarctions have a better prognosis than other stroke subtypes.1 However, a progressing course during the acute phase, leading to a more severe prognosis,2 3 4 5 6 7 8 is observed in 25% to 35% of patients. No reliable predictors for neurological worsening in lacunar infarctions currently exist, although some clinical factors have been associated with progression in a few published studies.5 6 7 8 A better understanding of the mechanisms involved in progression could lead to the development of new therapeutic strategies in lacunar strokes. Some authors have suggested that lacunar strokes be excluded from clinical trials on neuroprotection in the belief that glutamate and GABA receptors are not present in white matter.9 10 However, the molecular mechanisms underlying neurological deterioration in acute lacunar strokes are unknown. Although accumulating evidence suggests that the release of glutamate plays a role in the progression of territorial infarctions,11 it remains to be established whether excitotoxicity also plays a role in lacunar stroke progression. In this study, we investigated the association of excitatory and inhibitory amino acid concentrations in plasma and the progression of neurological deficit in lacunar infarctions.
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Subjects and Methods |
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We studied 113 consecutive patients (men, 56.6%; mean±SD age, 69.7±9.2 years) with a lacunar infarction within 24 hours of the onset of symptoms and 50 healthy control subjects. Patients were admitted in 2 university hospitals (69 and 44 patients) and were selected from a total of 284 patients included between October 1997 and December 1999 in a prospective stroke data bank of patients diagnosed as having lacunar infarction. The aim was to study new biochemical markers of neurological deterioration; hence, frozen plasma samples obtained at admission from each patient were stored in appropriate conditions. The protocol was approved by the ethics committees, and informed consent was given by patients or their relatives. Lacunar infarction was diagnosed if the patient had 1 of the characteristic clinical lacunar syndromes,2 12 neurological deficit lasting >24 hours, no evidence of cerebral cortical dysfunction, and computed tomography/magnetic resonance imaging (CT/MRI) that was normal or showed a deep focal infarction in an appropriate location with a diameter
15 mm. Exclusion
criteria, for the purpose of this investigation, were established after
the completion of the data bank. Reasons for exclusion were a lack of
stored blood samples in 30 patients, no follow-up CT scan or MRI in 53
patients, and admission >24 hours after stroke onset in 88 patients.
The exclusion of patients was agreed upon by 1 investigator from each
center (J.S. and J.C.) before neuroimaging evaluation and amino acid
determination. The control group, which has already been described,13 included subjects without neurological disorders subjected to epidural anesthesia (29 men and 21 women; mean age, 56±17 years). Plasma and cerebrospinal fluid (CSF) samples were obtained.
Stroke severity was quantified by an experienced neurologist
using the Canadian Stroke Scale (CSS) at admission and 48 hours after
inclusion. The CSS measures level of consciousness (alert=3,
drowsy=1.5); speech (normal=1, expressive deficit=0.5; receptive
deficit=0); orientation (oriented=1, disoriented or not applicable=0);
facial paresis (none=0.5, present=0); weakness in arm, hand, and
leg (none=1.5, mild=1, significant=0.5, total=0; scored individually
for each item), with a total score ranging from 1.5 (maximum deficit)
to 10 (absence of
deficit).14 Following
already published criteria aimed at giving the highest sensitivity and
specificity, progressing stroke was diagnosed when the CSS score
dropped 1 points during the first 48 hours after
admission.14 15
According to the diagnostic criteria of lacunar stroke,
only changes in the motor items of the CSS were considered. Outcome at
3 months was evaluated with the modified Rankin scale and the Barthel
Index. Measurements at hospital discharge were taken as final outcome
scores in 5 patients who failed to attend the appointment scheduled for
3 months after stroke.
CT scan was carried out at admission, and CT or MRI was repeated between days 3 and 7 of hospitalization. The control CT, or MRI when performed, was used as the gold standard in identifying lacunar infarcts. Parenchymal topography was assessed from the control examination by the same radiologist (J.M.P.), who had no knowledge of the patients’ clinical and biochemical results. Infarct location was classified as (1) internal capsule, (2) corona radiata, (3) centrum semiovale, (4) caudate nucleus, (5) putamen and globus pallidus nucleus, (6) thalamus, (7) midbrain, (8) pons, and (9) medulla in accordance with established template mapping.16 17 For the purpose of this study, the thalamus was included, along with caudate nucleus, putamen, and globus pallidus, as "basal ganglia." Infarct volume was not calculated because of the unreliability of CT in measuring small infarcts. Blood chemistry test, 12-lead electrocardiograms, chest radiography, and arterial supra-aortic trunk examination (color-coded duplex sonography in 93 patients, digital substraction angiography in 12, and MRI angiography in 8) were also performed in all patients. Transcranial Doppler was carried out systematically in 1 hospital (44 patients) following a protocol reported elsewhere.18 The suspected cause of lacunar infarctions was classified as large-artery atherosclerosis, cardioembolism, and small-vessel disease, following the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.19
Only patients who had a systolic blood pressure
220 mm Hg or a diastolic blood pressure 120
mm Hg received hypotensive drugs in the first 48 hours after
admission. Treatment with insulin for hyperglycemia (blood glucose
>160 mg/dL) and with intravenous metamizol for
hyperthermia (body temperature >37.5°C) was initiated early after
hospitalization. Subcutaneous low-dose heparin as a prophylaxis against
pulmonary thromboembolism and antiplatelet drugs were
prescribed. Anticoagulants were given to patients with a major
cardioembolic source but not as treatment of progressing lacunar
stroke. Two patients received a placebo as part of a short-term
clinical trial, and none was treated with recombinant tissue
plasminogen activator.
Laboratory Tests
Blood samples were taken on admission in the
Emergency Department in glass test tubes containing potassium edtate.
Suspensions of plasma were centrifuged at
3000g for 5 minutes and stored
at -80°C. Glutamate, glycine, and GABA were quantified by
high-performance liquid chromatography as
previously described.11
These measurements were made by technicians from an independent
laboratory who were unaware of the clinical outcome and neuroimaging
findings. The excitotoxic index was calculated as glutamate (in
µmol/L) times glycine (in µmol/L) divided by GABA (in nmol/L),
following the description of Globus et
al.20
Statistical Analyses
Proportions between progressing and nonprogressing
lacunar infarcts were compared by use of the
2 test. Continuous variables are
expressed as mean±SD and were compared by Student’s
t test or the Mann-Whitney test
as appropriate. The Kruskal-Wallis test was used to compare amino acid
concentrations between 5 groups of patients with different degrees of
improvement or worsening in CSS score between admission and 48 hours;
absolute differences were as follows: group 1, 2; group 2, 1.5 and
1.0; group 3, 0.5, 0, and -0.5; group 4, -1.0 and -1.5; and group
5, -2.0.
We used cutoff values, as described by Robert et al,21 to estimate the sensitivity, specificity, predictive values, and accuracy (with 95% confidence intervals [CIs]) of a specific concentration of plasma glutamate and GABA and of a particular cutoff in excitotoxic index for progressing lacunar stroke. This method is a probabilistic technique based on Bayes’ rules that provides the maximum probability of a correct classification. The importance of amino acids in the progression of lacunar stroke was assessed by logistic regression analysis with adjustment for those baseline variables related to neurological worsening in the univariate analysis. Amino acids were included as categorical variables because the cutoffs meant that there was a lack of linearity of the odds ratios (ORs; 1=high, 0=low). The potential interaction between glutamate and GABA concentrations was analyzed.
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Results |
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Of the 113 patients studied, 27 (23.9%) showed neurological worsening during the first 48 hours of hospitalization. The proportion of progression in the 171 excluded patients was not significantly different (19.9%, P=0.56). Patients with progressing lacunar infarct showed a higher prevalence of history of hypertension and higher leukocyte count on admission compared with those with nonprogressing stroke (Table 1
). No patients taking aspirin before the
onset of stroke showed worsening of the neurological deficit. There
were no significant differences between the 2 groups in lacunar
syndromes at admission and stroke subtypes.
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Among the factors potentially associated with neurological
deterioration, blood glucose levels at 24 and 48 hours after admission
were significantly higher in patients with progression
(P0.01), but systolic
and diastolic blood pressures and body temperature were not
(Table 2). Other potential causes for infarct
progression, such as decreased cardiac output, hypoxia for
pulmonary reasons, seizures, or metabolic causes or
infections, were not present or were present in similar
proportions in both groups. There were no statistically significant
differences in the proportion of patients receiving antihypertensive
drugs, insulin, metamizol, paracetamol, antiplatelet drugs, sodium
heparin, low-molecular-weight heparin, and other drug
treatments.
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The final neuroimaging test was CT scan in 63 patients and MRI in 50 patients. CT showed an acute lesion consistent with lacunar syndrome in 65% of patients; MRI, in 72%. Lacunar infarctions were located in the basal ganglia in 25 patients (1 in caudate, 11 in thalamus, and 13 in the lenticular nucleus), in supratentorial white matter in 42 (21 in internal capsule, 5 in corona radiata, and 16 in centrum semiovale), and in the brainstem in 10 patients (5 in pons, 3 in midbrain, and 2 in medulla). Old lacunar or territorial infarctions were seen in 42 and 11 patients, respectively. No differences in the frequency of old lesions were observed between the groups with and without acute lesions identified in the neuroimaging tests.
Early neurological deterioration occurred in 40% of
patients with lacunar infarctions affecting the basal ganglia compared
with only 9.5% of those located in white matter
(P=0.004)
(Figure 1).
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There was a 2-fold increase in plasma glutamate
concentrations, a 3-fold decrease in GABA levels, and a 6-fold increase
in the excitotoxic index in patients with neurological deterioration
compared with those who improved or remained stable (all
P<0.001). No differences in
glycine levels were observed between the 2 groups of patients. Levels
of GABA (P<0.001) but not of
glutamate (P=0.5) were
significantly lower in nonprogressing lacunar stroke than the values
obtained from our control group, which was not contemporary
(Table 3). Differences in plasma glutamate and GABA
concentrations and in the excitotoxic index between patients with and
without progressing stroke were found independently of the location of
the lacunar infarction
(Table 4).
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We did not observe a linear correlation between glutamate or
GABA concentrations and the degree of change in the CSS score 48 hours
after admission. In fact, there was a sharp cutoff between
concentrations in patients with progressing stroke and nonprogressing
stroke estimated at 200 µmol/L for glutamate and 240 nmol/L for GABA
(Figure 2). These values gave the highest positive
predictive value (67% and 84%, respectively) and retained a high
level of sensitivity (81% and 96%) and specificity (87% and 94%)
for progression. The excitotoxic index was similar in patients with
improving and stable lacunar infarctions but was higher in the group of
patients showing more severe neurological worsening
(Figure 2). The positive predictive value, sensitivity, and
specificity for progression of an excitotoxic index >106 were 85%,
89%, and 95%, respectively
(Table 5).
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Glutamate concentrations >200 µmol/L (OR, 30; 95%CI, 9 to 96) and GABA concentrations <240 nmol/L (OR, 421; 95%CI, 37 to 3771) but not a history of hypertension and increased leukocyte count on admission were independently and significantly associated with progressing stroke in the logistic regression analysis. There was no interaction between glutamate and GABA concentrations.
The prognosis of progressing lacunar infarctions was poor. At 3 months, dependency (modified Rankin scale >2) and a decrease in functional capacity (Barthel Index <85) were recorded in 44% and 44% of patients in the progressing group, whereas these figures were 13% and 15% in the nonprogressing group (all P<0.01).
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Discussion |
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The present results confirm the high frequency of early progression of neurological deficit reported in previous studies in patients with lacunar infarction and strengthens its association with a more severe prognosis.2 3 4 5 6 7 8 Despite the importance of the early clinical course on stroke outcome, no previous study has identified a clinical profile able to reliably predict which patients with lacunar infarct are likely to suffer neurological deterioration in the very early acute phase. Older and younger age, history of diabetes and arterial hypertension, stroke severity, hyperglycemia within the first 2 days after admission, and larger infarct volume have been associated with lacunar stroke progression.5 6 7 8 However, the ability to predict progression on the basis of these clinical factors was estimated as being <60% in a large study based on a stroke data bank.8 Our findings show that glutamate concentrations >200 µmol/L and GABA concentrations <240 nmol/L in blood within the first 24 hours after the onset of symptoms (mean time from onset to sampling, 10.3±6.9 hours; range, 40 minutes to 24 hours) are powerful predictors of subsequent neurological deterioration. These factors correctly classified 86% and 95% of cases. No other clinical or baseline biochemical factors were independently associated with lacunar stroke progression.
The underlying mechanisms of early deterioration in lacunar infarctions are unknown. The extension of the infarcted area after a proximal occlusion of a perforating artery has been suggested as the main cause of progression. This hypothesis was supported by the finding that progressing lacunar infarctions were slightly larger than nonprogressing infarctions in a series of 92 patients,7 and it has recently been observed by diffusion-weighted MRI in a single case report.22 Although a thrombus propagation with progressive occlusion of branches arising from a large perforating artery has been proposed as an explanation for large (>15 mm in diameter) spreading lesions,22 this mechanism is unlikely in the progression of small lacunes. Furthermore, the lack of collateral vessels for the perforating arteries causes a so-called "end-artery" infarction in which the existence of a surrounding penumbra is improbable. In the present study, we did not find a higher frequency of proximal arterial stenosis; hence, it must be seriously doubted that the enlargement of the ischemic region may be attributed exclusively to a focal hemodynamic insufficiency.
Conversely, the enlargement of cytotoxic edema showed by diffusion-weighted MRI and subsequent neurological worsening might be due to a delayed propagation of neuronal death mediated by multiple molecular and cellular mechanisms, such as excitotoxicity, free radical and nitric oxide generation, inflammation, and apoptosis.23 Our findings suggest that an imbalance between the neurotoxic effects of glutamate and the neuroprotective effects of GABA might play a role in the pathophysiology of progressing lacunar stroke in the absence of relevant changes in cerebral blood flow.
Glutamate is released in high concentrations in the core of the cerebral infarction and in the penumbral cortex, leading to a massive influx of calcium that activates a variety of catabolic processes that subsequently produce cell death.24 Plasma glutamate concentrations >200 µmol/L within the first 24 hours of the onset of symptoms have been associated with subsequent progression of cortical and subcortical ischemic stroke, giving a 97% positive predictive value for neurological deterioration.11 25 Plasma glutamate levels may reflect the magnitude of glutamate accumulation in an ischemic brain.26 This hypothesis is supported by the finding of a very high correlation between CSF and plasma concentrations of glutamate in human stroke11 and the sharp increase in plasma glutamate found 4 hours after permanent middle cerebral artery (MCA) occlusion in a rat stroke model, which is not observed for other amino acids unrelated to the excitotoxic theory of stroke damage.27 The role of glutamate in lacunar stroke is unknown because few patients were included in previous investigations. It has been proposed that glutamate does not exert a neurotoxic action in white matter ischemia because of a lack of synaptic glutamate receptors.28 However, there is a high density of glutamatergic neurones in certain regions of the deep brain, such as the thalamus, striatum, or brainstem, where lacunar infarctions are frequently located.29 In accordance with this anatomical distribution, the present results show that neurological deterioration is significantly less frequent in lacunar infarctions located in white matter (9.5%) than in those affecting basal ganglia (40%) and brainstem (50%). A further point of interest is that although mean glutamate concentrations in plasma are lower in lacunar infarctions than in territorial infarctions overall,13 concentrations >200 µmol/L are associated with neurological worsening. This cutoff in glutamate concentrations between patients with progressing and nonprogressing lacunar strokes has been described for cortical and subcortical large territorial infarctions.11 This finding suggests that there is a similar threshold of glutamate neurotoxicity in lacunar and territorial infarctions and that glutamate accumulation within or outside the ischemic area does not depend exclusively on infarct volume.
GABA neurotransmission results in increased chloride flux across the postsynaptic membrane and hyperpolarization.30 These actions counterbalance the toxic effects of glutamate during cerebral ischemia, as is supported by the neuroprotection of the GABAa receptor agonists in animal stroke models.30 A sustained increase in GABA outflow in the ischemic brain has been detected by microdialysis after permanent MCA occlusion in rats31 and after temporal lobe resection in humans.32 In contrast, in the present study, we have found decreased plasma levels of GABA in patients with lacunar stroke compared with control subjects, a finding that agrees with the reduction in plasma and CSF levels of GABA detected in patients with acute ischemic stroke33 and with the decrease in plasma GABA concentrations observed after global brain ischemia in cardiac surgery.34 Although the dynamics of GABA are unknown, the present findings suggest a reduction in GABA-ergic neuronal activity, an increase in neuronal or glial GABA uptake, or an enhanced binding of GABA to its receptors in the ischemic brain, particularly in progressing lacunar infarctions. This later hypothesis could provoke a reversal inflow of GABA from blood across the disturbed blood-brain barrier or from the CSF to the brain tissue and consequently a reduction in GABA levels in these fluids.
The vulnerability of certain regions of the brain has been
related to the varying distribution of the densities of glutamate and
GABAa
receptors.30 In the same
way, an excessive glutamate increase in the extracellular spaces, which
is not compensated for by a parallel increase in GABA, might neutralize
the cerebroprotective complex whose activation limits the extent of
injury. In this study, the excitotoxic index had the highest positive
predictive value for neurological deterioration. Most of its predictive
power was given by the GABA concentrations because glutamate levels had
a moderate predictive value (see
Table 5
). This finding supports the hypothesis that GABA
plays a role in the modulation of anoxic injury in deep brain and white
matter.35
In contrast to our findings in cortical and subcortical territorial infarctions,11 13 plasma glycine concentrations in lacunar strokes were not higher than the control values and were not different between patients with progressing and nonprogressing lacunar strokes. The lack of coincidence in the results for lacunar and territorial infarctions cannot be attributed to a different interval from stroke onset to sampling because this interval was 10 hours in the present series and 11 hours in our previous study.11 Increased levels of glycine in plasma were obtained 4 hours after permanent MCA occlusion in a rat stroke model,27 so glycine levels in the brain are likely to be detected in peripheral blood in large infarctions. These data suggest that the discrepancy might be explained by a smaller release of glycine in small infarctions.
Although an acute-phase reaction or systemic causes cannot be ruled out as producing an increase in plasma glutamate levels and a decrease in plasma GABA concentrations, several facts support the hypothesis that these changes are a reflection of the dynamics of neurotransmitters in the ischemic brain. GABA levels were particularly reduced (3-fold) and glutamate levels were increased (2-fold) in patients with subsequent progressing lacunar strokes in whom cardiovascular risk factors, stroke severity, stroke cause, biochemical parameters, and vital signs evaluated at the moment in which blood samples were taken (before progression) were similar to those of the nonprogressing group. Consequently, we cannot attribute differences in neurotransmitter concentrations to a different acute-phase response or to a distinct prior comorbidity. Furthermore, fever and other medical complications showed a similar frequency between groups, so differences in GABA and glutamate levels cannot be explained by biochemical responses to systemic problems after admission.
In conclusion, our findings suggest that an imbalance between excitatory and inhibitory neurotransmitters plays a role in the pathophysiology of progressing lacunar infarctions. However, it should be made clear that this remains to be proved because our study was not designed to investigate the mechanistic relationship between excitatory and inhibitory amino acid levels found in plasma and phenomena occurring in the brain. The excitotoxic index may be useful for the early detection of those patients with lacunar infarcts experiencing motor function deterioration in the 48 hours after admission. The effectiveness of the use of the excitotoxic index in the selection of patients with lacunar syndromes for neuroprotective interventions should be investigated.
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Acknowledgments |
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This study was partially supported by a grant from the Programa de Promoción Xeral da Investigación do Plan Galego de IDT da Xunta de Galicia (PGIDT99PX120803B). Dr Castellanos receives grants from the Fundació Doctor Josep Trueta, Girona. We thank Drs García and Gavaldà (Clinical Investigation Unit, Hospital Universitari Doctor Josep Trueta, Girona) for help with statistical analysis and Dr María Obón and R. Vega for technical support.
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Footnotes |
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Reprint requests to Dr Antoni Dávalos, Section of Neurology, Hospital Universitari Doctor Josep Trueta, E-17007 Girona, Spain.
Received October 23, 2000; revision received January 25, 2001; accepted January 26, 2001.
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  N. Vila, J. Castillo, A. Davalos, A. Esteve, A. M. Planas, and A. Chamorro Levels of Anti-Inflammatory Cytokines and Neurological Worsening in Acute Ischemic Stroke Stroke, March 1, 2003; 34(3): 671 - 675. [Abstract] [Full Text] [PDF]
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M. Castellanos, J. Castillo, M. M. Garcia, R. Leira, J. Serena, A. Chamorro, and A. Davalos Inflammation-Mediated Damage in Progressing Lacunar Infarctions: A Potential Therapeutic Target Stroke, April 1, 2002; 33(4): 982 - 987. [Abstract] [Full Text] [PDF]
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