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(Stroke. 1995;26:2035-2039.)
© 1995 American Heart Association, Inc.
Articles |
Amino Acid Transmitters in Patients With Headache During the Acute Phase of Cerebrovascular Ischemic Disease
From the Neurology Department, Hospital General de Galicia, Clínico Universitario, Santiago de Compostela, Spain.
Correspondence to José Castillo, MD, Servicio de Neurología, Hospital General de Galicia, Santiago de Compostela, Spain.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose The pathophysiology of headache occurring at stroke onset is unknown. Migraine and ischemia share an excessive release of neuroexcitatory amino acids. Inhibitory amino acids also may be implicated in both diseases. We investigated whether fluctuations of these amino acids occur in headache accompanying cerebral infarction.
Methods We studied 100 patients with infarction in the territory of the middle cerebral artery. Neurological impairment was assessed using the Canadian Neurological Scale and Barthel Index. Size of infarction was determined with CT. Twenty-eight patients developed headache. Glutamate, aspartate, and taurine were quantified in blood and cerebrospinal fluid (CSF) within 24 hours of stroke onset with cationic exchange chromatography.
Results Stroke subtypes, size of infarct on CT, and clinical scales were similar in patients with and without headache. Plasma glutamate level was 321.14±149.53 µmol/L in patients with headache and 233±107.23 µmol/L in those without headache (P<.005). Glutamate in CSF was higher in patients with headache (4.6±1.49 µmol/L) than in patients without headache (3.11±1.18 µmol/L) (P<.001). Aspartate concentrations in plasma and CSF were similar in both groups. Taurine concentrations in plasma were 103.10±52.82 µmol/L and 177.49±90.92 µmol/L in headache and nonheadache patients, respectively (P<.001). Taurine levels in CSF were 5.42±2.42 µmol/L in patients with headache and 9.27±5.31 µmol/L in those without headache (P<.001). No significant correlation was found between amino acid levels in plasma or CSF and size of infarction.
Conclusions Amino acid neurotransmitters play a role in the pathophysiology of headache that occurs at the onset of stroke. The ischemic penumbral area, more than the infarction itself, may cause a state of cortical hyperexcitability that would be responsible for the cortical release of amino acids and the induction of headache by altering pain perception mechanisms.
Key Words: glutamates • cerebral ischemia • amino acids, neurotransmitter • headache
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Introduction |
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Headache is present in 10% to 39% of patients during the acute phase of cerebral infarction.1 2 3 4 5 6 Its pathophysiology is unknown, although a connection with mechanisms involved in migraine and tension-type headache has been suggested. In many patients it has the features of migraine,3 and cerebral ischemia may trigger a painful crisis.7 Migraine and stroke share pathophysiological mechanisms. An enhanced liberation of amino acid neurotransmitters (glutamate, aspartate, and taurine) in blood and cerebrospinal fluid (CSF) has been demonstrated during both migraine8 9 10 and cerebral infarction.11 12 13
We investigated the possible fluctuations of neuroexcitatory and neuroinhibitory amino acids in plasma and CSF of patients with stroke and the relationship of these fluctutations with headache during the acute phase of cerebrovascular ischemic disease.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 100 patients with cerebral infarction of the middle cerebral artery who were admitted to the Cerebrovascular Disease Unit of the Neurology Department (Hospital General de Galicia, Clínico Universitario, Santiago de Compostela, Spain) during the acute phase. Experimental design was approved by the local clinical investigation committee. A CT study was performed on admission, and if not diagnostic it was repeated within a week. Diagnosis of cerebral infarction and its subtypes (atherothrombotic, cardioembolic, lacunar, and indeterminate) was made according to the Classification of Cerebrovascular Diseases III of the National Institute of Neurological Disorders and Stroke.14 We did not include patients with transient ischemic attack. Neurological impairment and evolution were assessed with the Canadian Neurological Scale (days 3 and 14) and the Barthel Index (day 14). Size of infarction was measured on the CT slice with a maximum lesion area and classified as small (<1 cm), medium (1 to 3 cm), and large (>3 cm). We excluded patients with sensitive aphasia or with low consciousness level (Glasgow Coma Scale score <14) who could not give informed consent for the procedures. Patients treated with antiepileptic drugs, sympathomimetic agents, or calcium channel blockers were also excluded.
Twenty-eight patients suffered headache. We studied the nature of
pain (pulsatile or not), laterality (ipsilateral, contralateral,
bilateral), severity (mild, moderate, severe), duration (hours, days,
weeks), and temporal relation with stroke (prodromic,
simultaneous, subsequent). A history of headache was also
investigated. Headache features are summarized in Table 1
. Age of patients without headache (n=72) was
64.6±11.7 years (range, 39 to 89 years), and in those with headache
(n=28) it was 64.8±10.7 years (range, 38 to 81 years). The male to
female ratios were 20/52 and 12/16 in the nonheadache and headache
groups, respectively. Sixty-eight patients from the nonheadache
group (94%) and 25 from the headache group (89.3%) had a negative
history of chronic headache.
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Blood and CSF samples were drawn within the first 24 hours and during the painful period in those patients with headache. Blood was obtained by venipuncture after at least 8 hours of fasting and collected in crystal tubes containing EDTA-K3. Plasma was prepared by centrifugation (3000g for 15 minutes) and stored at -70°C. Lumbar puncture was performed after informed consent was obtained. After centrifugation of CSF (2000g for 10 minutes), the supernatant was stored at -70°C. Quantification of amino acids was performed using an autoanalyzer model LKB/4151 Alpha Plus based on cationic exchange chromatography.15 A sample of 500 µL of plasma or CSF was mixed with 250 µL of 10% sulfosalicylic acid to deproteinize. After centrifugation, the supernatant was filtered, and a mixture of norleucine (1.66 µmol/mL) as an internal standard was added in a proportion of 5:1. A 250-µL aliquot of this mixture was introduced in the cationic exchange column (Ref 4418520). Graded pH buffers (LKB-43101191, Litium Chemical Kit) were injected. Temperature was controlled for selective separation of amino acids. The eluate was mixed with ninhydrin and then pumped through a high-temperature circuit. The resulting compounds were detected by a photometer, and a computerized system calculated the final concentrations of glutamate, aspartate, and taurine, expressed as micromoles per liter.
Biochemical data are expressed as mean±SD. Categorical data were
analyzed with the 
2 test. The
Kruskal-Wallis and Mann-Whitney rank-sum tests were used to compare
amino acid concentrations. A value of P<.05 was considered
significant. Linear regression analysis was used to investigate
the correlation between amino acid levels in the same sample.
Spearman's correlation coefficient was applied to study the
relationship between amino acid concentrations and the size of
infarction.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Stroke subtype, size of infarction, and degree of neurological impairment (evaluated with the Canadian Neurological Scale on days 3 and 14 from onset and the Barthel Index on day 14) in patients with and without headache are summarized in Table 2
. Differences
between groups were not statistically significant.
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Plasmatic glutamate concentrations were 233.00±107.23
µmol/L in patients without headache and 321.14±149.53 µmol/L in
those with headache (P<.005). Glutamate levels in CSF were
3.11±1.18 µmol/L in the nonheadache group and 4.60±1.49 µmol/L in
the headache group (P<.001) (Fig 1). The aspartate plasmatic
concentrations were 13.83±8.85 and 14.67±4.73 µmol/L for patients
without and with headache, respectively (P=.454). Aspartate
levels in CSF were 3.04±0.69 µmol/L for patients without headache
and 3.21±0.91 µmol/L for patients with headache (P=.551)
(Fig 2). Taurine levels in plasma were
177.49±90.92 and 103.10±52.82 µmol/L in nonheadache and headache
patients, respectively (P<.001). Taurine levels in CSF were
9.27±5.31 µmol/L in patients without headache and 5.42±2.42
µmol/L in those with headache (P<.001) (Fig 3).
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There was a weak positive correlation between glutamate and taurine in plasma (r=.44, R2=20.25, P<.05). No other significant correlations between amino acid levels in the same type of samples were observed. We observed no correlation between size of infarction and glutamate, aspartate, or taurine concentrations in plasma (r=.38, r=.26, and r=.21, respectively; P=NS) or CSF (r=.30, r=-.18, and r=-.21, respectively; P=NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The association of headache and stroke is not uncommon, frequently resembling a migraine crisis.2 3 4 5 6 7 The coexistence of stroke and headache is more frequently due to ischemia-induced migraine attacks than to migraine-related stroke.7 The mechanisms of headache that accompany cerebral infarction are unknown. A simple explanation would be a direct effect of the embolus or thrombus on the vascular wall, with or without reflex dilatation.16 However, this does not explain the variable incidence of headache in different stroke subtypes or in certain territories and other features of the association.3 4
The release of neuroexcitatory amino acids from the cortex during ischemia is a major mechanism of delayed neuronal damage.11 12 13 17 18 19 20 21 Glutamate antagonists reduce the volume of infarction in experimental ischemia.22 23 24 25 26 In animal models, the degree of glutamate release is correlated with the size of the infarct,13 finally accumulating in the extracellular space27 28 and the CSF.12 Also, during the migraine attack plasmatic8 and CSF9 levels of glutamate rise. Exposure of the cortex to glutamate leads to spontaneous depolarization phenomena such as spreading depression,29 one of the mechanisms hypothesized in migraine. Welch and Levine30 have stressed the relationship between migraine and cerebral infarction. The similarity of mechanisms between both diseases suggests that cerebral ischemia might trigger migrainous phenomena. Olesen et al7 believe that migraine at the onset of stroke reflects a lower pain threshold due to cerebral ischemia.
In our study, plasmatic and CSF levels of glutamate in patients with cerebral infarction who presented with headache were significantly higher than in those without headache, suggesting participation in the genesis of pain. Plasma and CSF glutamate levels seem to vary in parallel. Cerebral ischemia causes a central release of excitatory amino acids, leading to spontaneous depolarization and a state of neuronal hyperexcitability that could promote pain mechanisms.31 A direct vascular effect of glutamate seems unlikely.32 Glutamate may modify cerebral circulation by intermediate mechanisms, acting as a major stimulus for the production of nitric oxide. Neuronally derived nitric oxide potentiates local increases in cerebral blood flow and arteriolar vasodilatation.33 This mechanism may explain the glutamate-induced Chinese restaurant syndrome,34 the increased vasodilator response to exogenous nitric oxide donated from nitroglycerin, and increased headache response in migrainous patients.35
During ischemia, excitatory and also inhibitory amino acids such as taurine are released.36 37 38 39 The functions of taurine are not fully understood, but it usually has postsynaptic inhibitory effects on sensitive pathways in different brain regions, the brain stem, and the spinal cord, possibly modulating cerebral osmolarity, homeostasis, and pain perception.36 Pathological conditions that affect cortical areas and involve glial inflammation, such as ischemia, are associated with taurine release, probably caused by excessive depolarization.37 38 In patients experiencing migraine crisis, we observed higher plasmatic and CSF levels of taurine than in control subjects. Platelet hyperaggregability or an excessive release in the central nervous system could explain these findings. An increase of taurine could be a reactive mechanism against a parallel excess of glutamate.40 Also, during ischemia the release of taurine could counterbalance the excitotoxicity due to glutamate.38 With these considerations, our observations of lower taurine concentrations in stroke patients with headache compared with those without headache seem unexpected. A possible reason is different behavior of glia during ischemia. Hypoperfusion causes a redistribution of glutamate from neurons to glia, and the capacity of glial cells to metabolize glutamate is exceeded, contributing to an increase of its extracellular levels. This glial response is not observed for taurine.39 Different metabolic rates in patients with headache may explain lower taurine levels; this is probably due to preservation of the reuptake capacity of glial cells or different behavior of the glia in the management of excitatory and inhibitory amino acids, which has been demonstrated in experimental animals.41
The type of pain experienced by 71.4% of the patients was not pulsatile, and it was not accompanied by migrainous features. Also, in contrast to one report42 but in agreement with others,3 the incidence of a positive history of chronic headache was similar in both groups. Therefore, other mechanisms different from those proposed for migraine must be involved. Clinical and neuroimaging features of cerebral infarction were similar in patients with and without headache, which may suggest that the increment of CSF glutamate is relatively independent from the ischemic lesion. Modern theories tend to unify mechanisms for different types of headache.43 44 45 Release of amino acid transmitters may not be the cause but rather a consequence of pain.46 Although symptomatic spreading depression may be related to the cortical lesion,47 48 it is probably more associated with the hypoperfusion that develops in the surrounding ischemic penumbral area.49 50 This could explain the fact that glutamate levels in our patients were not correlated with the size of infarction. Patients with greater peripheral hypoperfusion also would have a higher glutamate release and consequently a greater tendency to develop headache. Neuroimaging studies support this concept, showing no correlation between size of infarction and the incidence of headache.3 16
Although timing of sample extraction in relation to stroke onset can cause variations in levels of neuroexcitatory amino acids,12 13 21 27 28 this factor did not influence our results. We did not observe significantly different plasmatic or CSF concentrations of aspartate in patients with and without headache. Intra-assay variables might have influenced this result.15 Temperature and pH were adjusted to achieve a greater sensibility for glutamate. Other conditions would have altered the sensibility of the method for glutamate measurement.
Our results suggest that glutamate plays a role in headache related to cerebrovascular disease. The ischemic penumbral area, more than the infarct itself, could cause a state of neuroexcitability that would be responsible for the release of amino acids and the phenomena that lead to the perception of pain. Other mechanisms, such as the release of nociception-stimulating agents through platelet aggregation or mechanic and chemical stimulation of the trigeminovascular system,3 51 52 53 would represent contributing factors for the genesis of headache.
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Acknowledgments |
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This study was supported by a grant from Xunta de Galicia, Investigation Project XUGA 20802B93.
Received March 24, 1995; revision received July 17, 1995; accepted July 27, 1995.
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