(Stroke. 1997;28:2437-2441.)
© 1997 American Heart Association, Inc.
Articles |
Poststroke Apathy and Regional Cerebral Blood Flow
From the Department of Internal Medicine III, Shimane Medical University, Izumo, Japan.
Correspondence to Kazunori Okada, MD, PhD, Department of Internal Medicine III, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan. E-mail okada{at}shimane-med.ac.jp
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Abstract |
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Background and Purpose Although apathy has been reported as one of the neuropsychiatric symptoms following stroke, there have been no studies on regional cerebral blood flow (rCBF) in patients with apathy. In this study we estimated the severity of apathy using the Apathy Scale and examined its relationship to rCBF in 40 stroke patients (mean age, 71.4 years).
Methods Neuropsychiatric batteries were performed including the Apathy Scale, verbal intelligence and frontal function tests, a depression scale, and an assessment of activities of daily living. The cortical rCBFs were measured by the 133Xe inhalation method.
Results Twenty patients (50%) showed apathy. These patients showed significantly lower scores on verbal intelligence and frontal function tests and a significantly higher depression score than the nonapathetic group. On MRI images there was no relationship between the apathy score and specific regional distribution of lesions. The rCBFs of the bilateral hemisphere were significantly lower in the apathetic group than in the nonapathetic group. The apathetic group showed a significantly reduced rCBF in the right dorsolateral frontal and left frontotemporal regions. Furthermore, the apathy score for all patients was significantly negatively correlated with rCBF in the same regions.
Conclusions These findings demonstrate that apathy is a frequent symptom among elderly stroke patients and may be accompanied by cognitive impairments, depressive state, and frontal dysfunction. The hypoactivity in the frontal lobe and anterior temporal regions may contribute to symptoms of apathy after stroke.
Key Words: cerebral blood flow • magnetic resonance imaging • depression
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There have been reports that stroke patients show specific neuropsychiatric symptoms including depression, generalized anxiety disorder, and apathy.1 2 3 4 Apathy is defined as the absence or lack of feeling, emotion, interest, or concern.5 This neuropsychiatric symptom is frequently observed in neurological degenerative diseases such as Parkinson's disease and Alzheimer's disease.6 7 Starkstein et al3 reported that apathy is a frequent finding among patients with the lesions of an acute stroke and may coexist with important emotional and cognitive poststroke disturbances. Although few studies report on the relationship of apathy with cerebral blood flow, Craig et al7 demonstrated the association of the apathetic syndromes in Alzheimer's disease with prefrontal and anterior temporal brain dysfunction. We studied the relationship between the severity of apathy and cerebral blood flow in poststroke patients.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
Forty serial subcortical infarction patients of the Department of Internal Medicine III, Shimane Medical University, were studied. They consisted of 22 admitted patients for acute stroke insults and 18 outpatients who were followed up since their stroke events. The patients who showed the combined neuropsychiatric changes of Alzheimer's disease were carefully excluded. The patients were subjected to a battery of neuropsychiatric tests and had their rCBF measured during the study period. Patients with aphasia and severe dementia who could not understand the meaning of questionnaires were excluded from this study. There were 23 men and 17 women with a mean age of 71.4 years. The patients who had cortical infarctions, transient ischemic attacks, and cerebral bleeding were not included because the samples were too small. Imaging was by MRI in 39 subjects and by CT in 1 subject. Duration of illness ranged from 1 to 156 months (mean±SD,16.2±33.5 months). Informed consent for the study was obtained from all patients, and the investigation was conducted in accordance with the guidelines of the Declaration of Helsinki.
Methods
We used the AS of Starkstein et al6 in Japanese
translation as a measure of apathy. Its original cutoff score is 14
points, but we used 16 points as a cutoff after preliminary studies on
Japanese patients. A study of the reliability of testing showed that
the results were reproducible (r=.956, P<.0001;
n=10). A normal control subject matched for age (mean±SD age,
70.2±5.0; n=39) had a low AS score of 8.7±6.6 points. For another 50
stroke patients, the clinical judgment of the existence of apathy by
two neurologists was compared with the AS score. The most reliable
results were obtained at a cutoff score of 16 points. The sensitivity
of AS was 81.3%, and the specificity was 85.3%. Intellectual
functions were estimated by Hasegawa's Intelligence
Scale.8 It scores intelligence on a scale from 0 to 30, and
a score of 20 or below indicates significant cognitive impairment.
Frontal functions were estimated by a battery of verbal fluency tests
that included listing Japanese words with the first syllable
shi and giving a list of vegetable names within 1 minute.
The severity of depression was estimated by Zung's SDS.9
We assessed ADL by the Rankin Disability Scale.10
The rCBF was measured by the 133Xe inhalation method, and the F1 value representing cortical cerebral blood flow was used for rCBF. This method is noninvasive, reliable, and reproducible.11 12 13 The rCBF measurements of a patient resting with eyes closed were made in a quiet room. Thirty-two collimated probes were placed around the skull surface, in a helmetlike fashion. After a 5-minute resting period, during which background gamma activity was measured, 740 MBq 133Xe gas was administered to the patient by inhalation through a face mask for 1 minute. Then the decreasing activity of the isotope was monitored on the scalp. End-tidal 133Xe activity was also measured to correct for recirculation to the brain. The rCBF (F1) value was calculated by the Fourier method with the use of a 32-channel NOVO-Cerebrograph. The end-tidal partial pressure of CO2 was also monitored by a capnograph.
Statistical Analysis
Statistical analysis included means and standard
deviations, factorial ANOVA, and Student's t tests.
Frequency distributions were analyzed with contingency tables
and 
2 tests. Multiple regression analysis was
applied to assess the relative importance of the independent
variables. All probability values are two tailed.
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Results |
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Twenty patients (50%) met the criteria of apathy based on the AS. There was no difference in age, sex, blood pressure, and hematocrit between groups with and without apathy (Table 1
). The apathetic group showed
significantly lower scores on verbal intelligence and the frontal lobe
function test of verbal fluency (shi test) than the
nonapathetic group (Table 2). Mild
vascular dementia was recognized in 13 subjects; 10 subjects had
apathy, and 3 subjects did not have apathy. This result showed
significant prevalence of apathy in dementia subjects
(P<.02). The apathetic group was more depressed than the
nonapathetic group as measured by the SDS. Twelve patients showed
apathy without depression, while 8 patients showed both apathy and
depression (2 of these last patients showed signs of a major
depression). There was no difference in verbal intelligence score and
frontal lobe function tests between the depressed group and the
nondepressed group. On Rankin's ADL scale, 25 subjects were grade 1,
11 subjects grade 2, 1 subject grade 3, and 3 subjects grade 4. There
was no significant difference in the AS score between these four
groups.
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For all patients, AS score showed the tendency to correlate positively
with age (r=.31, P<.1). Furthermore, AS score
correlated negatively with the score on the frontal lobe function tests
for fluency with shi in Japanese (Fig 1) and for the "vegetable names" test
(r=-.407, P<.02). The AS score was not
correlated with either the verbal intelligence or SDS scores.
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On MRI and CT images, 37 patients showed subcortical infarctions mainly
in the basal ganglia; no lesion was found in 3 patients. Of the
patients with cerebral infarctions, 25 showed multiple subcortical
lacunar infarcts, 8 had thalamic lesions, 3 had lesions involving the
caudate nuclei, 8 had lesions in the corona radiata, and 4 patients had
involvement of the posterior limb of the internal capsule. There was no
relationship between the regional distribution of the lesions and
apathy score by ANOVA. There was no relationship between age and total
number of lesions, but the duration of illness was positively
correlated with the number of lesions (r=.43,
P<.005). The mean number of lesions in the acute group was
significantly lower than that of the chronic groups over 1 year (Table 3).
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The mean rCBF of the right hemisphere was 49.0±12.3 mL/100 g brain per
minute in the apathetic group and was 56.8±11.9 mL/100 g brain per
minute in the nonapathetic group. The mean rCBF of the left hemisphere
was 49.1±12.7 mL/100 g brain per minute in the apathetic group and was
58.6±12.2 mL/100 g brain per minute in the nonapathetic group. Both
hemispheric rCBFs were significantly reduced in the apathetic group
compared with the nonapathetic group. Regionally, the apathetic group
showed a significantly reduced rCBF in the right dorsolateral frontal
and left frontotemporal region compared with the nonapathetic group.
Furthermore, the AS score for all patients was significantly negatively
correlated with rCBF in the right dorsolateral frontal and anterior
temporal, left premotor area, and left anterior temporal regions (Fig 2). The examination of only patients with
basal ganglia lesions showed the same relationship in AS and rCBF
between apathetic and nonapathetic patients (Fig 3).
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We performed multiple regression analysis for significant
variables for the AS score. The results revealed that the verbal
fluency test, which represents frontal lobe function,
correlated significantly with the severity of apathy (Table 4).
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Discussion |
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Clinical Features
The syndrome of apathy is frequent in neurological degenerative diseases and stroke.3 6 7 14 Starkstein et al3 observed apathy in 23% of stroke patients with a mean age of approximately 60 years. They found that apathetic patients were significantly older and had significantly more severe cognitive impairments and deficits in ADL than nonapathetic patients. In this study there was no difference in age between the groups with and without apathy, but there was a tendency for a positive correlation between age and AS. The high incidence of apathy in this study may be due to the age of our subjects. The patients included in this study (mean age, 71.4 years) were on average 10 years older than those studied by Starkstein et al.3 There was more severe cognitive impairment in apathetic patients than nonapathetic patients. Furthermore, we found that the apathetic group showed more severe impairment in tests of frontal function. The AS score was closely correlated with the results of a battery of frontal tests. Our results showed that impaired frontal function contributes most to the development of apathy and suggest that frontal hypoperfusion is probably responsible for apathetic symptoms. The close relationship between frontal lobe abilities and frontal perfusion is also reported in Parkinson's disease.15 There are some reports that apathy and depression may share similar mechanisms, although they are different clinical entities.3 16 In this study the apathetic group showed significantly higher depression scores than the nonapathetic group. Eight of 20 (40%) of the apathetic patients were also depressed; the others did not show signs of depression. These results confirm previous reports. There was no association between deficits in ADL and apathy because the subjects of this study showed only minor deficits in ADL. This study is only a preliminary report and excludes discussion of variation in ADL. It includes all the subjects, including those whose deficits were most severe. In addition, further studies about the course of poststroke apathy and imaging studies such as MRI are warranted.
Apathy and Regional Distribution
There are several disease syndromes that are associated with
apathy. Frontal lobe syndromes associated with anterior cerebral artery
lesions are the best known cause of apathy arising from neurological
damage.17 18 The most severe form of apathy is akinetic
mutism, caused by lesions of the cingulate gyrus, supplementary motor
area, and mesial motor area. These patients are usually characterized
as mute, akinetic, and abulic. An apathetic state may occur if they
improve sufficiently.19 20 Cummings21
summarized reports of patients with degenerative disease or focal
lesions involving the frontal lobe or linked subcortical structures and
addressed apathy with injury to the anterior cingulate circuit. Another
example of an apathy syndrome is exemplified by patients with bilateral
lesions of the amygdala and anterior temporal lobes,22 who
have been described as showing "blunted affect, apathy, and pet-like
compliance." This syndrome is thought to resemble the
Klüver-Bucy syndrome in temporal lobotomized monkeys. Similar
apathetic states occur in victims of right hemisphere stroke, who have
been described as showing a lack of emotional concern, lack of
emotional expression, and inappropriate cheerfulness or flat affect.
Right cerebral hemisphere lesions that produce "neglect" and "the
indifference reaction" may point to a mechanism for apathy that is in
some ways analogous to the mechanisms hypothesized for lesions to the
amygdala.23 These examples suggest that there is no single
pathogenic mechanism for apathy; rather, it is a syndrome characterized
by a group of symptoms with a shared pathological basis.
Marin24 summarized reports of lesions to several structures
that cause apathy. He separated them into four groups: the first group
involves lesions in the unilateral cingulate gyrus and supplementary
motor and mesial motor areas; the second, right hemisphere stroke; the
third, bilateral lesions of the amygdala and anterior temporal lobes;
and the final group of lesions results in frontal lobe damage. Although
a previous report suggested that apathy was significantly associated
with lesions involving the posterior limb of the internal
capsule,3 we failed to find any association in our study. A
high correlation between the AS score and the rCBF in supplementary
motor area suggested that supplementary motor area dysfunction plays
the most important role in producing apathy. Furthermore, the effect of
bilateral dorsolateral prefrontal and anterior temporal dysfunction is
also supported by our results. Focal reduction in rCBF is more
important in the production of apathetic symptoms than the
regional distribution in subcortical infarctions. In poststroke
psychiatric symptoms, there was a lateralizing effect in which
poststroke depression resulted predominantly from lesions to the left
anterior lobe.1 In addition, lesions of the left basal
ganglia, mainly in the head of the caudate nucleus, led to a
significantly higher frequency and severity of
depression.23 Castillo et al2 reported that
generalized anxiety disorder and depression are associated with
left-side lesions, while generalized anxiety disorder alone is
associated with right-side lesions. Our results suggest that poststroke
apathy may correlate more with left hemispheric dysfunction than with
right-side dysfunction. The subjects with cortical lesions were
excluded because we could obtain only 4 subjects who had cortical
lesions during the study period. Further study with a larger number of
subjects is necessary s to clarify the influence of cortical lesions on
the production of apathy.
Apathy and rCBF
First, the methodological limitations of this study should be
addressed. The subcortical lesions have been reported to produce
neuropsychiatric symptoms, and the cortical blood flow might be
interrupted by the existence of these lesions.13 23 25 26
Although the 133Xe inhalation method is reliable and
reproducible, it is limited to examining only the cortical cerebral
blood flow. Positron emission tomography and single-photon emission CT
studies revealed remote effects or diaschisis, which indicate the
association between subcortical lesions and the reduction of cortical
blood flow.27 28 29 The specific cortical areas might be
implicated in the modulation of emotion and would show significant
changes in rCBF in relation to temporal profiles of neuropsychiatric
symptoms after stroke.
There are few studies concerning the relationship between apathy and rCBF. Recently, Craig et al7 reported on the association of apathetic syndromes in Alzheimer's disease with prefrontal and anterior temporal brain dysfunction, using single-photon emission CT. They suggested that the pathological changes in anterior cingulate cortex, amygdala, medial temporal lobes, and damage to the cholinergic projection from the nucleus basalis of Meynert to the frontal cortex are responsible for the apathy in Alzheimer's disease. In this study, similar rCBF reductions in poststroke apathy were obtained with subcortical infarctions. This indicates that vascular damage to frontal-subcortical circuits (including those in the anterior cingulate, dorsolateral prefrontal, and cholinergic projection to the temporal cortex) is responsible for producing apathy in subcortical infarctions. Furthermore, there is an indication of common mechanisms leading to apathy and to depression. The rCBF pattern in various types of depression commonly reports hypoperfusion in the orbitofrontal and prefrontal areas.30 31 32 Depression in apathetic patients may be explained by rCBF reduction in their anterior frontal and dorsolateral area.
Our results show that symptoms of apathy are frequent in stroke patients and may be accompanied by cognitive impairments, depressive state, and frontal dysfunction. The hypoactivity in the bilateral frontal and anterior temporal regions may contribute to apathy symptoms after stroke. The pathophysiological mechanism suggests impairment of the biogenic amine pathways and cortical serotonergic deficits in patients with poststroke apathy.3 24 This suggests that dopaminergic agents and serotonergic agents are candidates for the treatment of apathy. We need further pathophysiological information, including rCBF studies, to develop a practical treatment for apathy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We would like to thank Drs K. Aoyama, H. Bokura, N. Suyama, and. T. Adachi for their support on this project. We would also like to thank M. Murao and C. Ishibashi for technical assistance.
Received March 24, 1997; revision received September 8, 1997; accepted September 8, 1997.
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