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(Stroke. 1995;26:946-949.)
© 1995 American Heart Association, Inc.

Articles

Silent Cerebral Infarctions in Patients With Late-Onset Mania

Tokumi Fujikawa, MD; Shigeto Yamawaki, MD Yoshikuni Touhouda, MD

From the Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine (T.F., S.Y.); and the Department of Psychiatry and Neurology, Hiroshima Prefectural Hospital (Y.T.), Hiroshima, Japan.

Correspondence to T. Fujikawa, MD, Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Previously we have studied the relationship between senile depression and silent cerebral infarctions (SCIs). The goal of this study was to clarify the relationship between late-onset mania and SCIs using MR imaging.

Methods Twenty manic patients who developed a bipolar disorder after 50 years of age (late-onset mania) were selected prospectively. These patients were compared with 20 age- and sex-matched patients who developed an affective disorder while younger than 50 years of age (early-onset affective disorder) and with 20 patients who developed major depression after 50 years of age (late-onset major depression). Patients with focal neurological symptoms were excluded from the study. All patients underwent MR imaging to assess the incidence of SCIs. Patients diagnosed with SCIs were subclassified according to whether the infarction type was perforating, cortical, or mixed.

Results The incidence of SCIs in patients with late-onset mania was 65.0%; this incidence was significantly higher than that of patients with early-onset affective disorders (P<.05). The incidence of the mixed type of SCI was 50.0% in patients with late-onset mania; this was significantly higher than that in patients with late-onset major depression (P<.05).

Conclusions Our findings suggest that approximately half of the cases of late-onset mania might be secondary mania related to SCIs. Because the mixed type of SCI is more prevalent in the patients with late-onset mania than in those with late-onset major depression, mania may be associated with the larger areas of brain damage and hence may be a more serious form of affective illness than major depression.

Key Words: cerebral infarction • manic disorders • magnetic resonance imaging • depression

	Introduction

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In recent years, various asymptomatic cerebrovascular lesions have been identified using magnetic resonance imaging (MRI). When a cerebral infarction detected by MRI or another imaging modality has no associated focal neurological symptoms, it is referred to as an asymptomatic or silent cerebral infarction (SCI). Such infarcts fit into classification III for cerebrovascular disorders, published by the National Institute of Neurological Disorders and Stroke.¹ However, classification III does not include cases associated with psychiatric symptoms, except for vascular dementia. Although localizing neurological symptoms are not observed in patients with SCI, the presence of psychiatric symptoms such as those observed in patients with affective or delusional disorders needs to be considered. Because the term "asymptomatic cerebral infarction" may be incorrect, such infarcts have been designated more often as SCI in recent years.

Previously we have studied the relationship between presenile and senile major depression and SCIs that have been detected using MRI. Our findings have suggested that organic depression related to SCIs is present in approximately half of the patients with presenile-onset (50 to 65 years) major depression and the majority of patients with senile-onset (>65 years) major depression.² Our data also suggest that patients with major depression and SCIs demonstrate a lower prevalence of family history of affective disorders but more frequently manifest risk factors for cerebral infarctions (eg, hypertension) than do patients without SCIs.³

Alternatively, mania in the elderly is less prevalent than depression. It is thought that organic factors may play an important role in the genesis of mania in elderly patients,^{4 5 6} yet the significance of mania in the elderly remains unclear.

In this study, we used MRI to determine the incidence and locations of SCIs in patients with late-onset mania and compared these data with those of patients with early-onset affective disorders and late-onset major depression.

	Subjects and Methods

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Individuals who were eligible for this study included patients treated at either the Department of Psychiatry and Neurology at Hiroshima Prefectural Hospital or the Department of Psychiatry and Neurosciences at Hiroshima University School of Medicine between April 1991 and March 1994. These patients developed their affective disorders after the age of 50 years and manifested bipolar disorder. The patients were selected prospectively at the time of the onset and initial treatment for mania (late-onset mania). All patients underwent MRI within 3 months of initial treatment for mania, and all fulfilled the Diagnostic and Statistical Manual of Mental Disorders, edition 3, revised (DSM-III-R) criteria for mania⁷ as determined by a clinical interview. All patients and their family members underwent detailed questioning regarding any previous episodes of a mood disorder. The patients also underwent neurological examination on the same day as their MRI study, and patients with evidence of stroke or focal neurological symptoms (n=7) were excluded from the study. Patients with alcoholism, cerebral degenerative disease or dementia, brain injury, antidepressant-induced mania, or systemic diseases that could induce a manic state also were excluded. Informed consent was obtained from all of the subjects according to the institutional guidelines.

The group of patients with late-onset mania that was studied included 9 men and 11 women with a mean age of 61.3±8.0 years. Three patients had no previous history of depression, whereas 17 had suffered depression before the mania. These patients were compared with 20 age- and sex-matched patients who had developed affective disorders while younger than 50 years of age (early-onset affective disorder). This group included 10 patients with bipolar disorder and 10 patients with unipolar disorder (major depression), with a mean age of 61.1±6.0 years. Twenty patients with late-onset major depression who had developed major depression after 50 years of age also were studied. The mean age of these patients was 61.3±6.2 years. All patients underwent MRI to determine the incidence, location, and infarction characteristics of the SCI.

MRI was performed in 14 patients with late-onset mania with a 0.5-T apparatus (Picker Co) at the Hiroshima Prefectural Hospital and in 6 patients with late-onset mania using a 1.5-T apparatus (General Electric Co) at the Hiroshima University School of Medicine. In the early-onset affective disorder group, 12 patients underwent MRI at the Hiroshima Prefectural Hospital, and 8 patients underwent MRI at the Hiroshima University School of Medicine. In the late-onset major depression group, 15 patients underwent MRI at the Hiroshima Prefectural Hospital, and 5 patients underwent MRI at the Hiroshima University School of Medicine.

T₂-weighted images (repetition time [TR], 2000 milliseconds; echo time [TE], 100 milliseconds) were obtained in the transverse plane that was parallel to the orbitomeatal line, and T₁-weighted images (inversion-recovery; TR, 2000 milliseconds; TE, 100 milliseconds) were obtained as coronal slices at 10-mm intervals. Twelve slices were obtained of each type of image.

The MRI lesions that demonstrated a low signal intensity on T₁-weighted images and a high signal intensity on T₂-weighted images included both état criblé (Virchow-Robin spaces) and cerebral infarctions. Braffman et al⁸ have reported that état criblé lesions are smaller than 5 mm in diameter. In contrast, cerebral infarctions are larger than 5 mm.

In this study, infarcts were defined as high-intensity lesions that were larger than 5 mm in diameter on T₂-weighted images and that coincided with low-intensity lesions on T₁-weighted images. To avoid overdiagnosis of SCI, the following diagnostic criteria were adopted: lesions measuring from 5 mm to 20 mm were defined as small infarcts (lacunar infarcts), whereas lesions larger than 20 mm were classified as large infarcts. Although detectable lesions that were smaller than 5 mm also may have represented small infarcts, these were excluded from analysis because they are difficult to distinguish from état criblé.

Regarding the number of small infarcts that can be interpreted as representative of an SCI, Shimada et al⁹ have reported that the mean number of small infarcts in asymptomatic, hypertensive elderly subjects is 2.8±4.6, whereas that in normotensive elderly subjects is 1.1±1.5. Matsubayashi et al¹⁰ have studied the relationship between small infarcts and cognitive function in normal elderly subjects and have reported that four or more small infarcts are associated with the development of cognitive impairment. Therefore, in the present study an SCI was defined as the presence of four or more small infarcts in the same cerebral hemisphere or as one or more large infarcts. Patients with fewer than four small infarcts and no large infarcts were classified as not having SCI. Periventricular hyperintensity was not assessed.

The cerebral infarctions were classified as one of three types of SCI. The perforating type of SCI refers to lesions in the basal ganglia, the internal capsules, and the thalami that belong to the perforating branch system. The cortical type of SCI refers to lesions in the cerebral cortex and subcortical white matter that belong to the cortical branch system. The mixed type of SCI refers to lesions with combinations of the characteristics of both types. More detail regarding the location and hemisphere of the SCI was not assessed because almost all patients have multiple infarct lesions.

For statistical analysis, mean±SD values were calculated for parametric data, and the Student's t test was used to compare groups. The ² test was used for the comparison of nonparametric numerical data in each group. A value of P<.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Incidence of SCI and characteristics of the infarct areas are shown in the Table. Seventeen of the 20 patients with late-onset mania had previously experienced the onset of depression at a mean age of 58.0±6.7 years. The current mean age of these patients was 62.6±8.2 years. Thus, the onset of mania occurred at a younger age in the 3 remaining patients whose mean age was only 57.8±5.6 years.

View this table: [in this window] [in a new window]   Table 1. Incidence of Silent Cerebral Infarctions and Characteristics of the Infarct Areas in Patients With Affective Disorders

SCIs were observed in 13 of the 20 patients with late-onset mania (65.0%), in 11 of the 20 patients with late-onset major depression (55.0%), and in 5 of the 20 patients with early-onset affective disorders (25.0%; ²=4.949, df=1, P<.05, compared with the late-onset mania group).

Regarding the infarction type, the perforating type of SCI was observed in 1 of the 20 patients with late-onset mania (5.0%) and in 6 of the 20 patients with late-onset major depression (30.0%; ²=2.771, df=1, NS). Alternatively, the cortical type of SCI was observed in 2 of the 20 patients with late-onset mania (10.0%) and in 2 of the 20 patients with late-onset major depression (10.0%). The mixed type of SCI was observed in 10 of the 20 patients with late-onset mania (50.0%) and in 3 of the 20 patients with late-onset major depression (15.0%; ²=4.103, df=1, P<.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Incidence of Silent Cerebral Infarctions in Patients With Late-Onset Mania
In recent years, mania in the elderly has been studied using CT and MRI. Broadhead and Jacoby⁶ used CT to study both elderly and young patients with mania. They concluded that "organic factors may play an important role in the genesis of affective disorder in old age."

Frequently, deep white matter lesions have been identified using MRI, and the relationship between such lesions and bipolar disorder has been studied. McDonald et al¹¹ reported that the detection of deep white matter lesions greater than 2.5 mm, 5.0 mm, and 10.0 mm by MRI occurred more often in 12 patients whose onset of mania occurred after the age of 50 years than in control subjects of the same age. Subsequently, Figiel et al¹² studied 18 patients younger than 60 years with bipolar disorder and compared them with 18 age-matched control subjects. Forty-four percent of the bipolar patients had deep white matter regions of hyperintensity, whereas only 6% of the control subjects demonstrated similar changes. The size of the lesions ranged from 2.5 mm to 16 mm. However, thus far standard criteria for the detection of infarcts with MRI have not been determined.

Kobayashi et al¹³ used MRI to study the incidence of SCIs in 246 neurologically normal adults. SCIs were found in 6% of healthy individuals in their forties, 17% of those in their fifties, 21% of those in their sixties, and 13% in all patients.

Previously we studied the incidence of SCIs detected with MRI in 205 patients with presenile (50 to 65 years) or senile (>65 years) major depression.² Among the patients with presenile major depression, SCIs were observed in 51.4% of the patients with presenile-onset depression. Among the patients with senile major depression, SCIs were observed in 93.7% of those with senile-onset depression. In addition, SCIs were significantly more common in patients whose onset of depression occurred after they reached a presenile age than in the subjects who were assessed by Kobayashi et al.¹³ These data suggest that approximately half of the cases of presenile-onset major depression, and most of the cases of senile-onset major depression, are actually cases of organic depression that are related to SCIs. Subsequently, we classified patients older than 50 years with major depression as those with and without SCIs according to MRI findings. Differences between these groups regarding family history of affective disorders or risk factors for cerebrovascular disease were investigated.³ We clarified that patients with major depression and SCIs demonstrate a lower incidence of positive family history for affective disorders but a higher incidence of risk factors for cerebrovascular disease (eg, hypertension) than patients with major depression without SCIs.

In this study, SCIs were observed in 65% of the patients with late-onset mania. This incidence was significantly higher than that in patients diagnosed with early-onset affective disorders but of the same frequency as that in patients with late-onset major depression. In 1978, Krauthammer and Klerman¹⁴ first described the concept of mania that develops after brain injury (secondary mania). They described the importance of its late onset and the lower rate of genetic predisposition to affective disorders found in patients with secondary mania. These data suggest that approximately half of the cases of mania with an initial onset after the patient has reached a presenile age might be cases of secondary mania that are due to SCIs.

Silent Cerebral Infarction Type in Late-Onset Mania
Akiskal¹⁵ and Tsuang et al¹⁶ have compared bipolar disorder with unipolar depression and have reported that mania is a more serious form of affective disorder. In elderly patients with mania, Shulman and Post⁴ have hypothesized that, compared with depression in old age, mania is (1) a more serious manifestation of an affective disorder, (2) associated with a preponderance of neurological disorders (eg, cerebrovascular disease), and (3) associated with a poor prognosis. Subsequently, Shulman et al⁵ compared patients with the onset of bipolar disorder after 65 years of age with age- and sex-matched patients with unipolar depression. Manic patients often manifested complicated neurological disorders with evidence of secondary mania and had a significantly higher mortality rate than the depressed patients. Shulman and Post concluded that mania appears to have a worse prognosis and is a more severe form of affective illness than unipolar depression.

As found in earlier reports, the patients in this study with late-onset mania had complicated mixed-artery infarctions with broader ischemic changes than patients with late-onset major depression. However, structural brain lesions are no more common in patients with late-onset mania than in those with late-onset major depression.

Etiology of Depression and Mania After Brain Injury
Krishnan et al¹⁷ and Husain et al¹⁸ have measured the volumes of subcortical structures with MRI. They have shown that the putamen and caudate are smaller in depressed patients than in age-matched control subjects. The caudate and putamen nuclei are integral to a number of basal ganglia circuits that receive afferent input from the medial temporal structures that are known to be involved with emotions (eg, hippocampus and amygdala) and terminate in the prefrontal cortex. It is hypothesized that damage to these circuits plays a role in depression. Frontal white matter lesions and changes in the caudate and putamen are likely to disrupt this circuit. Robinson et al^{19 20 21} have studied poststroke depression and the location of involved lesions; patients with left anterior cortical or subcortical lesions have demonstrated significantly higher mean depression scores than have patients with right anterior, right posterior, or left posterior lesion locations. Patients with both left cortical and subcortical lesions manifested higher depression scores when the lesion was closer to the frontal pole. Starkstein et al^{22 23 24} also studied secondary mania after brain injury and lesion location; the majority of their patients had right hemisphere injuries. The brain lesions in their patients with secondary mania were located mainly in the limbic or limbic-related areas (orbitofrontal and basotemporal cortex, caudate, and thalamus) that have strong connections with the frontal lobe. Lesions associated with organic mood disorder, organic depression, and secondary mania are located in the frontal lobe (orbitofrontal cortex), the basal ganglia (caudate, putamen), and the temporal lobes (hippocampus, amygdala).^{17 18 19 20 21 22 23 24}

There are some important differences between secondary mania and organic depression. The overall incidence of mania is relatively rare, and the incidence of mania after brain injury is less than 10% of that for depression. In addition, mania is associated with more severe ischemic change than depression. In our previous study regarding the relationship between depression and SCI,⁴ depression occurred either in patients with perforating artery infarctions with lesions in the basal ganglia or in patients with cortical artery infarctions with lesions in the frontal and temporal lobes. Alternatively, the majority of patients with mania demonstrated complicated mixed artery infarctions with lesions in the basal ganglia, frontal lobe, and temporal lobes.

Whereas depression might occur in cases of isolated ischemic change involving any of the basal ganglia circuits that connect the frontal lobe, the basal ganglia, and the temporal lobes, mania might occur in cases involving the ischemic change of all of the basal ganglia circuits. The conditions that cause mania after brain injury are more severe than those that cause depression, hence the incidence of mania is less than that of depression.

Received January 4, 1995; revision received March 14, 1995; accepted March 14, 1995.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujikawa, T. Articles by Touhouda, Y. Search for Related Content PubMed PubMed Citation Articles by Fujikawa, T. Articles by Touhouda, Y.