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Manic-Depressive and Pure Manic States After Brain Lesions Sergio E. Starkstein, Paul Fedoroff, Marcelo L. Berthier, and Robert G. Robinson
Although mania is a rare complication of brain lesions, recent reports have emphasized the importance of lesion location and genetic predisposition in these patients. In the present study we compared patients who developed a bipolar affective disorder (i.e., mania and depression) after a brain lesion with patients who only developed mania. Although no significant between-group differences were found on demographic variables, the manic-depressed group showed significantly more impairments on the Mini Mental State Exam than the mania only group. All the bipolar patients had subcortical lesions (mainly right head of the caudate and right thalamus), while patients with unipolar mania had significantly higher frequency of cortical involvement (mainly right orbitofrontal and basotemporal cortices). It is suggested that subcortical and cortical right hemisphere lesions may produce different neurochemical and~or remote metabolic brain changes that may underlie the production of either a bipolar disease or a unipolar mania.
Introduction Recent studies have suggested that mania may be a specific complication of brain lesions (Cummings and Mendez 1984; Starkstein et al 1988a; Shukla et al 1987). Lesion location has consistently been found to play an important role in secondary mania, with most patients having lesions in limbic areas of the right hemisphere [see Starkstein et al (1988a) for a review]. A genetic predisposition and the presence of subcortical atrophy have also been found to play an important permissive role in the development of mania (Robinson et al 1988; Starkstein et al 1987a). In patients with secondary mania after closed head injuries, a high frequency of seizure activity has also been described (Shukla et al 1987). In a previous study (Robinson et al 1988), we reported that one third of patients with secondary mania had depression at some time after the brain injury, whereas the rest of the patients showed only a single manic episode. Thus, in the present study we compared demographic, neurological, and radiological findings in patients having secondary mania with and without depression.
From the Departments of Psychiatry and Behavioral Science (SES, PF, RGR) and Nem'osciences (RGR), Johns Hopkins University School of Medicine, Baltimore, MD 21205, Institute of Neurological Research "Dr. Raui Carrea, ' Buenos Aires, Argentina (MLB), and Department of Psychiatry University of Iowa College of Medicine, Iowa City, IA 52242 (SES, RGR). Address reprint requests to Sergio E. Starkstein, M.D., Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242. Received January 13, 1990; revised July 20, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
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Material and M e t h o d s
Study Preparation A consecative series of patients admitted to the Johns H ,:,i:ins Hospital (Baltimore, MD) (n = 15) and the h|stitute of Neurological Research "Dr. Raui Carrea" (Buenos Aires, Argentina) (n = 4) with the diagnosis of both mania and bm~n pathology were included in the study [13 patients were previously reported (Robimon et al 1988) and 6 are new patients]. Neither aphasia nor aprosodia were considered exclusion criteria. Patients were divided into the following groups:
1. Manic-depressive group. This group consisted of patients who met the following inclusion criteria: (1) DSM-III-R (American Psychiatric Association 1987) criteria for Organic Mood Syndrome, manic, and Major Affectivc Disorder, manic episode, followed or preceeded by Organic Mood Syndrome, depressed (i.e., depression after the brain lesion); (2) computed tomography (CT) scan evidence of focal vascular, neoplastic, or traumatic brain lesions; and (3) no history of other neurological, toxic, or metabolic condition. 2. Mania Only group. This group consisted of patients who met the following criteria: (1) DSM-III-R criteria for Organic Mood Syndrome, manic, ~uadMajor Affective Disorder, manic episode, not followed or preceeded by depression; (2) CT scan evidence of vascular, neoplastic, or traumatic brain lesions; and (3) no history of other neurological, toxic, or metabolic condition. All patients were examined during the index r aanic episode by a psychiatrist using a standard clinical interview (i.e., diagnosis was e~tablished by clinical examination, and each patient was seen independently by two psychiatrists who agreed on the diagnosis). Cognitive impairments were examined during, the index manic episode using the MiniMental State Exam (MMSE) (Folstein et al 1975). The MMSE is an 11-item examination test that has been found to be reliable and valid in assessing a limited range of cognitive functions. Patients at the Institute of Neurological Research were examined with the Present State Exam (Wing et al 1974) by one of the neuropsychiatrists (SES) that also carried out examinations at Johns Hopkins. Although we did not ebtain detailed family histories using multiple informants (Andreasen et al 1977), we did obtain as much information about personal and family history as we could from the patients and/or relatives who were available at the time of the interview. All the neuropsychiatric data were obtained blind to group membership.
CT Scan Examination CT scans were read by one of us (SES) who was blind to group membership. All CT scans had a consistent slice thickness and angle to the canthomeatal line. Lesion volume (expressed as a percentage of total brain volume) was calculated from the ratio of the largest cross-sectional area of the lesion on any CT scan slice to the cross-sectional area of the wha!e brain on the slice passing through the body of the lateral ventricles. We have previ ausly demonstrated the reliability of this procedure and its high correlation with other methods of determining lesion volume (Robinson et al 1986). The anteriorposterior (A-P) location of each lesion was defined as the mean distance of the anterior border of the lesion from the frontal pole averaged over all slices in which the lesion was visible (Robinson et al 1986). This distance was expressed as the percentage of the
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Table 1. Demographic Data
Number of patients Age (mean years) Sex (% females) Handedness (% right-handed) Education (mean years) Fanfi|y history of psychiatric disorders (% positive) Personal history of psychiatric disorders (% positive)
Manic-depressed"
Maria only"
7 61.2 (15.9) 43 86 8.7 (2.2) 29
12 50.1 (16.9) 33 83 11.4 (3.6) 25
0
0
°SDs are in parentheses.
maximum distance between the anterior and posterior poles on the CT slice where the lesion was identified. The posterior border of each lesion was calculated using the same methods. In addition, the damaged area was mapped using an atlas (Matsui and Hirano 1978) and was localized in specific brain areas following the procedure of Levine and Grek (1984). Patients were considered to have cortical lesions if they had predominantly cortical damage with only a small amount of subcortical involvement but never including the basal ganglia, th;flamus, or the it~ternal capsule. Patients were considered to have subcortical lesions if they had purely subcortical lesions with no involvement of cortical tissue. Patients with cortico-subcortical lesions had lesions involving both locations (Starkstein et al 1987b).
Statistical Analysis Statistical analysis was carded out using means and standard deviations, and t-tests. Frequency distributions were analyzed using chi-square tests and Fisher's exact test. p values are two-tailed. Results
Background Characteristics Background information revealed no significant between-group differences in age, sex, race, education, handedness, or personal history of psychiatric disorder (Table 1). Two of the 7 manic-depressed patients had a positive family history of psychiatric disorders (affective disorder and alcoholism, respectively), and 3 of the 12 mania-only patients had a positive family history of psychiatric disorders (affective disorder in all 3 cases). Six of the seven manic-depressed patients showed depression within the first week after the brain lesion. Three patients developed mania 2 weeks later (one patient had 8 years of follow-up, and the other two patients were lost to follow-up after the manic episode). The other three patients developed mania 7 weeks, 3 months, and 6 months later, respectively (they had follow-up periods of 2 years, 1 year, and 1 year, respectively). In the remaining patient, the interval between the stroke and the onset of the manicdepressive disorder could not be determined (he had 10 years of follow-up). Only one of these patients received antidepressants during the period of depression.
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Table 2. Manic Symptoms (%)
Elation Irritability Hyperactivity Pressure of speech Flight of ideas Grandiose delusions Insomnia Hypersexuality Overspending Other delusions Hallucinations Mini-Mental State Exam" (mean score +_ SD)
Manic-depressed
Mania only
100 14 86 86 43 71 100 29 57 29 14 25.2 ± 4.7
100 50 83 92 75 83 67 33 50 25 25 28.6 "4- 1.8
"p < 0.05.
Five of the 12 patients with mania only showed manic symptoms within the first week after the brain lesion, and all had follow-up evaluations (6 months in one, 1 year in two, and 2 and 3 years in the two remaining cases, respectively). Three other patients showed manic symptoms 18 months, 2 years, and 4 years after the brain lesion, respectively, and two of them had follow-up evaluations 1 year later. The other four patients showed a brain lesion at the time of the index admission due to the manic episode, but the interval between brain injury and manic episode could not be determined (three patients had tumors, and one patient had a lacunar stroke). Thus, in these cases, the association between brain lesion and mania remains tentative. All four patients received follow-up evaluations [ 1 year, 2 years (in two cases), and 4 years, respectively].
Neurological Findings Motor deficits were present in 71% of manic-depressed patients, and in 42% of patients with mania only; visual field deficits were present in 29% and 50%, respectively; sensory deficits were present in 14% and 17%, respectively; and dysarthria was present in 29% and 8%, respectively. None of these differences was statistically significant.
Psychiatric Findings Manic symptoms for the manic-depressive and the mania only groups, which were observed at the initial evaluation of the first manic episode, are shown in Table 2. No significant between-group differences were observed. The mastic-depressive patients, however, showed a significantly lower MMSE score (t = 2.21, df = l, p < 0.05) (Table 2).
Lesion Location Six of the seven manic-depressed patients had lesions restricted to the right hemisphere, which involved the head of the caudate in two patients (both with ischemic infarctions),
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i,
Figure 1. Bipolargroup: Schematic templates of computed tomographic scan slices showing largest cross-sectional area of lesion for manic-depressivepatients. Lesions mainly involvedthe right head of the caudate and right thalamus.
the thalamus in three patients (two cases with thalamic hematomas and one with an ischem~c infarction), and ischemic infarctions in several cortical and subcortical regions (head c,f the caudate, dorsolateral frontal cortex, and basotemporal cortex) in one patient (Figure 1). The remaining patient developed mania after surgical removal ef a pituitary adenoma. Eight of the 12 patients with mania only had lesions restricted to the fight hemisphere (Figure 2). Three patients had ischemic infarctions involving the head of the caudate (one case), the basotemporal cortex, amygdala, hippocampus, and head of the caudate (one case), and the occipitotemporal cortex (one case); two patients had gliomas involving the inferior temporal lobe (one case) and the temporal and parietal lobes (one case); one patient had a hematoma in the inferior temporal lobe; one patient had an arteriovenous malformation in the inferior temporal lobe; and one patient had an orbitolrontal meningioma. Four patients had bilateral lesionsmtwo had orbitofrontal meningiomas, and two had brain lesions secondary to closed head injuries [right orbitofrontal white matter and left temporal tip (one case), and orbitofrontal lesions (one case)]. In summary, six of the seven manic-depressed patients had subcortical lesions, and the remaining one had a cortical-subcortical lesion. On the other hand, 9 of the 12 patients with mania only had cortical lesions, 1 had a cortical lesion with subcortical extension, and 2 had subcortical lesions. A hypothesis of unequal frequency of bipolar compared to unipolar disorder based on the presence of coitical or subcortical lesions
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Figure 2. Mania only group: Schematic templates of computed tomography scan slices showing largest cross-sectional area of lesion for mania only patients. Lesions mainly involved the orbitofrontal cortex and the right basotemporal cortex.
was statistically substantiated (Fisher test p < 0.005). The observed cells were as follows: manic-depressed patients with cortical lesions, no patients, and with subcortical lesions, six patients; mania-only patients with cortical lesions, 9 patients, and with subcortical lesions, two patients. Between-group differences remained significant even after patients with an unknown interval between the brain lesion and the manic episode were excluded (Fisher test p < 0.01) (observed cells were no patients, five patients, six patients, and one patient, respectively), and when the two manic patients without follow-ups of less than 1 year were excluded (Fisher test p < 0.025) (observed cells were zero, six, seven, and two patients, respectively). A hypothesis of unequal frequency of manic-depression or pure mania based on the presence of unilateral or bilateral lesions, however, was not statistically substantiated (×2 = 2.57, df = 1, p > 0.10). Patients with pure mania showed significantly larger lesions than did the depressedmanic patients (mean _+ SD--12.6 _+ 9.5 versus 2.8 _+ 4.2, respectively t = 2.16, d f = 15, p < 0.05). No significant differences were observed in either anterior (mean -+ SD---29.0 _+ 19.3 versus 37.4 _+ 8.5, respectively; t = 0.90, df = 15, p > 0.10), or posterior distances of the lesion from the frontal pole (mean + SD---59.0 + 24.1 versus 54.2 _+ 11.8, respectively; t = 0.41, df = 15, p > 0o 10). The dimensions of the lesions could not be measured in the manic-depressed patient with the surgical removal of a pituitary adenoma, or in the mania-only patient with multiple he~x~orrhagic contusions in the orbitofrontal cortex.
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Discussion There were three major findings from the present study. First, among patients with secondary mania, a prior episode of depression had occurred in 37%. Second, although all the manic-depressed patients had subcortical lesions (mainly involving the right head of the caudate or right thalamus), patients with pure m,'mia showed a significantly higher frequency of cortical lesions (mainly involving the right orbitofrontal and right inferior temporal cortex), and significantly larger lesion volumes. Third, raanic-depressed patients showed significantly greater cognitive impairments than patients with pure mania. Before further discussion, some limitations of this study should be pointed out. Although 10 of the 12 patients with pure mania had follow-ups that ranged from 6 months to 4 years after the onset of manic symptoms, 2 patients had no follow-up evaluations, and we cannot be sure they did not develop depression afterwards. However, these two patients developed mania 4 and 1.5 years after the brain injury, respectively, whereas all the manic-depressed patients showed depression immediately after the brain lesion, and before the onset of mania. Moreover, even when the two pure manic patients without a follow-up were excluded, between-group differences in cortical versus subcortical lesion location remained statistically significant. The possibility that some of the mania-only patients may have developed depression beyond the follow-up period cannot be excluded, and this issue will requh-e further studies with longer follow-ups. Another limitation is that one of the manic-depressive patients developed mania shortly after receiving treatment with nortriptyline for a poststroke depression, which might explain the development of mania. However~ the relevance of antidepressant treatment in the production of"pr~mary" (i.e., no known brian injury) mania has never been consistently demonstrated (Kupfer et al 1988), and manic episodes have never been reported after treatment of poststroke depression with antidepressants (Lipsey et al 1984; Reding et al 1986; Finklestein et al 1987). Finally,, a few patients developed mania several months after the brain injury, and a causal relationship between brain lesion and mood change remains tentative. It should be noted, however, that none of these patients had a personal history of psychiatric disorders, and the onset of mania occurred at a much later age than would be expected for patients with "functional" affective disorders. Although both the manic-depressive and the mania-only groups showed similar deficits on neurological examination, manic-depressives showed a significantly lower MMSE score. This finding was somewhat surprising, since patients with pure mania had larger lesions, and MMSE scores have been reported to have a negative correlation with lesion size (i.e., lower MMSE scores are associated with larger lesions and greater impairraent) (Robinson et al 1986; Eastwood et al 1989). In previous studies, however, we have shown that patients with poststroke depression had significantly lower MMSE scores than ageand lesion-matched nondepressed stroke patients (Starkstein et al 1988b), and similar results were obtained after using a more comprehensive neuropsychological test battery (Bolla-Wilson et al 1989). Thus, the presence of a previous depression may have produced more severe cognitive impairments in the manic-depressed group. Alternatively, it might be proposed that both cognitive and mood disturbances may be related to a more severe neurochemical dysfunction resulting from basal ganglia lesions than from cortical lesions. Finally, the greater intellectual impairment in manic-depressed compared with maniconly patients might be due to lesion location, because caudate and thalamic lesions have been reported to produce important deficits in intellectual functions (Starkstein et al 1988c; Graff-Radford et al 1984). It should be noted, however, that only two patients in the
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manic-depressed group had MMSE scores below the usual cutoff score of 23 points, and differences in MMSE scores between manic-depressed and mania-only patients may not have had clinical relevance. Future studies should be carried out using more comprehensive neuropsychological evaluations. The major question raised by this study is why some patients developed a unipolar mania, whereas others developed a bipolar disorder. Shulda et al (1987) reported a similar frequency of depression (30%, compared to our 37%) in their series of patients with mania after closed head injury. In the present study we did not find any significant differences in demographic variables between bipolar and unipolar groups. Although we have previously found that genetic factors play a role in the production of secondary mania (Robinson et al 1988), the frequency of a positive family history of psychiatric disorders was similar for the manic-depressed and mania-only groups. The main difference between the manic-depressive and pure mania groups was lesion location. Although 6 of 7 manic-depressive patients had subcortical lesions (the other patient had mixed cortical-subcortical damage), 10 of 12 patients with pure mania had cortical lesions. One of the two pure manics with subcortical lesions had a closed head injury and a s m ~ hemorrhagic contusion in the frontal white matter, and a magnetic resonance imaging (MRI) done 10 months after the trauma showed a pseudoporencephalic cyst in the left temporal tip. The other pure manic with a subcortical lesion showed a right head of the caudate infarction at the time of psychiatric hospitalization. Although there is no straightforward explanation for this finding, a tentative mechanism may be proposed. Patients with unipolar mania had lesions primarily involving the basotemporal and orbitofrontal cortices, which are important structures of the basolateral limbic system, and have main connections with septal, hypothalamic, and mesencephalic regions (Nauta 1971). In a previous study (Starkstein et al 1988a) we speculated that through this projection, the orbitofrontal and basotemporal cortices may modulate the effect of the limbic system on hypothalamic function (Nauta 1971). Disruption of this system may be related to the production of manic symptoms such as euphoria, hypersexuality, insomnia, hyperactivity, and irritability. In the case of manic-depressives, the mechanism may have been different. Subcortical lesions have been reported to produce hypometabolic effects in widespread regions including contralateral brain areas (crossedhemisphere and crossed-cerebeUar diaschisis) (Takano et al 1985; Pozzilli et al 1987; Pappata et al 1987); thus it is possible that subcortical lesions may have induced metabolic changes in left frontocortical regions. We have previously found that lesions of this area are associated with depression (Starkstein et al 1987b). Mania may develop at a later stage, when these metabolic changes become restricted to the orbitofrontal and/or basotemporal cortices of the right hemisphere (Starkstein et al 1990). The finding that patients developed mania between 2 weeks and 4 months after the depressive episode may be related to individual differences in the extension and recovery from remote metabolic deficits. In spite of the fact that the mechanism of bipolar versus unipolar affective syndromes following brain injury will require further investigation, this study has demonstrated that there are at least two different groups of patien:s with secondary mania--one with a secondary bipolar disease (depression and raania), and another with pure mania. Lesion location seemed to be the most important etiologic variable determining the clinical presentation of these disorders. Future clinical studies may examine whether this classification based on clinical-anatomic distinctions may be validated by intergroup differences in treatment response, or long-term outcome.
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This work was supported in part by the following National Institutes of Health grants: Research ScientistAward MH00163 (RGR), MH40355, and NS15080, a grant from the University of Buenos Aires (SES), a grant from the National Alliance for Research in Schizophrenia and Depression (NARSAD) (SES), and a grant from the Instituto Di Tella (MLB).
References American Psychiatric Association (1987): Diagnostic Criteria From Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Andreasen N, Endicott J, Spitzer RL (1977): The family history method using diagnostic criteria: Reliability and validity. Arch Gen PsychiatD, 34:577-582. Bolla-Wilson K, Robinson RG, Starkstein SE, Boston J, Price TR (1989): Lateralization of dementia in stroke patients. Am J Psychiatry 146:627-634. Cummings JL, Mendez MF (1984): Secondary mania with focal cerebrovascular lesions. Am J Psychiatry 141:1084-1087. Eastwood MR, Rifat SL, Nobbs H, Ruderman J (1989): Mood disorder following cerebrovascular accident. Br J Psychiatry 154:195-200. Finklestein SP, Weintraub RJ, Karmouz N, Askinaza C, Davar G, Baldessarini RJ (1987): Antidepressant drug treatment for poststroke depression: Retrospective study. Arch Phys Med Rehabil 68:772-776. Folstein MF, Folstein SE, McHugh PR (1975): Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198. Graff-Radford NR, Eslinger PJ, Damasio AR, Yamada T (1984): Nonhemorrhagic infarction of the thalamus: Behavioral, anatomic, and physiologic correlates. Neurology 34:14-23. Kupfer DJ, Carpenter LL, Frank E (1988): Possible role of antidepressants in precipitating mania and hypomania in recurrent depression. Am J Psychiatry 145:804-808. Levine DN, Grek A (1984): The anatomic basis of delusions after fight cerebral infarction. Neurology 34:577-582. Lipsey JR, Robinson RG, Pearlson GD, Rao K, Price TR (1984): Nortriptyline treatment for poststroke depression: A double blind study. Lancet i:297-300. Matsui T, Hirano A (1978): An Atlas of the Human Brain for Computerized Tomography. New York: Igaku-Shoin. Nauta WJH (1971): The problem of the frontal lobe: A reinterpretation. J Psychol Res 8:167-187. Pappata S, Dinh ST, Baron JC, Cambon H, Syrota A (1987): Remote metabolic effects of cerebrovascular lesions: Magnetic resonance and positron tomography imaging. Neuroradiology 29:1-6. Pozzilli C, Passafiume D, Bastianello S, D'Antona R, Lenzi GL (1987): Remote effects of caudate hemorrhage: A clinical and functional study. Cortex 23:341-349. Reding MJ, Otto LA, Winter SW, Fortuna IM, DiPonte P, McDowell FH (1986): Antidepressant therapy after stroke: A double-blind trial. Arch Neurol 43:763-765. Robinson RG, Bolla-Wilson K, Kaplan E, Rao K, Price TR (1986): Depression influences intellectual impairment in stroke patients. Br J Psychiatry 148:541-547. Robinson RG, Boston JD, Starkstein SE, Price TR (1988): Comparison of mania with depression following brain injury: Causal factors. Am J Psychiatry 145:172-178. Shukla S, Cook BL, Mukherjee S, Godwin C, Miller MG (1987): Mania following head trauma. Am J Psychiatry 144:93-96. Starkstein SE, Pearlson GD, Boston JD, Robinson RG (1987a): Mania after brain injury: A controlled ~tudy of causative factors. Arch Neurol 44:1069-1073. Starkstein .qE, Robinson RG, Price TR (1987b): Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 110:!045-1059.
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Starkstei,. 3E, Boston JD, Robinson RG (1988a): Mechanisms of mania after brain injury: 12 case reports and review of the literature. J Nerv Merit Dis 176:87-190. Starkstein SE, Robinson RG, Price TR (1988b): Comparison of patients with and without poststroke major depression matched for size and location of lesion. Arch Gen Psychiatry 45:247-252. Starkstein SE, Brandt J, Folstein S, et al (1988c): Neuropsychological end neuror~diological correlates in Huntington's disease. J Neurol Neurosurg Psychiatry 51:1259-1263. Starkstein SE, Berthier ML, Fedoroff P, et al (1990): Secondary mania: neuroradiological, metabolic, and neuropsychological findings. Ann Neurol (in press). Takano T , ,;gimura K, Nakamura M, et al (1985): Effect of small deep hemispheric infarction on the ipsilateral cortical blood flow in man. Stroke 16:64-69. Wing JK, Cooper E, Sartorius N (1974): Measurement and Classification of Psychiatric Symptoms. Cambridge: Cambridge University Press.
149
Manic-Depressive and Pure Manic States After Brain Lesions Sergio E. Starkstein, Paul Fedoroff, Marcelo L. Berthier, and Robert G. Robinson
Although mania is a rare complication of brain lesions, recent reports have emphasized the importance of lesion location and genetic predisposition in these patients. In the present study we compared patients who developed a bipolar affective disorder (i.e., mania and depression) after a brain lesion with patients who only developed mania. Although no significant between-group differences were found on demographic variables, the manic-depressed group showed significantly more impairments on the Mini Mental State Exam than the mania only group. All the bipolar patients had subcortical lesions (mainly right head of the caudate and right thalamus), while patients with unipolar mania had significantly higher frequency of cortical involvement (mainly right orbitofrontal and basotemporal cortices). It is suggested that subcortical and cortical right hemisphere lesions may produce different neurochemical and~or remote metabolic brain changes that may underlie the production of either a bipolar disease or a unipolar mania.
Introduction Recent studies have suggested that mania may be a specific complication of brain lesions (Cummings and Mendez 1984; Starkstein et al 1988a; Shukla et al 1987). Lesion location has consistently been found to play an important role in secondary mania, with most patients having lesions in limbic areas of the right hemisphere [see Starkstein et al (1988a) for a review]. A genetic predisposition and the presence of subcortical atrophy have also been found to play an important permissive role in the development of mania (Robinson et al 1988; Starkstein et al 1987a). In patients with secondary mania after closed head injuries, a high frequency of seizure activity has also been described (Shukla et al 1987). In a previous study (Robinson et al 1988), we reported that one third of patients with secondary mania had depression at some time after the brain injury, whereas the rest of the patients showed only a single manic episode. Thus, in the present study we compared demographic, neurological, and radiological findings in patients having secondary mania with and without depression.
From the Departments of Psychiatry and Behavioral Science (SES, PF, RGR) and Nem'osciences (RGR), Johns Hopkins University School of Medicine, Baltimore, MD 21205, Institute of Neurological Research "Dr. Raui Carrea, ' Buenos Aires, Argentina (MLB), and Department of Psychiatry University of Iowa College of Medicine, Iowa City, IA 52242 (SES, RGR). Address reprint requests to Sergio E. Starkstein, M.D., Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242. Received January 13, 1990; revised July 20, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
150
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Material and M e t h o d s
Study Preparation A consecative series of patients admitted to the Johns H ,:,i:ins Hospital (Baltimore, MD) (n = 15) and the h|stitute of Neurological Research "Dr. Raui Carrea" (Buenos Aires, Argentina) (n = 4) with the diagnosis of both mania and bm~n pathology were included in the study [13 patients were previously reported (Robimon et al 1988) and 6 are new patients]. Neither aphasia nor aprosodia were considered exclusion criteria. Patients were divided into the following groups:
1. Manic-depressive group. This group consisted of patients who met the following inclusion criteria: (1) DSM-III-R (American Psychiatric Association 1987) criteria for Organic Mood Syndrome, manic, and Major Affectivc Disorder, manic episode, followed or preceeded by Organic Mood Syndrome, depressed (i.e., depression after the brain lesion); (2) computed tomography (CT) scan evidence of focal vascular, neoplastic, or traumatic brain lesions; and (3) no history of other neurological, toxic, or metabolic condition. 2. Mania Only group. This group consisted of patients who met the following criteria: (1) DSM-III-R criteria for Organic Mood Syndrome, manic, ~uadMajor Affective Disorder, manic episode, not followed or preceeded by depression; (2) CT scan evidence of vascular, neoplastic, or traumatic brain lesions; and (3) no history of other neurological, toxic, or metabolic condition. All patients were examined during the index r aanic episode by a psychiatrist using a standard clinical interview (i.e., diagnosis was e~tablished by clinical examination, and each patient was seen independently by two psychiatrists who agreed on the diagnosis). Cognitive impairments were examined during, the index manic episode using the MiniMental State Exam (MMSE) (Folstein et al 1975). The MMSE is an 11-item examination test that has been found to be reliable and valid in assessing a limited range of cognitive functions. Patients at the Institute of Neurological Research were examined with the Present State Exam (Wing et al 1974) by one of the neuropsychiatrists (SES) that also carried out examinations at Johns Hopkins. Although we did not ebtain detailed family histories using multiple informants (Andreasen et al 1977), we did obtain as much information about personal and family history as we could from the patients and/or relatives who were available at the time of the interview. All the neuropsychiatric data were obtained blind to group membership.
CT Scan Examination CT scans were read by one of us (SES) who was blind to group membership. All CT scans had a consistent slice thickness and angle to the canthomeatal line. Lesion volume (expressed as a percentage of total brain volume) was calculated from the ratio of the largest cross-sectional area of the lesion on any CT scan slice to the cross-sectional area of the wha!e brain on the slice passing through the body of the lateral ventricles. We have previ ausly demonstrated the reliability of this procedure and its high correlation with other methods of determining lesion volume (Robinson et al 1986). The anteriorposterior (A-P) location of each lesion was defined as the mean distance of the anterior border of the lesion from the frontal pole averaged over all slices in which the lesion was visible (Robinson et al 1986). This distance was expressed as the percentage of the
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Table 1. Demographic Data
Number of patients Age (mean years) Sex (% females) Handedness (% right-handed) Education (mean years) Fanfi|y history of psychiatric disorders (% positive) Personal history of psychiatric disorders (% positive)
Manic-depressed"
Maria only"
7 61.2 (15.9) 43 86 8.7 (2.2) 29
12 50.1 (16.9) 33 83 11.4 (3.6) 25
0
0
°SDs are in parentheses.
maximum distance between the anterior and posterior poles on the CT slice where the lesion was identified. The posterior border of each lesion was calculated using the same methods. In addition, the damaged area was mapped using an atlas (Matsui and Hirano 1978) and was localized in specific brain areas following the procedure of Levine and Grek (1984). Patients were considered to have cortical lesions if they had predominantly cortical damage with only a small amount of subcortical involvement but never including the basal ganglia, th;flamus, or the it~ternal capsule. Patients were considered to have subcortical lesions if they had purely subcortical lesions with no involvement of cortical tissue. Patients with cortico-subcortical lesions had lesions involving both locations (Starkstein et al 1987b).
Statistical Analysis Statistical analysis was carded out using means and standard deviations, and t-tests. Frequency distributions were analyzed using chi-square tests and Fisher's exact test. p values are two-tailed. Results
Background Characteristics Background information revealed no significant between-group differences in age, sex, race, education, handedness, or personal history of psychiatric disorder (Table 1). Two of the 7 manic-depressed patients had a positive family history of psychiatric disorders (affective disorder and alcoholism, respectively), and 3 of the 12 mania-only patients had a positive family history of psychiatric disorders (affective disorder in all 3 cases). Six of the seven manic-depressed patients showed depression within the first week after the brain lesion. Three patients developed mania 2 weeks later (one patient had 8 years of follow-up, and the other two patients were lost to follow-up after the manic episode). The other three patients developed mania 7 weeks, 3 months, and 6 months later, respectively (they had follow-up periods of 2 years, 1 year, and 1 year, respectively). In the remaining patient, the interval between the stroke and the onset of the manicdepressive disorder could not be determined (he had 10 years of follow-up). Only one of these patients received antidepressants during the period of depression.
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Table 2. Manic Symptoms (%)
Elation Irritability Hyperactivity Pressure of speech Flight of ideas Grandiose delusions Insomnia Hypersexuality Overspending Other delusions Hallucinations Mini-Mental State Exam" (mean score +_ SD)
Manic-depressed
Mania only
100 14 86 86 43 71 100 29 57 29 14 25.2 ± 4.7
100 50 83 92 75 83 67 33 50 25 25 28.6 "4- 1.8
"p < 0.05.
Five of the 12 patients with mania only showed manic symptoms within the first week after the brain lesion, and all had follow-up evaluations (6 months in one, 1 year in two, and 2 and 3 years in the two remaining cases, respectively). Three other patients showed manic symptoms 18 months, 2 years, and 4 years after the brain lesion, respectively, and two of them had follow-up evaluations 1 year later. The other four patients showed a brain lesion at the time of the index admission due to the manic episode, but the interval between brain injury and manic episode could not be determined (three patients had tumors, and one patient had a lacunar stroke). Thus, in these cases, the association between brain lesion and mania remains tentative. All four patients received follow-up evaluations [ 1 year, 2 years (in two cases), and 4 years, respectively].
Neurological Findings Motor deficits were present in 71% of manic-depressed patients, and in 42% of patients with mania only; visual field deficits were present in 29% and 50%, respectively; sensory deficits were present in 14% and 17%, respectively; and dysarthria was present in 29% and 8%, respectively. None of these differences was statistically significant.
Psychiatric Findings Manic symptoms for the manic-depressive and the mania only groups, which were observed at the initial evaluation of the first manic episode, are shown in Table 2. No significant between-group differences were observed. The mastic-depressive patients, however, showed a significantly lower MMSE score (t = 2.21, df = l, p < 0.05) (Table 2).
Lesion Location Six of the seven manic-depressed patients had lesions restricted to the right hemisphere, which involved the head of the caudate in two patients (both with ischemic infarctions),
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i,
Figure 1. Bipolargroup: Schematic templates of computed tomographic scan slices showing largest cross-sectional area of lesion for manic-depressivepatients. Lesions mainly involvedthe right head of the caudate and right thalamus.
the thalamus in three patients (two cases with thalamic hematomas and one with an ischem~c infarction), and ischemic infarctions in several cortical and subcortical regions (head c,f the caudate, dorsolateral frontal cortex, and basotemporal cortex) in one patient (Figure 1). The remaining patient developed mania after surgical removal ef a pituitary adenoma. Eight of the 12 patients with mania only had lesions restricted to the fight hemisphere (Figure 2). Three patients had ischemic infarctions involving the head of the caudate (one case), the basotemporal cortex, amygdala, hippocampus, and head of the caudate (one case), and the occipitotemporal cortex (one case); two patients had gliomas involving the inferior temporal lobe (one case) and the temporal and parietal lobes (one case); one patient had a hematoma in the inferior temporal lobe; one patient had an arteriovenous malformation in the inferior temporal lobe; and one patient had an orbitolrontal meningioma. Four patients had bilateral lesionsmtwo had orbitofrontal meningiomas, and two had brain lesions secondary to closed head injuries [right orbitofrontal white matter and left temporal tip (one case), and orbitofrontal lesions (one case)]. In summary, six of the seven manic-depressed patients had subcortical lesions, and the remaining one had a cortical-subcortical lesion. On the other hand, 9 of the 12 patients with mania only had cortical lesions, 1 had a cortical lesion with subcortical extension, and 2 had subcortical lesions. A hypothesis of unequal frequency of bipolar compared to unipolar disorder based on the presence of coitical or subcortical lesions
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Figure 2. Mania only group: Schematic templates of computed tomography scan slices showing largest cross-sectional area of lesion for mania only patients. Lesions mainly involved the orbitofrontal cortex and the right basotemporal cortex.
was statistically substantiated (Fisher test p < 0.005). The observed cells were as follows: manic-depressed patients with cortical lesions, no patients, and with subcortical lesions, six patients; mania-only patients with cortical lesions, 9 patients, and with subcortical lesions, two patients. Between-group differences remained significant even after patients with an unknown interval between the brain lesion and the manic episode were excluded (Fisher test p < 0.01) (observed cells were no patients, five patients, six patients, and one patient, respectively), and when the two manic patients without follow-ups of less than 1 year were excluded (Fisher test p < 0.025) (observed cells were zero, six, seven, and two patients, respectively). A hypothesis of unequal frequency of manic-depression or pure mania based on the presence of unilateral or bilateral lesions, however, was not statistically substantiated (×2 = 2.57, df = 1, p > 0.10). Patients with pure mania showed significantly larger lesions than did the depressedmanic patients (mean _+ SD--12.6 _+ 9.5 versus 2.8 _+ 4.2, respectively t = 2.16, d f = 15, p < 0.05). No significant differences were observed in either anterior (mean -+ SD---29.0 _+ 19.3 versus 37.4 _+ 8.5, respectively; t = 0.90, df = 15, p > 0.10), or posterior distances of the lesion from the frontal pole (mean + SD---59.0 + 24.1 versus 54.2 _+ 11.8, respectively; t = 0.41, df = 15, p > 0o 10). The dimensions of the lesions could not be measured in the manic-depressed patient with the surgical removal of a pituitary adenoma, or in the mania-only patient with multiple he~x~orrhagic contusions in the orbitofrontal cortex.
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Discussion There were three major findings from the present study. First, among patients with secondary mania, a prior episode of depression had occurred in 37%. Second, although all the manic-depressed patients had subcortical lesions (mainly involving the right head of the caudate or right thalamus), patients with pure m,'mia showed a significantly higher frequency of cortical lesions (mainly involving the right orbitofrontal and right inferior temporal cortex), and significantly larger lesion volumes. Third, raanic-depressed patients showed significantly greater cognitive impairments than patients with pure mania. Before further discussion, some limitations of this study should be pointed out. Although 10 of the 12 patients with pure mania had follow-ups that ranged from 6 months to 4 years after the onset of manic symptoms, 2 patients had no follow-up evaluations, and we cannot be sure they did not develop depression afterwards. However, these two patients developed mania 4 and 1.5 years after the brain injury, respectively, whereas all the manic-depressed patients showed depression immediately after the brain lesion, and before the onset of mania. Moreover, even when the two pure manic patients without a follow-up were excluded, between-group differences in cortical versus subcortical lesion location remained statistically significant. The possibility that some of the mania-only patients may have developed depression beyond the follow-up period cannot be excluded, and this issue will requh-e further studies with longer follow-ups. Another limitation is that one of the manic-depressive patients developed mania shortly after receiving treatment with nortriptyline for a poststroke depression, which might explain the development of mania. However~ the relevance of antidepressant treatment in the production of"pr~mary" (i.e., no known brian injury) mania has never been consistently demonstrated (Kupfer et al 1988), and manic episodes have never been reported after treatment of poststroke depression with antidepressants (Lipsey et al 1984; Reding et al 1986; Finklestein et al 1987). Finally,, a few patients developed mania several months after the brain injury, and a causal relationship between brain lesion and mood change remains tentative. It should be noted, however, that none of these patients had a personal history of psychiatric disorders, and the onset of mania occurred at a much later age than would be expected for patients with "functional" affective disorders. Although both the manic-depressive and the mania-only groups showed similar deficits on neurological examination, manic-depressives showed a significantly lower MMSE score. This finding was somewhat surprising, since patients with pure mania had larger lesions, and MMSE scores have been reported to have a negative correlation with lesion size (i.e., lower MMSE scores are associated with larger lesions and greater impairraent) (Robinson et al 1986; Eastwood et al 1989). In previous studies, however, we have shown that patients with poststroke depression had significantly lower MMSE scores than ageand lesion-matched nondepressed stroke patients (Starkstein et al 1988b), and similar results were obtained after using a more comprehensive neuropsychological test battery (Bolla-Wilson et al 1989). Thus, the presence of a previous depression may have produced more severe cognitive impairments in the manic-depressed group. Alternatively, it might be proposed that both cognitive and mood disturbances may be related to a more severe neurochemical dysfunction resulting from basal ganglia lesions than from cortical lesions. Finally, the greater intellectual impairment in manic-depressed compared with maniconly patients might be due to lesion location, because caudate and thalamic lesions have been reported to produce important deficits in intellectual functions (Starkstein et al 1988c; Graff-Radford et al 1984). It should be noted, however, that only two patients in the
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manic-depressed group had MMSE scores below the usual cutoff score of 23 points, and differences in MMSE scores between manic-depressed and mania-only patients may not have had clinical relevance. Future studies should be carried out using more comprehensive neuropsychological evaluations. The major question raised by this study is why some patients developed a unipolar mania, whereas others developed a bipolar disorder. Shulda et al (1987) reported a similar frequency of depression (30%, compared to our 37%) in their series of patients with mania after closed head injury. In the present study we did not find any significant differences in demographic variables between bipolar and unipolar groups. Although we have previously found that genetic factors play a role in the production of secondary mania (Robinson et al 1988), the frequency of a positive family history of psychiatric disorders was similar for the manic-depressed and mania-only groups. The main difference between the manic-depressive and pure mania groups was lesion location. Although 6 of 7 manic-depressive patients had subcortical lesions (the other patient had mixed cortical-subcortical damage), 10 of 12 patients with pure mania had cortical lesions. One of the two pure manics with subcortical lesions had a closed head injury and a s m ~ hemorrhagic contusion in the frontal white matter, and a magnetic resonance imaging (MRI) done 10 months after the trauma showed a pseudoporencephalic cyst in the left temporal tip. The other pure manic with a subcortical lesion showed a right head of the caudate infarction at the time of psychiatric hospitalization. Although there is no straightforward explanation for this finding, a tentative mechanism may be proposed. Patients with unipolar mania had lesions primarily involving the basotemporal and orbitofrontal cortices, which are important structures of the basolateral limbic system, and have main connections with septal, hypothalamic, and mesencephalic regions (Nauta 1971). In a previous study (Starkstein et al 1988a) we speculated that through this projection, the orbitofrontal and basotemporal cortices may modulate the effect of the limbic system on hypothalamic function (Nauta 1971). Disruption of this system may be related to the production of manic symptoms such as euphoria, hypersexuality, insomnia, hyperactivity, and irritability. In the case of manic-depressives, the mechanism may have been different. Subcortical lesions have been reported to produce hypometabolic effects in widespread regions including contralateral brain areas (crossedhemisphere and crossed-cerebeUar diaschisis) (Takano et al 1985; Pozzilli et al 1987; Pappata et al 1987); thus it is possible that subcortical lesions may have induced metabolic changes in left frontocortical regions. We have previously found that lesions of this area are associated with depression (Starkstein et al 1987b). Mania may develop at a later stage, when these metabolic changes become restricted to the orbitofrontal and/or basotemporal cortices of the right hemisphere (Starkstein et al 1990). The finding that patients developed mania between 2 weeks and 4 months after the depressive episode may be related to individual differences in the extension and recovery from remote metabolic deficits. In spite of the fact that the mechanism of bipolar versus unipolar affective syndromes following brain injury will require further investigation, this study has demonstrated that there are at least two different groups of patien:s with secondary mania--one with a secondary bipolar disease (depression and raania), and another with pure mania. Lesion location seemed to be the most important etiologic variable determining the clinical presentation of these disorders. Future clinical studies may examine whether this classification based on clinical-anatomic distinctions may be validated by intergroup differences in treatment response, or long-term outcome.
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This work was supported in part by the following National Institutes of Health grants: Research ScientistAward MH00163 (RGR), MH40355, and NS15080, a grant from the University of Buenos Aires (SES), a grant from the National Alliance for Research in Schizophrenia and Depression (NARSAD) (SES), and a grant from the Instituto Di Tella (MLB).
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