BIOL PSYCHIATRY 1990;27:341-352
341
Progressive Ventricular Enlargement in Schizophrenia: Comparison to Bipolar Affective Disorder and Correlation with Clinical Course Bryan T. Woods, Deborah Yurgelun-Todd, Francine M. Benes, Frances R. Frankenburg, Harrison G. Pope, Jr., and Jennifer McSparren
Previous studies of long-term serial changes in ventricular size in schizophrenia (SCZ) have yielded mixed, albeit predominantly negative results. The current s~udy examined ventricular changes in CT scans over intervals of 1- to 4½years in chronic schizophrenic and bipolar patients. The results indicated significant progression of ventricular size from initial to final scan in the schizophrenia group but not in the bipolar or control groups; the percent increase in VBR over baseline was 25% (p < 0.01) in the schizophrenia group as compared with 11% (n.s.) in the bipolar group. The increases in ventric~:qr enlargement in the schizophrenic group did not correlate with duration of illness but diK appear to show an irregular stepwise pattern in several patients. It is concluded that progressive ventricular enlargement after onset of illness does occur in a su.~group of schizophrenic patients characterized by a chronic vr deteriorating clinical course. The etiological implications of this finding are discussed.
Introduction Mo~ than 50 years ago progressive ventficular enlargement in chronic schizophrenia was already an inconsistent finding; it had been noted in one pneumoencephalographic (PEG) study (Moore et al. 1935) but not in another (Lemke 1935). A somewhat later longitudinal PEG study (Huber 1957) found ventricular volume progression in 8 of 27 schizophrenics and related it to progressive cognitive deterioration. Shortly thereafter, Haug (1962) also linked progressive veatricular enlarf,ement in a subgroup of schizophrenic patients to clinical deterioration. In his sample of 24 patients with repeat PEG studies, the 4 patients with clear progression of ventricular enlargement were all among the subgroup of 8 who had deteriorated clinically. Although studies of schizophrenia with computerized tomography (CT) provide some indirect evidence for progressive ventricular enlargement in scl'tizophrenia (Woods and
From the Departmentsof Net~rology(B.T.W.) and Psychiatry (F.M.B., F.R.F., D.Y.-T., H.G.P.), Harvard Medical School, Boston; and the Departmentof Neurology (B.T.W.) and Mailman Research Center (F.M.B., H.G.P., D.Y.-T.), McLean Hospital, Belmont, MA. Address reprint requests to Dr. Woods, Depamnent of Neurology, McLean Hospital, 115 Mill Sm;et, Belmont, MA 02178. Received November 7, 1988; revised Much 28, 1989. @ 1990 Society of Biological Psychiauy
0006.3223/90/$03.50
342
BIOL PSYCHIATRY 1990;27:341-352
B.T. Woods et al.
Wolf 1983; Kemali et al. 1985), the failure of most studies to find a statistically significant correlation between ventricular size and duration of iri~less has led others to emphasize the static nature of the enlargement for those patients in whom it is present (Weinberger 1984). Although the initial CT studies of possible progression were based on correlations in cross-sectional studies, longitudinal studies are beginning to appear. Three of these studies have failed to find progressive veamcular enlargement in schizophrenia (NasraUah et al. 1986; lll+~wskyet al. 1988; Vita~: al. 1988), whereas a fourth does find a significant change (Kem:lli et al. 1989). Some patients with affective disorder also show ventricular enlargement (Pearlson et al. 1981; Standish-Barry et al. 1982) and several reports have indicated that in depregsed patients the ventricle-brain ratio (VBR) conelates positively with age (Standish-Barry et al. 1982; Kellner et al. 1983; Dolan et al. 1985). However, another study found this true only in patients over 50 (Reidec et al. 1983), and still others do not find any significant age-VBR correlation (Pe~lsor~ et al. 1984; Roy-Byrne et al. 1988). No longitudinal study of ventricular size in b i p o l a r ~ 9 , t s has been reported. All of the above-mentioned longitudinal studies of VE;i,. m ~cnizophrenia have been prospective and presumably +aonselective as to patient clinical~characteristics or initial ventricular size. On the other hand, the PEG studies (Hubcr 19~7; Haug 1962) that had indicated progressive ventricular changes in schizophrenia as~pciated it with clinical deterioration. The current study, which was retrospective, tend[d to select strongly for patients with poor outcomes, that is, patients who required repeated hospitalizations or long-term residential treatment. Thus, the results are properly applicable primarily to this subgroup of patients.
Methods
Patient Selection McLean Hospital files were searched for all inpatients who had had repeated CT scans on comparable (i.e+, third-generation) scanners since 1981. Patients between the age; of 15 and 65 with at least two such scans more than 12 months apart formed the initial study subject pool. In addition, individuals who were currently inpatients (incluLding hospit~! residential faci!;~typatients) were se~ened to see if they had had a prior CT scan more than 12 months earlier, and if so, their informed consent was sought for a followup scan. Scans from all patients meeting these criteria (n - 44) were then masked to conceal name, age, and scan date. All scans for each patient were then blindly screened by another author (FMB) to ensure that each scan included the areas of interest (celia media, CM; anterior horns, AH) and was comparable with the others in slice level and angulation. Patients whose scans failed to meet these criteria (n = 9) were excluded from the study. The records of this patient pool were then screened by another author (DY-T) who had no .knowledge of any CT scan findings. All patients who failed to meet DSM-HI (APA 1980) criteria for an Axis I diagnosis of schizophrenia (SCZ) or bipolar (BP) disorder were also excluded, yielding two final groups of 9 schizophrenic and 9 bipolar patients. Using a previously described methodo!ogy (Benes et al. 1982), the scans were planimetrically measured, and the VBR (Synek et al. 1976) was determined at the levels of botti the celia media (VBR-CM) and the anterior horns (VBR-AH). A further detailed review of all clinical information, including hospital records, reports from neuropharmacological, neurological, and neuropsychological consultants (excluding
Ventricular Enlargement in Schizophrenia
BIOL PSYCHIAT]F:Y 1990;27:341-352
343
CT or MRI findings), and outpatient and residential treatment program records, was carried out for each of the DSM-Ill-diagnosed schizophrenic patients. Based on documented clinical data, and while maintaining blindness to CT results, one author (DY-T) assigned each patient a score reflecting level of functioning based on the Global Assessment Scale (GAS) (Endicott et al. 1976). Each study subject was rated at the intervals over the course of their illness for which contemporaneous documentation (notes, consults, case conferences, et al.) was available. This methodology attempted to quantify, in retrospect, the changes in clinical state which were described for these patients. In addition, each record was examined for information regarding head injury, substance abuse, neuroleptic treatment, electroconvulsive therapy, tardive dyskinesia, and family history of neurological psychiatric illness. Variables derived from this data were then given a scaled score ranging from 0 (absent) to 3 + (present to a marked degree).
Data Analysis Each scan yielded two measurements: the VBR-CM and VBR-AH. In addition, a.-."VBR is an area measurement but the variable of interest is actr ally a volume, we also utilized a correction of VBR-CM for the nonlinear relationship r,t' area-to-volume measurements. This correction, the volume index (VI), is as follows:
VI -
(Measured VBR-CM~ 3/2 \ ~ V'~--C-I~ /
(The derivation of this formula, and the justification for its use in preference to the VBR, is described elsewhere [Woods and Matthysse, 1989]). The importance of the correc:.~on is that uncorrected VBR changes that appear similar may actually represent quite different volume changes, depending on the absolute VBR. Identic~ changes in VBR represent larger volume changes when the ventricles are large than they do when the ventricles are small; in consequence the VBR underestimates ventricular volume increases, and overestimates ventricular volume decreases. Nonetheless, all results were analyzed utilizing both the VBR and the Vl. Paired t-test comparisons were made for each group using ini6al (1) and final (F) measurement scores for both the AH and the CMI. In addition, a one-way analysis of variance (ANOVA) was performed on each score (VBR-CMI, VBR-CMF; VBR-AHI, VBR-AHF; VII, VIF) by study group. For both groups, the correlation of change scores with between-scan intervals and of initial, final, and change scores with age of onset and duration of illness were also determined.
Results The demographic and course-of-illness characteristics of the two groups are shown in Table 1. Ages at onset of illness and at time of initial scanning do no~ differ significantly between groups, though the schizophrenic group was 6 years younger at the time of initial scanning. Interscan interval and gender ratio de not differ significantly between the SCZ and BP groups. Figure 1 shows the GAS scores for each patient at the different points during the course of illness for which data was available. A paired t-test comparison of the GAS scores for each patient at time of onset of p~y~h,~.;.c illness and time when last
344
B.T. Woods et al.
BIOL PSYCHIATRY 1990;27:3,~1-352
Table 1. Demographic Characteristics and Relations of Scem Intervals to Onset and Duration of Illness Ratio Dx
N
(M/F)
SCZ
9
7/2
BP
9
6/3
Age at onset of illness (yr)
Age at initial scan (yr)
Duration of illness prior to initial scan (months)
Interval between initial and final scans (months)
18.89 (2.71)' 22.44 (9.86)
24.89 C5.67) 31.00 (15.72)
79.1 (66.3) 101.7 (95.2)
29.7 (1 !.6) 22.6 ( 1I. 9)
QStandard deviation in parentheses. SCZ -- schizophrenia; BP = bipolar disorder.
observed showed that the group mean decreased significantly from an initial score of 49.4 (SD 14.9) to a final score of 23.9 (SD 8.9), t ~> 4.82, p ~< 0.002 (two-tailed). Table 2 shows the data for each patient on the presence or absence of nine factors, which at one time or another have been suggested to be associated with cerebral damage or ventricular enlargement. All the patients had been psychotic at some point and all had been treated with neuroleptics, though some had received them longer and in higher doses than others. Otherwise, no single factor was present in more than 3 of the 9 patients, and no patient was positive for more than four factors (exclusive of psychosis and neuroleptic exposure). It should be noted that the presence of minor neurological and electroencephalographic (EEG) abnormalities in schizophrenic patients is relatively common (Woods and Short 1985; Woods et al. 1986) and does not indicate that any patient had a primary neurological diagnosis. Figure 2 shows the individual changes in VI for each group, along with the group means (horizontal bars). Six of the 9 SCZ patients have changes greater than any of the BP patients. The VI scores for each schizophrenic patient's individual scans are shown in Figure 3. Eight of the 9 had had at least some increase in VI by the final scan. Moreover, it will be seen that of the 6 patients with more than two scans, the changes in 4 (A, B, D, and S) give an impression of nonlinear progression. (Because it would be necessary to have repeated sc~uas at more regaiat inte~'ais to conciud¢ wi~a any confidence that the changes seen are truly nonlinear, this must remain a subject for future study.) The results of the t-test analyses of VBR-CM and VI are shown in Table 3. There is a significant increase between the initial and final measurements of ventricular size in the SCZ group with both indices. There is a trend to an increase with VI but not VBR in the BP group. ANOVA of both the VBR and VI scores of the SCZ and BP groups shows (1) a nonsignificant trend for the initial scans of the SCZ patients to be larger (p < 0.10); and (2) a significantly greater increase in ventricular size in the SCZ patients than in the BP patients: for VBR F = 5.35, p < 0.05 (DF 1,16); for VI F = 8.94, p < 0.01 (DFI, 16). No significant changes in any VBR-AH score were seen within any group, or on the between-gro,Jp ANOVA. There was no significant correlation between difference in VBR or VI and either scan inter~al or dut~ation of illness. Furthermore, the greater change in ventfieular size in the SCZ group did not appear to be related to that group's initially large ventricles, as there was no correlation in the SCZ group between initial VBR or Vl and degree of subsequent enlargement. Finally, there was no significant correlation
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Figure l. GAS scores for each patient at the different points during the course of illness for which data was available.
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341
Progressive Ventricular Enlargement in Schizophrenia: Comparison to Bipolar Affective Disorder and Correlation with Clinical Course Bryan T. Woods, Deborah Yurgelun-Todd, Francine M. Benes, Frances R. Frankenburg, Harrison G. Pope, Jr., and Jennifer McSparren
Previous studies of long-term serial changes in ventricular size in schizophrenia (SCZ) have yielded mixed, albeit predominantly negative results. The current s~udy examined ventricular changes in CT scans over intervals of 1- to 4½years in chronic schizophrenic and bipolar patients. The results indicated significant progression of ventricular size from initial to final scan in the schizophrenia group but not in the bipolar or control groups; the percent increase in VBR over baseline was 25% (p < 0.01) in the schizophrenia group as compared with 11% (n.s.) in the bipolar group. The increases in ventric~:qr enlargement in the schizophrenic group did not correlate with duration of illness but diK appear to show an irregular stepwise pattern in several patients. It is concluded that progressive ventricular enlargement after onset of illness does occur in a su.~group of schizophrenic patients characterized by a chronic vr deteriorating clinical course. The etiological implications of this finding are discussed.
Introduction Mo~ than 50 years ago progressive ventficular enlargement in chronic schizophrenia was already an inconsistent finding; it had been noted in one pneumoencephalographic (PEG) study (Moore et al. 1935) but not in another (Lemke 1935). A somewhat later longitudinal PEG study (Huber 1957) found ventricular volume progression in 8 of 27 schizophrenics and related it to progressive cognitive deterioration. Shortly thereafter, Haug (1962) also linked progressive veatricular enlarf,ement in a subgroup of schizophrenic patients to clinical deterioration. In his sample of 24 patients with repeat PEG studies, the 4 patients with clear progression of ventricular enlargement were all among the subgroup of 8 who had deteriorated clinically. Although studies of schizophrenia with computerized tomography (CT) provide some indirect evidence for progressive ventricular enlargement in scl'tizophrenia (Woods and
From the Departmentsof Net~rology(B.T.W.) and Psychiatry (F.M.B., F.R.F., D.Y.-T., H.G.P.), Harvard Medical School, Boston; and the Departmentof Neurology (B.T.W.) and Mailman Research Center (F.M.B., H.G.P., D.Y.-T.), McLean Hospital, Belmont, MA. Address reprint requests to Dr. Woods, Depamnent of Neurology, McLean Hospital, 115 Mill Sm;et, Belmont, MA 02178. Received November 7, 1988; revised Much 28, 1989. @ 1990 Society of Biological Psychiauy
0006.3223/90/$03.50
342
BIOL PSYCHIATRY 1990;27:341-352
B.T. Woods et al.
Wolf 1983; Kemali et al. 1985), the failure of most studies to find a statistically significant correlation between ventricular size and duration of iri~less has led others to emphasize the static nature of the enlargement for those patients in whom it is present (Weinberger 1984). Although the initial CT studies of possible progression were based on correlations in cross-sectional studies, longitudinal studies are beginning to appear. Three of these studies have failed to find progressive veamcular enlargement in schizophrenia (NasraUah et al. 1986; lll+~wskyet al. 1988; Vita~: al. 1988), whereas a fourth does find a significant change (Kem:lli et al. 1989). Some patients with affective disorder also show ventricular enlargement (Pearlson et al. 1981; Standish-Barry et al. 1982) and several reports have indicated that in depregsed patients the ventricle-brain ratio (VBR) conelates positively with age (Standish-Barry et al. 1982; Kellner et al. 1983; Dolan et al. 1985). However, another study found this true only in patients over 50 (Reidec et al. 1983), and still others do not find any significant age-VBR correlation (Pe~lsor~ et al. 1984; Roy-Byrne et al. 1988). No longitudinal study of ventricular size in b i p o l a r ~ 9 , t s has been reported. All of the above-mentioned longitudinal studies of VE;i,. m ~cnizophrenia have been prospective and presumably +aonselective as to patient clinical~characteristics or initial ventricular size. On the other hand, the PEG studies (Hubcr 19~7; Haug 1962) that had indicated progressive ventricular changes in schizophrenia as~pciated it with clinical deterioration. The current study, which was retrospective, tend[d to select strongly for patients with poor outcomes, that is, patients who required repeated hospitalizations or long-term residential treatment. Thus, the results are properly applicable primarily to this subgroup of patients.
Methods
Patient Selection McLean Hospital files were searched for all inpatients who had had repeated CT scans on comparable (i.e+, third-generation) scanners since 1981. Patients between the age; of 15 and 65 with at least two such scans more than 12 months apart formed the initial study subject pool. In addition, individuals who were currently inpatients (incluLding hospit~! residential faci!;~typatients) were se~ened to see if they had had a prior CT scan more than 12 months earlier, and if so, their informed consent was sought for a followup scan. Scans from all patients meeting these criteria (n - 44) were then masked to conceal name, age, and scan date. All scans for each patient were then blindly screened by another author (FMB) to ensure that each scan included the areas of interest (celia media, CM; anterior horns, AH) and was comparable with the others in slice level and angulation. Patients whose scans failed to meet these criteria (n = 9) were excluded from the study. The records of this patient pool were then screened by another author (DY-T) who had no .knowledge of any CT scan findings. All patients who failed to meet DSM-HI (APA 1980) criteria for an Axis I diagnosis of schizophrenia (SCZ) or bipolar (BP) disorder were also excluded, yielding two final groups of 9 schizophrenic and 9 bipolar patients. Using a previously described methodo!ogy (Benes et al. 1982), the scans were planimetrically measured, and the VBR (Synek et al. 1976) was determined at the levels of botti the celia media (VBR-CM) and the anterior horns (VBR-AH). A further detailed review of all clinical information, including hospital records, reports from neuropharmacological, neurological, and neuropsychological consultants (excluding
Ventricular Enlargement in Schizophrenia
BIOL PSYCHIAT]F:Y 1990;27:341-352
343
CT or MRI findings), and outpatient and residential treatment program records, was carried out for each of the DSM-Ill-diagnosed schizophrenic patients. Based on documented clinical data, and while maintaining blindness to CT results, one author (DY-T) assigned each patient a score reflecting level of functioning based on the Global Assessment Scale (GAS) (Endicott et al. 1976). Each study subject was rated at the intervals over the course of their illness for which contemporaneous documentation (notes, consults, case conferences, et al.) was available. This methodology attempted to quantify, in retrospect, the changes in clinical state which were described for these patients. In addition, each record was examined for information regarding head injury, substance abuse, neuroleptic treatment, electroconvulsive therapy, tardive dyskinesia, and family history of neurological psychiatric illness. Variables derived from this data were then given a scaled score ranging from 0 (absent) to 3 + (present to a marked degree).
Data Analysis Each scan yielded two measurements: the VBR-CM and VBR-AH. In addition, a.-."VBR is an area measurement but the variable of interest is actr ally a volume, we also utilized a correction of VBR-CM for the nonlinear relationship r,t' area-to-volume measurements. This correction, the volume index (VI), is as follows:
VI -
(Measured VBR-CM~ 3/2 \ ~ V'~--C-I~ /
(The derivation of this formula, and the justification for its use in preference to the VBR, is described elsewhere [Woods and Matthysse, 1989]). The importance of the correc:.~on is that uncorrected VBR changes that appear similar may actually represent quite different volume changes, depending on the absolute VBR. Identic~ changes in VBR represent larger volume changes when the ventricles are large than they do when the ventricles are small; in consequence the VBR underestimates ventricular volume increases, and overestimates ventricular volume decreases. Nonetheless, all results were analyzed utilizing both the VBR and the Vl. Paired t-test comparisons were made for each group using ini6al (1) and final (F) measurement scores for both the AH and the CMI. In addition, a one-way analysis of variance (ANOVA) was performed on each score (VBR-CMI, VBR-CMF; VBR-AHI, VBR-AHF; VII, VIF) by study group. For both groups, the correlation of change scores with between-scan intervals and of initial, final, and change scores with age of onset and duration of illness were also determined.
Results The demographic and course-of-illness characteristics of the two groups are shown in Table 1. Ages at onset of illness and at time of initial scanning do no~ differ significantly between groups, though the schizophrenic group was 6 years younger at the time of initial scanning. Interscan interval and gender ratio de not differ significantly between the SCZ and BP groups. Figure 1 shows the GAS scores for each patient at the different points during the course of illness for which data was available. A paired t-test comparison of the GAS scores for each patient at time of onset of p~y~h,~.;.c illness and time when last
344
B.T. Woods et al.
BIOL PSYCHIATRY 1990;27:3,~1-352
Table 1. Demographic Characteristics and Relations of Scem Intervals to Onset and Duration of Illness Ratio Dx
N
(M/F)
SCZ
9
7/2
BP
9
6/3
Age at onset of illness (yr)
Age at initial scan (yr)
Duration of illness prior to initial scan (months)
Interval between initial and final scans (months)
18.89 (2.71)' 22.44 (9.86)
24.89 C5.67) 31.00 (15.72)
79.1 (66.3) 101.7 (95.2)
29.7 (1 !.6) 22.6 ( 1I. 9)
QStandard deviation in parentheses. SCZ -- schizophrenia; BP = bipolar disorder.
observed showed that the group mean decreased significantly from an initial score of 49.4 (SD 14.9) to a final score of 23.9 (SD 8.9), t ~> 4.82, p ~< 0.002 (two-tailed). Table 2 shows the data for each patient on the presence or absence of nine factors, which at one time or another have been suggested to be associated with cerebral damage or ventricular enlargement. All the patients had been psychotic at some point and all had been treated with neuroleptics, though some had received them longer and in higher doses than others. Otherwise, no single factor was present in more than 3 of the 9 patients, and no patient was positive for more than four factors (exclusive of psychosis and neuroleptic exposure). It should be noted that the presence of minor neurological and electroencephalographic (EEG) abnormalities in schizophrenic patients is relatively common (Woods and Short 1985; Woods et al. 1986) and does not indicate that any patient had a primary neurological diagnosis. Figure 2 shows the individual changes in VI for each group, along with the group means (horizontal bars). Six of the 9 SCZ patients have changes greater than any of the BP patients. The VI scores for each schizophrenic patient's individual scans are shown in Figure 3. Eight of the 9 had had at least some increase in VI by the final scan. Moreover, it will be seen that of the 6 patients with more than two scans, the changes in 4 (A, B, D, and S) give an impression of nonlinear progression. (Because it would be necessary to have repeated sc~uas at more regaiat inte~'ais to conciud¢ wi~a any confidence that the changes seen are truly nonlinear, this must remain a subject for future study.) The results of the t-test analyses of VBR-CM and VI are shown in Table 3. There is a significant increase between the initial and final measurements of ventricular size in the SCZ group with both indices. There is a trend to an increase with VI but not VBR in the BP group. ANOVA of both the VBR and VI scores of the SCZ and BP groups shows (1) a nonsignificant trend for the initial scans of the SCZ patients to be larger (p < 0.10); and (2) a significantly greater increase in ventricular size in the SCZ patients than in the BP patients: for VBR F = 5.35, p < 0.05 (DF 1,16); for VI F = 8.94, p < 0.01 (DFI, 16). No significant changes in any VBR-AH score were seen within any group, or on the between-gro,Jp ANOVA. There was no significant correlation between difference in VBR or VI and either scan inter~al or dut~ation of illness. Furthermore, the greater change in ventfieular size in the SCZ group did not appear to be related to that group's initially large ventricles, as there was no correlation in the SCZ group between initial VBR or Vl and degree of subsequent enlargement. Finally, there was no significant correlation
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Figure l. GAS scores for each patient at the different points during the course of illness for which data was available.
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