2I
Psychiatry Research: Neuroimaging. 40:2 1-29
Elsevier
Stability of Ventricular in Schizophrenia Scott R. Sponheim, Received 1991.
October
William
18, 1990;
Size After the Onset of Psychosis
G. lacono, and Morton
revised
version
received
February
Beiser 1. 1991;
accepted
March
31.
Abstract. This study examined whether ventricular enlargement in schizophrenia is progressive by scanning 15 schizophrenic patients at the onset of their first psychotic episodes and again l-3 years later. Sizes of the body of the lateral ventricles, the frontal horns, and the third ventricle were assessed. The results indicated no tendency for the ventricles to get larger in this sample, with lateral ventricular size actually showing a significant decrease across the rescanning interval when the ventricle-to-brain ratio was used as the dependent variable. Methodological issues related to computed tomography and the quantification of ventricular size were considered by developing an alternative method of calculating ventricle-to-brain ratios and examining the reliability of measurements made on a group of 11 medical patients who were scanned twice on the same day. Key Words. Schizophrenia, onset.
computed
tomography,
cerebral
ventricles,
psychosis
There ate many reports of ventricular enlargement in patients with schizophrenia (for a review, see Shelton and Weinbetger, 1986). Studies reporting ventricular enlargement have predominantly used chronic schizophrenic patients, and have generally scanned subjects on only one occasion (e.g., Weinberger et al., 1979; Nastallah et al., 1982; DeLisi et al., 1986). In these investigations, it is unclear whether the ventricular enlargement is present at the onset of the disorder or whether it arises as a consequence of having the disorder and being treated for it. Also, since many studies find a correlation between age and ventricular enlargement, it is possible that ventricular enlargement is progressive and worsens with aging (Owens et al., 1985). An important issue to address, then, is the extent to which ventricular size reflects alterations in brain structure as schizophrenia progresses from disotdet onset, before the cumulative effects of aging, treatment, and years of institutionalization become evident. To date, four studies have examined the progressive nature of lateral ventricular enlargement in schizophrenic patients by performing computed tomographic (CT)
Scott R. Sponheim, B.A., is a Ph.D. candidate,
and William G. Iacono, Ph.D., is Professor, Department of Psychology, University of Minnesota, Minneapolis, MN. Morton Beiser, M.D., F.R.C.P.(C), is Professor, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. (Reprint requests to Dr. W.G. Iacono, 75 East River Rd., N218 Elliott Hall, University of Minnesota, Minneapolis, MN 55455, USA.) 0165-1781/91/$03.50
@ 1991 Elsevier Scientific
Publishers
Ireland
Ltd.
22 scans on two occasions. Three of these studies found no evidence of progressive lateral ventricular enlargement (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al., 1988). The fourth study found a significant increase in ventricular size among 18 schizophrenic patients over a 3-year period (Kemali et al., 1989), with the increase being especially prominent in four of the patients. In addition to these prospective studies, Woods et al. (1990) carried out a retrospective analysis using hospital files and reported a significant increase in ventricular size for nine schizophrenic patients and no increase for nine bipolar patients. While the results of the Woods et al. study are dramatic, the authors were careful to note the limitations of their investigation. Woods et al. point out that the retrospective nature of the study may have produced a biased sample, one consisting of patients who were both hospitalized more than once and deemed to have a clinical picture that led to CT scans being ordered on multiple occasions. They also mention that their results may be limited to poor-outcome schizophrenic patients and bipolar patients requiring repeated hospitalizations. In aggregate, these studies provide a mixed picture of the extent to which ventricular enlargement is progressive in schizophrenia. Left unaddressed is how ventricular size changes from the onset of schizophrenia. It is not possible to determine from these reports whether changes in ventricular size may have occurred between the onset of illness and the establishment of a chronic course. The present study extends earlier research by examining CT findings on two occasions shortly after the onset of schizophrenia. Unlike previous studies of progressive ventricular enlargement, this study also examines enlargement of the frontal horns of the lateral ventricles and width of the third ventricle. Studies that have examined the stability of ventricular size have noted extreme ventricle-to-brain ratio (VBR) variation within some individuals and have questioned the adequacy of VBR methods for assessing ventricular size (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al., 1988). By using a sample of medical patients scanned twice on the same day and a new measurement procedure designed to provide an alternative estimate of the largest cross-sectional area of the lateral ventricles, the present study examines methodological reasons for intraindividual variation in VBR measurement. Methods Subjects. The 15 retested schizophrenic patients were part of an original group of 36 firstfirst-episode episode schizophrenic patients who received CT scans. The 15 retested schizophrenic patients underwent CT scanning at two times approximately 2 years apart (mean days = 737, range = 348-1010). Members of the original group were a supplemented sample of a larger study of first-episode psychosis that has been described in detail elsewhere (Iacono et al., 1988). Retested schizophrenic patients were all of those from the original group who could be contacted during the 3 months over which the study was conducted and who consented to receive a repeat CT scan. The VBRs of the retested schizophrenic patients were not representative of the larger group of 36 first-episode schizophrenic patients. On average, the 15 retested schizophrenic patients had larger VBRs at intake than the remaining group of 21 (t = 1.93, p = 0.03). Patients were diagnosed using DSM-III criteria (American Psychiatric Association, 1980) with information obtained from a structured interview (Present State Examination; Wing et al., 1974), hospital chart review, and an interview with at least one family member or friend
23
who knew the patient well. To make the diagnosis, a consensus was reached by at least two diagnosticians who reviewed all the case material (psychiatrists and clinical psychologists). The mean age of the 11 male and 4 female schizophrenic patients at intake was 23.4 (range = 15-36). The mean number of days of hospitalization between initial scanning (time 1) and later retest scanning (time 2) was 78.83 (SD = 48.11, range = 10-175). The level of functioning was indexed by ratings on DSM-IZZ Axis V and was approximately equal at times 1 and 2. On average, patients showed marked impairment in either social relations or occupational functioning, or moderate impairment in both (time 1: mean = 5.0, SD = 0.85, range = 3-6; time 2: mean = 4.75, SD = 1.22, range = 3-7). Eleven medical patients, scanned twice during the same day, were also included. Their scans were used to assess the reliability of the scanning process and to help identify sources of error in VBR measurement. The mean age of the medical patients was 23.7 years (range 17-31); four were male, and seven were female. The patients were referred for CT scanning to investigate headaches, rule out space-occupying lesions, rule out multiple sclerosis, investigate suspected seizure disorder, and investigate intracerebral calcification. All scans were reported to be within normal limits with no significant radiological findings. CT scanning for all schizophrenic and medical patients was accomplished using a high resolution, third generation, total body scanner (Siemens Somatom DR2). The scanner window width was set at 80, and the level at 27. Thirteen to 16 cross-sections, each 8-mm thick, were obtained of the brain. Scans were taken from the base of the skull to the top of the cranial vault in planes approximately parallel to the canthomeatal line. Data from the scans were represented in a 256 X 256 matrix of tissue density values which was reproduced on x-ray film. Medical patients were scanned twice within an 8-hour period. For each medical patient, one set of scans was taken without contrast solution and the other set was taken with contrast solution (con-ray 60) injected into the blood supply. It was assumed that the presence of contrast solution did not affect the amount of ventricular volume represented on the CT scans. All the scans for schizophrenic patients were made without contrast solution. Scanning.
of CT Scans. To ensure that the quantification of the scans was carried out blindly, before analyzing the x-ray films, opaque tape was used to block out subject identification data, the date of the scan, and whether contrast solution was used. In addition, those working with the scans did not know how to identify whether a scan involved the use of contrast solution solely by examining the cranial image. Lateral ventricular size was assessed for both the schizophrenic and medical patients by calculating the VBR. The scan that maximally revealed the lateral ventricles was selected for VBR measurement and enlarged to approximately 60% of life size. The perimeter of the brain and lateral ventricles was measured by tracing these areas with a planimeter to calculate their area. To compute the VBR, lateral ventricular area was divided by the brain area and multiplied by 100. As a measure of the size of the lateral ventricles, the VBR provides an imperfect estimate because the size of the ventricles on the CT image is partially dependent on how the subject’s head and the scanner intersect. To provide a more accurate and complete estimate of lateral ventricular size, we calculated a composite ventricle-brain ratio (CVBR). The CVBR was derived by examining scans that revealed portions of the lateral ventricles and superimposing them to determine an estimate of the largest cross-sectional area of the body of the lateral ventricles. The scans used to calculate the CVBR included: (1) the scan that maximally revealed the frontal horns and all scans up to and including the scan that revealed the body of the lateral ventricles at their maximal width, and (2) the scan that maximally revealed the occipital horns and all the scans up to and including the scan that revealed the body of the lateral ventricles at their maxima1 width. The selected CT scans for each subject were enlarged to approximate life size. and the ventricle and brain perimeters evident in each scan were traced with pencil onto paper. These tracings were aligned and superimposed on one another using a light table. A composite Quantification
24 tracing of the ventricles was then made by taking as the border the trace line from any scan that maximized ventricular area. The same method was used in tracing the maximum composite brain border. The result is a maximal composite representation of lateral ventricle and brain areas. The composite is not the same as summing ventricular area measurements across scans because the composite is formed by superimposing scans. Overlapping ventricular areas between scans do not contribute to CVBR. Composite brain and lateral ventricle areas were measured with a planimeter from the composite tracings. The composite lateral ventricle area was divided by the composite brain area and multiplied by 100 to arrive at the CVBR. The scan that maximally revealed the frontal horns of the lateral ventricles was selected to calculate the frontal-horn-to-brain ratio (FHBR). The original scan was enlarged to life size, and the frontal horn and brain areas were determined using a planimeter. Frontal horn area was divided by brain area and multiplied by 100 to derive the FHBR. The maximum width of the third ventricle was measured using an Ehrenreick Profile projector model EPOI LP-6 and converted to life-size values. Scans were again enlarged, and the width of the broadest aspect of the third ventricle (in life-size mm) served as the dependent measure.
Results Measurements of ventricular size were made twice, each time without knowledge of subject identity, time of scan, and the previous measurement. The ventricular area measures showed high reliability (ICC = 0.98) as did the measurement of third
ventricle width (ICC = 0.86). Table 1 summarizes the results. The VBR values of the schizophrenic patients were significantly smaller at the time of the second assessment. Otherwise, there were no significant changes in any of the measures for either the schizophrenic or medical patient groups. Because the ventricular size of the medical patients presumably did not change on the day they received their two sets of CT scans, the correlation between times 1 and 2 for this group can be viewed as an index of reliability that Table 1. Ventricular size indices for schizophrenic and medical patients Size
Time 1 Mean SD
Time 2 Mean SD
t
Time l-2 correlation
2.13
-2.48’
0.83
2.92
0.18
0.77
2.94
0.70
0.32
0.46
3.52
0.94
-2.06
0.68
Group
index
Schizophrenic (n = 15)
VBR
10.45
2.70
9.49
CVBR
14.94
2.52
15.03
FHBR
2.88
0.64
3.92
0.91
TVw Medical (n = 11)
(mm)
7.69
3.05
8.31
2.28
1.32
0.87
CVBR
VBR
11.96
3.61
11.99
3.86
0.07
0.91
FHBR
2.79
0.99
2.76
1.22
-0.12
0.76
JWV (mm)
2.77
0.65
3.07
0.69
1.76
0.59
Note. Correlations are Pearson r’s, A negative t value indicates that ventricular size was smaller at time 2 than at time 1, VBR = ventricle-to-brain ratio. CVBR = composite-ventricle-to-brain ratio. FHBR = frontal-horn-to-brain ratio. TVW = third ventricle width. Time interval between time 1 and time 2: schizophrenic patients, mean = 737 days; medical patients, mean < 1 day. 1. p
1.51 units (1.51 units = 1 SD of time 1 - time 2 difference score) were rated as showing more occipital horn at time 1 than at time 2. In Figs. 1 and 2, these three schizophrenic patients are numbered 4,6, and 12. As can be seen, CVBR reduced the measured change in ventricular size for the three subjects (mean VBR change = 3.15 units, mean CVBR change = 1.06 units), suggesting that the angle at which the CT scanner intersected their lateral ventricles led to less ventricle being visible at time 2 than at time 1 rather than a real reduction occurring in the size of their ventricular systems. Overall, 40% of the schizophrenic patients were judged as having more occipital horn visible at time 1 than at time 2 on scans selected for VBR measurement, and no schizophrenic patient was judged as having more occipital horn visible at time 2 than at time 1. Fig. 2. Plot of composite-ventricle-to-brain ratios (CVBRs) for schizophrenic patients (identified by subject number) at intake (time 1) and approximately 2 years later (time 2)
41 0
200
400 Time
600 (days)
800
1000
27
Discussion Our findings extend those of other investigators by showing that enlargement of the ventricles in schizophrenia does not take place during the first several years following the onset of psychosis. These results, coupled with those from several of the studies reviewed in the introduction to this report, suggest that ventricular enlargment, when present, predates the appearance of psychotic symptoms and, other than natural changes brought about by aging, is relatively stable from that point onward. Our results also supplement this literature by illustrating that size of the frontal horns and width of the third ventricle, in addition to the body of the lateral ventricles, do not become progressively larger over the time interval studied. Various researchers have suggested that assessing changes in VBR over scanning sessions can be prone to error (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al,, 1988; Kemali et al., 1989). Our report is in accord with this appraisal and provides some additional insight into the problems associated with repeat scanning. Our use of the CVBR measure, which maximizes the likelihood of being able to map the entire extent of the lateral ventricles, showed that there was no change in ventricular size for schizophrenic patients over time. The VBR, however, was significantly smaller at time 2. The disparity in results between these two measures appears to have been due to the scanner depicting less of the lateral ventricles at time 2 than at time 1. In particular, our data illustrate that the occipital horns of the lateral ventricles were likely to be missed at time 2. Why this happened at time 2 rather than at time 1 was in part an artifact of our inadvertently recruiting from the original group of 36 schizophrenic patients 15 rescan subjects who, rather than being representative of the original group, had significantly larger VBRs than those not recruited for rescanning. In other words, our rescan subjects were drawn disproportionately from the top half of the VBR distribution. Some of these individuals’ VBRs were large because the first scans fortuitously intersected the ventricles in a way that depicted them at their fullest extent. A decrease in meiisured VBR occurred with the repeat scans; with the second assessment, the scanner was less likely to provide an image with as full a view of the ventricular space. This conclusion is supported not only by our analysis of occipital horn prominence, but also by the fact that at time 2, the VBRs of the rescanned schizophrenic patients were not significantly larger than the remaining 21 of the original group at time I (t = 0.76, NS). Our reliability data suggest that despite the problem brought on by being unable to generate slices with precisely the same angle and at exactly the same level on each of two CT scanning occasions, the scanning procedure nevertheless demonstrated high reliability. The one exception to this rule derived from the assessment of third vemricle width. Our interrater measurement of third ventricle width was high (ICC = 0.86) when the same scan was independently measured twice, but the retest reliability (0.590.68) was only moderate. The lower reliability evident in the assessment of this structure probably stems from its small size and the resulting poor resolution on CT scans.
28 Our data indicated that a difference in ventricular width of 1 pixel across scanning sessions was common, occurring 86% of the time where a difference was observed in an individual. Because 1 pixel was equivalent to 27% of the average third ventricle width of the subjects in this study, this single pixel variation across occasions nevertheless accounted for much measurement variability. In conclusion, our data echo the findings of other investigators by demonstrating that ventricular enlargement in most schizophrenic patients probably progresses little after the onset of schizophrenia. They further jllustrate some of the limitations inherent to CT scanning methods for assessing ventricular size. To circumvent problems with variation in scanning angle, it is important to use the same scanning methodology across multiple assessments of ventricular morphology, and to use indices such as volume measures or CVBR that include the full extension of the ventricular system. Acknowledgments. This work was supported by grants from the United States Public Health Service (National Institute of Mental Health MH-44643 and MH-17069-08), and the Graduate School of the University of Minnesota. We thank Dan Hansen, M.D., and Geoff Smith, Ph.D., for their assistance and helpful suggestions.
References American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: Author, 1980. DeLisi, L.E.; Goldin, L.R.; Hamovit, J.R.; Maxwell, M.E.; Kurtz, D.; and Gershon, ES. A family study of the association of increased ventricular size with schizophrenia. Archives of General Psychiatry, 431148-153, 1986. lacono, W.G.; Smith, G.N.; Moreau, M.; Beiser, M.; Fleming, J.A.E.; Lin, T.; and Flak, B. Ventricular and sulcal size at the onset of psychosis. American Journal of Psychiatry, 145:820824, 1988. Illowsky, B.P.; Juliano, D.M.; Bigelow, L.B.; and Weinberger, D.R. Stability of CT scan findings in schizophrenia: Results of an 8 year follow-up study. Journal of Neurology, Neurosurgery and Psychiatry, 56:209-2 13, 1988. Kemali, D.; Maj, M.; Galderisi, S.; Milici, N.; and Salvati, A. Ventricle-to-brain ratio in schizophrenia: A controlled follow-up study. Biological Psychiatry, 26:753-756, 1989. Nasrallah, H.A.; Jacoby, C.G.; McCalley-Whitters, M.; and Kuperman, S. Cerebral ventricular enlargement in subtypes of chronic schizophrenia. Archives of Genera/ Psychiatry, 39:774-777. 1982.
2’3 Nasrallah, H.A.; Olson, S.C.; McCalley-Whitters, M.; Chapman, S.; and Jacoby. C.G. Cerebral ventricular enlargement in schizophrenia: A preliminary follow-up study. Archives of General
Psychiatry,
431157-159,
1986.
Owens, D.G.C.; Johnstone, E.C.; Crow, T.J.; Frith, CD.; Jagoe, J.R.; and Kreel, L.. Lateral ventricular size in schizophrenia: Relation to the disease process and its clinical manifestations. Psychological Medicine, 15:27-41, 1985. Shelton, R.C., and Weinberger, D.R. X-ray computerized tomography studies in schizophrenia: A review and synthesis. In: Nasrallah, H.A., ed. Handbook of Schizophrenia.. Vol. 1. The Neurology OfSchizophrenia. Amsterdam: Elsevier Science Publishers, 1986. Vita, A.; Sacchetti, G.; and Cazzullo, C.L. Brain morphology in schizophrenia: A 2- to 5-year CT scan follow-up study. Acta Psychiatrica Scandinavica, 78:618-621, 1988. Weinberger, D.R.; Torrey, E.F.; Neophytides, A.N.; and Wyatt, R.J. Structural abnormalities in the cerebral cortex of chronic schizophrenic patients. Archives of Genera/ Psychiatry,
36:935-939,
1979.
J.E.; and Sartorius, N. The Measurement and Classification c!f London: Cambridge University Press, 1974. Woods, B.T.; Yurgelun-Todd, D.; Benes, F.M.; Frankenburg, F.R.; Pope, H.G.: and McSparren, J. Progressive ventricular enlargement in schizophrenia: Comparison to bipolar affective disorder and correlation with clinical course. Biological Psychiatry, 27:341-352, 1990. Wing,
Psychiatric
J.K.;
Cooper,
Symptoms.
Psychiatry Research: Neuroimaging. 40:2 1-29
Elsevier
Stability of Ventricular in Schizophrenia Scott R. Sponheim, Received 1991.
October
William
18, 1990;
Size After the Onset of Psychosis
G. lacono, and Morton
revised
version
received
February
Beiser 1. 1991;
accepted
March
31.
Abstract. This study examined whether ventricular enlargement in schizophrenia is progressive by scanning 15 schizophrenic patients at the onset of their first psychotic episodes and again l-3 years later. Sizes of the body of the lateral ventricles, the frontal horns, and the third ventricle were assessed. The results indicated no tendency for the ventricles to get larger in this sample, with lateral ventricular size actually showing a significant decrease across the rescanning interval when the ventricle-to-brain ratio was used as the dependent variable. Methodological issues related to computed tomography and the quantification of ventricular size were considered by developing an alternative method of calculating ventricle-to-brain ratios and examining the reliability of measurements made on a group of 11 medical patients who were scanned twice on the same day. Key Words. Schizophrenia, onset.
computed
tomography,
cerebral
ventricles,
psychosis
There ate many reports of ventricular enlargement in patients with schizophrenia (for a review, see Shelton and Weinbetger, 1986). Studies reporting ventricular enlargement have predominantly used chronic schizophrenic patients, and have generally scanned subjects on only one occasion (e.g., Weinberger et al., 1979; Nastallah et al., 1982; DeLisi et al., 1986). In these investigations, it is unclear whether the ventricular enlargement is present at the onset of the disorder or whether it arises as a consequence of having the disorder and being treated for it. Also, since many studies find a correlation between age and ventricular enlargement, it is possible that ventricular enlargement is progressive and worsens with aging (Owens et al., 1985). An important issue to address, then, is the extent to which ventricular size reflects alterations in brain structure as schizophrenia progresses from disotdet onset, before the cumulative effects of aging, treatment, and years of institutionalization become evident. To date, four studies have examined the progressive nature of lateral ventricular enlargement in schizophrenic patients by performing computed tomographic (CT)
Scott R. Sponheim, B.A., is a Ph.D. candidate,
and William G. Iacono, Ph.D., is Professor, Department of Psychology, University of Minnesota, Minneapolis, MN. Morton Beiser, M.D., F.R.C.P.(C), is Professor, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. (Reprint requests to Dr. W.G. Iacono, 75 East River Rd., N218 Elliott Hall, University of Minnesota, Minneapolis, MN 55455, USA.) 0165-1781/91/$03.50
@ 1991 Elsevier Scientific
Publishers
Ireland
Ltd.
22 scans on two occasions. Three of these studies found no evidence of progressive lateral ventricular enlargement (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al., 1988). The fourth study found a significant increase in ventricular size among 18 schizophrenic patients over a 3-year period (Kemali et al., 1989), with the increase being especially prominent in four of the patients. In addition to these prospective studies, Woods et al. (1990) carried out a retrospective analysis using hospital files and reported a significant increase in ventricular size for nine schizophrenic patients and no increase for nine bipolar patients. While the results of the Woods et al. study are dramatic, the authors were careful to note the limitations of their investigation. Woods et al. point out that the retrospective nature of the study may have produced a biased sample, one consisting of patients who were both hospitalized more than once and deemed to have a clinical picture that led to CT scans being ordered on multiple occasions. They also mention that their results may be limited to poor-outcome schizophrenic patients and bipolar patients requiring repeated hospitalizations. In aggregate, these studies provide a mixed picture of the extent to which ventricular enlargement is progressive in schizophrenia. Left unaddressed is how ventricular size changes from the onset of schizophrenia. It is not possible to determine from these reports whether changes in ventricular size may have occurred between the onset of illness and the establishment of a chronic course. The present study extends earlier research by examining CT findings on two occasions shortly after the onset of schizophrenia. Unlike previous studies of progressive ventricular enlargement, this study also examines enlargement of the frontal horns of the lateral ventricles and width of the third ventricle. Studies that have examined the stability of ventricular size have noted extreme ventricle-to-brain ratio (VBR) variation within some individuals and have questioned the adequacy of VBR methods for assessing ventricular size (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al., 1988). By using a sample of medical patients scanned twice on the same day and a new measurement procedure designed to provide an alternative estimate of the largest cross-sectional area of the lateral ventricles, the present study examines methodological reasons for intraindividual variation in VBR measurement. Methods Subjects. The 15 retested schizophrenic patients were part of an original group of 36 firstfirst-episode episode schizophrenic patients who received CT scans. The 15 retested schizophrenic patients underwent CT scanning at two times approximately 2 years apart (mean days = 737, range = 348-1010). Members of the original group were a supplemented sample of a larger study of first-episode psychosis that has been described in detail elsewhere (Iacono et al., 1988). Retested schizophrenic patients were all of those from the original group who could be contacted during the 3 months over which the study was conducted and who consented to receive a repeat CT scan. The VBRs of the retested schizophrenic patients were not representative of the larger group of 36 first-episode schizophrenic patients. On average, the 15 retested schizophrenic patients had larger VBRs at intake than the remaining group of 21 (t = 1.93, p = 0.03). Patients were diagnosed using DSM-III criteria (American Psychiatric Association, 1980) with information obtained from a structured interview (Present State Examination; Wing et al., 1974), hospital chart review, and an interview with at least one family member or friend
23
who knew the patient well. To make the diagnosis, a consensus was reached by at least two diagnosticians who reviewed all the case material (psychiatrists and clinical psychologists). The mean age of the 11 male and 4 female schizophrenic patients at intake was 23.4 (range = 15-36). The mean number of days of hospitalization between initial scanning (time 1) and later retest scanning (time 2) was 78.83 (SD = 48.11, range = 10-175). The level of functioning was indexed by ratings on DSM-IZZ Axis V and was approximately equal at times 1 and 2. On average, patients showed marked impairment in either social relations or occupational functioning, or moderate impairment in both (time 1: mean = 5.0, SD = 0.85, range = 3-6; time 2: mean = 4.75, SD = 1.22, range = 3-7). Eleven medical patients, scanned twice during the same day, were also included. Their scans were used to assess the reliability of the scanning process and to help identify sources of error in VBR measurement. The mean age of the medical patients was 23.7 years (range 17-31); four were male, and seven were female. The patients were referred for CT scanning to investigate headaches, rule out space-occupying lesions, rule out multiple sclerosis, investigate suspected seizure disorder, and investigate intracerebral calcification. All scans were reported to be within normal limits with no significant radiological findings. CT scanning for all schizophrenic and medical patients was accomplished using a high resolution, third generation, total body scanner (Siemens Somatom DR2). The scanner window width was set at 80, and the level at 27. Thirteen to 16 cross-sections, each 8-mm thick, were obtained of the brain. Scans were taken from the base of the skull to the top of the cranial vault in planes approximately parallel to the canthomeatal line. Data from the scans were represented in a 256 X 256 matrix of tissue density values which was reproduced on x-ray film. Medical patients were scanned twice within an 8-hour period. For each medical patient, one set of scans was taken without contrast solution and the other set was taken with contrast solution (con-ray 60) injected into the blood supply. It was assumed that the presence of contrast solution did not affect the amount of ventricular volume represented on the CT scans. All the scans for schizophrenic patients were made without contrast solution. Scanning.
of CT Scans. To ensure that the quantification of the scans was carried out blindly, before analyzing the x-ray films, opaque tape was used to block out subject identification data, the date of the scan, and whether contrast solution was used. In addition, those working with the scans did not know how to identify whether a scan involved the use of contrast solution solely by examining the cranial image. Lateral ventricular size was assessed for both the schizophrenic and medical patients by calculating the VBR. The scan that maximally revealed the lateral ventricles was selected for VBR measurement and enlarged to approximately 60% of life size. The perimeter of the brain and lateral ventricles was measured by tracing these areas with a planimeter to calculate their area. To compute the VBR, lateral ventricular area was divided by the brain area and multiplied by 100. As a measure of the size of the lateral ventricles, the VBR provides an imperfect estimate because the size of the ventricles on the CT image is partially dependent on how the subject’s head and the scanner intersect. To provide a more accurate and complete estimate of lateral ventricular size, we calculated a composite ventricle-brain ratio (CVBR). The CVBR was derived by examining scans that revealed portions of the lateral ventricles and superimposing them to determine an estimate of the largest cross-sectional area of the body of the lateral ventricles. The scans used to calculate the CVBR included: (1) the scan that maximally revealed the frontal horns and all scans up to and including the scan that revealed the body of the lateral ventricles at their maximal width, and (2) the scan that maximally revealed the occipital horns and all the scans up to and including the scan that revealed the body of the lateral ventricles at their maxima1 width. The selected CT scans for each subject were enlarged to approximate life size. and the ventricle and brain perimeters evident in each scan were traced with pencil onto paper. These tracings were aligned and superimposed on one another using a light table. A composite Quantification
24 tracing of the ventricles was then made by taking as the border the trace line from any scan that maximized ventricular area. The same method was used in tracing the maximum composite brain border. The result is a maximal composite representation of lateral ventricle and brain areas. The composite is not the same as summing ventricular area measurements across scans because the composite is formed by superimposing scans. Overlapping ventricular areas between scans do not contribute to CVBR. Composite brain and lateral ventricle areas were measured with a planimeter from the composite tracings. The composite lateral ventricle area was divided by the composite brain area and multiplied by 100 to arrive at the CVBR. The scan that maximally revealed the frontal horns of the lateral ventricles was selected to calculate the frontal-horn-to-brain ratio (FHBR). The original scan was enlarged to life size, and the frontal horn and brain areas were determined using a planimeter. Frontal horn area was divided by brain area and multiplied by 100 to derive the FHBR. The maximum width of the third ventricle was measured using an Ehrenreick Profile projector model EPOI LP-6 and converted to life-size values. Scans were again enlarged, and the width of the broadest aspect of the third ventricle (in life-size mm) served as the dependent measure.
Results Measurements of ventricular size were made twice, each time without knowledge of subject identity, time of scan, and the previous measurement. The ventricular area measures showed high reliability (ICC = 0.98) as did the measurement of third
ventricle width (ICC = 0.86). Table 1 summarizes the results. The VBR values of the schizophrenic patients were significantly smaller at the time of the second assessment. Otherwise, there were no significant changes in any of the measures for either the schizophrenic or medical patient groups. Because the ventricular size of the medical patients presumably did not change on the day they received their two sets of CT scans, the correlation between times 1 and 2 for this group can be viewed as an index of reliability that Table 1. Ventricular size indices for schizophrenic and medical patients Size
Time 1 Mean SD
Time 2 Mean SD
t
Time l-2 correlation
2.13
-2.48’
0.83
2.92
0.18
0.77
2.94
0.70
0.32
0.46
3.52
0.94
-2.06
0.68
Group
index
Schizophrenic (n = 15)
VBR
10.45
2.70
9.49
CVBR
14.94
2.52
15.03
FHBR
2.88
0.64
3.92
0.91
TVw Medical (n = 11)
(mm)
7.69
3.05
8.31
2.28
1.32
0.87
CVBR
VBR
11.96
3.61
11.99
3.86
0.07
0.91
FHBR
2.79
0.99
2.76
1.22
-0.12
0.76
JWV (mm)
2.77
0.65
3.07
0.69
1.76
0.59
Note. Correlations are Pearson r’s, A negative t value indicates that ventricular size was smaller at time 2 than at time 1, VBR = ventricle-to-brain ratio. CVBR = composite-ventricle-to-brain ratio. FHBR = frontal-horn-to-brain ratio. TVW = third ventricle width. Time interval between time 1 and time 2: schizophrenic patients, mean = 737 days; medical patients, mean < 1 day. 1. p
1.51 units (1.51 units = 1 SD of time 1 - time 2 difference score) were rated as showing more occipital horn at time 1 than at time 2. In Figs. 1 and 2, these three schizophrenic patients are numbered 4,6, and 12. As can be seen, CVBR reduced the measured change in ventricular size for the three subjects (mean VBR change = 3.15 units, mean CVBR change = 1.06 units), suggesting that the angle at which the CT scanner intersected their lateral ventricles led to less ventricle being visible at time 2 than at time 1 rather than a real reduction occurring in the size of their ventricular systems. Overall, 40% of the schizophrenic patients were judged as having more occipital horn visible at time 1 than at time 2 on scans selected for VBR measurement, and no schizophrenic patient was judged as having more occipital horn visible at time 2 than at time 1. Fig. 2. Plot of composite-ventricle-to-brain ratios (CVBRs) for schizophrenic patients (identified by subject number) at intake (time 1) and approximately 2 years later (time 2)
41 0
200
400 Time
600 (days)
800
1000
27
Discussion Our findings extend those of other investigators by showing that enlargement of the ventricles in schizophrenia does not take place during the first several years following the onset of psychosis. These results, coupled with those from several of the studies reviewed in the introduction to this report, suggest that ventricular enlargment, when present, predates the appearance of psychotic symptoms and, other than natural changes brought about by aging, is relatively stable from that point onward. Our results also supplement this literature by illustrating that size of the frontal horns and width of the third ventricle, in addition to the body of the lateral ventricles, do not become progressively larger over the time interval studied. Various researchers have suggested that assessing changes in VBR over scanning sessions can be prone to error (Nasrallah et al., 1986; Illowsky et al., 1988; Vita et al,, 1988; Kemali et al., 1989). Our report is in accord with this appraisal and provides some additional insight into the problems associated with repeat scanning. Our use of the CVBR measure, which maximizes the likelihood of being able to map the entire extent of the lateral ventricles, showed that there was no change in ventricular size for schizophrenic patients over time. The VBR, however, was significantly smaller at time 2. The disparity in results between these two measures appears to have been due to the scanner depicting less of the lateral ventricles at time 2 than at time 1. In particular, our data illustrate that the occipital horns of the lateral ventricles were likely to be missed at time 2. Why this happened at time 2 rather than at time 1 was in part an artifact of our inadvertently recruiting from the original group of 36 schizophrenic patients 15 rescan subjects who, rather than being representative of the original group, had significantly larger VBRs than those not recruited for rescanning. In other words, our rescan subjects were drawn disproportionately from the top half of the VBR distribution. Some of these individuals’ VBRs were large because the first scans fortuitously intersected the ventricles in a way that depicted them at their fullest extent. A decrease in meiisured VBR occurred with the repeat scans; with the second assessment, the scanner was less likely to provide an image with as full a view of the ventricular space. This conclusion is supported not only by our analysis of occipital horn prominence, but also by the fact that at time 2, the VBRs of the rescanned schizophrenic patients were not significantly larger than the remaining 21 of the original group at time I (t = 0.76, NS). Our reliability data suggest that despite the problem brought on by being unable to generate slices with precisely the same angle and at exactly the same level on each of two CT scanning occasions, the scanning procedure nevertheless demonstrated high reliability. The one exception to this rule derived from the assessment of third vemricle width. Our interrater measurement of third ventricle width was high (ICC = 0.86) when the same scan was independently measured twice, but the retest reliability (0.590.68) was only moderate. The lower reliability evident in the assessment of this structure probably stems from its small size and the resulting poor resolution on CT scans.
28 Our data indicated that a difference in ventricular width of 1 pixel across scanning sessions was common, occurring 86% of the time where a difference was observed in an individual. Because 1 pixel was equivalent to 27% of the average third ventricle width of the subjects in this study, this single pixel variation across occasions nevertheless accounted for much measurement variability. In conclusion, our data echo the findings of other investigators by demonstrating that ventricular enlargement in most schizophrenic patients probably progresses little after the onset of schizophrenia. They further jllustrate some of the limitations inherent to CT scanning methods for assessing ventricular size. To circumvent problems with variation in scanning angle, it is important to use the same scanning methodology across multiple assessments of ventricular morphology, and to use indices such as volume measures or CVBR that include the full extension of the ventricular system. Acknowledgments. This work was supported by grants from the United States Public Health Service (National Institute of Mental Health MH-44643 and MH-17069-08), and the Graduate School of the University of Minnesota. We thank Dan Hansen, M.D., and Geoff Smith, Ph.D., for their assistance and helpful suggestions.
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