Lateral Cerebral Ventricular Enlargement in Chronic Schizophrenia Daniel R.
Weinberger, MD;
E. Fuller
\s=b\ To investigate if cerebral ventricular enlargement is associated with chronic schizophrenia, computerized tomography scans from 73 psychiatric patients were compared with 56 asymptomatic volunteers all less than 50 years old. Ventricular size was significantly greater in the subgroup of 58 chronic schizophrenic patients than in the controls. Of the chronic schizophrenic patients, 40% were outside the control range; 53% exceeded 2 SDs of the control mean. Neither duration of illness nor length of hospitalization correlated with ventricular size. The 44 chronic schizophrenic patients who had never been treated with electroshock therapy (EST) had larger ventricles than controls. A group of seven nonchronic schizophrenic patients also had enlarged ventricles; the eight patients who were either schizoaffective or nonschizophrenic did not differ from controls. This study shows that lateral cerebral ventricular enlargement is associated with chronic schizophrenia; it suggests that this is not a result of treatment.
(Arch
Gen
Torrey, MD; Andreas
observation that some chronic schizophrenic have enlarged cerebral ventricles dates back at least 50 years to Jacobi and Winkler,1 who evaluated 19 patients with pneumoencephalography and diagnosed "in¬ ternal hydrocephalus" in all but one. In more than 30 other pneumoencephalography studies of schizophrenic patients, cases of ventricular enlargement were found. Huag2 and Bliss3 have briefly reviewed some of this extensive but relatively ignored literature. This pneumoencephalography finding, however, has been difficult to interpret because most of these studies used biased patient selection, inade¬ quate controls, unspecified or nonuniform diagnostic crite¬ ria, and inadequately validated standards for normal ventricular size. In addition, changes in ventricular morphology may result from the pneumoencephalography procedure itself.' '
Postmortem neuropathological studies, primarily during the first half of the century, failed to confirm ventricular enlargement and led to the widely held notion that struc¬ tural brain changes do not occur in schizophrenia. Recent studies, however, have shown that cerebral ventricles usually are smaller at autopsy than during life."7 Agonal premortem events, coincident illnesses, edema, and post¬ mortem extraction and fixation procedures all may obscure premortem ventricular enlargement, especially if such
Accepted for publication April 20, 1979. From the Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program (Drs Weinberger, Torrey, and Wyatt), National Institute of Mental Health, St Elizabeths Hospital, Washington, DC, and the Department of Neurology (Dr Neophytides), New York University School of Medicine, New York. Reprint requests to William A. White Bldg, Room 536, National Institute of Mental Health, St Elizabeths Hospital, Washington, DC 20032 (Dr Weinberger).
Neophytides, MD; Richard Jed Wyatt, MD
enlargement is only modest." The advent of computerized tomography (CT)
intro¬ duced a noninvasive and more reliable method of assessing ventricular morphology during life.*" In the only other controlled study of schizophrenic patients evaluated by this method, larger ventricles were found in 17 chronically institutionalized patients as compared with eight normal controls."'" This finding has been questioned, however, because of the small control group, the advanced age of the patients (mean age, 58 years), possible effects of prolonged institutionalization (mean number of inhospital years, 32), and possible effects of somatic treatment (eg, drugs and EST).12·*· The present study was designed to answer some of these questions. SUBJECTS AND METHODS Patients
Psychiatry 36:735-739, 1979)
Thepatients
N.
Seventy-three psychiatric inpatients and recently discharged outpatients in treatment at St Elizabeths Hospital, Washington, DC, had CT scans. The patients were either volunteers in a clinical research division or patients from a general adult psychiatric unit that serves a designated catchment area. Only patients younger than age 50 years were asked to participate. The nature of the procedure was described and consent was obtained. Of 41 patients on the research wards during the six-month study period, 38 consented and cooperated with the procedure. Of 50 available patients in the general psychiatric unit, 35 consented and cooper¬ ated.
Diagnosis was determined by the ward psychiatrist prior to the CT scan, using Research Diagnostic Criteria (RDC)." The diag¬ noses fell into the following categories: 65 cases of schizophrenia; four of schizoaffective disorder; and three of affective disorder. One patient's condition was diagnosed as being mental retarda¬ tion (etiology unknown). The schizophrenic cases were then cate¬ gorized by course of illness as follows: acute (present episode, including onset period, of less than six months' duration, with complete recovery from previous episodes) (three patients); subacute (present episode of less than one year's duration, with complete recovery from previous episodes) (four patients); subchronic (present episode of less than two years' duration or incomplete recovery from prior episodes) (16 patients); and chronic (more than two years of continuous illness) (42 patients). Length of illness, defined as current age minus the age of onset, and years spent living on a psychiatric inpatient ward were also determined. All schizophrenic patients, except for the acute ones, also met the criteria for schizophrenia proposed by Feighner et al." No patients had evidence of a neurological disorder except for two with oral-facial dyskinesia thought to be drug-induced. A complete blood cell count, VDRL, and laboratory studies to determine the values for total protein, albumin, calcium, phosphorus, cholesterol, glucose, BUN, uric acid, creatinine, total bilirubin, alkaline phosphatase, and SGOT, and a urinalysis were performed at least once within a year of the scan for each patient, and the results were either negative or within normal limits. The research patients had
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 1—Ventricular Sizes for Control
Subjectst Age, yr* 20-29 30-39 40-49 Total population
3.1 4.1
±
3.8 3.5
±
±
±
Present 2.2 (
( 2.0(N 2.3 (N
2.6
=
=
=
=
28) 17) 11) 56)
area by the intracranial area and multiplying by 100 produces a ventricular brain ratio (VBR). This method for deter¬ mining ventricular size was used because it has been shown to correlate well with computer-derived ventricular volume.18 Linear measurements (eg, Evans' ratio1" or Huckman's measure2") were not used because they correlate poorly with ventricular volume and are less reliable."'2'-'2 Expressing ventricular size as a ratio controls for magnification variance and provides a simple numer¬ ical value. To assess reliability, the same evaluator selected ten scans of varied ventricular size for repeated measurement at a later date. The correlation coefficient for original and repeated measures was 0.98. The mean difference in absolute magnitude was 0.7 VBR units (range, 0.06 to 1.29). Except where stated, all statistical tests for significance were two-tailed t tests.
ventricular
Groups
Barren et al" 3.1 ± 0.6 ( 15) 4.2 ± 0.8 ( 15) 4.4 ± 0.8 (N 15) 3.9 ± 0.9 (N = 45) =
=
=
*Age factor for present controls nonsignificant (one-way analysis variance). fVentricular size expressed by mean ventricular brain ratio ±SD.
of
RESULTS Control Subjects
20
I5
• I0
V
.St.
I ACUTE AND
SUBACUTE
L-SCHIZOPHRENICSUBJECTS
SCHIZ0- OTHER
AFFECTIVES
Fig 1 —Ventricular size for control subjects and patients grouped by diagnosis. Bar represents mean ventricular brain ratio (VBR) ±SD. Asterisk indicates comparison to control group (P < .006) (Mann-Whitney U Test); double asterisk, comparison to control group
The VBRs for the control group categorized by age are in Table 1. Age is not a significant determinant of ventricular size in this group. In Table 1, this group is compared with the one published by Barron et al," the only other series of asymptomatic volunteers evaluated by the same method. Ventricular size does not differ significantly between these groups. The values for normal ventricular size agree with results from the four other studies2427 that used comparable methods but "symptomatic" normals; however, the present control group defines a slightly broader normal range. It is possible that finding some subjects with ventricles larger than those seen in other studies of normals results from the inclusion of some
given
subjects with preclinical Huntington's disease. Patients
(P < .0001).
following factors were not significant determinants of patient ventricular size: race, sex, patient location (ie, whether research or general psychiatric patients), and history of alcohol abuse (six patients). The difference in VBR between patients with a diagnosis of chronic schiz¬ ophrenia (N 42, mean VBR ± SD 8.9 ± 4.0) and subchronic schizophrenia (N 16, mean VBR ± SD 8.1 ± 3.4) was not statistically significant; therefore, The
thyroid function tests whose results were also normal. The results of Wechsler Adult Intelligence Scale (WAIS) testing done within one year e-f the CT scan were available for 19 patients. Control
Subjects
The control group consisted of 56 healthy, asymptomatic volun¬ teers less than 50 years of age who had undergone head CT scanning for other research projects at the National Institutes of Health, Washington, DC. Forty-eight had first-degree relatives with Huntington's disease but had no clinical manifestations of the illness themselves. The remaining eight were volunteers between the ages of 40 and 50 years who were free of similar genetic risk. By linear measurements (according to the method of Enzmann and Lane'"), the CT scans of the control group could not be differentiated from those of a group of normal volunteer subjects with no known genetic risk for Huntington's disease."
Methods 160 head scanner at All CT scans were performed with a 160 the National Institutes of Health. A minimum of eight and a maximum of 12 cuts were taken for each subject; most scans consisted of ten to 12. The CT slice showing the ventricles at their largest (through the body of the lateral ventricles in all except five controls where the body of the lateral ventricles was not visible) was selected for each subject. The chosen cuts, in the form of either self-developing prints or transparent film, were coded and mixed randomly for blind measurement. One person, using a fixed-arm planimeter, measured the area of the lateral ventricles and the area of the intracranial space in each cut. This involved tracing the perimeter of the lateral ventricles and the inner table of the skull, respective¬ ly. The instrument determines area by mechanical integration. Each area was traced five times and the mean used. Dividing the
=
-
=
=
these groups were combined and are hereafter referred to as the chronic schizophrenic patients. Figure 1 illustrates the distribution of ventricular size for diagnostic groups and controls. Chronic Schizophrenics.—The difference in ventricular size between chronic schizophrenic patients and control subjects is highly significant (P < .0001, Fig 1). Of the chronic schizophrenics, 23 (40%) are outside the control range; 31 (53%) are beyond 2 SDs of the control mean. This level of significance holds for each decade compared indi¬ vidually; age, itself, is not a significant factor in ventricu¬ lar size for this group of chronic schizophrenic patients (Table 2). The distribution of VBR values does not differ significantly from a Gaussian distribution ( 2 11.3, =
df= 7).
Ventricular size does not correlate significantly with either length of illness (Fig 2) or duration of hospitaliza¬ tion (Fig 3). Of the chronic schizophrenic patients, 13 were ill for less than five years (mean VBR ± SD 8.0 ± 4.0); ten were ill for more than 20 years (mean VBR 10.0 ± 4.6). Ventricular size does not differ sig¬ ± SD nificantly between these groups. Comparisons of years of illness and hospitalization for the chronic schizophrenic and =
=
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 2.—Ventricular Size
by Age for Controls and Chronic Schizophrenic Patients* Chronic
Age, yr_Controls_Schizophrenics 30, 40,
Fig 3.—Correlation of ventricular brain ratio (VBR) with length of inpatient hospital stay for chronic schizophrenic patients (Pear¬ son r .05; nonsignificant).
IO
=
5
Fig 2.—Correlation
IO I5 20 YEARS OF ILLNESS
25
30
of ventricular brain ratio (VBR) with illness for chronic schizophrenic patients (Pearson
nonsignificant).
=
length
of
.21;
r —
nonschizophrenic patients are further evidence against a primary role for these factors. The mean length of illness in years ± SD is 10.6 ± 7.7 for the 58 chronic schizophren¬ ics, whereas the four nonschizophrenics had a mean length of 11.2 ± 5.3. The mean length of hospital stay was 6.5 ± 7.1 years for the chronic schizophrenics, and it was 7.9 ± 5.6 years for the four nonschizophrenics. These intergroup comparisons were nonsignificant (Mann-Whitney U Test). Thus, the lengths of illness and hospitalization for the nonschizophrenics are considerable and not significant¬ ly different from those for the chronic schizophrenics. A history of electroshock therapy (EST) is associated with larger ventricles. The 16 patients who had received EST had larger ventricles (9.9 ± 5.2) than the 57 patients who had not (7.5 ± 3.3) (P < .04). However, EST does not account for the ventricular enlargement seen in the chronic schizophrenic patients. When the chronic schizophrenic patients with a history of EST are excluded and the remaining (44 patients, 7.9 ± 3.3) are compared with controls, the high degree of statistical significance persists (P < .0001). Within one year of their scans, 19 patients had completed WAIS testing. These were all performed as part of a routine evaluation and not as follow-up for suggested deficits. Table 3 gives the results of this testing. On all WAIS subtests, as well as the full scale, chronic schizo¬ phrenic patients performed significantly worse than the other patients. Among the chronic schizophrenic patients, no significant correlation could be demonstrated by linear regression analysis for any WAIS subtest and ventricular size.
Other Patients.—The acute and subacute schizophrenic patients have been grouped together in Fig 1 because they are small in number and because they do not differ significantly with respect to ventricular size (P .1, Mann-Whitney U Test). Comparing this combined group to controls, however, may be misleading because only the subacute patients differ significantly from the control subjects (Mann-Whitney U Test, < .004). Neither the schizoaffective nor the nonschizophrenic patients had significantly larger ventricles than the control subjects.
COMMENT
This investigation demonstrates that lateral cerebral ventricular enlargement is associated with chronic schiz¬ ophrenia. Ventricular size, determined quantitatively from CT scans, is significantly greater in the chronic schizo¬ phrenic patients than in the asymptomatic control subjects. This finding challenges the widely held belief that structural brain abnormalities do not occur in schiz¬ ophrenia and demands careful interpretation and further research. The etiology and clinical importance of this finding are unknown. Since the data do not differentiate between cause and association, it is important to consider the possibility that ventricular enlargement may relate not to the illness but to its treatment.
Impact
of Treatment
Institutionalization.—Chronic institutionalization could lead to ventricular enlargement if it predis¬ posed patients to malnutrition, intercurrent infections, metabolic deficiency states, or other stigmata of neglect. Although prospective studies are needed to evaluate this possibility conclusively, the present investigation found no support for it. None of the patients in this study had been confined to so-called back wards and neglected. None were clinically malnourished or suffering from other major illnesses. More importantly, the length of hospitalization did not correlate significantly with ventricular size. Medication.—Neuroleptic medication is another impor¬ tant part of the treatment of chronic schizophrenia that
theoretically
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 3.—Wechsler Adult
Results*
Intelligence Scale IQ Scores
±
enlargement in schizophrenia, were suited to investigate the effects of EST. Of the five studies2·28- '" that ventricular
compared ventricular size in treated patients, four2M·'-'" found no difference.
SO
and untreated
"
Group_
FullScale
Verbal
Performance
(V)
(P)
V
-
Brain
Chronic schiz¬
ophrenics (N 14) =
Other patients
(N
=
5)
78.4 ±17.4 83.1
±
106.8 ±12.3 109.0
±
•For all group comparison,
Weinberger, MD;
E. Fuller
\s=b\ To investigate if cerebral ventricular enlargement is associated with chronic schizophrenia, computerized tomography scans from 73 psychiatric patients were compared with 56 asymptomatic volunteers all less than 50 years old. Ventricular size was significantly greater in the subgroup of 58 chronic schizophrenic patients than in the controls. Of the chronic schizophrenic patients, 40% were outside the control range; 53% exceeded 2 SDs of the control mean. Neither duration of illness nor length of hospitalization correlated with ventricular size. The 44 chronic schizophrenic patients who had never been treated with electroshock therapy (EST) had larger ventricles than controls. A group of seven nonchronic schizophrenic patients also had enlarged ventricles; the eight patients who were either schizoaffective or nonschizophrenic did not differ from controls. This study shows that lateral cerebral ventricular enlargement is associated with chronic schizophrenia; it suggests that this is not a result of treatment.
(Arch
Gen
Torrey, MD; Andreas
observation that some chronic schizophrenic have enlarged cerebral ventricles dates back at least 50 years to Jacobi and Winkler,1 who evaluated 19 patients with pneumoencephalography and diagnosed "in¬ ternal hydrocephalus" in all but one. In more than 30 other pneumoencephalography studies of schizophrenic patients, cases of ventricular enlargement were found. Huag2 and Bliss3 have briefly reviewed some of this extensive but relatively ignored literature. This pneumoencephalography finding, however, has been difficult to interpret because most of these studies used biased patient selection, inade¬ quate controls, unspecified or nonuniform diagnostic crite¬ ria, and inadequately validated standards for normal ventricular size. In addition, changes in ventricular morphology may result from the pneumoencephalography procedure itself.' '
Postmortem neuropathological studies, primarily during the first half of the century, failed to confirm ventricular enlargement and led to the widely held notion that struc¬ tural brain changes do not occur in schizophrenia. Recent studies, however, have shown that cerebral ventricles usually are smaller at autopsy than during life."7 Agonal premortem events, coincident illnesses, edema, and post¬ mortem extraction and fixation procedures all may obscure premortem ventricular enlargement, especially if such
Accepted for publication April 20, 1979. From the Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program (Drs Weinberger, Torrey, and Wyatt), National Institute of Mental Health, St Elizabeths Hospital, Washington, DC, and the Department of Neurology (Dr Neophytides), New York University School of Medicine, New York. Reprint requests to William A. White Bldg, Room 536, National Institute of Mental Health, St Elizabeths Hospital, Washington, DC 20032 (Dr Weinberger).
Neophytides, MD; Richard Jed Wyatt, MD
enlargement is only modest." The advent of computerized tomography (CT)
intro¬ duced a noninvasive and more reliable method of assessing ventricular morphology during life.*" In the only other controlled study of schizophrenic patients evaluated by this method, larger ventricles were found in 17 chronically institutionalized patients as compared with eight normal controls."'" This finding has been questioned, however, because of the small control group, the advanced age of the patients (mean age, 58 years), possible effects of prolonged institutionalization (mean number of inhospital years, 32), and possible effects of somatic treatment (eg, drugs and EST).12·*· The present study was designed to answer some of these questions. SUBJECTS AND METHODS Patients
Psychiatry 36:735-739, 1979)
Thepatients
N.
Seventy-three psychiatric inpatients and recently discharged outpatients in treatment at St Elizabeths Hospital, Washington, DC, had CT scans. The patients were either volunteers in a clinical research division or patients from a general adult psychiatric unit that serves a designated catchment area. Only patients younger than age 50 years were asked to participate. The nature of the procedure was described and consent was obtained. Of 41 patients on the research wards during the six-month study period, 38 consented and cooperated with the procedure. Of 50 available patients in the general psychiatric unit, 35 consented and cooper¬ ated.
Diagnosis was determined by the ward psychiatrist prior to the CT scan, using Research Diagnostic Criteria (RDC)." The diag¬ noses fell into the following categories: 65 cases of schizophrenia; four of schizoaffective disorder; and three of affective disorder. One patient's condition was diagnosed as being mental retarda¬ tion (etiology unknown). The schizophrenic cases were then cate¬ gorized by course of illness as follows: acute (present episode, including onset period, of less than six months' duration, with complete recovery from previous episodes) (three patients); subacute (present episode of less than one year's duration, with complete recovery from previous episodes) (four patients); subchronic (present episode of less than two years' duration or incomplete recovery from prior episodes) (16 patients); and chronic (more than two years of continuous illness) (42 patients). Length of illness, defined as current age minus the age of onset, and years spent living on a psychiatric inpatient ward were also determined. All schizophrenic patients, except for the acute ones, also met the criteria for schizophrenia proposed by Feighner et al." No patients had evidence of a neurological disorder except for two with oral-facial dyskinesia thought to be drug-induced. A complete blood cell count, VDRL, and laboratory studies to determine the values for total protein, albumin, calcium, phosphorus, cholesterol, glucose, BUN, uric acid, creatinine, total bilirubin, alkaline phosphatase, and SGOT, and a urinalysis were performed at least once within a year of the scan for each patient, and the results were either negative or within normal limits. The research patients had
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 1—Ventricular Sizes for Control
Subjectst Age, yr* 20-29 30-39 40-49 Total population
3.1 4.1
±
3.8 3.5
±
±
±
Present 2.2 (
( 2.0(N 2.3 (N
2.6
=
=
=
=
28) 17) 11) 56)
area by the intracranial area and multiplying by 100 produces a ventricular brain ratio (VBR). This method for deter¬ mining ventricular size was used because it has been shown to correlate well with computer-derived ventricular volume.18 Linear measurements (eg, Evans' ratio1" or Huckman's measure2") were not used because they correlate poorly with ventricular volume and are less reliable."'2'-'2 Expressing ventricular size as a ratio controls for magnification variance and provides a simple numer¬ ical value. To assess reliability, the same evaluator selected ten scans of varied ventricular size for repeated measurement at a later date. The correlation coefficient for original and repeated measures was 0.98. The mean difference in absolute magnitude was 0.7 VBR units (range, 0.06 to 1.29). Except where stated, all statistical tests for significance were two-tailed t tests.
ventricular
Groups
Barren et al" 3.1 ± 0.6 ( 15) 4.2 ± 0.8 ( 15) 4.4 ± 0.8 (N 15) 3.9 ± 0.9 (N = 45) =
=
=
*Age factor for present controls nonsignificant (one-way analysis variance). fVentricular size expressed by mean ventricular brain ratio ±SD.
of
RESULTS Control Subjects
20
I5
• I0
V
.St.
I ACUTE AND
SUBACUTE
L-SCHIZOPHRENICSUBJECTS
SCHIZ0- OTHER
AFFECTIVES
Fig 1 —Ventricular size for control subjects and patients grouped by diagnosis. Bar represents mean ventricular brain ratio (VBR) ±SD. Asterisk indicates comparison to control group (P < .006) (Mann-Whitney U Test); double asterisk, comparison to control group
The VBRs for the control group categorized by age are in Table 1. Age is not a significant determinant of ventricular size in this group. In Table 1, this group is compared with the one published by Barron et al," the only other series of asymptomatic volunteers evaluated by the same method. Ventricular size does not differ significantly between these groups. The values for normal ventricular size agree with results from the four other studies2427 that used comparable methods but "symptomatic" normals; however, the present control group defines a slightly broader normal range. It is possible that finding some subjects with ventricles larger than those seen in other studies of normals results from the inclusion of some
given
subjects with preclinical Huntington's disease. Patients
(P < .0001).
following factors were not significant determinants of patient ventricular size: race, sex, patient location (ie, whether research or general psychiatric patients), and history of alcohol abuse (six patients). The difference in VBR between patients with a diagnosis of chronic schiz¬ ophrenia (N 42, mean VBR ± SD 8.9 ± 4.0) and subchronic schizophrenia (N 16, mean VBR ± SD 8.1 ± 3.4) was not statistically significant; therefore, The
thyroid function tests whose results were also normal. The results of Wechsler Adult Intelligence Scale (WAIS) testing done within one year e-f the CT scan were available for 19 patients. Control
Subjects
The control group consisted of 56 healthy, asymptomatic volun¬ teers less than 50 years of age who had undergone head CT scanning for other research projects at the National Institutes of Health, Washington, DC. Forty-eight had first-degree relatives with Huntington's disease but had no clinical manifestations of the illness themselves. The remaining eight were volunteers between the ages of 40 and 50 years who were free of similar genetic risk. By linear measurements (according to the method of Enzmann and Lane'"), the CT scans of the control group could not be differentiated from those of a group of normal volunteer subjects with no known genetic risk for Huntington's disease."
Methods 160 head scanner at All CT scans were performed with a 160 the National Institutes of Health. A minimum of eight and a maximum of 12 cuts were taken for each subject; most scans consisted of ten to 12. The CT slice showing the ventricles at their largest (through the body of the lateral ventricles in all except five controls where the body of the lateral ventricles was not visible) was selected for each subject. The chosen cuts, in the form of either self-developing prints or transparent film, were coded and mixed randomly for blind measurement. One person, using a fixed-arm planimeter, measured the area of the lateral ventricles and the area of the intracranial space in each cut. This involved tracing the perimeter of the lateral ventricles and the inner table of the skull, respective¬ ly. The instrument determines area by mechanical integration. Each area was traced five times and the mean used. Dividing the
=
-
=
=
these groups were combined and are hereafter referred to as the chronic schizophrenic patients. Figure 1 illustrates the distribution of ventricular size for diagnostic groups and controls. Chronic Schizophrenics.—The difference in ventricular size between chronic schizophrenic patients and control subjects is highly significant (P < .0001, Fig 1). Of the chronic schizophrenics, 23 (40%) are outside the control range; 31 (53%) are beyond 2 SDs of the control mean. This level of significance holds for each decade compared indi¬ vidually; age, itself, is not a significant factor in ventricu¬ lar size for this group of chronic schizophrenic patients (Table 2). The distribution of VBR values does not differ significantly from a Gaussian distribution ( 2 11.3, =
df= 7).
Ventricular size does not correlate significantly with either length of illness (Fig 2) or duration of hospitaliza¬ tion (Fig 3). Of the chronic schizophrenic patients, 13 were ill for less than five years (mean VBR ± SD 8.0 ± 4.0); ten were ill for more than 20 years (mean VBR 10.0 ± 4.6). Ventricular size does not differ sig¬ ± SD nificantly between these groups. Comparisons of years of illness and hospitalization for the chronic schizophrenic and =
=
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 2.—Ventricular Size
by Age for Controls and Chronic Schizophrenic Patients* Chronic
Age, yr_Controls_Schizophrenics 30, 40,
Fig 3.—Correlation of ventricular brain ratio (VBR) with length of inpatient hospital stay for chronic schizophrenic patients (Pear¬ son r .05; nonsignificant).
IO
=
5
Fig 2.—Correlation
IO I5 20 YEARS OF ILLNESS
25
30
of ventricular brain ratio (VBR) with illness for chronic schizophrenic patients (Pearson
nonsignificant).
=
length
of
.21;
r —
nonschizophrenic patients are further evidence against a primary role for these factors. The mean length of illness in years ± SD is 10.6 ± 7.7 for the 58 chronic schizophren¬ ics, whereas the four nonschizophrenics had a mean length of 11.2 ± 5.3. The mean length of hospital stay was 6.5 ± 7.1 years for the chronic schizophrenics, and it was 7.9 ± 5.6 years for the four nonschizophrenics. These intergroup comparisons were nonsignificant (Mann-Whitney U Test). Thus, the lengths of illness and hospitalization for the nonschizophrenics are considerable and not significant¬ ly different from those for the chronic schizophrenics. A history of electroshock therapy (EST) is associated with larger ventricles. The 16 patients who had received EST had larger ventricles (9.9 ± 5.2) than the 57 patients who had not (7.5 ± 3.3) (P < .04). However, EST does not account for the ventricular enlargement seen in the chronic schizophrenic patients. When the chronic schizophrenic patients with a history of EST are excluded and the remaining (44 patients, 7.9 ± 3.3) are compared with controls, the high degree of statistical significance persists (P < .0001). Within one year of their scans, 19 patients had completed WAIS testing. These were all performed as part of a routine evaluation and not as follow-up for suggested deficits. Table 3 gives the results of this testing. On all WAIS subtests, as well as the full scale, chronic schizo¬ phrenic patients performed significantly worse than the other patients. Among the chronic schizophrenic patients, no significant correlation could be demonstrated by linear regression analysis for any WAIS subtest and ventricular size.
Other Patients.—The acute and subacute schizophrenic patients have been grouped together in Fig 1 because they are small in number and because they do not differ significantly with respect to ventricular size (P .1, Mann-Whitney U Test). Comparing this combined group to controls, however, may be misleading because only the subacute patients differ significantly from the control subjects (Mann-Whitney U Test, < .004). Neither the schizoaffective nor the nonschizophrenic patients had significantly larger ventricles than the control subjects.
COMMENT
This investigation demonstrates that lateral cerebral ventricular enlargement is associated with chronic schiz¬ ophrenia. Ventricular size, determined quantitatively from CT scans, is significantly greater in the chronic schizo¬ phrenic patients than in the asymptomatic control subjects. This finding challenges the widely held belief that structural brain abnormalities do not occur in schiz¬ ophrenia and demands careful interpretation and further research. The etiology and clinical importance of this finding are unknown. Since the data do not differentiate between cause and association, it is important to consider the possibility that ventricular enlargement may relate not to the illness but to its treatment.
Impact
of Treatment
Institutionalization.—Chronic institutionalization could lead to ventricular enlargement if it predis¬ posed patients to malnutrition, intercurrent infections, metabolic deficiency states, or other stigmata of neglect. Although prospective studies are needed to evaluate this possibility conclusively, the present investigation found no support for it. None of the patients in this study had been confined to so-called back wards and neglected. None were clinically malnourished or suffering from other major illnesses. More importantly, the length of hospitalization did not correlate significantly with ventricular size. Medication.—Neuroleptic medication is another impor¬ tant part of the treatment of chronic schizophrenia that
theoretically
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
Table 3.—Wechsler Adult
Results*
Intelligence Scale IQ Scores
±
enlargement in schizophrenia, were suited to investigate the effects of EST. Of the five studies2·28- '" that ventricular
compared ventricular size in treated patients, four2M·'-'" found no difference.
SO
and untreated
"
Group_
FullScale
Verbal
Performance
(V)
(P)
V
-
Brain
Chronic schiz¬
ophrenics (N 14) =
Other patients
(N
=
5)
78.4 ±17.4 83.1
±
106.8 ±12.3 109.0
±
•For all group comparison,
