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5. Cerebral ventricular abnormalities in schizophrenia: Evidence of their early origin and stability over time
189 criteria for schizophrenia (26 M. 21 F. mean age 35.3+ 12.3, range 20-65) consented to MRI. using a Slemens magnetom (1.5 T). as previously described (Waddington et al., 1990): resultant images were evaluated qualitatively by a MR neuroradiologist ‘blind’ to subject status. and total lateral ventricular volume was computed for those SubJccts having contiguous 0.6 cm axial sl~ccs through the ventricular system In 45 schizophremc patients. ventricular volume exceeded that In 22 controls (14.4Ok9.98 vs. 10.X2+8.64 ml. respectively: + 33%. P< 0.05. Mann-Whitney 1: tat). and this was especially eLident in young males under the age of 30 (13.22~5.28 ml. II= I5 \s. 6.41 i3.90 ml. ,I= 5: +91”/0. P45: P
iic,Xrlol~./~,cl~c,r?~cn/.This wsork was supported of God Order.
by the St. John
Jorgensen, 0,s.. Brooksbank. B.W. and Balazs. R. (1990) Neuronal plasticity and astrocytic reaction m Down syndrome and Allheimer disease. J. Neural. Sci. 9X. 63 79. Murra]. R.M. and Lewis. S.W. (1987) Is schizophrenia a neurodcvelopmental disorder’! Br. Med. J. 295. 6X I -6X2. O’Callaghan. E.. Larkin, C.. Kinsclla. A. and Waddington, J.L. (1991) Familial. obstetric and other clinical correlates of minor physical anomalics in schizophrenia. Am. J. Psychiatry. in press. Waddington. J.L. and Torrey. E.F. (1991) Schizophrenia, neurodevclopment and disease. Proc. Fifth Biannual Winter Workshop. Arch. Gen. Psychiatry. in press. Waddington. J.L., O’Callaghan. E. and Larkin. C. (198X) Premorbid neuropathology in schizophrema. Lancet ii. 959-960. Waddington. J.L.. O’Callaghan, E.. Larkin. C.. Redmond. 0.. Stack, J. and Ennis. J.T. (1990) Magnetic resonance imaging and spectroscopy In schizophrenia. Br. J. Psychiatry I57 (suppl. 9). 56-65. Weinberger. D.R. (1987) Implications of normal brain developmcnt for the pathogenesis of schizophrenia. Arch. Gcn. Psychiatry 44. 660-669
5. CEREBRAL VENTRICULAR ABNORMALITIES IN SCHIZOPHRENIA: EVIDENCE OF THEIR EARLY ORIGIN AND STABILITY OVER TIME A. Vita
Enlargement of the lateral cerebral ventricles has been consIstently found in schizophrenic patients (for a review see Coffman, 1989). but the pathophysiological signifcance of this abnormality 1s not completely understood. The specification of the timing of appearance and course of the structural brain change would improve our knowledge of the nature. whether developmental or degenerative. and of the underlying neuropathological process. Our research findings suggest an early origin and stability of the ventricular abnormalities in schizophrenia. Cross .~~~/ionnl &trr. (a) Among 199 patients with a diagnosis of schizophrenia according to the DSM-III criteria who had undergone computed tomography of the brain we found that ventricular size (measured by manual planimetry and expressed as ventricular-bran-ratio (VBR) (Synek and Reuben. 1976) was not correlated to patients’ age (mean=26.6*6.9) and duration of schizophrenic illness (mean = 6.2 k 5.2 years) (both p>O.l) (b) Ventricular size did not differ between patients with ‘early schizophrenia’ (defined as patients who had been
190 TABLE
5.1
Varirthle
VBR increuvr (n=Y)
No incrmse in= 12)
Te.st
P
Sex (M/F) Age (years) Duration of illness (y) Age at onset (y) FH (ii-)” oc (+:l-)h Symptoms at onset (posneg)’ Response to neuroleptics ( + :I- )“ VBR at 1st scan Cortical atrophy ( + )I~ )’
7,‘2 25.7i6.2 6.6 * 3.9 19.1 i3.2 2’7 4:4 6.1 0:8 6.3 & 3.4 4;5
1:5 25.6& 5.8 4.3i4.1 21.214.3 4:7 I,11 5,6 7,4 4.8k3.7 9.3
Fisher / I / Fisher Fisher Fisher Fisher I Fisher
NS NS NS NS NS 0.06 NS 0.006 NS NS
“Family history for schizophrenic disorder in 1st degree relatives. ‘Obstetric complication, rated as present;absent. ‘Symptoms prevalent at the disease onset. dConsidered in a 1 year clinical follow-up as a significant decrease over time of BPRS scores. ‘Rated as present (scores 2-3) or absent (scores 0-I) on a four-point visual scale.
ill for a period of 6612 months since the first psychotic symptoms) (n = 3 I) and patients with chronic schizophrema (more than 2 years of illness) (n= 137). The mean VBR and incidence of ventricular enlargement were respectively 5.53 & 2.7 and 5.44k2.8 (r=0.20,p=NS). and 26% and 23%. (c) Ventricular enlargement was also found, with similar incidence. in patients with first episode schizophreniform disorder (19 men and 10 women: age range 16-41). The mean VBR of the 29 cases analyzed was 5.96 + 2.8 and ventricular enlargement was found in 9 (3 I %) of them. Longitudinul dara. 21 patients (14 males, 7 females: age range I8842 years) had a second CT scan after a time ranging from 20 to I08 months (mean 43.8k20.9 months) since the initial scan. The first and second scan were mixed. coded and analyzed ‘in blind’ by two raters. The mean VBR at baseline was 5.4613.66. that at follow-up 5.5023.74 (paired r=0.041, p= NS) with a high I.C.C. between the two measures (rzO.936). There was no overall variation of VBR values over a period of 2-8 years in our schizophrenic sample, but some patients showed an increase in VBR. We compared such increase to that expected in normal individuals of the same age and after the same age interval. We evaluated 131 healthy subjects (70 men. 61 women. age range 13-93) who underwent CT scan for minor accidental head trauma without loss of consciousness for normative data (no history of alcohol or drug abuse. neurological or psychiatric disorder. recent steroid intake or weight loss). The age-VBR relationship fitted a curvilinear model (y = ox+ hx’ + c) with ventricular size progressively enlargmg starting from age 50. The equation for the curve was VBR= age x (~O.l1718)+age2 x (0.00218)+4.7559. The 95% confidence limits of the curve provided our limit of normality for each year of age. Nine of our patients showed a VBR increase higher than expected but the mean excess of VBR increase. year was only 0.34kO.20 VBR units.
The comparison of the available anamnestic, clinical and CT characteristics of patients with and without VBR increase (as previously defined) is presented in Table 5. I. In line with the results from other groups (Nyback et al.. 1982: Weinberger et al.. 1982; Nasrallah et al., 1986: Turner et al., 1986). the whole of our cross-sectional and longitudinal studies indicates that VE is not likely to be a secondary change due to chronicity or treatment in schizophrenia, but may be a primary and early anomaly, probably predating its overt clinical onset, and stable over time. These findings are compatible with the hypothesis of a neurodevelopmental nature of the brain pathologic process underlymg the CT finding of ventricular enlargement in schizophrenia.
Coffman. J.A. (1989) Computed tomography. In: N.C. Andreasen (Ed.), Brain Imaging: Application in Psychiatry. A.P.A. Press, Washington, DC. pp. l-65. Nasrallah. H.A.. Olson. SC.. McCallay-Whitters. M.. et al. (1986) Cerebral ventricular size in schtzophrenia. A prelimtnary follow-up study. Arch. Gen. Psychiatry 43. 157- 159. Nyback. H.. Wiesel, F.A.. Berggren. B.M.. et al. (1982) Computed tomography of the brain in patients with acute psychosis and healthy volunteers. Acta Psychiatr. Stand. 65. 403-414. Synek, V. and Reuben, J.R. (1976) The ventricular brain ratio using planimetric measurement of EM1 scans. Br. J. Radiol. 49, 233-237. Turner, S.W., Toone, B.K. and Brett-Jones, J.R. (1986) Computed tomographic scan changes in early schizophrenia. Preliminary findings. Psychol. Med. 16, 219. Weinberger. D.R.. DeLisi. L.E., Perman, G.P., et al. (1982) Computed tomography in schizophreniform disorder and other acute psychiatric disorders. Arch. Gen. Psychtatry 39. 7788783.
iic,Xrlol~./~,cl~c,r?~cn/.This wsork was supported of God Order.
by the St. John
Jorgensen, 0,s.. Brooksbank. B.W. and Balazs. R. (1990) Neuronal plasticity and astrocytic reaction m Down syndrome and Allheimer disease. J. Neural. Sci. 9X. 63 79. Murra]. R.M. and Lewis. S.W. (1987) Is schizophrenia a neurodcvelopmental disorder’! Br. Med. J. 295. 6X I -6X2. O’Callaghan. E.. Larkin, C.. Kinsclla. A. and Waddington, J.L. (1991) Familial. obstetric and other clinical correlates of minor physical anomalics in schizophrenia. Am. J. Psychiatry. in press. Waddington. J.L. and Torrey. E.F. (1991) Schizophrenia, neurodevclopment and disease. Proc. Fifth Biannual Winter Workshop. Arch. Gen. Psychiatry. in press. Waddington. J.L., O’Callaghan. E. and Larkin. C. (198X) Premorbid neuropathology in schizophrema. Lancet ii. 959-960. Waddington. J.L.. O’Callaghan, E.. Larkin. C.. Redmond. 0.. Stack, J. and Ennis. J.T. (1990) Magnetic resonance imaging and spectroscopy In schizophrenia. Br. J. Psychiatry I57 (suppl. 9). 56-65. Weinberger. D.R. (1987) Implications of normal brain developmcnt for the pathogenesis of schizophrenia. Arch. Gcn. Psychiatry 44. 660-669
5. CEREBRAL VENTRICULAR ABNORMALITIES IN SCHIZOPHRENIA: EVIDENCE OF THEIR EARLY ORIGIN AND STABILITY OVER TIME A. Vita
Enlargement of the lateral cerebral ventricles has been consIstently found in schizophrenic patients (for a review see Coffman, 1989). but the pathophysiological signifcance of this abnormality 1s not completely understood. The specification of the timing of appearance and course of the structural brain change would improve our knowledge of the nature. whether developmental or degenerative. and of the underlying neuropathological process. Our research findings suggest an early origin and stability of the ventricular abnormalities in schizophrenia. Cross .~~~/ionnl &trr. (a) Among 199 patients with a diagnosis of schizophrenia according to the DSM-III criteria who had undergone computed tomography of the brain we found that ventricular size (measured by manual planimetry and expressed as ventricular-bran-ratio (VBR) (Synek and Reuben. 1976) was not correlated to patients’ age (mean=26.6*6.9) and duration of schizophrenic illness (mean = 6.2 k 5.2 years) (both p>O.l) (b) Ventricular size did not differ between patients with ‘early schizophrenia’ (defined as patients who had been
190 TABLE
5.1
Varirthle
VBR increuvr (n=Y)
No incrmse in= 12)
Te.st
P
Sex (M/F) Age (years) Duration of illness (y) Age at onset (y) FH (ii-)” oc (+:l-)h Symptoms at onset (posneg)’ Response to neuroleptics ( + :I- )“ VBR at 1st scan Cortical atrophy ( + )I~ )’
7,‘2 25.7i6.2 6.6 * 3.9 19.1 i3.2 2’7 4:4 6.1 0:8 6.3 & 3.4 4;5
1:5 25.6& 5.8 4.3i4.1 21.214.3 4:7 I,11 5,6 7,4 4.8k3.7 9.3
Fisher / I / Fisher Fisher Fisher Fisher I Fisher
NS NS NS NS NS 0.06 NS 0.006 NS NS
“Family history for schizophrenic disorder in 1st degree relatives. ‘Obstetric complication, rated as present;absent. ‘Symptoms prevalent at the disease onset. dConsidered in a 1 year clinical follow-up as a significant decrease over time of BPRS scores. ‘Rated as present (scores 2-3) or absent (scores 0-I) on a four-point visual scale.
ill for a period of 6612 months since the first psychotic symptoms) (n = 3 I) and patients with chronic schizophrema (more than 2 years of illness) (n= 137). The mean VBR and incidence of ventricular enlargement were respectively 5.53 & 2.7 and 5.44k2.8 (r=0.20,p=NS). and 26% and 23%. (c) Ventricular enlargement was also found, with similar incidence. in patients with first episode schizophreniform disorder (19 men and 10 women: age range 16-41). The mean VBR of the 29 cases analyzed was 5.96 + 2.8 and ventricular enlargement was found in 9 (3 I %) of them. Longitudinul dara. 21 patients (14 males, 7 females: age range I8842 years) had a second CT scan after a time ranging from 20 to I08 months (mean 43.8k20.9 months) since the initial scan. The first and second scan were mixed. coded and analyzed ‘in blind’ by two raters. The mean VBR at baseline was 5.4613.66. that at follow-up 5.5023.74 (paired r=0.041, p= NS) with a high I.C.C. between the two measures (rzO.936). There was no overall variation of VBR values over a period of 2-8 years in our schizophrenic sample, but some patients showed an increase in VBR. We compared such increase to that expected in normal individuals of the same age and after the same age interval. We evaluated 131 healthy subjects (70 men. 61 women. age range 13-93) who underwent CT scan for minor accidental head trauma without loss of consciousness for normative data (no history of alcohol or drug abuse. neurological or psychiatric disorder. recent steroid intake or weight loss). The age-VBR relationship fitted a curvilinear model (y = ox+ hx’ + c) with ventricular size progressively enlargmg starting from age 50. The equation for the curve was VBR= age x (~O.l1718)+age2 x (0.00218)+4.7559. The 95% confidence limits of the curve provided our limit of normality for each year of age. Nine of our patients showed a VBR increase higher than expected but the mean excess of VBR increase. year was only 0.34kO.20 VBR units.
The comparison of the available anamnestic, clinical and CT characteristics of patients with and without VBR increase (as previously defined) is presented in Table 5. I. In line with the results from other groups (Nyback et al.. 1982: Weinberger et al.. 1982; Nasrallah et al., 1986: Turner et al., 1986). the whole of our cross-sectional and longitudinal studies indicates that VE is not likely to be a secondary change due to chronicity or treatment in schizophrenia, but may be a primary and early anomaly, probably predating its overt clinical onset, and stable over time. These findings are compatible with the hypothesis of a neurodevelopmental nature of the brain pathologic process underlymg the CT finding of ventricular enlargement in schizophrenia.
Coffman. J.A. (1989) Computed tomography. In: N.C. Andreasen (Ed.), Brain Imaging: Application in Psychiatry. A.P.A. Press, Washington, DC. pp. l-65. Nasrallah. H.A.. Olson. SC.. McCallay-Whitters. M.. et al. (1986) Cerebral ventricular size in schtzophrenia. A prelimtnary follow-up study. Arch. Gen. Psychiatry 43. 157- 159. Nyback. H.. Wiesel, F.A.. Berggren. B.M.. et al. (1982) Computed tomography of the brain in patients with acute psychosis and healthy volunteers. Acta Psychiatr. Stand. 65. 403-414. Synek, V. and Reuben, J.R. (1976) The ventricular brain ratio using planimetric measurement of EM1 scans. Br. J. Radiol. 49, 233-237. Turner, S.W., Toone, B.K. and Brett-Jones, J.R. (1986) Computed tomographic scan changes in early schizophrenia. Preliminary findings. Psychol. Med. 16, 219. Weinberger. D.R.. DeLisi. L.E., Perman, G.P., et al. (1982) Computed tomography in schizophreniform disorder and other acute psychiatric disorders. Arch. Gen. Psychtatry 39. 7788783.