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Developmental abnormalities and cortical sulcal enlargement in psychosis
SCHIZOPHRENIA RESEARCH ELS EVI ER
SchizophreniaResearch 16 ( 1995) 121-125
,
Developmental abnormalities and cortical sulcal enlargement in psychosis William G. Honer
a,b,, Elizabeth Squires-Wheeler b, Geoffrey N. Smith a, Zafar Sharif b Steve Chan c, George Gewirtz b,c,1
Department of Psychiatry, University of British Columbia, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6 b Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA ~Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA Received 18 April 1994; revised 20 September 1994; accepted 28 September 1994
Abstract
Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities. Keywords: CT scan; Cortical atrophy; Neurodevelopment; Psychosis; (Schizophrenia)
1. Introduction
Epidemiological, clinical, brain imaging and pathological studies have all implicated abnormalities of brain development in the pathogenesis of schizophrenia and possibly bipolar affective disorder (NasraUah, 1991; Nasrallah, 1993; Waddington, 1993b). The 'developmental hypothesis' of these disorders is supported by brain imaging studies which have revealed at least two relevant domains o f pathology (Waddington, 1993a). First, a wide range of abnormalities of brain development such as cavum septum pellutDr. Gewirtzdied on August 19, 1994. We are deeplysaddened to have lost a colleague with such energy, creativity, and devotion to the care of the severelymentally ill. *Corresponding author. Tel: + 1604-875-4827; fax: + 1 604-875-4497. 0920-9964/95/$09.50© 1995 ElsevierScienceB.V. All rights reserved SSDI 0920-9964(94)00070-0
cidum is observed in patients with psychosis (reviewed in Gewirtz et al., 1994; Lewis, 1989 and see also DeLisi et al., 1993; Scott et al., 1993; Wolf et al., 1994). Second, enlargement of the lateral ventricles and reduction in the size of temporal lobe structures were reported to be present at the onset of schizophrenia, and appeared to be both largely non-progressive and unrelated to the duration of illness (Breslin and Weinberger, 1991: Marsh et al., 1994; Pfefferbaum et al., 1988). Although developmental abnormalities and structural pathology may both represent correlates of altered processes of brain development, the relationship between these two domains of pathology is unknown. Since developmental abnormalities are relatively rare, studies of large numbers of patients are required to investigate a possible association with structural pathology. The first purpose
122
V~ G. Honer et al./Schizophrenia Research 16 (1995) 121 125
of the present investigation was to provide further information regarding the range and frequency of developmental brain abnormalities in psychosis. The second objective was to test the hypothesis that the presence of developmental abnormalities would be correlated with cortical sulcal enlargement in patients with schizophrenia.
2. Materials and methods
The patient sample comprised 168 individuals who had received a CT scan for the clinical indication of psychosis (Gewirtz et al., 1994). Four scans revealed unsuspected cerebral infarctions. These were excluded from the present study since vascular disease could have contributed to cortical sulcal enlargement. The remaining 164 patients consisted of 79 males and 85 females. The mean age was 34.4 years (sd 12.0 years, range 18-66 years). The DSM-III-R diagnoses were: schizophrenia 80 (49%), schizophreniform 11 (7%), schizoaffective 22 (13%), bipolar with psychosis 23 (14%), depression with psychosis 14 (9%), delusional disorder 3 (2%), brief reactive psychosis 2 (1%) and psychosis not otherwise specified 9 (5%). Fifteen individuals (9%) had concurrent substance abuse diagnoses. Rates of developmental abnormalities were compared between patients with schizophrenia and patients with all other forms of psychosis, since the sample size for each of the other individual diagnostic groups was small. The neuroradiological reports were reviewed to identify scans with developmental abnormalities and to assess cortical sulcal enlargement (or cortical 'atrophy' as described by radiologists). The reliability of the rating of cortical sulcal enlargement by the neuroradiologists was previously determined to have a kappa statistic value of 0.70 in this sample (Gewirtz et al., 1994). The reliability of describing developmental abnormalities (venous angioma, arachnoid cyst, anomalies of the septum pellucidum, cavum septum pellucidum, cavum vergae, enlarged cisterna magna or superior cerebellar cistern, coarctation of the frontal horn, colloid cyst of the third ventricle, and pineal cyst) was determined in the same series of scans. The reliability of the original report compared to the
review by an independent neuroradiologist was determined to have a kappa statistic value of 0.76. To assess the association between developmental abnormalities and sulcal enlargement, contingency table analysis was performed and the Chi-square statistic was calculated. The potentially confounding effect of increasing age on relationships with sulcal enlargement was investigated with logistic regression analysis. The effect of age was also studied by stratifying the sample (age less than 40 years, or 40 years or more), since the effect of age on frequency of sulcal enlargement in this sample was well described by a step function such that frequency of enlargement increased after age 40 (Gewirtz et al., 1994). Contingency table analysis was then performed to assess the relationship between developmental abnormalities and sulcal enlargement for each age group.
3. Results
Developmental abnormalities were observed in 18 scans (11%). Relative to the remainder of the sample, patients with developmental abnormalities did not differ in age or in gender distribution. The frequency of developmental abnormalities in patients with schizophrenia (10%) did not differ from that in non-schizophrenic psychosis (12%) (Z=0.15, p=0.70). Midline abnormalities were most common (11 scans, 7%), and comprised defects of the septum pellucidum (three cavum septum pellucidum, one coincident cavum vergae), abnormalities of the posterior fossa (two enlarged superior cerebellar cistern, four enlarged cisterna magna), and cysts (one colloid cyst of the third ventricle and one pineal cyst). Coarctation of the frontal horn was observed in five cases (3%). Two arachnoid cysts were described, one in the left temporal lobe, and one in the left occipital lobe. Cortical sulcal enlargement was absent on 99 scans (60%), mild on 62 scans (38%) and moderate on 3 scans (2%). The frequency of sulcal enlargement in patients with schizophrenia (39%) did not differ from that in patients with other psychotic illnesses (Gewirtz et al., 1994). In the overall sample (Table 1), the presence of developmental abnormalities was unrelated to the presence of
W.G. Honer et aL /Schizophrenia Research 16 (1995) 121-125
Table 1 Diffuse cortical sulcal enlargement in CT scans with, and without developmental abnormalities according to age groups Development abnormality
Total sample Present Absent Schizophrenia Present Absent
Age (years)
Cortical sulcal enlargement n (%) None
Mild
Moderate
18-39 40 ÷~ 18-39 40 +a
8 (80) 6 (75) 69 (69) 16 (35)
2 (20) 2 (25) 31 (31) 27 (59)
0 (0) 0 (0) 0 (0) 3 (7)
18-39 40 ÷ 18-39 40 +
5 (71) 1(100) 36 (63) 7 (47)
2 (29) 0 (0) 21 (37) 7 (47)
0 (0) 0 (0) 0 (0) 1 (6)
Significant difference in frequency of cortical sulcal enlargement, abnormality present versus abnormality absent group (~=4.57, p=0.03).
cortical sulcal enlargement (g=2.56, p=0.11). When logistic regression analysis was used to control for the effect of age, the association between developmental abnormalities and sulcal enlargement also failed to demonstrate conventional levels of statistical significance (p=0.06). However, as seen in Table 1, in patients 40 years of age or older the presence of developmental abnormalities was negatively related to the presence of sulcal enlargement (X=4.57, p=0.03). When the patients with schizophrenia were considered separately, developmental abnormalities remained unassociated with sulcal enlargement (X=0.71, p=0.40). Logistic regression analysis indicated a similar result after controlling for age (p = 0.44), as did separate contingency table analyses of the 18-39 and 40 years or over age groups. Exclusion of the patients with concurrent substance abuse did not alter the results significantly.
4. Discussion
The present study is a description of neurodevelopmental abnormalities in psychosis, and their relationship with cortical sulcal enlargement on CT scan. A wide range of developmental abnormalities was observed, and these were equally
123
frequent in patients with schizophrenia and those with other psychotic illnesses. No evidence was found to support the hypothesis that patients with schizophrenia and developmental abnormalities would have more frequent cortical sulcal enlargement. Comparison of the frequency of abnormalities observed here (11%) with other studies is difficult due to differences in the definition of abnormalities. Lewis (1990) described a total of 7 focal congenital abnormalities in two series of 228 and 50 CT scans of patients with schizophrenia, but enlarged fluid spaces such as the cisterna magna or the superior cerebellar cistern were excluded from consideration. In contrast, in the study of Jurjus et al. (1993) the definition of abnormalities was almost exclusively related to enlargement or asymmetry of fluid spaces. As well, the present study used CT which is less sensitive than magnetic resonance imaging to detect developmental abnormalities, particularly in the posterior fossa. However, although present in only a minority of the present scans, several different forms of neurodevelopmental abnormalities were observed. Different abnormalities are believed to originate at different times of intrauterine development, and could provide clues to the timing of events associated with the predisposition to schizophrenia. Midline abnormalities were the most common form of developmental abnormality observed here. Increased rates of midline abnormalities such as cavum septum pellucidum were reported in schizophrenia (Degreef et al., 1992; DeLisi et al., 1993: Scott et al., 1993). Abnormalities such as enlargement of the cisterna magna and superior cerebellar cistern are proposed to occur on a continuum with more severe malformations of the posterior tbssa (Barkovich et al., 1989). Both midline and posterior fossa anomalies may relate to the early ventral induction phase of neural development (Van der Knapp and Valk, 1988). One patient had an arteriovenous malformation. This abnormality also originates early in brain development, likely during the first two to three months (Van der Knapp and Valk, 1988). Timing of the origin of colloid, arachnoid and pineal cysts is uncertain. Coarctation of the frontal horn of the lateral ventricle was observed in several cases, is due to
124
V£ G. Honer et al./Schizophrenia Research 16 (1995) 121 125
adhesion between the ependymal cell layers and may originate in the sixth intrauterine month (Newton and Potts, 1978). The clinical significance of neuroradiological developmental abnormalities in psychosis is uncertain. However, neuroradiological abnormalities may be markers of more subtle abnormalities of development that do have functional implications. As an example, one study indicated that cavum septum pellucidum and cavum vergae were associated with the presence of mental retardation (Miller et al., 1986). In the patients with schizophrenia, there was no association between the presence of developmental abnormalities and cortical sulcal enlargement. This suggests that a unitary mechanism may not be involved in the genesis of sulcal enlargement and developmental abnormalities in schizophrenia. Cortical sulcal enlargement is only one of several changes in brain structure reported in schizophrenia. Other findings, such as ventricular enlargement or reduction in the size of temporal lobe structures could have a different association with developmental abnormalities. However, in a related report on patients with schizophrenia, no association between cavum septum pellucidum and ventricular or temporal lobe size was found (DeLisi et al., 1993). The implication of the negative association between cortical sulcal enlargement and neurodevelopmental abnormalities in older patients in the overall group remains unclear. This result needs to be assessed more thoroughly in larger samples of diagnostically homogeneous groups of patients. Further studies are also required to more completely investigate the relationship between developmental abnormalities and the full range of structural abnormalities in schizophrenia, and to determine the clinical significance of pathology in different domains of brain structure.
Acknowledgements W.G.H. was supported by the Medical Research Council of Canada. Z.S. was supported by the National Alliance for Research on Schizophrenia and Depression. G.G. was supported by a Faculty Scholar Award from the National Institute of
Mental Health. The authors thank Dr. Donald Klein for comments on an earlier version of the manuscript.
References Barkovich, A.J., Kjos, B.O., Norman, D. and Edwards, M.S. (1989) Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging. Am. J. Neuroradiol. 10, 977-988. Breslin, N.A. and Weinberger, D.R., Neurodevelopmental implications of findings from brain imaging studies of schizophrenia, In Mednick SA, Cannon TD, Barr CE, Lyon M (Eds.), Fetal Neural Development and Adult Schizophrenia, Cambridge University Press, Cambridge, 1991, 199-215. Degreef, G., Bogerts, B., Falkai, P., Greve, B., Lantos, G., Ashtari, M. and Lieberman, J. (1992) Increased prevalence of the cavum septum pellucidtun in magnetic resonance scans and post-mortem brains of schizophrenic patients. Psychiatry Res. Neuroimaging 45, 1-13. DeLisi, L.E., Hoff, A.L., Kushner, M. and Degreef, G. (1993) Increased prevalence of cavum septum pellucidum in schizophrenia. Psychiatry Res. Neuroimaging 50, 193-199. Gewirtz, G., Squires-Wheeler, E., Sharif, Z. and Honer, W.G. (1994) Clinical CT scans in psychosis. Br. J. Psychiatry 164, 789-795. Jurjus, G.J., Nasrallah, H.A., Brogan, M. and Olson, S.C. (1993) Developmental brain anomalies in schizophrenia and bipolar disorder: a controlled MRI study. J. Neuropsychiatry Clin. Neurosci. 5, 375-378. Lewis, S.W. (1989) Congenital risk factors for schizophrenia. Psychol. Med. 19, 5-13. Lewis, S.W. (1990) Computerised tomography in schizophrenia 15 years on. Br. J. Psychiatry 157 (suppl 9), 16-24. Marsh, L., Suddath, R.L., Higgins, N. and Weinberger, D.R. (1994) medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophr. Res. 11,225-238. Miller, M.E., Kido, D. and Homer, F. (1986) Cavum vergae: association with neurologic abnormality and diagnosis by magnetic resonance imaging. Arch. Neurol., 43, 821-823. Nasrallah, H.A. (1991 ) Neurodevelopmental aspects of bipolar affective disorder. Biol. Psychiatry 29, 1 2. Nasrallah, H.A. (1993) Neurodevelopmental pathogenesis of schizophrenia. Psychiatric Clin. North America 16, 269-280. Newton, T.H. and Potts, D.G., eds. (1978) Ventricles and Cisterns. Radiology of the Skull and Brain; vol Four, St. Louis: C.V. Mosby, p. 3532. Pfefferbaum, A., Zipursky, R.B., Lira, K.O., Zatz, L.M., Stahl, S.M. and Jeruigan, T.L. (1988) Computed tomographic evidence for generalized sulcal and ventricular enlargement in schizophrenia. Arch. Gen. Psychiatry 45, 633-640. Scott, T.F., Price, T.R.P., George, M.S., Brillman, J. and
V~ G. Honer et al./Schizophrenia Research 16 (1995) 121-125
Rothfus, W. (1993) Midline cerebral malformations and schizophrenia. J. Neuropsychiatry 5, 287-293. Van der Knapp, M. and Valk, J. (1988) Classification of congenital abnormalities of the CNS. Am. J. Neuroradiol. 9, 315-326. Waddington, J.L, (1993a) Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophrenia Bull, 19, 55-69.
125
Waddington, J.L. (1993b) Schizophrenia: developmental neuroscience and pathobiology. Lancet 341,531-536. Wolf, S.S., Hyde, T.M. and Weinberger, D.R. (1994) Malformations of the septum pellucidum: two distinctive cases in association with schizophrenia. J. Psychiatry Neurosci., 19, 140 144.
SchizophreniaResearch 16 ( 1995) 121-125
,
Developmental abnormalities and cortical sulcal enlargement in psychosis William G. Honer
a,b,, Elizabeth Squires-Wheeler b, Geoffrey N. Smith a, Zafar Sharif b Steve Chan c, George Gewirtz b,c,1
Department of Psychiatry, University of British Columbia, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6 b Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA ~Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA Received 18 April 1994; revised 20 September 1994; accepted 28 September 1994
Abstract
Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities. Keywords: CT scan; Cortical atrophy; Neurodevelopment; Psychosis; (Schizophrenia)
1. Introduction
Epidemiological, clinical, brain imaging and pathological studies have all implicated abnormalities of brain development in the pathogenesis of schizophrenia and possibly bipolar affective disorder (NasraUah, 1991; Nasrallah, 1993; Waddington, 1993b). The 'developmental hypothesis' of these disorders is supported by brain imaging studies which have revealed at least two relevant domains o f pathology (Waddington, 1993a). First, a wide range of abnormalities of brain development such as cavum septum pellutDr. Gewirtzdied on August 19, 1994. We are deeplysaddened to have lost a colleague with such energy, creativity, and devotion to the care of the severelymentally ill. *Corresponding author. Tel: + 1604-875-4827; fax: + 1 604-875-4497. 0920-9964/95/$09.50© 1995 ElsevierScienceB.V. All rights reserved SSDI 0920-9964(94)00070-0
cidum is observed in patients with psychosis (reviewed in Gewirtz et al., 1994; Lewis, 1989 and see also DeLisi et al., 1993; Scott et al., 1993; Wolf et al., 1994). Second, enlargement of the lateral ventricles and reduction in the size of temporal lobe structures were reported to be present at the onset of schizophrenia, and appeared to be both largely non-progressive and unrelated to the duration of illness (Breslin and Weinberger, 1991: Marsh et al., 1994; Pfefferbaum et al., 1988). Although developmental abnormalities and structural pathology may both represent correlates of altered processes of brain development, the relationship between these two domains of pathology is unknown. Since developmental abnormalities are relatively rare, studies of large numbers of patients are required to investigate a possible association with structural pathology. The first purpose
122
V~ G. Honer et al./Schizophrenia Research 16 (1995) 121 125
of the present investigation was to provide further information regarding the range and frequency of developmental brain abnormalities in psychosis. The second objective was to test the hypothesis that the presence of developmental abnormalities would be correlated with cortical sulcal enlargement in patients with schizophrenia.
2. Materials and methods
The patient sample comprised 168 individuals who had received a CT scan for the clinical indication of psychosis (Gewirtz et al., 1994). Four scans revealed unsuspected cerebral infarctions. These were excluded from the present study since vascular disease could have contributed to cortical sulcal enlargement. The remaining 164 patients consisted of 79 males and 85 females. The mean age was 34.4 years (sd 12.0 years, range 18-66 years). The DSM-III-R diagnoses were: schizophrenia 80 (49%), schizophreniform 11 (7%), schizoaffective 22 (13%), bipolar with psychosis 23 (14%), depression with psychosis 14 (9%), delusional disorder 3 (2%), brief reactive psychosis 2 (1%) and psychosis not otherwise specified 9 (5%). Fifteen individuals (9%) had concurrent substance abuse diagnoses. Rates of developmental abnormalities were compared between patients with schizophrenia and patients with all other forms of psychosis, since the sample size for each of the other individual diagnostic groups was small. The neuroradiological reports were reviewed to identify scans with developmental abnormalities and to assess cortical sulcal enlargement (or cortical 'atrophy' as described by radiologists). The reliability of the rating of cortical sulcal enlargement by the neuroradiologists was previously determined to have a kappa statistic value of 0.70 in this sample (Gewirtz et al., 1994). The reliability of describing developmental abnormalities (venous angioma, arachnoid cyst, anomalies of the septum pellucidum, cavum septum pellucidum, cavum vergae, enlarged cisterna magna or superior cerebellar cistern, coarctation of the frontal horn, colloid cyst of the third ventricle, and pineal cyst) was determined in the same series of scans. The reliability of the original report compared to the
review by an independent neuroradiologist was determined to have a kappa statistic value of 0.76. To assess the association between developmental abnormalities and sulcal enlargement, contingency table analysis was performed and the Chi-square statistic was calculated. The potentially confounding effect of increasing age on relationships with sulcal enlargement was investigated with logistic regression analysis. The effect of age was also studied by stratifying the sample (age less than 40 years, or 40 years or more), since the effect of age on frequency of sulcal enlargement in this sample was well described by a step function such that frequency of enlargement increased after age 40 (Gewirtz et al., 1994). Contingency table analysis was then performed to assess the relationship between developmental abnormalities and sulcal enlargement for each age group.
3. Results
Developmental abnormalities were observed in 18 scans (11%). Relative to the remainder of the sample, patients with developmental abnormalities did not differ in age or in gender distribution. The frequency of developmental abnormalities in patients with schizophrenia (10%) did not differ from that in non-schizophrenic psychosis (12%) (Z=0.15, p=0.70). Midline abnormalities were most common (11 scans, 7%), and comprised defects of the septum pellucidum (three cavum septum pellucidum, one coincident cavum vergae), abnormalities of the posterior fossa (two enlarged superior cerebellar cistern, four enlarged cisterna magna), and cysts (one colloid cyst of the third ventricle and one pineal cyst). Coarctation of the frontal horn was observed in five cases (3%). Two arachnoid cysts were described, one in the left temporal lobe, and one in the left occipital lobe. Cortical sulcal enlargement was absent on 99 scans (60%), mild on 62 scans (38%) and moderate on 3 scans (2%). The frequency of sulcal enlargement in patients with schizophrenia (39%) did not differ from that in patients with other psychotic illnesses (Gewirtz et al., 1994). In the overall sample (Table 1), the presence of developmental abnormalities was unrelated to the presence of
W.G. Honer et aL /Schizophrenia Research 16 (1995) 121-125
Table 1 Diffuse cortical sulcal enlargement in CT scans with, and without developmental abnormalities according to age groups Development abnormality
Total sample Present Absent Schizophrenia Present Absent
Age (years)
Cortical sulcal enlargement n (%) None
Mild
Moderate
18-39 40 ÷~ 18-39 40 +a
8 (80) 6 (75) 69 (69) 16 (35)
2 (20) 2 (25) 31 (31) 27 (59)
0 (0) 0 (0) 0 (0) 3 (7)
18-39 40 ÷ 18-39 40 +
5 (71) 1(100) 36 (63) 7 (47)
2 (29) 0 (0) 21 (37) 7 (47)
0 (0) 0 (0) 0 (0) 1 (6)
Significant difference in frequency of cortical sulcal enlargement, abnormality present versus abnormality absent group (~=4.57, p=0.03).
cortical sulcal enlargement (g=2.56, p=0.11). When logistic regression analysis was used to control for the effect of age, the association between developmental abnormalities and sulcal enlargement also failed to demonstrate conventional levels of statistical significance (p=0.06). However, as seen in Table 1, in patients 40 years of age or older the presence of developmental abnormalities was negatively related to the presence of sulcal enlargement (X=4.57, p=0.03). When the patients with schizophrenia were considered separately, developmental abnormalities remained unassociated with sulcal enlargement (X=0.71, p=0.40). Logistic regression analysis indicated a similar result after controlling for age (p = 0.44), as did separate contingency table analyses of the 18-39 and 40 years or over age groups. Exclusion of the patients with concurrent substance abuse did not alter the results significantly.
4. Discussion
The present study is a description of neurodevelopmental abnormalities in psychosis, and their relationship with cortical sulcal enlargement on CT scan. A wide range of developmental abnormalities was observed, and these were equally
123
frequent in patients with schizophrenia and those with other psychotic illnesses. No evidence was found to support the hypothesis that patients with schizophrenia and developmental abnormalities would have more frequent cortical sulcal enlargement. Comparison of the frequency of abnormalities observed here (11%) with other studies is difficult due to differences in the definition of abnormalities. Lewis (1990) described a total of 7 focal congenital abnormalities in two series of 228 and 50 CT scans of patients with schizophrenia, but enlarged fluid spaces such as the cisterna magna or the superior cerebellar cistern were excluded from consideration. In contrast, in the study of Jurjus et al. (1993) the definition of abnormalities was almost exclusively related to enlargement or asymmetry of fluid spaces. As well, the present study used CT which is less sensitive than magnetic resonance imaging to detect developmental abnormalities, particularly in the posterior fossa. However, although present in only a minority of the present scans, several different forms of neurodevelopmental abnormalities were observed. Different abnormalities are believed to originate at different times of intrauterine development, and could provide clues to the timing of events associated with the predisposition to schizophrenia. Midline abnormalities were the most common form of developmental abnormality observed here. Increased rates of midline abnormalities such as cavum septum pellucidum were reported in schizophrenia (Degreef et al., 1992; DeLisi et al., 1993: Scott et al., 1993). Abnormalities such as enlargement of the cisterna magna and superior cerebellar cistern are proposed to occur on a continuum with more severe malformations of the posterior tbssa (Barkovich et al., 1989). Both midline and posterior fossa anomalies may relate to the early ventral induction phase of neural development (Van der Knapp and Valk, 1988). One patient had an arteriovenous malformation. This abnormality also originates early in brain development, likely during the first two to three months (Van der Knapp and Valk, 1988). Timing of the origin of colloid, arachnoid and pineal cysts is uncertain. Coarctation of the frontal horn of the lateral ventricle was observed in several cases, is due to
124
V£ G. Honer et al./Schizophrenia Research 16 (1995) 121 125
adhesion between the ependymal cell layers and may originate in the sixth intrauterine month (Newton and Potts, 1978). The clinical significance of neuroradiological developmental abnormalities in psychosis is uncertain. However, neuroradiological abnormalities may be markers of more subtle abnormalities of development that do have functional implications. As an example, one study indicated that cavum septum pellucidum and cavum vergae were associated with the presence of mental retardation (Miller et al., 1986). In the patients with schizophrenia, there was no association between the presence of developmental abnormalities and cortical sulcal enlargement. This suggests that a unitary mechanism may not be involved in the genesis of sulcal enlargement and developmental abnormalities in schizophrenia. Cortical sulcal enlargement is only one of several changes in brain structure reported in schizophrenia. Other findings, such as ventricular enlargement or reduction in the size of temporal lobe structures could have a different association with developmental abnormalities. However, in a related report on patients with schizophrenia, no association between cavum septum pellucidum and ventricular or temporal lobe size was found (DeLisi et al., 1993). The implication of the negative association between cortical sulcal enlargement and neurodevelopmental abnormalities in older patients in the overall group remains unclear. This result needs to be assessed more thoroughly in larger samples of diagnostically homogeneous groups of patients. Further studies are also required to more completely investigate the relationship between developmental abnormalities and the full range of structural abnormalities in schizophrenia, and to determine the clinical significance of pathology in different domains of brain structure.
Acknowledgements W.G.H. was supported by the Medical Research Council of Canada. Z.S. was supported by the National Alliance for Research on Schizophrenia and Depression. G.G. was supported by a Faculty Scholar Award from the National Institute of
Mental Health. The authors thank Dr. Donald Klein for comments on an earlier version of the manuscript.
References Barkovich, A.J., Kjos, B.O., Norman, D. and Edwards, M.S. (1989) Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging. Am. J. Neuroradiol. 10, 977-988. Breslin, N.A. and Weinberger, D.R., Neurodevelopmental implications of findings from brain imaging studies of schizophrenia, In Mednick SA, Cannon TD, Barr CE, Lyon M (Eds.), Fetal Neural Development and Adult Schizophrenia, Cambridge University Press, Cambridge, 1991, 199-215. Degreef, G., Bogerts, B., Falkai, P., Greve, B., Lantos, G., Ashtari, M. and Lieberman, J. (1992) Increased prevalence of the cavum septum pellucidtun in magnetic resonance scans and post-mortem brains of schizophrenic patients. Psychiatry Res. Neuroimaging 45, 1-13. DeLisi, L.E., Hoff, A.L., Kushner, M. and Degreef, G. (1993) Increased prevalence of cavum septum pellucidum in schizophrenia. Psychiatry Res. Neuroimaging 50, 193-199. Gewirtz, G., Squires-Wheeler, E., Sharif, Z. and Honer, W.G. (1994) Clinical CT scans in psychosis. Br. J. Psychiatry 164, 789-795. Jurjus, G.J., Nasrallah, H.A., Brogan, M. and Olson, S.C. (1993) Developmental brain anomalies in schizophrenia and bipolar disorder: a controlled MRI study. J. Neuropsychiatry Clin. Neurosci. 5, 375-378. Lewis, S.W. (1989) Congenital risk factors for schizophrenia. Psychol. Med. 19, 5-13. Lewis, S.W. (1990) Computerised tomography in schizophrenia 15 years on. Br. J. Psychiatry 157 (suppl 9), 16-24. Marsh, L., Suddath, R.L., Higgins, N. and Weinberger, D.R. (1994) medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophr. Res. 11,225-238. Miller, M.E., Kido, D. and Homer, F. (1986) Cavum vergae: association with neurologic abnormality and diagnosis by magnetic resonance imaging. Arch. Neurol., 43, 821-823. Nasrallah, H.A. (1991 ) Neurodevelopmental aspects of bipolar affective disorder. Biol. Psychiatry 29, 1 2. Nasrallah, H.A. (1993) Neurodevelopmental pathogenesis of schizophrenia. Psychiatric Clin. North America 16, 269-280. Newton, T.H. and Potts, D.G., eds. (1978) Ventricles and Cisterns. Radiology of the Skull and Brain; vol Four, St. Louis: C.V. Mosby, p. 3532. Pfefferbaum, A., Zipursky, R.B., Lira, K.O., Zatz, L.M., Stahl, S.M. and Jeruigan, T.L. (1988) Computed tomographic evidence for generalized sulcal and ventricular enlargement in schizophrenia. Arch. Gen. Psychiatry 45, 633-640. Scott, T.F., Price, T.R.P., George, M.S., Brillman, J. and
V~ G. Honer et al./Schizophrenia Research 16 (1995) 121-125
Rothfus, W. (1993) Midline cerebral malformations and schizophrenia. J. Neuropsychiatry 5, 287-293. Van der Knapp, M. and Valk, J. (1988) Classification of congenital abnormalities of the CNS. Am. J. Neuroradiol. 9, 315-326. Waddington, J.L, (1993a) Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophrenia Bull, 19, 55-69.
125
Waddington, J.L. (1993b) Schizophrenia: developmental neuroscience and pathobiology. Lancet 341,531-536. Wolf, S.S., Hyde, T.M. and Weinberger, D.R. (1994) Malformations of the septum pellucidum: two distinctive cases in association with schizophrenia. J. Psychiatry Neurosci., 19, 140 144.