Increased prevalence of the cavum septum pellucidum in magnetic resonance scans and post-mortem brains of schizophrenic patients

Psychiatry Research: Neuroimaging,

45:

I - I3

I

Elsevier

Increased Prevalence of the Cavum Septum Pellucidum in Magnetic Resonance Scans and Post-mortem Brains of Schizophrenic Patients Gustav Degreef, Bernhard Bogerts, Peter Falkai, Beno Greve, George Lantos, Manzar Ashtari, and Jeffrey Lieberman Received July 12, 1991; revised version received November 15, 1991; accepted December 7, 1991. Abstract. A cavum septum pellucidurn (CSP) has been regarded as an incidental finding of little clinical importance. However, an association between this developmental anomaly and a diagnosis of psychosis has previously been reported. We determined the prevalence of the CSP in parallel studies of brain scans obtained with magnetic resonance (MR) imaging and in the post-mortem brains of schizophrenic patients compared with normal controls. We found a significantly increased prevalence of the CSP in both the MR scans and postmortem brains of schizophrenic patients compared with controls. In the MR study, 17 of 81 (21%) schizophrenic patients but only 1 of 46 (2%) control subjects had a CSP. In the post-mortem study, 17 of 28 (61%) schizophrenic patients and 12 of 39 (31%) normal controls had a CSP. The increased prevalence of a CSP in schizophrenic patients further indicates that anomalous development of the limbic system is an important aspect of this disorder.

Words. Brain imaging, anomaly, cavum Vergae.

Key

limbic

system, neuropathology,

developmental

The septum pellucidurn is a thin triangular membrane consisting of two glial layers and fiber tracts that separate the frontal horns of the lateral ventricles (Andy and Stephan, 1968; Bruyn, 1977) and extend between the anterior portions of the corpus callosum and the body of the fornix. It consists of two thin laminae with a potential space (or cavum) between them. Two types of cavum septum have been described: communicating and noncommunicating. A communicating cavum is accompanied by a tear in the septal laminae through which its interior communicates with the ventricular system. Communicating cava are usually associated with other neuropathologic abnormalities and are often found in boxers with traumatic encephalopathy (Spillane, 1962; Corsellis et al., 1973). A noncommunicating cavum is a closed space and appears to be a developmental anomaly (Bruyn, 1977; Shaw and Alvord, 1969). The caudal portion of the cavum lying posterior to the columns

Gustav Degreef, M.D., is Clinical Director, Magnetic Resonance Imaging Studies, and Jeffrey Lieberman, M.D., is Director of the Psychiatry Research Department, Hillside Hospital, Long Island Jewish Medical Center, Albert Einstein College of Medicine, Glen Oaks, NY. Bernhard Bogerts, M.D., Peter Falkai, M.D., and Beno Greve, M.D., are Staff Psychiatrists at the Department of Psychiatry, University of Dusseldorf, Dtisseldorf, Federal Republic of Germany. George Lantos, M.D., is Director of Neuroradiology and Manzar Ashtari, Ph.D., G.D., is MRI Physicist, Department of Radiology, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, NY. (Reprint requests to Dr. J. Lieberman, Hillside Hospital, P.O. Box 38, Glen Oaks, NY 11004, USA.) 0165-1781/92/%05.00 @ 1992 Elsevier Scientific Publishers Ireland Ltd.

of the fornix is termed the cavum Vergae (CV). The CSP and CV, if they are present. are essentially the same structure and usually communicate freely. At times they may be partially or completely separated by the columns of the fornix or by a bridge ol cerebral tissue (Shaw and Alvord. 1969). These two cavities are not part of the true ventricular system (Rakic and Yakovlev, 1968). although they are lined with ependyma (Bruyn, 1977; Liss and Mervis, 1984). In most. if not all, fetuses, the two layers of the septum pellucidum are separated by a cavity of varying size (Shaw and Alvord, 1969; Laroche and Baudey, 1961) which begins to disappear before birth but is seen in about 80% of infants at term (Williams, 1985). The CSP usually shrinks and disappears long before adulthood (Shaw and Alvord, 1969), but it persists and can be seen in a smail percentage of adults (Shaw and Alvord, 1969; Nakano et al.. 198 1). The CV begins to contract posteriorly after about 6 gestational months and is absent at term in 70% of infants (Williams, 1985). The CSP and CV vary greatly in size, and there is considerable disagreement in the literature about their prevalence in normal persons (Hughes et al.. 1955; Laroche and Baudey, 1961; Shaw and Alvord. 1969; Bruyn, 1977). The belief that noncommunicating cavum septi are accompanied by neuropsychiatric disturbances has been frequently debated (Shaw and Alvord, 1969; Bruyn,

1977; Lewis and Mezey, 1985). Recently, an association with this developmental anomaly and atypical psychoses has again been described (Lewis and Mezey. 1985). This study was undertaken to determine if the increased prevalence of the CSP in first episode schizophrenic patients (Degreef et al., 1991) could be replicated in chronic schizophrenic patients and in post-mortem specimens from schizophrenic patients. In addition, we wanted to compare the frequency and severity of the CSP at two centers with two different techniques. The samples at both centers were examined by the same investigators using similar criteria to define the CSP. Methods Magnetic Resonance Imaging (MRI). MRI scans of 81 schizophrenic cases were selected from two research protocols being conducted at Hillside Hospital-Long Island Jewish Medical Center. The first study (described in detail in Lieberman et al., 1990) ascertained 62 patients who had entered the hospital in their first episodes of schizophrenia before they received neuroleptic treatment. Diagnoses were determined by Research Diagnostic Criteria (Spitzer et al., 1977) on the basis of information from a structured diagnostic interview, the Schedule for Affective Disorders and Schizophrenia (Spitzer and Endicott, 1977) and were confirmed by 1-3 years' followup reevaluations. The results of other MRI studies in a subset of the first episode schizophrenic patients have been presented elsewhere (Bogerts et al., 1990~; Degreef et al., in press). The second was a study of multi-episode chronic schizophrenic patients (described in detail in Kane et al., 1988). Nineteen patients ascertained for this study were diagnosed as having chronic schizophrenia by DSM-III-R (American Psychiatric Association, 1987) by a research psychiatrist on the basis of a comprehensive clinical evaluation. Patients in the second study were resistant to treatment, with persistence of psychotic symptoms at a significant level of severity despite adequate independent trials of three neuroleptics (6 weeks of 1000 mg/day of chlorpromazine or equivalent dose of another neuroleptic) from two different biochemical classes. Forty-six control subjects were recruited from medical center staff and the community through advertisements. Patients and controls were screened for medical and psychiatric

3 iliness and history of substance abuse. None of the patients or controls had a history of substance dependence or current abuse, or history of chronic neurological or medical illnesses or drug treatment (e.g., corticosteroids) known to affect the brain. No schizophrenic patients demonstrated clinical signs of raised intracranial pressure or gross neurologic deficits. Control and schizophrenic subjects had approximately the same age and race distribution. Table 1 presents the demographic characteristics of the subjects. Education was ranked according to the Hollingshead-Redlich classification (Hollingshead, 1965). Four patients exhibited gross neuropathological changes in their MR scans not typically associated with schizophrenia (e.g., evidence of infarction). These four subjects were dropped from the study and were not included in this sample.

Table 1. Demographic characteristics: Magnetic resonance imaging studv Normal control Sex Male/female Mean age (SD) Mean educational

First episode schizophrenic

Chronic schizophrenic

22124

33129

1712

28.8 (7.5)

24.1 (5.8)

29.t (5.7)

2.0 (0.9)

3.4 (1.1)

3.5 (0.9)

level’

(SD1 Race % Caucasian Duration

of illness fvr)

69

44

92

1.02 Il.71

9.19 (5.61

1. Educational level: 2 = college graduate, 3 = partial college, 4 = high school graduate.

Subjects were scanned in a 1.0 tesla whole body MR system (Siemens Magnetom) using a dedicated head coil. Brain images were acquired in the coronal plane using a 50” flip angle nonselective FLASH sequence with repetition time (TR) of 40 msec and echo time (TE) of 15 msec (described in detail in Ashtari et al., 1990). This sequence provided 63 contiguous slices of 3.1 mm width in 11 minutes. A standard T2 weighted sequence was used to acquire axial images with TR 2500 msec, TE 35 msec and 1 excitation. The axial sequence obtains 16-20 parallel sections which are 7-mm thick with 2-mm gaps between sections. Images were displayed in a 256 X 256 matrix with no zoom factor and with an in-plane resolution of 1.0 mm X 1.0 mm. Video film hard copies were printed for visual qualitative evaluation. MR scans of all patients and controls were combined in randomized order and were reviewed without knowledge of diagnostic group by a neuroradiologist (G.L.) and a psychiatrist (B.B.) trained in neuroanatomy. Each rating was assigned on the basis of a consensus between the two raters. The presence of a CSP was determined by visual inspection and graded on a scale of 0 to 3 (0 = absent, 1 = questionable, 2 = small, 3 = moderate and large). Figs. la, I b, Ic, and Id illustrate grade 0, 1, 2, and 3 CSP. Post-mortem Study. Brains of 67 subjects were investigated. The sample included 28 schizophrenic patients (14 male and 14 female) and 39 controls (25 male and 14 female). Mean age at the time of death in controls (55.7 years) did not significantly differ from that in schizophrenic patients (53.1). Only patients with well-preserved and extensive clinical records were selected for this study (described in detail in Bogerts et al., 1990b). The mean disease duration (time between first hospitalization and death) was 19.5 years (range 2-39 years). All patients, including seven with a late onset of the disease (> 40 years), fulfilled ICD-9 (World Health Organization, 1978) and DSM-III-R (American Psychiatric Association, 1987) criteria

Fig. 1. Cavum septum pellucidum on magnetic resonance imaging

The cavum septum pellucldum appears as a midline cerebrosprnal fiuld contalnlng space separated from the frontal horns by thin parallel septa. Panels a, b. c and d. respectively. represent the normal, grade 1. grade 2. and grade 3 cavum (open arrowheads). All scans are from schlzophremc pattents (a a Z-year-old female: b a Wvear-old male c a 33-year-old male, d a 38-year-old fem;li&> schizophrenia and were treated with neuroleptic medications for the greater parr of their disease duration. Table 2 presents the demographic data for the patients and controls. Patients died in psychiatric hospitals in or near Diisseldorf. Germany, in the years of 1985-1990. and their brains were obtained from pathological institutes in or near Diisseldorf. Three patients died from suicide: their brains were* obtained from medical examiners’offices that were also in or near Diisseldorf. Control brains from 34 subjects without a history of neuropsychiatric disorders (25 male and 14 female) were obtained from the same pathological or forensic institutes during the same period. The mean time between death and fixation of the brains of the control subjects was 43 hours and that of the schizophrenic patients was 42.5 hours. This study includes the I8 patients and 21 controls in the study of Rogerts et al. (199Oh). for

Histological Methods. Complete brains (i.e.. without dissection into blocks) from patients and controls were uniformly fixed in 10% (by volume) formalin for about 7 months. Then, the brainstem was removed, and the frontal and occipital poles were separated from the middle part of the brain by coronal sectioning anterior to the genu of the corpus callosum and posterior to the splenium. The remaining middle brain part was about g-cm long and contained both hemispheres with the posterior parts of the frontal lobes, the entire septum and septum pellucidurn, nearly the whole parietal brain, all diencephalic structures. striatum, pallidurn, and the rostra1 parts of the midbrain. The middle block was embedded in paraplast and cut into 20 /J thick coronal serial sections. Each 50th section was then Nissl (cresylechtviolet) and myelin (Heidenhain-Wiilcke or 1~x01 fast blue) stained. The mean section thickness was about 2Oy (range 16-25). All stained sections were reviewed in each case for this study. Post-mortem specimens of all patient and control subjects were combined in randomized

5 Table 2. Demoaraohic characteristics: Post-mortem studv Control

~hizophrenj~

Sex Male/female

25114

14114

Mean age (SD)

55.7 (11.3)

53.1 (9.4)

Mean duration of illness in 19.5 (2-39)

years (range)

order and were reviewed under blind conditions by two psychiatrists trained in neuroanatomy (P.F. and B.B.). Each rating was assigned on the basis of a consensus between the two raters. The presence of a CSP was determined by visual inspection using the same criteria as in the MRI study. Figs. 2a, 2b, 2c, and 2d illustrate grade 0, 1, 2, and 3 CSP from the post-mortem specimens.

Fig. 2. Cavum septum pellucidum in post-mortem brains

d

Panels a, b, c, and d, respectively, represent the normal, grade 1, grade 2, and grade 3 cavum (thin arrows]. Brains are from a. a 47-year-old male control; b. a 50-year-old male control; c. a 41 -year-old male schizophrenic: d. a 48-year-old female schizophrenic. Black numbers indicate section number and subject identification.

Results Tables 3 and 4 summarize the ratings of CSP from the MRI and post-mortem studies. For the initial analysis (in both the MRI and post-mortem studies). subjects who had a grade of 0 or 1 were combined and rated as not having a CSP. This was done because grade 1 cava in the MRI study were extremely small and probably the most liable to misclassification, and in the post-mortem study were smaller than 1 mm. Statistical comparisons for both MRI and post-mortem studies were performed using ~2 analyses or Fisher’s exact tests when expected cell sizes were < 5.

Table 3. Prevalence of the cavum septum pellucidum: Magnetic resonance imaging study

Grade 0

Normal control (n = 46)

First-episode schizophrenia

39

I

ij

II

1

III

0

Chronic schizophrenia

(n = 62)

(n = 19)

40

:4

8

2

12

3

2

0

II-III

1

14

3

l-111

7

22

5 -~

Table 4. Prevalence of cavum septum pellucidum: Post-mortem study Grade

Control

Schizophrenic

(n = 39)

(n = 28)

0

14

7

I

13

4

II

9

8

III

3

11-111 l-ill

-~

9

12

17

25

21

MRI Study. A CSP was found in the MRI scans of 14 of the first-episode patients (23%), 3 of the chronic treatment-resistant patients (16%), and only I of the 46 control subjects (2.2%). Two first-episode patients had a grade 3 CSP on MRl scans. Compared with the control group, both the first-episode patients (FI = 9.98, df = 1, p < 0.002) and the total schizophrenic group (FI = 9.52, df = I, p = 0.002) showed a significantly higher prevalence of CSP. Schizophrenic patients with (mean = 25.4 years) and without (mean = 23.9 years) a CSP did not differ significantly in age. When grade I cava were combined with grades 2 and 3 cava, there were still significant differences between first episode schizophrenic patients and controls (~2 = 5.52, df = 1, p < 0.02), as well as between all schizophrenic patients and controls h2=4.9I,df’== I,p
7 significantly higher prevalence of CSP. Comparing the rate of grade 3 CSP also revealed significant differences between schizophrenic patients and controls (FI = 5.83, df = 1,~ < 0.027). Schizophrenic patients with (mean = 53.2 years) and without (mean = 51.6 years) a CSP did not significantly differ in age. Fig. 3. Cavum septum pellucidum (CSP): 5 X magnification of the septum pellucidum in post-mortem brains (open arrowheads)

The brains are the same as in Fig. 2: a. grade 0; b. grade 2; c. grade 3. Black dots superior and inferior to the CSP are wax pen markings.

Statistical Analysis. To examine further factors that may have influenced the results of the study, a log-linear analysis was performed on the data from both centers. In this

analysis, diagnosis, gender, and method (M RI or post-mortem~ were the dependem variables and CSP status was the independent variabfe- A four-way table was generated and then examined in three separate analyses. The first analysis allowed CSP grade to range from 0 to 3; the second and third analyses grouped CSP grade into nor-ma1 versus abnormal. In the second analysis, grade 0 was considered normal and grades I, 2, and 3, abnormal. In the third analysis, grades 0 and I were considered normal and grades 2 and 3, abnormal. All three analyses confirmed the significant differences in cavum septum status between patients and controls. There was no CSP status :t method interaction in any of the three analyses. The absence of a significant interaction indicated that the CSP rates did not differ significantly between MRI and post-mortem studies Q? Z= 1.92. 0.04, 1.38 with p < 0.17, 0.85, 0.24. respectively). The three analyses also demonstrated a significant difference in gender composition in the MRI versus pos~-nlo~e~~ groups (an excess of male schizophrenic patients and an excess of maie corm-ok. respectiveIy). There was also a significant. effect of gender (~2 = 17.45, 12.24, 3.92 with ~2 < 0.0001, 0.0005. 0.05. respectively) m all three analyses, demonstrating that males have a greater prevafence of the CSP. However. there was no gender X diagnosis interaction (x* = 2.09, I .X 1,0.21with p <:IO.I5.O.I& 0.65, respectively) in any of the three analyses in either the MRI or post-mortem groups. ‘There was no history of significant head trauma in patients (in either the MRI or the post-mortem study) with a C’SP, nor did there appear to be any cases with a break in the septai laminae indicative of a traumatic etiology. Only three subjects had a 0’: one male and one female schizophrenic patient (both with grade 3 cava) in the MRI study and one maie schizophrenic patient (also with a grade 3 cavumi in the post-mortem series. Fig. 4, Cavum Vergae (CV)

Panel a shows an axial view of a magnetic rescxunce Imaging scan (Tz weighted) in a Wyasr-old male schirophrenic with a cavum septum pellucidurn (CSP) and CV (arrowheads] which are continuous. Panel b shows a coronal section of a post-mortem brain in a 77-year-old male showing a CV (open arrowheads).

9 Discussion This study reports a significantly higher prevalence of the CSP in schizophrenic compared with normal control subjects in the MRI and post-mortem studies. Perhaps the higher prevalence has not been noted in earlier computed tomographic (CT) studies of schizophrenic patients because of partial volume effects that are produced with slices that are 8-10 mm in thickness (de Groot, 1984) and with interslice gaps of 2-3 mm as were obtained by the CT scanners used in such studies. Cava smaller than 3 mm have been described in autopsy studies (Corsellis et al., 1973), and Shaw and Alvord (1969) have noted that in the case of small cavities, any post-mortem technique short of thin coronal sections through precisely the correct part of the septum could miss its presence entirely. In contrast, our MRI technique acquires 3.1 mm thick contiguous slices of the whole brain. It is also possible that the presence of a CSP in schizophrenic patients has been overlooked because all previous CT studies in schizophrenic samples have been performed with an axial orientation. In addition, the increased prevalence of CSP in schizophrenic samples could have been overlooked in previous CT or MRI studies because it was not the focus of attention, A significantly larger area of the septum pellucidurn (as seen in midsagittal MRI scans) has been reported in schizophrenic patients compared with controls {Mathew et al, 1985; Uematsu and Kaiya, 1989). However, the relationship of a larger area of the septum pellucidurn to the CSP is not known since neither those studies nor our own examined both axial and sagittal views of the septum pellucidurn. The prevalence of a CSP (conservatively defined) in our normal controls was 2.2%, a figure that is similar to estimates in groups of normal subjects examined by means of pneumoencephalography (PEG) and CT (Bruyn, 1977; Harwood-Nash~ 1977; Nakano et al., 198 1). PEG studies of mixed samples yield prevalence figures between 2% and 4% (Bonitz, 1969; Sonntag et al., 1971; Bruyn, 1977). The prevalence of such cava on CT scans in a mixed sample of 22,000 subjects was found to be 0.15% (Lewis and Mezey, 1985). Previous post-mortem studies have yielded rates of 2-30% in normal adults (Shaw and Alvord, 1969; Sonntag et al., 1971; Corsellis et al., 1973; Bruyn, 1977). Differences in technique and the population studied are believed to be the factors most responsible for variations in rates between post-mortem studies (Swenson, 1944). Our post-mortem study demonstrated a 31% rate in the normal control subjects that is at the upper end of the range of previous post-mortem studies. The difference between the 2% rate of CSP in the MRI control cases and the 31% rate in the post-mortem controls probably reflects the fact that cava smaller than 3 mm can be seen in the post-mortem sections, which are much thinner and give higher resolution than can be achieved with our MRI technique. Partial volume effects are virtually nonexistent in the post-mortem brains. However, for small structures, they are still a considerable factor for MRI studies, even those such as ours which acquired images in thin contiguous slices. It is probable that a certain proportion of grade 1 cava in the MRI scans would probably be more clearly visualized and rated as grade 2 with a post-mortem technique. The higher rate of CSP in the post-mortem versus MRI controls may also be due to the excess of male

I!)

controls in the post-mortem study (of’ i 2 post-mortem controls with a CSP. IO were male). It has been noted that mates have a higher rate of CSP than females (Schwidde. 1952: Bruyn, 1977: Lewis and Mezey. 1985). which we also found in OUI- study. This higher prevalence was noted in both the schizophrenic and control males at both centers, but we found no sex X diagnosis interaction in our log linear analysis. The absence of such an interaction indicates that our results were not due to sampling bias and the male schizophrenic patients are not selectively affected. When less conservative criteria were used (combining grade I, 2, and 3 cava), the 15.204 rate in our MRI controls was comparable to. though somewhat lower than. the rate in our own and previous post-mortem studies. The IS% rate in the MRI controls using these liberal criteria was, however, still significantly lower than the 33% rate in the MRI scans of the schizophrenic patients. and the 31% rate in the post-mortem controls was also significantly lower than the 61% rate in the postmortem schizophrenic patients. In comparisons of the rates of the largest (grade 3) CSP (and also CV), the schizophrenic samples (both MRI and post-mortem) also had a significantly higher rate than the control groups. Therefore, by any criteria that we used to define CSP and by either high resolution method that we employed. the prevalence of CSP was significantly higher in the schizophrenic patients. In clinical neurology, it is generally believed that the CSP has little, if any, clinical significance (Urich. t 976). However, a relationship between a relatively wide cavum and a diagnosis of epilepsy or mental disorder has been reported. The increased prevalence of CSP and CV in the schizophrenic subjects indicate an arrest of normal maturation within the limbic system, a region of the brain with critical responsibilities for the integration of sensory and motor functions. One hypothesis of the pathogenesis of schizophrenia is that it is a developmental disorder that may be related to maldevelopment of limbic system structures (Bogerts. 1990). The septum peltucidum blends into the septum verum (true septum) (Andy and Stephan, 1968). which consists of a series of subcorticat nuclei with rich interconnections to the hippocampus. The septum has thus been described as a nodal point or central relay station in the limbic system (Swanson, 1978, 1983; Mesulam. 1986). Because of the septum’s efferent projections from most areas of the neocortex, amygdala and brainstem. and its projections to cingulate cortex, hypothalamus, midbrain reticular formation, striatum. substantia nigra and (via the pontine gray) cerebellum, this system can influence the activity in most of the major neural systems of the brain (Swanson, 1978, 1983). It remains to be shown, however, that the presence of a CSP in any way demonstrates the existence of dysfunction of the septo-hippocampal system. Nonetheless, the presence of a CSP suggests that the function of efferent and afferent pathways to the septum verum may be disturbed. Since septal nuclei have extensive bidirectional projections to other limbic structures, factors leading to the development of a CSP may also affect these limbic structures and in turn be closely related to the development of schizophrenia. If a septal cavum results from an arrest of prenatal or postnatal neural development, then this should be reflected by behavioral and motor problems dating

11 to early infancy.

In fact, delays in reaching motor milestones and childhood emotional and conduct disorders have been noted in the histories of schizophrenic subjects (Fish, 1977). Neurologic abnormalities and behavioral differences have also been recently noted in home movies of the early infancy period of subjects who later developed schizophrenia (Walker and Lewine, 1990). In a related MRI study of a pediatric population, Bodensteiner et al. (1991) found a 56% rate of mental retardation in the subjects with CSP compared with a 22% rate in subjects without a CSP @ < 0.001). The 2% to 30% rate of CSP in the normal controls indicates that a CSP does not necessarily lead to a mental disorder. It may, however, increase the likelihood or reflect a vulnerability to develop psychiatric disorders such as schizophrenia. We suggest that the presence of a factor or factors that lead to the persistence of a CSP predisposes to the development of schizophrenia. Additional factors are probably required to cause the development of psychoses in individuals so predisposed. We propose that the occurrence of CSP parallels the presence of ventricular enlargement in normal subjects, and both may be indirect evidence for risk factors for the development of schizophrenia but are not invariably associated with psychosis. Ventricular enlargement is not diagnostic of schizophrenia, but its increased incidence in schizophrenic patients compared with its incidence in controls has been a consistent finding and indicates a developmental anomaly or a degenerative process. The presence of a CSP (in the first-episode patients) cannot be explained by a degenerative process and convincingly demonstrates that early developmental disturbances of the brain are important in the pathogenesis of schizophrenia. Both ventricular enlargement and the presence of a CSP probably represent vulnerability factors. In conclusion, septal cava may demonstrate the presence of an underlying functional abnormality in a subgroup of patients that is implicated in the pathogenesis of schizophrenia. We plan to establish if there are clinical correlates of this developmental anomaly and to examine the relationship of the CSP to other subtle brain abnormalities such as lateral ventricular enlargement and cortical sulcal prominence that have been noted in schizophrenia. The MRI studies were supported in part by U.S. Public Health Service grants MH-00537, MH41646, and MH-41960, an American Psychiatric Association Kempf Fund Award (G. Degreef), and a grant from Helen and Irving Schneider and Family. The post-mortem studies were supported by grants from Alfried Krupp van Bohlen and HalbackStiftung and by the Deutsche Forschungsgemeinschaft (BO-799[1-31). Thanks are due to Jeanine Springer for help in editing and compilation of the manuscript. Acknowledgments.

References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 1987. Andy, O.J., and Stephan, H. The septum in the human brain. Journal of Comprehensive Neurology,

133:383-410, 1968.

Ashtari, M.; Zito, J.L.; Gold, B.I.; Lieberman, J.A.; Borenstein, M.T.; and Herman, P.G. Computerized volume measurement of brain structure. Investigative Radiology, 25:798-805, 1990.

I’ Bodensteiner, J.B.; Breeding, Prevalence and clinical features in Bogerts, B. The neuropathology mental implications. In: Mednick. Neural development

i,.M.; and Cowan. 1,. The cavum septum pellucidurn: a pediatric population. Neurology, 41(Suppl.):306, 1991. of schizophrenia: Pathophysiological and ncurodevelopS.A.: Cannon, T.D.; Barr. C.E.; and Lyon, M., eds. Frrai and Adult .Sch~~(?phr~,~?iu.Cambridge: Cambridge I!ni~ersit>- Prest.

1990. Bogerts, B.; Ashtari, M.; Degreef. G.; Alvir, J.M.J.; Bilder, R.M.; and Licberman. J.A. Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Research: Neuroimaging, 35: I-1 3. 1990~. Bogerts, B.; Falkai, P.: Haupts, M.; Greve, B.; Ernst, S.: Tapernon-Franz, U.; and Heinzman, U. Post-mortem volume measurements of iimbic system and basal ganglia structures in chronic schizophrenics. S~hi~ophre~zja Research, 3:295-301, 1990b. Bonitz, G. Zur kI~nischdiagnostischen Bedeutung des erweiterten und kommunizierenden Cavum septi pellucidi. Nervenarzr, 40: 121-128. 1969. Bruyn, G.W. Agenesis septi pellucidi, cavum septi pellucidi, cavum Vergae and cavum veli interpositi. In: Vinken P.J., and Bruyn, G.W., eds. Handbook of Clinical Neuro1og.v. Amsterdam: ElsevierjNorth-Holland. 1977. pp 299-336. Corsellis, J.A.N.; Bruton, C.J.; and Freeman-Browne, I). The aftermath of boxing. Psychological Medicine, 3:270-303.

1973.

Degreef, G.; Ashtari, M.; Bogerts, B.; Bilder, R.M.; Jody, D.N.; Alvir. J.M.; and Lieberman, J. Volumes of ventricular system subdivisions measured from magnetic resonance images in first episode schizophrenic patients. rlrchives of General Psychiatry, in press. Degreef, G.; Ashtari, M.; Wu, H.: Borenstein, M.; Geisler, S.; and Lieberman, J. Follow-up MRI study in first episode schizophrenia. Presented at “Longitudinal Perspectives on the Pathophysioiogy of Schizophrenia: Examining the Neurodevelopment~ vs. Neurodegenerative Hypotheses,” a satellite meeting at the Annual Meeting of the American College of Neuropsychopharmacology, San Juan, PR, 199 I. de Groot, J. Correlative Neuroanatomy of Computed Tomography and Magnetic Resonance Imaging. Philadelphia: Lea and Febiger, 1984. pp. 31-44. Fish, B. Neurologic antecedents of schizophrenia in children: Evidence for an inherited, congenital neurointegrative deficit. Archives qf General Psychiatry, 34:1297-1313. 1977. Harwood-Nash. D.C. Congenital craniocerebral abnormaiit~es. seminars in Roentgenology. 12:39-5 1, 1977. Hollingshead, A.B. Two-factor Index of Social Position. Yale Station, New Haven, CT. 1965. Hughes, R.A.; Kernohan, J.W.; and Craig, W.M. Caves and cysts of the septum pellucidum. Archives of Neurology and Psychiatry, 74:259-266, 1955. Kane, J.; Honigfeld, G.; Singer, J.; Meltzer, H.; and the Clozaril Collaborative Study Group. Clozapine for the treatment-resistant schizophrenic: A double blind comparison with chlorpromazine/benztropine. Archives of General Psychiatry, 45789-796, 1988. Laroche, J.C., and Baudey, J. Cavum septi lucidi, cavum Vergae, cavum veii interpositi: cavities de la ligne mtdiane. Etude anatomique et pneumoencbphalographique dans la periode nCo-natale. Biologia Neonatorum, 3: 193-236, I96 1. Lewis, S.W., and Mezey, C.G. Clinical correlates of septum pellucidurn cavities: An unusual association with psychosis. Psychological Medicine, 15:43-54, 1985. Lieberman, J.; Jody, D.; Geisler, S.; Vital-Herne, J.; Alvir, J.; Walsleben, J.; and Woerner, M. Treatment outcome of first episode schizophrenia. Psychopharmacology Bulletin. 25:9296, 1990.

Liss, L., and Mervis, L. The ependymal lining of the cavum septi pellucidi: A histological and histochemical study. Journal of Neuropathology and Experimental Neurology, 23:355367, 1984.

Mathew, R. J.; Partain, C. L.; Prakash, M.V.; Kulkarni, M.V.; Logan, T.P.; and Wilson, W.H. A study of the septum pellucidurn and corpus callosum in schizophrenia with MR imaging. Acta Psychiatrica Scandinavica, 72:414-421. 1985.

13 Mesulam, M.M. Patterns in behavioral neuroanatomy: Association areas, the limbic system, and hemispheric specialization. In: Mesulam, M.M., ed. Principles of Behavioral Neurology. Philadelphia: Davis, 1986. pp. l-70. Nakano, S.; Hojo, H.; Kataoka, K.; and Yamasaki, S. Age related incidence of cavum septi pellucidi and cavum Vergae on CT scans of pediatric patients. Journal of Computer Assisted Tomography,

5348-349,

1981.

Rakic, P., and Yakovlev, PI. Development of the corpus callosum and cavum septi in man. Journal of Comprehensive Neurology, 132~45-72, 1968. Schwidde, J.T. Incidence of cavum septi pellucidi and cavum Vergae in 1302 human brains. Archives of Neurology and Psychiatry, 67:625-632,

1952.

Shaw, C.M., and Alvord, E.C. Cava septi pellucidi et Vergae: Their normal and pathological states. Brain, 92:213-224, 1969. Sonntag, I.; Nadjmi, M.; Lajosi, F.; and Fuchs, G. Anlagebedingte Gehirnanomalien der Mittellinie. Nervenarzt, 42:53 l-539, 197 1. Spillane, J.D. Five boxers. British Medical Journal, 2:1205-1210, 1962. Spitzer, R.L., and Endicott, J. Schedule for Affective Disorders and Schizophrenia (SADS). 3rd ed. New York: New York State Psychiatric Institute, 1977. Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. New York: New York State Psychiatric Institute, 1977. Swanson, L.W. The anatomical organization of septo-hippocampal projections. In: Elliott, K., and Whelan, I., eds. Functions of the Septo-hippocampal System. Ciba Foundation Symposium 58. Amsterdam: Elsevier/North-Holland, 1978. pp 25-43. Swanson, L.W. The hippocampus and the concept of limbic system. In: Seifert, W., ed. Neurobiology of the Hippocampus. London: Academic Press, 1983. pp. 3-19. Swenson, 0. Nature and occurrence of the cavum septi pellucidi. Archives of Pathology, 37:119-123,

1944.

Uematsu, M., and Kaiya, H. Midsagittal cortical pathomorphology of schizophrenia: A magnetic resonance imaging study. Psychiatry Research, 30: 1I-20, 1989. Urich, H. Malformations of the nervous system, perinatal damage and related conditions in early life. In: Blackwood, W., and Corsellis, J.A.N., eds. Greenfeldk Neuropathology. London: Edward Arnold, 1976. pp. 361-470. Walker, E., and Lewine, R.J. Prediction of adult-onset schizophrenia from childhood home movies of the patients. American Journal of Psychiatry, 147:1052-1056, 1990. Williams, A.L. Congenital anomalies. In: Williams, A.L., and Haughton, V.M., eds. Cranial Computed Tomography: A Comprehensive Text. St. Louis: C.V. Mosby, 1985. pp. 316-349. World Health Organization. Mental Disorders: Glossary and Guide to Their Classification in Accordance

With the Ninth Revision of the International Classification of Disease-ICD 9.

Geneva: WHO, 1978.