Schizophrenia Research 125 (2011) 1–12

Contents lists available at ScienceDirect

Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Are cavum septum pellucidum abnormalities more common in

schizophrenia spectrum disorders? A systematic review and meta-analysis
Clarissa Trzesniak a,b, Irismar R. Oliveira c, Matthew J. Kempton b, Amanda Galvão-de Almeida c,d,
Marcos H.N. Chagas a, Maria Cecília F. Ferrari a, Alaor S. Filho a, Antonio W. Zuardi a,
Daniel A. Prado a, Geraldo F. Busatto e, Phillip K. McGuire b,
Jaime E.C. Hallak a, José Alexandre S. Crippa a,⁎
a
Department of Neuroscience and Behavior, Medical School, University of São Paulo (USP), Ribeirão Preto (SP), Brazil and INCT Translational Medicine, Brazil
b
Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
c
Affective Disorders Center, Universidade Federal da Bahia (UFBA), Salvador (BA), Brazil
d
Post Graduation Program, Universidade Federal de São Paulo (UNIFESP), and Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo (SP), Brazil
e
Department of Psychiatry, Medical School, University of São Paulo (USP), São Paulo (SP), Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in
Received 9 June 2010 association with schizophrenia. These include a higher incidence of cavum septum pellucidum
Received in revised form 7 September 2010 (CSP), which is consistent with a neurodevelopmental model for this disorder. In this meta-
Accepted 23 September 2010
analytic review, we describe and discuss the main CSP MRI findings in schizophrenia spectrum
Available online 20 October 2010
disorders (SSDs) to date. We adopted as keywords cavum and schizophrenia or psychosis, and
the inclusion criteria were articles in English, with samples of SSD patients compared to healthy
Keywords: subjects, which used MRI to assess CSP, without time limit. From 18 potential reports, fifteen
Cavum septum pellucidum were eligible to be part of the current review. These studies included 1054 patients with SSD
Magnetic resonance imaging
and 866 healthy volunteers. Six out of 15 studies pointed to a higher prevalence of CSP of any
Schizophrenia
size in SSD patients, while five out of 15 showed that subjects with SSD had a greater
Meta-analysis
occurrence of a large CSP than healthy individuals. However, the meta-analysis demonstrated
that only the incidence of a large CSP was significantly higher in SSD relative to healthy
comparisons (odds ratio = 1.59; 95%CI 1.07–2.38; p = 0.02). Overall our results suggest that
only a large CSP is associated with SSD while a small CSP may be considered a normal
neuroanatomical variation. Our review revealed a large degree of variability in the methods
employed across the MRI studies published to date, as well as evidence of publication bias.
Studies in large, community-based samples with greater standardization of methods should
clarify the true significance of CSP in SSD.
© 2010 Elsevier B.V. All rights reserved.

⁎ Corresponding author. Departamento de Neurociências e Ciências do
Comportamento — FMRP-USP, Avenida Bandeirantes 3900, 14048-900
Ribeirão Preto, SP, Brazil. Tel.: + 55 16 3602 2201; fax: + 55 16 3602 2544.
E-mail addresses: clarissaf@hotmail.com (C. Trzesniak),
irismar.oliveira@uol.com.br (I.R. Oliveira), matthew.kempton@iop.kcl.ac.uk
(M.J. Kempton), amandacgalvao@yahoo.com.br (A. Galvão-de Almeida),
setroh@hotmail.com (M.H.N. Chagas), cecilia_pqu@yahoo.com.br
(M.C.F. Ferrari), alaorsantos@hotmail.com (A.S. Filho),
awzuardi@fmrp.usp.br (A.W. Zuardi), alprado_psi@yahoo.com.br
(D.A. Prado), geraldo.busatto@hcnet.usp.br (G.F. Busatto),
philip.mcguire@kcl.ac.uk (P.K. McGuire), jhallak@fmrp.usp.br (J.E.C. Hallak),
jcrippa@fmrp.usp.br (J.A.S. Crippa).
1. Introduction
Despite more than a century of research, the etiology of
schizophrenia remains unknown. It is widely accepted that
the interaction between environmental and biological (i.e.,
genetic, biochemical, physiological and developmental) fac-
tors is crucial to the manifestation of this disabling disorder.
Among several etiological hypotheses for schizophrenia, the
neurodevelopmental model is one of the most prominant. In
its simplest form the model posits that schizophrenia is the
behavioral outcome of an aberration in neurodevelopmental

0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2010.09.016
2 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
processes that begins long before the onset of clinical
symptoms and is caused by a combination of environmental
and genetic factors (Murray and Lewis, 1987; Weinberger,
1987). Several post-mortem and neuroimaging studies
support this hypothesis by demonstrating that a significant
number of patients with schizophrenia show brain develop-
mental alterations, such as agenesis of the corpus callosum,
arachnoid cysts, and other abnormalities (Hallak et al., 2007;
Kuloglu et al., 2008). Additionally, animal models of schizo-
phrenia suggest that rats with early neurodevelopmental
lesions show delayed aberrant behavior occurring during
adolescence (for review, see Shenton et al., 2001). Conversely,
in recent years, longitudinal brain imaging studies of both
early and adult onset populations indicate that brain changes
are more dynamic than previously thought, with gray matter
volume loss particularly striking in adolescence and appear-
ing to be an exaggeration of the normal developmental
pattern, as well as progressive volumetric reductions in adult
patients. Indeed a recent meta-analysis has confirmed
progression of lateral ventricular volume in patients with
schizophrenia (Kempton et al., 2010). Some investigators
have suggested that, for a proportion of individuals develop-
ing schizophrenia, there are disruptions in early (pre- and
perinatal) and late (postpubertal) neurodevelopment, based
on evidence of observed changes occurring before, during,
and after illness onset (Pantelis et al., 2005). Thus, schizo-
phrenia may be a disorder of early and late brain develop-
ment (Cannon et al., 2003; Pantelis et al., 2003), in which
genetic and nongenetic influences are important in under-
standing the brain structural abnormalities observed (DeLisi,
1997; Harrison and Weinberger, 2005; Rapoport et al., 2005).
This progressive neurodevelopmental model may also be
useful in understanding the neuropsychological deficits and
behavioral manifestations seen in the disorder.
The septum pellucidum, a component of the limbic
system, is a thin plate of two laminae that forms the medial
walls of the lateral ventricles. When these laminae fail to fuse,
they form a cavity known as cavum septum pellucidum (CSP)
(Sarwar, 1989). The CSP is present in 100% of fetuses and
premature infants, but the posterior half of the leaves are
normally fused by the age 3–6 months (Shaw and Alvord,
1969). The presence of a CSP later in life might reflect
developmental abnormalities of structures bordering the
septum pellucidum, such as the corpus callosum and
hippocampus (Rakic and Yakovlev, 1968). Thus, the CSP can
be considered a marker of limbic system dysgenesis, a forme
fruste of midline abnormalities, or both (Nopoulos et al.,
1998). The complete nonfusion of the two leaflets of the
septum pellucidum, an anomaly termed combined CSP and
cavum vergae (CV), is considered the most extreme form of
CSP (Fig. 1).
Magnetic resonance imaging (MRI) is an important
method for investigating strutural brain abnormalities in
schizophrenia spectrum disorders (SSD), such as the CSP.
Nevertheless, there are some difficulties in interpreting the
published literature to date. In 2001, Shenton et al. reviewed
12 published MRI studies reporting CSP prevalence in
schizophrenia. The finding that 11 of the studies reported a
higher prevalence of CSP (large/any size) in schizophrenia
compared to controls, led the authors to conclude that the
CSP was one of the most robust MRI findings in schizophrenia.
However, 13 new studies have been performed in the last
nine years, with contrasting results both in relation to the
presence and the length of CSP.
The application of recent meta-analytic methods offer a
strategy for combining data from multiple brain imaging
studies for qualitative and quantitative analyses. Some
advantages of this approach include: 1) increment in
statistical power; 2) the possibility of teasing apart the
influence of factors causing heterogeneity in the results
reported by individual studies; 3) the opportunity to combine
findings from all studies, improving the estimation of the
overall effect size (Thompson et al., 1997). Taking advantage
of this, we present herein a systematic review and meta-
analysis providing a qualitative and quantitative integration
of the MRI findings of CSP in SSD published to date.
2. Methods
Searches were performed in the Medline and Web of
Science databases using the keywords cavum and schizo-
phrenia or psychosis, with no time limit. References of
selected articles were also hand-searched for additional
citations. All studies involving human patient samples
reporting MRI data of CSP in psychotic disorders were
incorporated in this analysis.
To be included in this review, the studies had to meet the
following criteria: 1) to be published in English; 2) in a
population predominantly diagnosed as having schizophre-
nia or schizoaffective disorder; 3) to use MRI to assess the
CSP; 4) to have a comparison group of healthy subjects. As the
brain is still developing in childhood (Pratt, 2002), we have
excluded one study that included only children in its sample
(Nopoulos et al., 2000).
In order to select the potentially relevant studies, three
independent reviewers (AGA, CT, and MHNC) evaluated the
abstracts identified in the literature search. Next, the same
three reviewers, working independently, decided which of
those papers fulfilled the inclusion criteria. Disagreement at
any stage was resolved by consensus. For each study
investigated, a data collection form was used, and these
data were obtained independently by the three reviewers.
The MRI studies included in this review are summarized in
Table 1, which lists the sociodemographic characteristics of
each study sample by first author and year.
Statistical analyses were performed using the Compre-
hensive Meta-Analysis Software, version 2.2.048, November
7, 2008 (Borenstein et al., 2009). For each study, odds ratios
and 95% confidence intervals were calculated. We used a
random effects model that weighted the studies according to
the inverse variance, and provided the odds ratio and the
corresponding confidence interval.
In order to ascertain whether pooling was viable among
the selected studies (p N 0.05), a Q test of homogeneity for the
odds ratios across studies was calculated. The proportion of
patients from the included studies who presented CSP
compared to those who did not was broken down into 2 × 2
contingency tables. We used Egger's regression test, which is
a formal method of estimating publication bias (Egger et al.,
1997). The effect of the year of publication was assessed in a
random effects meta-regression model by using the
 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
A B
Fig. 1. Complete fusion defect of the septum pellucidum leaflets in coronal (A) and axial (B) MR images showing (arrow) the presence of Cavum Septi Pellucidi/
Cavum Vergae severely enlarged in a patient with schizophrenia (28-years-old) (de Souza Crippa et al., 2006).
appropriated command in the software. The default option
using residual maximum likelihood (REML) was selected.
3. Results
Twenty studies that examined the prevalence of CSP in
schizophrenia and schizoaffective disorder fulfilled inclusion
criteria for this meta-analysis. Among these, one study was
excluded due to inconsistency regarding CSP prevalence, i.e.
presentation of two different values along the report
(Rajarethinam et al., 2008). We were unable to make contact
with the author for the correct data. Three articles (DeGreef
et al., 1992b; Fukuzako et al., 1996; Hagino et al., 2001) were
excluded because their samples were already included in
other studies (DeGreef et al., 1992a; Fukuzako and Kodama,
1998; Takahashi et al., 2007, respectively). The study by Scott
et al. (1993) was rejected for not including a healthy
comparison group. Thus 15 studies provided comparative
data from patients with and without CSP (Table 1).
Among the 15 studies analyzed in this review, all
investigated the presence of CSP regardless of its size. The
incidence of CSP ranged from 1.1% (Shioiri et al., 1996) to
89.7% (Takahashi et al., 2008) in healthy volunteers, and from
10.0% (Keshavan et al., 2002) to 89.5% (Takahashi et al., 2008)
in patients with SSD. An increased occurrence of CSP of any
size in patients with schizophrenia was observed both in
chronic (Degreef et al., 1992a; Galarza et al., 2004; Jurjus
et al., 1993; Rajarethinam et al., 2001; Shioiri et al., 1996) and
first-episode SSD subjects (Degreef et al., 1992a; DeLisi et al.,
1993). However, nine out of 15 studies failed to find
significant differences in the prevalence of CSP between SSD
patients and healthy subjects (de Souza Crippa et al., 2006;
Flashman et al., 2007; Fukuzako and Kodama, 1998; Kasai
et al., 2004; Keshavan et al., 2002; Kwon et al., 1998;
Nopoulos et al., 1997; Takahashi et al., 2007, 2008). As
shown in Fig. 2, the presence of CSP of any size did not differ
between individuals with SSDs in comparison with healthy
subjects (odds ratio = 1.19; 95%CI 0.82–1.72; p = 0.37). There
3
was significant between-study heterogeneity for the studies
included in the present meta-analysis (I2 = 56.7%, Q = 32.3,
p b 0.01), and no evidence of publication bias (p = 0.30).
Contradictory results were also evident when considering
the prevalence of large CSPs: rates varied from 0 (Keshavan
et al., 2002) to 11.5% (Takahashi et al., 2008) in healthy
individuals, and from 1.2% (DeLisi et al., 1993) to 26.7%
(Kwon et al., 1998) in SSD patients. Using a qualitative
assessment that consisted of visual inspection (see below),
six (DeGreef et al., 1992a; DeLisi et al., 1993; Flashman et al.,
2007; Galarza et al., 2004; Jurjus et al., 1993; Keshavan et al.,
2002) out of seven articles did not observe differences in the
presence of large CSP between patients and healthy subjects,
while only Shioiri et al. (1996) reported significant results. On
the other hand, with a more quantitative approach, four (de
Souza Crippa et al., 2006; Kasai et al., 2004; Kwon et al., 1998;
Nopoulos et al., 1997) out of nine (de Souza Crippa et al.,
2006; Flashman et al., 2007; Fukuzako and Kodama, 1998;
Kasai et al., 2004; Kwon et al., 1998; Nopoulos et al., 1997;
Rajarethinam et al., 2001; Takahashi et al., 2007, 2008)
studies observed an increased incidence of large CSP in SSD
patients, although the prevalence of CSP of any size did not
differ between patients and healthy volunteers in several
studies (de Souza Crippa et al., 2006; Kasai et al., 2004; Kwon
et al., 1998; Nopoulos et al., 1997). In the random effects
quantitative meta-analysis, patients with SSDs had signifi-
cantly increased rates of large CSP relative to the healthy
group (odds ratio = 1.59; 95%CI 1.07–2.38; p = 0.02), with
patients with schizophrenia or schizoaffective disorder
presenting 1.59 times the incidence of large CSP than healthy
individuals (Fig. 3). Although there was no between-study
heterogeneity (I2 = 0, Q = 13.7, p = 0.47), we found evidence
of publication bias (p b 0.01) across the studies.
We also identified differences in the degree of significance
of between-group differences in regard to the presence of CSP
of any size (Fig. 4), but not specifically in regard to the
prevalence of a large CSP. By carrying out a meta-regression
taking year of publication as a moderator, we verified that,
 4
Table 1
Demographic and clinical characerization of the samples.

Reference Subjects N (M/F) Mean age + SD Duration of Antipsy- Diagnostic Comments / Healthy controls origin
(years) illness (years) chotics criteria

Degreef et al. (1992a) FE SCHZ 62 (33/29) 24.1 ± 5.8 1.0 ± 1.7 drug- RDC CTRL: members of the community, hospital staff
naïve
CHR SCHZ 19 (17/2) 29.1 ± 5.7 9.19 ± 5.6 Yes DSM-III-R
CTRL 46 (22/24) 28.8 ± 7.5 – –
Jurjus et al. (1993) CHR SCHZ 67 (49/18) ND ND ND DSM-III-R CTRL: ND
CTRL 37 (ND) ND
DeLisi et al. (1993) FE SCHZ + SCHZA + SCHZT + 85 (48/37) 26.6 ± 7.3 ND ND DSM-III-R CTRL: members of the community

C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12

NOS
CTRL 47 (29/18) 26.6 ± 6.6
Shioiri et al. (1996) CHR SCHZ 40 (21/19) 32.2 ± 11.3 8.7 ± 9.5 ND DSM-III-R age: difference between groups CTRL: hospital staff and
CTRL 92 (34/98) 38.8 ± 14.0 – members from the comunity
Nopoulos et al. (1997) CHR SCHZ + SCHZA 55 (37/18) 29.7 ± 9.0 ND ND DSM-III-R CTRL: members of the community
CTRL 75 (39/36) 27.3 ± 7.8
Fukuzako and Kodama (1998) CHR SCHZ 72 (53/19) 28.7 ± 9.1 ND Yes DSM-III-R CTRL: members of the community, hospital staff, university students
CTRL 41 (30/11) 32.0 ± 7.9 –
Kwon et al. (1998) CHR SCHZ a 15 (15/0) ND ND ND DSM-III-R CTRL: hospital staff
CTRL a 15 (15/0) ND
Rajarethinam et al. CHR SCHZ 73 (56/17) 35.3 ± 11.5 ND ND DSM-III-R CTRL: members of the community
(2001) CTRL 43 (21/22) 35.6 ± 13.1
Keshavan et al. (2002) FE SCHZ + FE SCHZA 40 (25/15) 24.7 ± 7.5 NA drug- DSM-III-R CTRL: members of the community
naïve
CTRL 59 (29/30) 21.4 ± 7.5 – – DSM-IV
Galarza et al. (2004) CHR SCHZ 32 (0/32) 52.9 ± 9.2 28.0 ± 9.8 Yes DSM-III-R CTRL: ND
CTRL 19 (0/19) 51.1 ± 12.7 –
Kasai et al. (2004) FE SCHZ 33 (28/5) 24.7 ± 6.5 NA Yes DSM-IV CTRL: members of the community
CTRL 56 (44/12) 24.0 ± 3.9 – –
De Souza Crippa et al. CHR SCHZ 38 (26/12) 29.9 ± 10.0 10.3 ± 8.2 Yes DSM-IV CTRL: members of the community
(2006) CTRL 38 (26/12) 29.7 ± 9.7 –
Flashman et al. (2007) CHR SCHZ + SCHZA + NOS 77 (57/20) 34.3 ± 10.5 ND ND DSM-IV CTRL: ND
CTRL 55 (32/33) 32.7 ± 11.0
Takahashi et al. (2007) CHR SCHZ 154 (74/80) 28.0 ± 7.8 5.1 ± 5.5 Yes ICD-10 CTRL: members of the community, hospital staff, university students
CTRL 163 (97/66) 27.0 ± 8.0 – – DSM-IV
Takahashi et al. (2008) FE SCHZ 103 (76/27) 21.2 ± 3.3 0.2 ± 0.2 Yes DSM-III-R gender: M N F in CHR compared with other all groups age:
CHR SCHZ 89 (76/13) 34.9 ± 9.6 12.8 ± 9.9 Yes CHR SCHZ N other groups CTRL: similar sociodemographic areas as pacintes
CTRL 87 (55/32) 26.9 ± 10.1 NA – by hospital staff; members of the community

CHR, chronic; CTRL, controls; CSP, cavum septum pellucidum; DSM, Diagnostic Statistical Manual; F, female; FE, first episode; ICD, International Classification of Diseases; M, male; NA, not applied; ND, not described; NOS,
patients with psychosis not otherwise specified; RDC, Research Diagnostic Criteria; SCHZ, schizophrenics; SCHZA, schizoaffectives; XCHZT, schizotypicals; SD, standard deviation.
a
Number of subjects in the study who were not included in posterior studies in the list.
 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12 5

rs Odds ratio and 95% CI

Fig. 2. The odds ratio of the 15 studies that investigated the prevalence of cavum septum pellucidum of any size in patients with schizophrenia spectrum disorder
and in healthy volunteers. The mean data shows no significant differences between patients and healthy comparison subjects (p N 0.05). CI, confidence interval;
CSP, cavum septum pellucidum; OR, odds ratio.

during the 1990s, the majority of the findings showed higher
prevalence of CSP of any size in SSD patients when compared
to healthy volunteers (Fig. 4). On the other hand, this
significant difference in the incidence rates between patients
and controls disappears when considering all the studies
conducted in 2000s.
4. Discussion
This meta-analysis demonstrates the considerable effort
that has been directed towards investigating the relationship
between CSP and SSD. The results indicate that the occur-
rence of a small-sized CSP may simply reflect normal

Large CSP / Total (N)

Study Patients Healthy Volunteers Odds ratio and 95% CI
Degreef et al. (1993) 2 / 81 0 / 46
Jurjus et al. (1993) 4 / 67 2 / 37
DeLisi et al. (1993) 1 / 85 0 / 47
Shioiri et al. (1996) 2 / 40 0 / 92
Nopoulos et al. (1997) 6 / 55 1 / 75
Fukuzako et al. (1998) 7 / 72 2 / 41
Kwon et al. (1998) 4 / 15 1 / 15
Rajarethinam et al. (2001) 3 / 73 1 / 43
Keshavan et al. (2002) 1 / 40 0 / 59
Galarza et al., (2004) 1 / 32 0 / 19
Kasai et al. (2004) 6 / 33 4 / 56
De Souza Crippa et al. (2006) 8 / 38 1 / 38
Flashman et al. (2007) 11 / 77 5 / 55
Takahashi et al. (2007) 10 / 154 12 / 163
Takahashi et al. (2008) 19 / 192 10 / 87
Total 85 / 1054 39 / 866
0.01 0.10 1.00 10.00 100.00
Healthy volunteers Patients

OR=1.59; 95%CI 1.07-2.38; p=0.02 Test for heterogeneity: I2=0; Q=13.7; p=0.48

Fig. 3. The odds ratio of the 15 studies that investigated the prevalence of large cavum septum pellucidum in patients with schizophrenia spectrum disorder and in
healthy volunteers. The mean data shows significant differences between patients and healthy comparison subjects (p b 0.05). CI, confidence interval; CSP, cavum
septum pellucidum; OR, odds ratio.
6 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
Meta-regression of year on Log odds ratio
3.00
2.50
2.00
1.50
Log odds ratio
1.00
0.50
0.00
-0.50
-1.00
-1.50
1990 1992 1994
Fig. 4. Meta-regression taking year of publication as moderator showing the odds ratio of the prevalence of the cavum septum pellucidum of any size in patients
with schizophrenia spectrum disorder and healthy comparison subjects (Slope = − 0.082; ±s.e. = 0.029; z = − 2.828; p = 0.005). The circle size indicates the
weight of each study; the bigger the stronger.
anatomical variability, since our statistical comparisons failed
to reveal significant differences in the prevalence of CSP of
any size between SSD patients and healthy subjects. On the
other hand, our analyses showed that the incidence of a large
CSP was higher in SSD patients than in healthy volunteers.
We therefore propose that the clinical significance of a CSP
may depend more on its size than whether it is present or
absent, as suggested by Nopoulos et al. (1998) and de Souza
Crippa et al. (2006). In the same way, based on the finding
that an enlarged CSP was more prevalent in individuals at
ultra-high risk for psychosis (Choi et al., 2008) it could also be
speculated that alterations in the cavity indicates an
increased susceptibility to psychosis. Despite this, it is
important to emphasize that an enlarged CSP occurs in only
a subgroup of individuals with schizophrenia, with preva-
lence rates ranging from 4% (Rajarethinam et al., 2001) to 30%
(Kwon et al., 1998), respectively. Therefore, this midline
structural abnormality should at most be regarded as an early
neurodevelopmental risk factor that may be related to the
presence of schizophrenia in a subgroup of patients, rather
than being a strong causative determinant of the disorder.
It is well known that fusion of the septi pellucidi is
associated with rapid growth of the hippocampus, corpus
callosum and other midline structures (Sarwar, 1989; Shaw
and Alvord, 1969) that have consistently been linked to
schizophrenia (Shenton et al., 2001). Therefore, the pres-
ence of CSP in patients with schizophrenia could represent
an early marker of a developmental defect involving these
brain regions. Similarly, it is unlikely that a disturbance in a
localized structure such as the CSP would lead to widespread
manifestations of schizophrenia and other disorders. A more
plausible possibility is that abnormalities in the formation
and maturation of the septum pellucidum are a marker of an
overall aberrance of early neurodevelopment of more
widespread proportions and etiopathological significance
to psychosis.
It is also important to stress that CSP abnormalities are not
specific to schizophrenia or psychosis in general, since these
findings are also observed in other disorders of developmen-
tal origin, such as fetal alcohol syndrome (prevalence of 20%
in patients; Swayze et al., 1997), Sotos (38–40% of the
patients have CSP, being 94–100% CV, Lim and Yoon, 2008;
1996 1998 2000 2002 2004 2006 2008 2010
Year
Schaefer et al., 1997), and Apert's syndrome (prevalence of
15% in patients; Renier et al., 1996). In addition, although the
size and prevalence of CSP are normal in subjects with other
psychiatric conditions such as panic disorder (patients have
76% of any CSP; Crippa et al., 2004), there have been reports of
a higher prevalence of CSP in subjects with first-episode
affective psychosis (any CSP: 81%; large CSP: 15%, Kasai et al.,
2004); bipolar affective disorder (BAD) (any CSP: 7%, Shioiri
et al., 1996) and schizotypal personality disorder (SPD) (large
CSP: 20%, Dickey et al., 2007). Based on this, some authors
have speculated that psychosis associated with schizophrenia
and BAD may share, at least to some extent, neurodevelop-
mental abnormalities involving midline structures (Kasai
et al., 2004) and that SPD may be a milder form on a
continuum of SSD (Kwon et al., 1998).
4.1. Methodological aspects: sample characteristics
The wide discrepancy in the reported prevalence and size
of CSP in association with SSD may be, in great part,
explained by differences in the methodology among the
studies published to date. Similarly, this methodological
variation may have also be the reason for the differences in
the prevalence of CSP of any size during the 1990s and the
2000s. First, not all of the studies used homogeneous
samples of patients (DeLisi et al., 1993; Flashman et al.,
2007; Jurjus et al., 1993; Keshavan et al., 2002; Nopoulos
et al., 1997); i.e., the patient groups in these studies had
more than one disorder and it was not possible to evaluate
the rates in each diagnostic category separately. Besides
schizophrenia, most of the samples also included other
conditions related to psychosis, such as schizotypal person-
ality (DeLisi et al., 1993) and schizoaffective disorder (DeLisi
et al., 1993; Flashman et al., 2007; Jurjus et al., 1993;
Keshavan et al., 2002; Nopoulos et al., 1997). Although some
authors hypothesized that psychosis in general may share,
at least to some extent, neurodevelopmental abnormalities
involving midline structures (Kasai et al., 2004; Kwon et al.,
1998), the variability of the diagnoses across different
studies makes it difficult to compare their results. The
methods for recruitment of healthy comparison groups
could also be considered a source of bias, since most studies
 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
to date recruited hospital staff, university students; or
members of community by advertisements (Table 1). More-
over, some studies did not detail the recruitment of their
healthy control samples (Flashman et al., 2007; Galarza
et al., 2004; Jurjus et al., 1993).
In all but one of the MRI studies to date, the samples of SSD
patients and controls were not matched by sex (Takahashi
et al., 2008). Although the authors of these studies did not
attribute their negative findings to this unbalance, two articles
found that male individuals showed higher incidence of CSP of
any size than female subjects (Jurjus et al., 1993; Nopoulos
et al., 1997). There is also evidence that male patients may
present a higher occurrence of any (Rajarethinam et al., 2001)
or large (de Souza Crippa et al., 2006; Nopoulos et al., 1997)
CSP than male healthy subjects. In contrast to such gender-
related differences, the age of subjects did not seem to
influence the variability of CSP prevalence in samples of SSD,
since none of the MRI studies to date showed significant
correlations between this variable and CSP measures.
There is evidence of volumetric differences in brain
structures in the vicinity of the CSP, such as reduced volume
of the hippocampus and reduced cross-sectional area of the
corpus callosum, when first-episode psychosis patients are
directly compared with chronic patients with SSD (Ellison-
Wright et al., 2008; Meisenzahl et al., 2008). This indicates
that it is also important to control for the duration of illness in
MRI studies when evaluating the CSP in psychotic disorders.
Given that the fusion of the septi pellucidi probably results
from the rapid growth of the hippocampus (Sarwar, 1989;
Shaw and Alvord, 1969), it could be speculated that
volumetric alterations in this brain structure over the course
of time could also lead to changes in morphological
parameters related to the CSP, i.e. length, area and volume.
Indeed, although the septum pellucidum fuses early in life,
there is evidence of higher prevalence of CSP in professional
boxers, probably due to repeated head trauma (Aviv et al.,
2010; Zhang et al., 2003). None of the eight (de Souza Crippa
et al., 2006; DeGreef et al., 1992a; Galarza et al., 2004; Kasai
et al., 2004; Keshavan et al., 2002; Shioiri et al., 1996;
Takahashi et al., 2007, 2008) studies that controlled their
findings for duration of illness in this review found
significant correlations between this variable and measures
of CSP. However, it has been reported that patients with
chronic schizophrenia display higher incidences of large CSP
than healthy individuals, while patients with first-episode
psychosis show an intermediate prevalence (Kwon et al.,
1998).
There is no mention about the use of antipsychotics in
seven studies (DeLisi et al., 1993; Flashman et al., 2007;
Jurjus et al., 1993; Kwon et al., 1998; Nopoulos et al., 1997;
Rajarethinam et al., 2001; Shioiri et al., 1996). This lack of
information regarding treatment status possibly relates to
the view that the presence of CSP is entirely established
during early life, and therefore CSP incidence indices would
not be affected by the use of antipsychotic medications.
Nonetheless, Dickey et al. (2007) suggest that these drugs
may influence measures of CSP, given that the use of these
drugs in SSD have already been related to morphological
alterations in brain regions related to the CSP, such as the
hippocampus (Chakos et al., 2005; McClure et al., 2006) and
corpus callosum (Girgis et al., 2006).
7
4.2. Methodological aspects: experimental designs and
characterization of CSP
The variation in the acquisition parameters across differ-
ent MRI studies may influence the results obtained in the
studies of CSP in SSDs. In relation to the intensity of the
magnetic field, only one study used a 1.0 T scanner (DeGreef
et al., 1992a). In contrast, the other 14 studies used
equipment with magnetic field of 1.5 T, which probably
contributed to improve the quality of the MRI data acquired.
There has been a great degree of variability in the
thickness of MRI slices acquired across different studies to
date, ranging from 0.94 mm (Kasai et al., 2004; Takahashi
et al., 2008) to 5.0 mm (DeLisi et al., 1993; Jurjus et al., 1993;
Shioiri et al., 1996). There is also variation in the inter-slice
gaps across MRI studies, ranging from 1.5 mm (Shioiri et al.,
1996) to 5 mm (Jurjus et al., 1993). Thinner and contiguous
slices are considered the ‘gold-standard’ method, since these
allow more accurate estimates not only of the prevalence of
CSPs, but also their size (Nopoulos et al., 1997). It is well-
known that with thicker slices, such as 3.0 to 5.0 mm, gaps
may occasionally miss small CSPs, as well as leading to partial
volume effects. This factor may have contributed to the
discrepancy in the findings of CSP of any size between the
studies conducted in the 1990s and 2000s, given that the first
studies were carried out with thick and non contiguous slices
(Table 2).
There is also great variation in the way that the studies
determined the presence of the CSP, as well as the parameters
for evaluating whether this cavity is classified as large or not
(Table 2). Concerning the criteria for detection, many authors
have categorized the CSP using a qualitative approach,
consisting of both visual inspection and ranking findings on
grades of severity. Scales of severity are often created for each
study individually, and are established from previous knowl-
edge about characteristics of the CSPs. These scales may range
from 0 (absent CSP) to 3 (severe CSP) (DeGreef et al., 1992a;
DeLisi et al., 1993); from 1 (absent CSP) to 3 (severe CSP)
(Keshavan et al., 2002); and from 0 (absent CSP) to 4 (severe
CSP), with five distinctive levels (Flashman et al., 2007; Jurjus
et al., 1993; Shioiri et al., 1996). Using a different approach,
Galarza et al. (2004) used embryological types of CSP (from I
to III) as parameters for rating the severity of the cavity.
Thereafter, each CSP of the sample is classified according to its
size, and placed in the appropriated category. Limitations in
such qualitative forms of assessing CSPs may contribute to the
contradictory findings among the articles published to date,
as the scales differ across studies and the ratings given by
each examiner are somewhat subjective.
In order to minimize these discrepancies, recent studies
have adopted more quantitative methods for classifying the
CSP, by counting the number of slices in which the cavity
clearly appears, especially on coronal MRI views. When this
technique is used, the number of slices can be multiplied by
their thickness, allowing the calculation of the anterior-to-
posterior length of the CSP. This methodology, now consid-
ered the state-of-art technique to assess the presence and
severity of CSP, was first used by Nopoulos et al. (1996), and
employed in most of the subsequent studies (de Souza Crippa
et al., 2006; Flashman et al., 2007; Kasai et al., 2004; Kwon
et al., 1998; Nopoulos et al., 1997; Rajarethinam et al., 2001;
 8
C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
Table 2
Magnetic resonance imaging studies of the csp in schizophrenia spectrum.

References Magnetic Slice length / Criteria of Criteria of Subjects Prevalence Prevalence Measures Findings Comments
Field (T) gap (mm) detection of CSP large CSP of any of large of CSP
CSP (%) a CSP (%) b (prevalence)

Degreef et al. 1.0 3.1 Visual inspection based Grade 3 FE SCHZ 34.5 3.2 any CSP ↑ in FE and in
(1992a) on a grade (0–3) CHR x
CHR SCHZ 26.3 0 Grade 3 CTRL
CTRL 15.2 0 NS
Jurjus et al. 1.5 5.0 / 5.0 Visual inspection based Grade 4 CHR SCHZ 25.4 6.0 any CSP NS male had higher rates of CSP than
(1993) on a grade (0–4) CTRL 18.9 5.4 Grade 3–4 NS female subjects
DeLisi et al. 1.5 5.0 / 2.0 Visual inspection based Grade 3 FE SCHZ 44.7 1.2 any CSP ↑ in psychotics NS differences between CSP grades
(1993) on a grade (0–3) + SCHZA and the size of ventricles, TC and
+ SCHZT CC or asymetries
+ NOS
CTRL 29.8 0 Grade 3 NS
Shioiri et al. 1.5 5.0 / 1.5 Visual inspection based Grade 4 CHR SCHZ 17.5 5.0 any CSP ↑ in SCHZ x CTRL
(1996) on a grade (0–4) CTRL 1.1 0 Grade 3–4 ↑ in SCHZ x CTRL
Nopoulos et al. 1.5 1.5 Number of 1.5 mm slices in N 4 slices CHR SCHZ 58.2 10.1 any CSP NS male had higher incedence of any
(1997) which CSP was visualized + SCHZA CSP than female subjects male
(N6 mm) CTRL 58.7 1.3 large CSP ↑ in psychotics psychotics had higher incidence of
large CSP than male CTRL
Fukuzako and 1.5 1.0 Number of 1 mm slices in N 5 mm CHR SCHZ 47.2 9.7 any CSP NS SCHZ with long-term admissions
Kodama (1998) which CSP was visualized CTRL 39.0 4.9 large CSP NS had higher incidence of CSP
Kwon et al. 1.5 1.5 Number of 1.5 mm slices N 4 slices CHR SCHZ 73.3 26.7 any CSP NS number of slices of CSP negatively
(1998) in which CSP was visualized Nopoulos CTRL 86.7 6.7 large CSP ↑ in SCHZ x CTRL ↑ correlated with left and right vol.
et al. (1997) Nopoulos in SCHZ x CTRL of hippocampus in CHR SCHZ
criteria criteria (trend)
Rajarethinam 1.5 1.0 Number of 1 mm N 6 slices CHR SCHZ 60.3 4.1 any CSP ↑ in SCHZ male SCHZ had higher incidence of
et al. (2001) slices in which CSP any CSP than male CTRL
was visualized (N6 mm) CTRL 41.9 2.3 large CSP NS male CTRL
 Keshavan 1.5 3.0 Visual inspection based Grade 3 FE SCHZ+FE SCHZA 10.0 2.5 any CSP NS
et al. (2002) on a grade (1–3) CTRL 11.9 0 Grade 3 NS
Galarza et al. 1.5 1.0 Based on embryological NA CHR SCHZ 43.8 NA any CSP ↑ in SCHZ
(2004) types (I–III) CTRL 10.5 NA Type I NS
Type II NS
Type III NS
Kasai et al. 1.5 0.94 Number of 0.94 mm slices N 6 slices FE SCHZ 59.0 18.2 any CSP NS SCHZ: number of slices of CSP
(2004) in which CSP was visualized (N5.6 mm) CTRL 81.7 7.1 large CSP ↑ in SCHZ × CTRL positively correlated with thinking
disturbance; CSP rating negatively
correlated with left PHG volume
De Souza Crippa 1.5 1.0 Number of 1 mm slices in N 6 slices CHR SCHZ 78.9 21.1 any CSP NS 1 SCHZ had carvum vergae Large CSP
et al. (2006) which CSP was visualized (N6 mm) CTRL 86.8 2.6 length NS commoner in male SCHZ than male
large CSP ↑ in SCHZ CTRL Large CSP not associated with
vol NS absent adhesio interthalamic
Flashman 1.5 1.0 Visual inspection based Grade 4N CHR SCHZ 68.8 14.3 any CSP NS large CSP psychotics showed worse
et al. (2007) on a grade (0–4) Number + SCHZA performance on CVLT-II CSP length
of 1 mm slices in which + NOS positively correlated with negative

C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12

CSP was visualized 6 slices CTRL 76.4 9.1 length NS symptoms (SANS) CSP length positively
(N6 mm) correlated with reaction time and
grade 4 NS vigilance of the CPT in psychotics;
large CSP NS negatively correlated in CTRL
Takahashi et al. 1.5 1.0 Number of 1 mm slices in N 6 slices CHR SCHZ 76.0 6.5 any CSP NS large CSP psychotics showed ↓
(2007) which CSP was visualized (N6 mm) CTRL 81.6 7.4 length NS bilateral amygdala and left posterior
large CSP NS PHG vol. x psychotics with small CSP
Takahashi et al. 1.5 0.94 Number of 0.94 mm slices N 6 slices FE SCHZ 89.5 9.3 any CSP NS CSP length negatively correlated with
(2008) in which CSP was visualized (N5.6 mm) CHR SCHZ 87.6 11.2 length NS amygdala and left posterior PHG vol.
CTRL 89.7 11.5 large CSP NS in psychotics

↓, decreased; ↑, increased; CC, corpus callosum; CHR, chronic; CPT, Continuous Performance Test; CSP, cavum septum pellucidum; CTRL, controls; CVLT-II, The California Verbal Learning Test II; FE, first episode; L, left; mm,
millimeter; NA, not applied; ND, not described; NOS, patients with psychosis not otherwise specified; NS, no significant; PHG, parahippocampal gyrus; R, right; SANS, scale for the assessment of negative symptoms; SCHZ,
schizophrenics; SCHZA, schizoaffectives; T, Tesla; TC, temporal cortex; vol., volume.
a
The prevalence was calculated as follows: 100 × (number of subjects with any CSP/number of all subjects).
b
The prevalence was calculated as follows: 100 × (number of subjects with large CSP/number of all subjects).

9
10 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
Takahashi et al., 2007, 2008). This has proven to be the most
sensitive and reliable way to classify CSP (Kwon et al., 1998;
Nopoulos et al., 1997).
Despite the advances brought by this more quantitative
method, there are still conflicting results among the studies
that employed such technique. Six out of nine research
reports observed higher prevalence of large CSP in SSD
patients relative to healthy individuals (de Souza Crippa et al.,
2006; Fukuzako and Kodama, 1998; Kasai et al., 2004; Kwon
et al., 1998; Nopoulos et al., 1997). Such disagreement could
be explained by the variability of criteria for determining the
definition of a large CSP across studies, as well as clinical and
demographic differences among samples. Fukuzako and
Kodama (1998) defined a large CSP as a cavity visible in
more than five 1 mm MRI slices (i.e., N5 mm). However,
based on post-mortem findings (Shunk, 1963), most authors
have defined CSPs with anterior-to-posterior length spanning
6 or more millimeters as large. Therefore, in both studies in
which the thickness of the contiguous slices was 1.5 mm, the
authors considered cavities greater than or equal to 4 slices as
large (≥6 mm; Kwon et al., 1998; Nopoulos et al., 1997).
When the thickness of the slices was 0.94 (Kasai et al., 2004;
Takahashi et al., 2008) or 1.0 mm contiguous, CSPs were
classified as large when greater or equal to 6 slices (≥5.6–
6.00 mm; de Souza Crippa et al., 2006; Flashman et al., 2007;
Kasai et al., 2004; Rajarethinam et al., 2001; Takahashi et al.,
2007, 2008).
4.3. Correlations with quantitative and qualitative variables
Considering all the CSP studies in SSD, including post-
mortem investigations, there have been reports correlating
the presence of CSP in SSD patients to poor prognosis
(Fukuzako and Kodama, 1998) and a family history of
psychosis (Uematsu and Kaiya, 1989). Moreover, small CSPs
have been previously linked to decreased volume of the
frontal and temporal lobe tissues (Nopoulos et al., 1996).
Although not always replicated, the presence of large CSP in
SSD has also been associated with reduced IQ (Nopoulos et al.,
2000), more negative symptoms (Flashman et al., 2007) and
more severe thinking disturbance (Kasai et al., 2004), higher
suicide rates (Filipović et al., 2005), higher rates of exposure
to in utero infection (Brown et al., 2009) and greater cognitive
deficits (Flashman et al., 2007; Nopoulos et al., 2000).
Moreover, although our group failed to find an association
between the presence of CSP and patterns of autonomic
system activity in subjects with schizophrenia (Crippa et al.,
2007), it was demonstrated that patients with large CSP had
more pronounced right N left brain volume asymmetry and
reduced volumes of the left temporal lobe (Nopoulos et al.,
1996), bilateral hippocampus (Kwon et al., 1998), bilateral
amygdala and left parahippocampal gyrus relative to controls
(Kasai et al., 2004; Takahashi et al., 2007). Taken together,
these findings suggest that patients with a large CSP may have
greater psychopathological impairment, possibly reflecting
distinct patterns of disturbed brain morphology.
4.4. Limitations
The main difficulty in analyzing the 15 articles included in
the meta-analysis arose from the wide variation in the
methodological variables across studies, as discussed above.
Additionally, even though these MRI investigations were
rigorous in many ways—particularly the recent ones—few of
them reached satisfactory criteria for inclusion in the meta-
analysis, both in respect to the clinical and demographic
characteristics of the samples studied, and in the parameters
of image acquisition. The less than ideal use of thick slices
(3.0–5.0 mm) and inter-slice gaps in the imaging acquisition
protocols, variability in the criteria used for categorizing CSP,
and the use of samples unmatched for critical demographic
variables are among the factors likely to add variability to the
findings reported across different studies. Using optimal
inclusion criteria regarding the number of SSD patients
included (N20 subjects), an adequate matching between the
samples of patients and controls, acquisition of thinner and
contiguous slices (≤1.0 mm), and quantitative analysis of CSP
size, five well-designed studies can be selected from the
literature (de Souza Crippa et al., 2006; Flashman et al., 2007;
Kasai et al., 2004; Rajarethinam et al., 2001; Takahashi et al.,
2007). Four out of five of these studies failed to find a higher
incidence of CSP of any size in SSD compared to healthy
individuals (Table 2). This reinforces the proposition that the
presence of a small CSP should be considered part of the
normal neuroanatomical variability (Nopoulos et al., 1997).
However, only two of these papers observed higher preva-
lence of large CSP in patients (de Souza Crippa et al., 2006;
Kasai et al., 2004).
It is important to highlight some limitations of the present
review. As with all meta-analyses, the findings are dependent
on the quality of the primary studies. We excluded duplicated
samples and results when there was indication of more than
one publication based on the same dataset. However, we
cannot exclude the possibility that our findings were
influenced by confounding factors, or methodological het-
erogeneity among the articles. In addition, several types of
study bias could arise during publication of the primary
studies (Naylor, 1997). In our meta-analysis, we detected
evidence of publication bias across the studies concerning the
prevalence of large CSP. This phenomenon is related to the
fact that articles which report positive or significant results
are more likely to be published than studies reporting
negative findings (Dwan et al., 2008). As observed in Fig. 3,
although most of the 15 studies included in this review point
to higher prevalence of large CSP in SSP, the last two
(Takahashi et al., 2007, 2008), which included a large number
of patients, show negative results. We believe that this is the
reason for the significant value related to the publication bias
we found. Although this finding does not invalidate our
analysis, it casts doubts on the real implication of large CSP in
SSD.
4.5. Conclusion
In summary, the results of the present meta-analysis
suggest that there is no increase in the prevalence of CSP of
any size in SSD patients. In terms of a large CSP, the published
literature suggests this is more common in SSD patients,
however there is also evidence that studies finding the
opposite result may have not been published. Thus, further
investigations are warranted to reconcile some conflicting
findings in the literature to date. First, there is a need for
 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
studies evaluating the prevalence of psychosis in large,
community-based samples of individuals presenting with
CSP. Second, since many clinical aspects of SSD are hetero-
geneous, standardizantion of MRI methodology and clear
reporting of clinical variables such as duration of illness and
medication use is advisible. Given that the fusion of the septi
pellucidi is associated with hippocampal growth, volumetric
alterations in the later, over the course of time or due to
antipsychotic use could also lead to changes in morphological
parameters related to the CSP, even in adulthood. Finaly, a
more judicious selection of the subjects—such as in first
episode psychosis population-based investigations with
longitudinal designs, is likely to generate more reliable
conclusions concerning the role of CSP in SSD, as well as
elucidating the complex clinical and functional effects of this
neurodevelopmental anomaly.
Role of funding source
Supported in part by grants from ‘Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior’(CAPES-Brazil, process number 5797/09-8),
‘Conselho Nacional de Desenvolvimento Científico e Tecnológico’ (CNPq-
Brazil) and from ‘Fundação de Amparo à Pesquisa do Estado de São Paulo
fellowship’ (FAPESP-Brazil). JASC, GFB, JECH and AWZ are recipients of a
CNPq (Brazil) fellowship Award. The funding agencies had no further role in
study design; in the collection, analysis and interpretation of data; in the
writing of the report; and in the decision to submit the paper for publication.
Contributors
CT participated the literature review, the data extraction and drafted the
first manuscript. JASC and JECH participated in the conception and provided
scientific supervision. IRO and MJK provided statistical advice and scientific
supervision. MCFF, ASF and DAP helped to draft manuscript. AGA and MHNC
contributed data extraction, literature review and made contributions to the
written manuscript. MJK, PKM, GBF and AWZ contributed content knowl-
edge and made contribuitions to the written manuscript. All authors read
and approved the final manuscript.
Conflict of interest
The authors declare that they have no competing interests.
Acknowledgement
We thank to Prof. Tsutomu Takahashi and Kiyoto Kasai, who kindly
provided the raw data necessary for our analysis.
References
Aviv, R.I., Tomlinson, G., Kendall, B., Thakkar, C., Valentine, A., 2010. Cavum
septi pellucidi in boxers. Can. Assoc. Radiol. J. 61 (1), 29–32.
Borenstein, M., Hedges, L., Higgins, J., Rothstein, H., 2009. Comprehensive
meta-analysis. Available at: http://www.meta-analysis.com/.
Brown, A.S., Deicken, R.F., Vinogradov, S., Kremen, W.S., Poole, J.H., Penner, J.D.,
Kochetkova, A., Kern, D., Schaefer, C.A., 2009. Prenatal infection and cavum
septum pellucidum in adult schizophrenia. Schizophr. Res. 108, 285–287.
Cannon, T.D., van Erp, T.G., Bearden, C.E., Loewy, R., Thompson, P., Toga, A.W.,
Huttunen, M.O., Keshavan, M.S., Seidman, L.J., Tsuang, M.T., 2003. Early
and late neurodevelopmental influences in the prodrome to schizophre-
nia: contributions of genes, environment, and their interactions.
Schizophr. Bull. 29 (4), 653–669.
Chakos, M.H., Schobel, S.A., Gu, H., Gerig, G., Bradford, D., Charles, C.,
Lieberman, J.A., 2005. Duration of illness and treatment effects on
hippocampal volume in male patients with schizophrenia. Br. J.
Psychiatry 186, 26–31.
Choi, J.S., Kang, D.H., Park, J.Y., Jung, W.H., Choi, C.H., Chon, M.W., Jung, M.H.,
Lee, J.M., Kwon, J.S., 2008. Cavum septum pellucidum in subjects at ultra-
high risk for psychosis: compared with first-degree relatives of patients
with schizophrenia and healthy volunteers. Prog. Neuropsychopharma-
col. Biol. Psychiatry 32 (5), 1326–1330.
Crippa, J.A., Uchida, R., Busatto, G.F., Guimarães, F.S., Del-Ben, C.M., Zuardi, A.W.,
Santos, A.C., Araújo, D., McGuire, P.K., Graeff, F.G., 2004. The size and
11
prevalence of the cavum septum pellucidum are normal in subjects with
panic disorder. Braz. J. Med. Biol. Res. 37 (3), 371–374.
Crippa, J.A., Waldo Zuardi, A., Trzesniak, C., Hallak, J.E., Busatto, G.F., McGuire,
P.K., 2007. No association between electrodermal hyporesponsivity and
enlarged cavum septi pellucidi in schizophrenia. Schizophr. Res. 95 (1–
3), 256–258.
de Souza Crippa, J.A., Zuardi, A.W., Busatto, G.F., Sanches, R.F., Santos, A.C.,
Araújo, D., Amaro, E., Hallak, J.E., Ng, V., McGuire, P.K., 2006. Cavum
septum pellucidum and adhesio interthalamica in schizophrenia: an MRI
study. Eur. Psychiatry 21 (5), 291–299.
Degreef, G., Bogerts, B., Falkai, P., Greve, B., Lantos, G., Ashtari, M., Lieberman,
J., 1992a. Increased prevalence of the cavum septum pellucidum in
magnetic resonance scans and post-mortem brains of schizophrenic
patients. Psychiatry Res. 45 (1), 1–13.
Degreef, G., Lantos, G., Bogerts, B., Ashtari, M., Lieberman, J., 1992b.
Abnormalities of the septum pellucidum on MR scans in first-episode
schizophrenic patients. AJNR Am. J. Neuroradiol. 13 (3), 835–840.
DeLisi, L.E., 1997. Is schizophrenia a lifetime disorder of brain plasticity,
growth and aging? Schizophr. Res. 23 (2), 119–129.
DeLisi, L.E., Hoff, A.L., Kushner, M., Degreef, G., 1993. Increased prevalence of
cavum septum pellucidum in schizophrenia. Psychiatry Res. 50 (3),
193–199.
Dickey, C.C., McCarley, R.W., Xu, M.L., Seidman, L.J., Voglmaier, M.M.,
Niznikiewicz, M.A., Connor, E., Shenton, M.E., 2007. MRI abnormalities
of the hippocampus and cavum septi pellucidi in females with
schizotypal personality disorder. Schizophr. Res. 89, 49–58.
Dwan, K., Altman, D.G., Arnaiz, J.A., Bloom, J., Chan, A.W., Cronin, E., Decullier,
E., Easterbrook, P.J., Von Elm, E., Gamble, C., Ghersi, D., Ioannidis, J.P.,
Simes, J., Williamson, P.R., 2008. Systematic review of the empirical
evidence of study publication bias and outcome reporting bias. PLoS ONE
28 (3), e3081 (8).
Egger, M., Davey Smith, G., Schneider, M., Minder, C., 1997. Bias in
metaanalysis detected by a simple, graphical test. Bmj 315 (7109),
629–634.
Ellison-Wright, I., Glahn, D.C., Laird, A.R., Thelen, S.M., Bullmore, E., 2008. The
anatomy of first-episode and chronic schizophrenia: an anatomical
likelihood estimation meta-analysis. Am. J. Psychiatry 165 (8),
1015–1023.
Filipović, B., Kovacević, S., Stojicić, M., Prostran, M., Filipović, B., 2005.
Morphological differences among cavum septi pellucidi obtained in
patients with schizophrenia and healthy individuals: forensic implica-
tions. A post-mortem study. Psychiatry Clin. Neurosci. 59 (1), 106–108.
Flashman, L.A., Roth, R.M., Pixley, H.S., Cleavinger, H.B., McAllister, T.W.,
Vidaver, R., Saykin, A.J., 2007. Cavum septum pellucidum in schizophre-
nia: clinical and neuropsychological correlates. Psychiatry Res. 154 (2),
147–155.
Fukuzako, H., Kodama, S., 1998. Cavum septum pellucidum in schizophrenia.
Biol. Psychiatry 43 (6), 467.
Fukuzako, T., Fukuzako, H., Kodama, S., Hashiguchi, T., Takigawa, M., 1996.
Cavum septum pellucidum in schizophrenia: a magnetic resonance
imaging study. Psychiatry Clin. Neurosci. 50 (3), 125–128.
Galarza, M., Merlo, A.B., Ingratta, A., Albanese, E.F., Albanese, A.M., 2004.
Cavum septum pellucidum and its increased prevalence in schizophre-
nia: a neuroembryological classification. J. Neuropsychiatry Clin. Neu-
rosci. 16 (1), 41–46.
Girgis, R.R., Diwadkar, V.A., Nutche, J.J., Sweeney, J.A., Keshavan, M.S., Hardan, A.Y.,
2006. Risperidone in first-episode psychosis: a longitudinal, exploratory
voxel-based morphometric study. Schizophr. Res. 82 (1), 89–94.
Hagino, H., Suzuki, M., Kurokawa, K., Mori, K., Nohara, S., Takahashi, T.,
Yamashita, I., Yotsutsuji, T., Kurachi, M., Seto, H., 2001. Magnetic
resonance imaging study of the cavum septi pellucidi in patients with
schizophrenia. Am. J. Psychiatry 158 (10), 1717–1719.
Hallak, J.E., Crippa, J.A., Pinto, J.P., Machado de Sousa, J.P., Trzesniak, C.,
Dursun, S.M., McGuire, P., Deakin, J.F., Zuardi, A.W., 2007. Total agenesis
of the corpus callosum in a patient with childhood-onset schizophrenia.
Arq. Neuropsiquiatr. 65 (4B), 1216–1219.
Harrison, P.J., Weinberger, D.R., 2005. Schizophrenia genes, gene expression,
and neuropathology: on the matter of their convergence. Mol. Psychiatry
10 (1), 40–68 (image 5).
Jurjus, G.J., Nasrallah, H.A., Olson, S.C., Schwarzkopf, S.B., 1993. Cavum
septum pellucidum in schizophrenia, affective disorder and healthy
controls: a magnetic resonance imaging study. Psychol. Med. 23 (2),
319–322.
Kasai, K., McCarley, R.W., Salisbury, D.F., Onitsuka, T., Demeo, S., Yurgelun-
Todd, D., Kikinis, R., Jolesz, F.A., Shenton, M.E., 2004. Cavum septi
pellucidi in first-episode schizophrenia and first-episode affective
psychosis: an MRI study. Schizophr. Res. 71 (1), 65–76.
Kempton, M.J., Stahl, D., Williams, S.C., DeLisi, L.E., 2010. Progressive lateral
ventricular enlargement in schizophrenia: a meta-analysis of longitudi-
nal MRI studies. Schizophr. Res. 120 (1–3), 54–62.
12 C. Trzesniak et al. / Schizophrenia Research 125 (2011) 1–12
Keshavan, M.S., Jayakumar, P.N., Diwadkar, V.A., Singh, A., 2002. Cavum septi
pellucidi in first-episode patients and young relatives at risk for
schizophrenia. CNS Spectr. 7 (2), 155–158.
Kuloglu, M., Caykoylu, A., Yilmaz, E., Ekinci, O., 2008. A left temporal lobe
arachnoid cyst in a patient with schizophrenia-like psychosis: a case
report. Prog. Neuropsychopharmacol. Biol. Psychiatry 32 (5),
1353–1354.
Kwon, J.S., Shenton, M.E., Hirayasu, Y., Salisbury, D.F., Fischer, I.A., Dickey, C.C.,
Yurgelun-Todd, D., Tohen, M., Kikinis, R., Jolesz, F.A., McCarley, R.W.,
1998. MRI study of cavum septi pellucidi in schizophrenia, affective
disorder, and schizotypal personality disorder. Am. J. Psychiatry 155 (4),
509–515.
Lim, J.J., Yoon, S.H., 2008. The first neurosurgical analysis of 8 Korean children
with Sotos syndrome. J. Korean Neurosurg. Soc. 44 (4), 240–244.
McClure, R.K., Phillips, I., Jazayerli, R., Barnett, A., Coppola, R., Weinberger, D.R.,
2006. Regional change in brain morphometry in schizophrenia associated
with antipsychotic treatment. Psychiatry Res. 148 (2–3), 121–132.
Meisenzahl, E.M., Koutsouleris, N., Bottlender, R., Scheuerecker, J., Jäger, M.,
Teipel, S.J., Holzinger, S., Frodl, T., Preuss, U., Schmitt, G., Burgermeister,
B., Reiser, M., Born, C., Möller, H.J., 2008. Structural brain alterations at
different stages of schizophrenia: a voxel-based morphometric study.
Schizophr. Res. 104 (1–3), 44–60.
Murray, R.M., Lewis, S.W., 1987. Is schizophrenia a neurodevelopmental
disorder? Brit. Med. J. 295 (6600), 681–682.
Naylor, C.D., 1997. Meta-analysis and the meta-epidemiology of clinical
research. Br. Med. J. 315, 617–619.
Nopoulos, P., Swayze, V., Andreasen, N.C., 1996. Pattern of brain morphology
in patients with schizophrenia and large cavum septi pellucidi. J.
Neuropsychiatry Clin. Neurosci. 8 (2), 147–152.
Nopoulos, P., Swayze, V., Flaum, M., Ehrhardt, J.C., Yuh, W.T., Andreasen, N.C.,
1997. Cavum septi pellucidi in normals and patients with schizophrenia
as detected by magnetic resonance imaging. Biol. Psychiatry 41 (11),
1102–1108.
Nopoulos, P.C., Giedd, J.N., Andreasen, N.C., Rapoport, J.L., 1998. Frequency
and severity of enlarged cavum septi pellucidi in childhood-onset
schizophrenia. Am. J. Psychiatry 155 (8), 1074–1079.
Nopoulos, P., Krie, A., Andreasen, N.C., 2000. Enlarged cavum septi pellucidi
in patients with schizophrenia: clinical and cognitive correlates. J.
Neuropsychiatry Clin. Neurosci. 12 (3), 344–349.
Pantelis, C., Yücel, M., Wood, S.J., McGorry, P.D., Velakoulis, D., 2003. Early
and late neurodevelopmental disturbances in schizophrenia and their
functional consequences. Aust. N.Z.J. Psychiatry 37 (4), 399–406.
Pantelis, C., Yücel, M., Wood, S.J., Velakoulis, D., Sun, D., Berger, G., Stuart, G.W.,
Yung, A., Phillips, L., McGorry, P.D., 2005. Structural brain imaging evidence
for multiple pathological processes at different stages of brain development
in schizophrenia. Schizophr. Bull. 31 (3), 672–696.
Pratt, H.D., 2002. Neurodevelopmental issues in the assessment and
treatment of deficits in attention, cognition, and learning during
adolescence. Adolesc. Med. 13 (3), 579–598.
Rajarethinam, R., Miedler, J., DeQuardo, J., Smet, C.I., Brunberg, J., Kirbat, R.,
Tandon, R., 2001. Prevalence of cavum septum pellucidum in schizo-
phrenia studied with MRI. Schizophr. Res. 48 (2–3), 201–205.
Rajarethinam, R., Sohi, J., Arfken, C., Keshavan, M.S., 2008. No difference in
the prevalence of cavum septum pellucidum (CSP) between first-
episode schizophrenia patients, offspring of schizophrenia patients and
healthy controls. Schizophr. Res. 103 (1–3), 22–25.
Rakic, P., Yakovlev, P.I., 1968. Development of the corpus callosum and
cavum septi in man. J. Comp. Neurol. 132 (1), 45–72.
Rapoport, J.L., Addington, A.M., Frangou, S., Psych, M.R., 2005. The
neurodevelopmental model of schizophrenia: update 2005. Mol.
Psychiatry 10 (5), 434–449.
Renier, D., Arnaud, E., Cinalli, G., Sebag, G., Zerah, M., Marchac, D., 1996. Prognosis
for mental function in Apert's syndrome. J. Neurosurg. 85 (1), 66–72.
Sarwar, M., 1989. The septum pellucidum: normal and abnormal. Am. J.
Neuroradiol. 10 (5), 989–1005.
Schaefer, G.B., Bodensteiner, J.B., Buehler, B.A., Lin, A., Cole, T.R., 1997. The
neuroimaging findings in Sotos syndrome. Am. J. Med. Genet. 68 (4),
462–465.
Scott, T.F., Price, T.R., George, M.S., Brillman, J., Rothfus, W., 1993. Midline
cerebral malformations and schizophrenia. J. Neuropsychiatry Clin.
Neurosci. 5 (3), 287–293.
Shaw, C.M., Alvord Jr., E.C., 1969. Cava septi pellucidi et vergae: their normal
and pathogical states. Brain 92 (1), 213–223.
Shenton, M.E., Dickey, C.C., Frumin, M., McCarley, R.W., 2001. A review of MRI
findings in schizophrenia. Schizophr. Res. 49 (1–2), 1–52.
Shioiri, T., Oshitani, Y., Kato, T., Murashita, J., Hamakawa, H., Inubushi, T.,
Nagata, T., Takahashi, S., 1996. Prevalence of cavum septum pellucidum
detected by MRI in patients with bipolar disorder, major depression and
schizophrenia. Psychol. Med. 26 (2), 431–434.
Shunk, H., 1963. Congenital dilatations of the septi pellucidum. Radiology 81,
610–618.
Swayze II, V.W., Johnson, V.P., Hanson, J.W., Piven, J., Sato, Y., Giedd, J.N.,
Mosnik, D., Andreasen, N.C., 1997. Magnetic resonance imaging of brain
anomalies in fetal alcohol syndrome. Pediatrics 99 (2), 232–240.
Takahashi, T., Suzuki, M., Hagino, H., Niu, L., Zhou, S.Y., Nakamura, K., Tanino,
R., Kawasaki, Y., Seto, H., Kurachi, M., 2007. Prevalence of large cavum
septi pellucidi and its relation to the medial temporal lobe structures in
schizophrenia spectrum. Prog. Neuropsychopharmacol. Biol. Psychiatry
31 (6), 1235–1241.
Takahashi, T., Yung, A.R., Yücel, M., Wood, S.J., Phillips, L.J., Harding, I.H., Soulsby,
B., McGorry, P.D., Suzuki, M., Velakoulis, D., Pantelis, C., 2008. Prevalence of
large cavum septi pellucidi in ultra high-risk individuals and patients with
psychotic disorders. Schizophr. Res. 105 (1–3), 236–244.
Thompson, S.G., Smith, T.C., Sharp, S.J., 1997. Investigating underlying risk as
a source of heterogeneity in meta-analysis. Stat. Med. 16, 2741–2758.
Uematsu, M., Kaiya, H., 1989. Midsagittal cortical pathomorphology of
schizophrenia: a magnetic resonance imaging study. Psychiatry Res. 30
(1), 11–20.
Weinberger, D.R., 1987. Implications of normal brain development for the
pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44 (7), 660–669.
Zhang, L., Ravdin, L.D., Relkin, N., Zimmerman, R.D., Jordan, B., Lathan, W.E.,
Uluğ, A.M, 2003. Increased diffusion in the brain of professional boxers: a
preclinical sign of traumatic brain injury? AJNR Am. J. Neuroradiol. 24
(1), 52–57.