Second edition

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In this regard one may recall Bleuler’s opinion (Bleuler 1950)
that a full cure, a restitutio ad integrum, never occurs;
although he saw ‘far reaching improvements’ to the point of
‘social restitution’, he was always able, upon careful examination,
to ‘see distinct signs of the disease’.
Etiology
Both computed tomographic (CT) and magnetic resonance
imaging (MRI) studies have amply demonstrated
the presence of ventricular dilation and cortical atrophy,
most prominently in the temporal cortex (Andreasen et al.
1990b; Chua and McKenna 1995; Jaskiw et al. 1994;
Nopoulos et al. 1995; Suddah et al. 1989; Turner et al.
1986). Furthermore, several studies have also demonstrated
a correlation between the degree of atrophy seen in
the left temporal cortex and the severity of such psychotic
symptoms as loosening of associations and auditory hallucinations
(Barta et al. 1990; Hirayasu et al. 2000; Menon
et al. 1995; Shenton et al. 1992). Autopsy studies support
the results of neuroimaging, demonstrating a reduced volume
in the medial temporal lobe structures (Bogerts et al.
1985, 1990) and a prominence of ventricular enlargement
in the temporal horn (Crow et al. 1989).
Microscopic studies have demonstrated the presence of
an excessive number of interstitial neurons within the
white matter (Akbarian et al. 1993a,b, 1996; Rioux et al.
2003) and neuronal disarray within the temporal lobe,
specifically the hippocampus (Conrad et al. 1991).
Furthermore, although not without controversy, some
subcortical structures may suffer neuronal loss (Byne et al.
2002; Kreczmanski et al. 2007). Strikingly, and importantly,
gliosis is absent (Bogerts et al. 1985; Bruton et al.
1990; Roberts et al. 1987).
Although the mechanism underlying these anatomic
changes is not known with certainty, it is strongly suspected
that they represent a disorder of neuronal migration.
In the normal course of development, neurons
migrate along radial glial fibers from the ventricular area
through the embryonic white matter to the overlying cortical
subplate, where they come to rest in an orderly fashion
to create the laminated cortex. Furthermore, and again
normally, a small number of these neurons fail to migrate
through the white matter and remain there as interstitial
neurons. The findings noted above of an increased number
of interstitial neurons and neuronal disarray in the cortex
are consistent with the hypothesis of a failure of normal
migration in schizophrenia.
The mechanism underlying such a failure of normal
migration, although not clear, may involve one or more
environmental insults acting on a genetically determined
vulnerability. As noted earlier, schizophrenia occurs in
about 1 percent of the general population; however,
among first-degree relatives the prevalence rises to about 5
percent, whereas among dizygotic twins it is about 20 percent
and among monozygtic twins the concordance rate
20.1 Schizophrenia 611
rises to about 50 percent. Furthermore, adoption studies
have made clear that the increased prevalence in firstdegree
relatives reflects genetic and not environmental factors
(Kendler and Gruenberg 1984; Kety 1987; Tienari et al.
2003). Of course, genetics cannot explain the entire picture
or one would expect a much higher concordance rate in
monozygotic twins, and consequently one must look to
environmental factors. Several have been proposed,
including obstetrical complications (Kendell et al. 1996),
maternal malnutrition (Susser and Lin 1992), and in utero
exposure to certain viral illnesses (Murray 1994), for example
influenza and rubella (Brown et al. 2001). All of these
factors can cause disorders of neuronal migration, and it
may be that what is inherited in schizophrenia is not the
disease per se but rather a defect that renders the fetal brain
particularly vulnerable to certain of these factors.
If indeed the neuropathology of schizophrenia represents
a non-progressive disorder of neuronal migration,
one must also explain why the onset of the disease is
delayed until the late teenage or early adult years. One
hypothesis is that the phenotypic expression of the disease
is dependent upon an interaction between the fixed neuronal
migration defect and the normally evolving neuroanatomic
changes seen during adolescence. During
normal childhood and adolescence there is a progressive
and selective ‘pruning’ of dendrites, and, according to this
hypothesis, the ability of the fixed neuronal migration
defect to express itself clinically may have to wait until a
specific degree and type of ‘pruning’ has ‘cleared the way’.
Although this neurodevelopmental theory of the etiology
of schizophrenia has much to recommend it, the case is not
proven and readers are encouraged to watch the literature.
Differential diagnosis
Although a host of disorders enters the differential diagnosis,
only certain of them play a large part, thus making the
differential task a little less daunting. These include mood
disorders (i.e., bipolar disorder and major depressive disorder),
schizoaffective disorder, delusional disorder, alcoholic
psychoses, several personality disorders, and two
putative disorders known as schizophreniform disorder
and brief psychotic disorder.
Bipolar disorder, discussed in Section 20.5, is characterized
by episodes of mania and depression, whereas major
depressive disorder, as noted in Section 20.6, is marked by
depressive episodes alone. Both manic episodes, as seen in
bipolar disorder, and depressive episodes, as seen in either
bipolar disorder or major depressive disorder, may be
characterized by psychotic symptoms.
Manic episodes, discussed in Section 6.3, often show a
progression in which typical manic symptoms are joined by
hallucinations and delusions and, in some, disorganized
speech, and if one sees the patient at this stage of mania and
if there is no history, consideration might be given to a diagnosis
of hebephrenic, catatonic or paranoid schizophrenia.