Secondary Schizophrenia (37 page)

is variable in terms of age at onset, duration, and fre-The possible roles of psychological factors, neurotox-quency; it is uncertain whether kindling can be per-icity of anticonvulsant drugs, deficiencies (e.g. folic
manent; patients usually have generalized seizures and
acid), and abnormal experiences seem to be of sec-widespread pathology; and kindling currently imputes
ondary importance.

the dopamine hypothesis of psychosis, support for
which is inconsistent. Postlobectomy psychosis has
Psychosis is a direct consequence of

been suggested to be a result of downstream kindling

due to persistent ictal activity and perhaps decreased
I have previously referred to mechanisms by which
seizure frequency
[125].
Delayed psychosis after right
seizures may directly result in ictal, postictal, and
temporoparietal stroke has been reported in one series
BIP: continuous subictal activity, homeostatic mech-of eight patients, seven of whom developed seizures
anisms that help reduce epileptic excitability, and neu-before the psychosis
[137].

rochemical and neuroendocrine changes produced by
Another mechanism by which frequent seizures
the seizures. These explanations are inadequate for
may bring about chronic behavioral disturbance is the
chronic SLP although they may account for some fluc-production of plastic regenerative changes affecting, in
tuation of symptoms.

particular, the medial temporal lobes. Some of the cel-Kindling has been proposed as one possible mech-lular and molecular consequences of repeated seizures
anism for the occurrence of chronicity. Studies of
are summarized in
Table 6.7.
The consequences may be
behavioral and pharmacological kindling in animals,
somewhat different depending upon whether seizures
and the development of mirror foci, suggest that
occur in childhood or adulthood. There may also be
the potential exists for repetitive epileptiform dis-genetic susceptibility to brain changes. In mice, there
charges to facilitate subsequent propagation along
are strain-dependent differences in kainite-induced
specific pathways that may cause interictal distur-cell death in the hippocampus
[138].
It has been
bance. Electrical and pharmacological kindling of
shown that stimulation of the hippocampus leads to
the ventral tegmentum and amygdaloid kindling by
an anomalous axonal sprouting from dentate gran-cocaine and apomorphine in the cat
[135]
have been
ule cells before the development of seizures
[139].

suggested as model psychoses. The long duration
Expansion of glutamatergic presynaptic mossy fibers
of epilepsy before the onset of psychosis, the fre-and an increase in perforated postsynaptic densities
quency of the partial seizures, and the limbic origin
on granule cell dendrites have been demonstrated in
of the seizures provide evidence for this hypothesis.

temporal lobectomy specimens
[140],
changes possi-Kindling may thus explain some aspects of the rela-bly produced by increased expression of messenger

tionship between epilepsy and psychosis, especially
RNA for c-fos and NGF by recurrent limbic seizures.

Organic Syndromes of Schizophrenia – Section 3

In addition, there is neurogenesis as well as neuronal
brains of schizophrenic persons
[147],
and there is also
loss, in varying combinations. There is also activa-evidence for synaptic reorganization
[148].
These dis-tion and proliferation of glial cells. Synaptic function
turbances either have a genetic basis or may be due
and ion channel function may be altered. The aberrant
to prenatal, perinatal, or early developmental insults.

regeneration and the resultant “miswiring” alone or in
If similar developmental abnormalities underlie both
combination with the other morphological and func-epilepsy and schizophrenia, it is not surprising that
tional changes interact with the baseline neuropathol-some epilepsy patients develop SLP. The evidence that
ogy. This may be the underlying basis for chronic
SLP is more likely to develop in epileptic patients with
schizophrenia-like psychosis. The superimposition of
developmental brain abnormalities
[109, 111,
127]
is
seizures on this may further modify the expression
consistent with this suggestion. That epilepsy and psy-of the psychopathology, producing both exacerba-chosis have different ages at onset may be due to dif-tions and remissions depending upon their nature and
ferent functional consequences of the abnormalities,
frequency.

depending on the stage of neurodevelopment. Epileptic activity may, in addition, exacerbate an underlying
Both psychosis and epilepsy are symptomatic

dysgenesis, setting the stage for psychosis.

of an underlying neuropathological or

Diffuse brain damage hypothesis

Although there has been extensive neuropathological
The following major possibilities may be considered:
interest in the temporal lobe, there is evidence that
i) neurodevelopmental abnormalities leading to cor-brain abnormalities in the brains of schizophrenic sub-tical dysgenesis as the common factor; ii) diffuse
jects are widespread
[115].
Most neuropathological
brain damage causing both epilepsy and psychosis; and
studies of epilepsy and psychosis have been limited to
iii) an imbalance of excitation and inhibition.

the examination of resected temporal lobes. The studies by Stevens
[125]
and Bruton and colleagues
[110]

are exceptions, revealing excess pathology that was
Neuropathological studies of temporal lobe epilepsy
widespread and not dissimilar to some of the pathol-suggest that about two-thirds of the patients show hip-ogy reported for schizophrenia. These findings argue
pocampal cell loss and sclerosis, particularly in the
that SLP may be related to degenerative or regenerative
prosubiculum and CA1 regions, and a substantial pro-changes in the brain not directly related to the classic
portion of TLE patients
[141]
have other pathologies,
epileptic pathology.

in particular gliomas, hamartomas, and heterotopias.

The presence of these alien tissue lesions suggests
Imbalance of cortical excitation and inhibition

defective neuroembryogenesis. Patients with mesial
Epileptic conditions are presumed to involve a chronic
sclerosis commonly have heterotopias, hippocampal
imbalance of excitatory and inhibitory influences
[87],

neuronal loss of about 20% to 50%
[141],
and synap-whereas increased inhibition plays an important role
tic reorganization in the hippocampus. Veith
[142]

in the development and maintenance of the interictal
reported heterotopias in 37% of TLE patients but only
state
[149].
Human TLE is associated with enhanced
4% of nonepileptic comparison subjects. Heterotopic
inhibition
[150]
, which contrasts it from neocortical
abnormalities have also been described in primary
epilepsy, in which the epileptogenic regions demon-generalized epilepsies
[143, 144].
Cryptic insults such
strate reduced after-discharge thresholds
[151].
The
as childhood viruses, fever, or minor hypoxia may lead
role these inhibitory processes play in the genesis of
to synaptic reorganization in vulnerable brains, exac-psychosis has not been adequately examined. Active
erbating the problem. There is now considerable evi-inhibitory processes may produce focal reversible
dence that schizophrenia is associated with cortical
deficits, but is it possible that chronic SLP is a mani-maldevelopment
[145].
More than a decade ago it was
festation of similar processes bilaterally in the limbic
demonstrated that schizophrenic patients had a dis-and frontal cortices?

organization of the pyramidal cell layer
[146],
which
Abnormalities of cortical inhibition have been
was thought to represent a problem in the migration
implicated in schizophrenia. Patients with schizophre-of primitive neurons into the presumptive hippocam-nia have reduced sensorimotor gating, which has been

pal plate. Heterotopias have been demonstrated in the
attributed to the disinhibition of cortical inhibitory
Chapter 6 – Schizophrenia-like psychosis and epilepsy

processes due to excessive dopamine excitation

[152]
. The motor abnormalities of schizophrenia,
(Neurodevelopmental or Acquired Abnormality)

which range from excitation to catatonic stupor, have
Excitation/inhibition imbalance

been attributed to reduced cortical inhibition
[153].

CRYPTIC INSULTS

Schizophrenic patients have impaired inhibition of
POSTICTAL

event-related potentials to paired auditory stimuli
PSYCHOSIS

EPILEPSY (?TEMPORAL LOBE)

[154].
In a direct examination of cortical inhibition
Repeat

SEIZURES

Episodes

using transcranial magnetic stimulation, it was shown
BRIEF

INTERICTAL

that unmedicated schizophrenic patients had deficits
PSYCHOSOCIAL

LOBECTOMY

PSYCHOSIS

FACTORS

of cortical inhibition that was corrected by medication
DRUGS

[155].

The important neurotransmitters involved in the

Cellular &

inhibitory processes are GABA, opioids, and adeno-Inhibition

sine, whereas glutamate is the key excitatory amino

acid. Both GABA
[156]
and glutamic acid
[157]
have
been implicated in the development of psychosis. Glu-

Figure 6.1
Possible pathophysiological mechanisms for the
association between epilepsy and schizophrenia-like psychosis.

tamate is also important for the maintenance of brain
plasticity and surges in its levels may be responsi-catecholamine and pre-and postsynaptic glutamater-ble for mossy fiber sprouting in the hippocampus
gic and GABAergic activity, modulate the expression
in TLE. These plastic brain changes associated with
of the psychosis or act as brakes, sometimes leading to
epilepsy raise the question whether repeated seizures,
the impression of antagonism. There may be long-term
and indeed the occurrence of PIP, eventually leads to
changes in the balance between excitation and inhibi-chronic psychosis. There is a suggestion that this may
tion. The picture is further complicated by drug ther-indeed be the case in some subjects
[158].

apy, with its potential for neurotoxicity, and psychoso-

cial factors related to epilepsy, a chronically disabling
and stigmatizing illness.

An attempt at a synthesis of the various hypotheses
is presented in
Figure 6.1.
According to this view,
epilepsy patients who develop chronic SLP have a

brain lesion that makes them vulnerable to psychosis.

Although the relationship between epilepsy and SLP

This lesion may be neurodevelopmental, leading to
has in itself been an intriguing clinical issue, it car-cortical dysgenesis, or be acquired through trauma,
ries within it the potential to provide understanding of
hypoxia, infection, and so on. The abnormality may be
the pathogenesis of the schizophrenias in general. The
widespread but is particularly likely to involve the lim-newer epidemiological studies have been more sophis-bic structures, leading to abnormalities of connectivity
ticated, but more work remains to be done. For exam-of these structures to their afferent and efferent projec-ple, the question of whether SLP is specific to TLE

tion regions. Because the development of medial tem-should be further investigated by using extratempo-poral structures is asymmetric, it may explain some of
ral partial epilepsy and generalized epilepsy patients
the laterality data. The abnormality is likely to cause
as comparison subjects and performing longitudinal
electrical storms in the limbic cortex, with seizures
studies. The determinants of the interval between the
occurring at an early age. The occurrence of frank
onset of epilepsy and that of psychosis should be stud-seizures or microseizures exacerbates the abnormalied in a longitudinal investigation of TLE patients
ity owing to kindling mechanisms or the regenera-beginning in the first or early second decade of life. It is
tive and neuroplastic changes involving axonal sprout-important that brief psychoses be distinguished from
ing, synaptic reorganization, dendritic changes, glial
the chronic psychoses in such investigations. Longi-changes, and so on. In due course, these result in dis-tudinal studies are also necessary to determine the
ruption of anatomically distributed functional systems
factors that lead to chronicity of psychosis in patients
and lead to SLP, accounting for the “affinity” between
with repeated postictal and interictal psychoses.