Secondary Schizophrenia (34 page)

rotransmitter labels, using positron emission tomog-in both temporal and mesial frontal regions and the
raphy (PET) are more likely to help sort out these
left lateral frontal region
[59].
Fong and colleagues
[60]

possibilities.

reported a marked right temporal and left basal gan-In summary, understanding the mechanisms of
glia hyperperfusion in PIP in two patients. It is worth
the postictal state can provide useful insights into the
considering that the CBF response in patients with
pathogenesis of PIP, which may further inform the
PIP is aberrant, and this may in some way be related
pathogenesis of psychosis in general. Manipulation of
to the psychosis. A difficulty in the interpretation of
some of these mechanisms with drugs may produce
these findings is created by the fact that seizures may
valuable strategies to prevent psychosis and other psy-uncouple cerebral perfusion from metabolic activity
chiatric and cognitive disturbances of the postictal

by altering cerebrovascular autoregulation, as has been
state (see
Table 6.2).

Organic Syndromes of Schizophrenia – Section 3

suggested that it is more likely to occur with primary

generalized epilepsy
[70].

Brief psychotic episodes can also develop when
The neurophysiological basis of FN is not defi-seizures are infrequent or fully controlled. These psy-nitely known. One suggestion is that it reflects ongoing
choses last from days to weeks, they are usually self-subcortical or mesial temporal epileptic activity with
limiting, and their separation from postictal psychoses
enhanced cortical inhibition
[64, 70].
This has been
may be difficult. The phenomenology is characterized
referred to as an “inhibitory surround” in response to
by paranoid delusions and auditory hallucinations, but
ongoing seizures. This explanation argues that ongo-multiple other features, including affective symptoms,
ing epileptic activity is necessary for the maintenance
may occur
[62, 63, 64, 65].
Tellenbach
[62]
pointed out
of inhibition as well as the development of psychosis.

the presence of premonitory symptoms such as insom-Although the role of inhibition in response to seizure
nia, anxiety, feelings of oppression, and withdrawal as
activity, as a homeostatic mechanism against ictal
heralding the psychosis, and Wolf
[66]
suggested that
activity, is an appealing hypothesis to explain FN, it
treatment with anxiolytics at this stage may prevent
is possible that it does not represent ongoing epilep-development of the psychosis.

tiform activity, but is a prolonged response to preced-The relationship of brief interictal psychoses (BIP)
ing epileptiform activity. It is known that occasionally
to seizures and EEG abnormality has received much
patients may develop prolonged unconsciousness after
attention. Interictal implies that these psychoses occur
a seizure or a series of seizures, especially in elderly
in-between seizures rather than in close proximity
or ill patients
[71]
. Todd’s paralysis has been reported
with them. The favored description is of an alternat-to last for up to 36 hours
[72].
It is therefore possi-ing psychosis
[62],
that is, a brief psychosis alternating
ble that inhibition after a seizure or a series of seizures
with periods of increased seizure activity such that the
may be fairly prolonged. It is also important to under-seizures and psychosis appear antagonistic. Unlike PIP,
stand the sources of the EEG abnormalities. The scalp
this psychosis can be ameliorated by the occurrence
EEG is a reflection of groups or populations of neu-of one or more seizures
[66].
Alternating psychoses
rons that fire in a synchronous manner. The pyramidal
are uncommon, and Schmitz and Wolf
[67]
reported
neurons of layers IV and V of the cortex are consid-three cases of alternating psychosis in 697 epilepsy
ered to be responsible for scalp EEG activity, but both
patients.

radially and tangentially oriented currents may make a
The concept of forced normalization (forcierte
contribution to the EEG signal. Sources of EEG abnor-Normalisierung) (FN) was introduced by Landolt
[68]

mality in epilepsy may lie close to the surface or deep
for the puzzling observation that the EEGs of epilepsy
in the brain, and the latter are less likely to be picked
patients often looked less pathological when their
up on the scalp. The inhibitory events described pre-behavior had deteriorated. This phenomenon, also
viously are most likely to occur in close proximity to
called “paradoxical” or “spurious” normalization
[66],

the seizure focus, thereby reducing the electrical cur-has been documented by a number of authors
[65,

rent generated from the focus, and this may be the
66, 69]
with the additional observations that: 1) the
basis for the normalization. Even a reduction in the
EEG may become more, rather than entirely, nor-frequency of epileptic events will produce a relative
mal; 2) the manifestation is not always of psychosis,
normalization.

and other disturbances, such as affective symptoms,
Patients with BIP have been reported to suffer from
an anxiety or dissociative state, and behavioral dis-either partial complex epilepsy or primary general-turbance, may be present; and 3) not all BIPs mani-ized epilepsy. Although a temporal lobe onset is com-fest this phenomenon
[63].
Ramani and Gumnit
[63]

mon, Wolf
[66]
argued that all of these patients also
observed FN in only one of nine epilepsy patients who
had generalized seizures. Kanemoto and colleagues
became psychotic while being treated in the hospital
[37]
reported the frequent presence of mesial temporal
for their epilepsy. Forced normalization is not exclu-sclerosis in patients with interictal psychosis, who also
sive to interictal psychosis and has been occasionally
were likely to have experienced the onset of epilepsy
described with PIP, suggesting a complexity of the rela-before the age of 10 years. Ictal fear and autonomic
tionship of seizure activity with psychosis. Interest-aura have been more commonly reported in patients
ingly, Landolt described this phenomenon in relation
who develop BIP
[73]
, but this is not invariably

to childhood absence seizures, and some authors have
supported.

Chapter 6 – Schizophrenia-like psychosis and epilepsy

Special relationships between BIP and two drug
Table 6.3
The relative risk of seizures with antipsychotic drug
classes should be highlighted.

used
∗

High risk

Intermediate risk

Clozapine (HD to MD)

Clozapine (LD)

Haloperidol

Anticonvulsant drugs have been reported to precipi-Chlorpromazine (HD)
Chlropromazine

Trifluoperazine

tate psychosis, although the published literature is con-

(MD to LD)

founded by the inclusion of affective and confusional
Olanzapine

Fluphenazine

psychoses in this category. The facts that the control
Quetiapine

Flupenthixol

of seizures may induce psychosis in a few patients and
that neuroleptic drugs, which are proconvulsant, are
Thioridazine

Pimozide

useful in treating such a psychosis are consistent with
Molindone

the concept of alternating psychosis and forced nor-Risperidone
malization. Gibbs
[74]
first drew attention to this in
HD high dose; MD moderate dose; LD low dose
∗

relation to phenacetylurea, and Landolt
[75]
impli-Adapted from Alldredge, 1999 [82].

cated the succinimides. Wolf
[66]
further emphasized
the relationship with ethosuximide and reported that
valproate did not produce the same result. Others
establish, but the risk is considered to be lower with
have reported psychosis in association with clobazam,
haloperidol, trifluoperazine, pimozide, and molin-phenytoin, carbamazepine, barbiturates, and benzo-done. Although there is a clear increase of seizure inci-diazepines
[1].
Psychosis related to vigabatrin, a new
dence in cases of antipsychotic overdose and with high
antiepileptic drug that is an irreversible inhibitor of
doses of these drugs, an elevated risk over placebo is
GABA aminotransferase, has excited much interest,
generally not established for low to moderate doses.

but the psychoses reported are multiform, and a rela-The newer antipsychotics are not free of this effect,
tionship to seizure control in those who present with
and in fact, clozapine is the most epileptogenic of
psychosis has not been reported
[76].
Topiramate
the antipsychotics, with myoclonus or frank seizures
has been associated with FN and psychosis, espe-reported in 0.3% to 5% of patients treated with thera-cially in patients who were concurrently on vigaba-peutic doses
[5].
In the premarketing studies of cloza-trin
[77].
Forced normalization has also been reported
pine, the overall incidence of seizures was 2.9%: 4.4%

with levetiracetam
[78]
, but is rare with lamotrigine
with high doses (600–900 mg/day), 2.7% with moder-and gabapentin
[79].
Another group of drugs that
ate doses (300–599 mg/day), and 1.0% with low doses
are potent anticonvulsants in animal models is the
(299 mg/day or less)
[63]
. A subsequent postmarketing
NMDA antagonists, for example, MK-801, ketamine,
surveillance study of 5,629 patients reported a rate of
and phencyclidine. These drugs are also potent psy-1.3%, which was again dose dependent
[83].
The rates
chotogens
[80].
The psychoses related to phenytoin are
are lower with the other atypical drugs, with a seizure
likely to be toxic in nature.

rate of 0.9% reported for olanzapine and quetiapine (cf.

0.5% for placebo) and 0.3% for risperidone
[84].
The
Antipsychotic drugs and epilepsy

relative risks of commonly used antipsychotic drugs
All antipsychotic drugs have the propensity to cause
are summarized in
Table 6.3.
In spite of these increased
paroxysmal EEG abnormalities and induce seizures,
rates, antipsychotics can be safely used in the manage-and the effect is related to drug type and dose
[81].
The
ment of psychosis in patients with epilepsy, with the
phenothiazines have been the most widely studied for
preference for low to moderate doses, although this
their seizure propensity. They have been reported in
clinical question has rarely been examined in a sys-9% of patients who received high-dose phenothiazines
tematic study. In a study of thioridazine for behav-

(>
=
1,000 mg/day chlorpromazine or its equivalent),
ioral disturbance in epilepsy, seizure frequency was
0.7% of patients who received moderate doses, and
improved in 41% of test subjects and unchanged in
0.3% of patients who received low doses (>
=
200

20%, with the improvement being attributed to bet-mg/day chlorpromazine or its equivalent)
[82].
From
ter control of emotional triggers for the seizures
[85].

the published literature, the relative risk of seizures
Clozapine can be used in low doses without seizure

with the various typical antipsychotics is difficult to
exacerbation. If a seizure occurs, the dose can be
Organic Syndromes of Schizophrenia – Section 3

lowered or the patient switched to another drug such as

olanzapine.

The investigation of the relationship between epilepsy
and chronic SLP was brought into the modern era
Are postictal and brief interictal

by Slater and colleagues
[88].
For some time, there
psychoses distinct?

was high expectation that this would become a
model psychosis that would reveal the pathogenesis of
The previous descriptions suggest that there is a clas-schizophrenia. Despite a great deal of further work,
sical distinction between PIP and BIP, with the for-many aspects of this relationship remain controversial,
mer being closely related to a flurry of seizures, and
and the promised insights have been slow to arrive.