Epilepsia, 54(Suppl.

1):1933, 2013
doi: 10.1111/epi.12102

PSYCHIATRIC DISORDERS IN EPILEPSY

Basic treatment principles for psychotic disorders

in patients with epilepsy
*Naoto Adachi, Kousuke Kanemoto, Bertrand de Toffol, Nozomi Akanuma,
Tomohiro Oshima, #Adith Mohan, and #Perminder Sachdev

*Adachi Mental Clinic, Sapporo, Japan; Department of Neuropsychiatry, Aichi Medical University,
Nagakute, Japan; Department of Neurology, Francois-Rabelais University & INSERM U 930, Tours, France;
South London and Maudsley NHS Foundation Trust, London, United Kingdom; School of Psychiatry,
The University of New South Wales, Sydney, New South Wales, Australia; and #Neuropsychiatric Institute,
Prince of Wales Hospital, Sydney, New South Wales, Australia

ment from the patient, whenever possible, (2) opti-

SUMMARY
In patients with epilepsy, coexisting psychoses,
either interictal (IIP) or postictal (PIP), are associ-
ated with serious disturbance in psychosocial func-
tion and well-being, and often require the care of a
specialist. Unfortunately, evidence-based treat-
ment systems for psychosis in patients with epi-
lepsy have not yet been established. This article
aims to propose concise and practical treatment
procedures for IIP and PIP based on currently
available data and international consensus state-
ments, and primarily targeting nonpsychiatrist
epileptologists who are often the first to be
involved in the management of these complex
patients. Accurate and early diagnosis of IIP and
PIP and their staging in terms of acuity and severity
form the essential first step in management. It is
important to suspect the presence of psychosis
whenever patients manifest unusual behavior.
Knowledge of psychopathology and both individual
and epilepsy-related vulnerabilities relevant to IIP
and PIP facilitate early diagnosis. Treatment for IIP
involves (1) obtaining consent to psychiatric treat-
mization of antiepileptic drugs, and (3) initiation of
antipsychotic pharmacotherapy in line with symp-
tom severity and severity of behavioral and
functional disturbance. Basic psychosocial inter-
ventions will help reinforce adherence to treat-
ment and should be made available. Due
consideration must be given to patients ability to
provide informed consent to treatment in the
short term, with the issue being revisited regularly
over time. Given the often prolonged and recur-
rent nature of IIP, treatment frequently needs to
be long-term. Treatment of PIP consists of two
aspects, that is, acute protective measures and pre-
ventive procedures in repetitive episodes. Protec-
tive measures prioritize the management of risk in
the early stages, and may involve sedation with or
without the use of antipsychotic drugs, and the judi-
cious application of local mental health legislation if
appropriate. As for preventative procedures, opti-
mizing seizure control by adjusting antiepileptic
drugs or by surgical treatment is necessary.
KEY WORDS: Epilepsy, Psychosis, Interictal psy-
chosis, Postictal psychosis, Treatment, Guideline.

Although psychotic illnesses in patients with epi-
lepsy have been long studied, the literature thus far
has leaned toward descriptive psychopathology and
establishment of etiologic and neuropathologic links.
In contrast, there are only a few systematic studies
that have evaluated treatment strategies (Adachi, 2005;
Address correspondence to Naoto Adachi, Adachi Mental Clinic,
Kitano 7-5-12, Kiyota, Sapporo 004-0867, Japan. E-mail: adacchan@
tky2.3web.ne.jp
Wiley Periodicals, Inc.
2013 International League Against Epilepsy
Sachdev, 2007). The responsibility for initial manage-
ment of these patients can fall on a range of profes-
sionals in addition to epileptologists, and experience in
the management of psychotic disorders can vary,
depending for instance on whether the treatment set-
ting is in a tertiary referral center with access to neu-
ropsychiatric expertise. We aim to propose treatment
procedures, based on available data, for two main
types of epilepsy-related psychoses (i.e., interictal psy-
chosis and postictal psychosis), that are practical and
clinically meaningful.

19
20
N. Adachi et al.
Interictal Psychosis
People with epilepsy have a twofold to threefold
increased risk of developing psychosis (Qin et al., 2005),
which may indicate that epilepsy per se plays some role,
although establishing a causal association remains contro-
versial (Adachi, 2006). With regard to their temporal asso-
ciation with seizures, the psychosis may be regarded as
interictal psychosis (IIP) or postictal psychosis (PIP; Sach-
dev, 1998). In contrast to recent advances in clinical
research in PIP, studies of IIP remain limited. In particu-
lar, there are few systematic studies of effective treatment
strategies for IIP. Existing recommendations (Kerr et al.,
2011) are extrapolated from those established for the treat-
ment of schizophrenia and related psychotic illnesses with
some additional guidance from anecdotal evidence or
expert opinions.
A range of factors influence the choice of psychiatric
treatments for IIP patients. In this article, we summarize
treatment procedures in three stages depending on the
severity of psychotic symptoms and the level of psychoso-
cial disturbance.
1 Mild: Although patients clearly show some psychotic
symptoms, they are not distressed by the symptoms,
and their overall psychosocial function is maintained.
2 Moderate: Patients have distinct psychotic symptoms;
day to day functioning is disrupted, and overall psycho-
social functioning is affected to some degree.
3 Severe: Patients have overwhelming psychotic symp-
toms, behavioral consequences of these symptoms put
them or other people at risk, and their psychosocial
function is significantly impaired.
Definition of IIP
The term psychosis encompasses a broad spectrum of
mental disturbance. Clinically, in accordance with Inter-
national Classification of Diseases, Tenth Revision (ICD
10) (World Health Organization, 1992), the syndrome of
psychosis is defined by the presence of hallucinations,
delusions, and/or a limited number of severe behavioral
abnormalities, such as gross excitement and overactivity,
marked psychomotor retardation, and catatonic behavior.
Thought disorder is a salient feature of psychosis, which
may be characterized by disordered content, as repre-
sented by delusions, or disordered thought form. Disor-
dered thought form broadly comprises disorders of the
mechanisms of thinking, that is, concrete thinking, loos-
ening of associations, incoherence, overinclusion, and
illogicality. There may be associated disorder of language
and speech, that is, derailment, neologisms, retarded/pov-
erty of speech, pressured speech, and flight of ideas (Cut-
ting & Murphy, 1988). Despite reports of frequent
occurrence in patients with epilepsy, in particular those
with psychiatric or neurobehavioral disorders (Slater
et al., 1963; Caplan et al., 1997), formal thought disorder
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
is not commonly considered in diagnostic workup for IIP
(Adachi, 2006).
Contributions from British neuropsychiatrists (Hill,
1953; Pond, 1957; Slater et al., 1963; Slater & Roth,
1969) defined IIP as any psychosis in clear consciousness
that occurs in someone who has previously been diag-
nosed with epilepsy, and the psychosis is not exclusively
during or immediately following a seizure. This criterion
is concise and practical, and has often been used for
approximately three decades. There is an implication that
the psychosis is, in some manner, secondary to the epi-
lepsy (Diagnostic and Statistical Manual of Mental Disor-
ders, Fourth Edition; DSM-IV, American Psychiatric
Association, 1994) or is an organic mental disorder
(ICD-10) in line with a conceptually orthodox dichotomy
between organic and functional psychoses (Adachi et al.,
2010b). Such orthodoxy is often not possible to sustain.
Several recent studies have demonstrated some vulnera-
bility factors, such as the presence of family history of
psychosis (Adachi et al., 2000a; Qin et al., 2005) and
impaired intellectual functioning (Adachi et al., 2000a;
Mellers et al., 2000) that are common to both non-
organic psychosis and psychosis in epilepsy (IIP). These
findings have shed light on pathogenesis of psychosis in
patients with epilepsy in a wider context. Although evi-
dence is still limited, recent findings suggest common vul-
nerabilities among learning disability, developmental
disorders, and psychosis (Craddock & Owen, 2010).
In this article, we have adopted Slaters definition for
practical use. Previous authors have employed various
forms of subclassifications in IIP according to its duration
(e.g., acute/brief/transient and chronic) or presumptive eti-
ologies (e.g., drug-induced and forced normalization;
Sachdev, 1998, 2007; Fig. 1). These subclassifications
Figure 1.
Possible pathophysiologic mechanisms for the associa-
tion between epilepsy and schizophrenia-like psychosis
(with permission from Sachdev, 2007).
Epilepsia ILAE
 21
Treatment of Psychosis in Epilepsy

have not been validated. It needs to be kept in mind that
the same patient can exhibit different forms of IIP at dif-
ferent times, for example, drug-induced and nondrug-
induced, or acute and chronic.
Diagnosing IIP
People with epilepsy are at an increased risk of psycho-
sis. Every year, 34 of 1,000 adult patients with epilepsy
with no past history of psychosis exhibit some psychotic
symptoms for the first time (Onuma et al., 1995; Tadok-
oro et al., 2007). The risk is approximately 23 times
higher than that of first-episode schizophrenia in the
general population aged 1565 years. The first step for
making a diagnosis is to be aware that any patient with
epilepsy can develop IIP, and to suspect IIP when they
show unusual behavior.
Identifying IIP may be straightforward when patients
exhibit frank psychotic symptoms. It is, however, not
uncommon that patients conceal their psychotic experi-
ences (Koutroumanidis et al., 2010). Viron et al. (2012)
proposed a set of screening questions for psychosis
(Table 1). Nonverbal cues (e.g., sullen, preoccupied,
monotonous, or unnatural behaviors) are vital in under-
standing abnormal inner experiences, as verbally provided
information cannot be relied upon exclusively. Obtaining
collateral history from their family, friends, and carers is
also important (Koutroumanidis et al., 2010).
To confirm the diagnosis of IIP, it is necessary to
exclude ictal, preictal, and postictal psychotic phenomena.
Criteria for these phenomena are detailed in the PIP sec-
tion of this article. Because patients may not clearly
remember precedent seizures, clinical clues indicating the
presence of seizure activity around the time of onset of the
psychotic episode should be sought meticulously.
Associated characteristics
Constant characteristics
Characteristics that remain constant during the course
of illness in each patient appear to be associated with vul-
nerabilities relevant to the development of IIP (Fig. 1). A
number of recent studies have shown common vulnerabil-
ities between epilepsy and psychosis (Qin et al., 2005;
Adachi et al., 2011). Epilepsy patients with a family his-
tory of psychosis are predisposed to developing IIP, even
in the absence of overt cerebral insult related to epilepsy
(Adachi et al., 2010a). The rate of family history of psy-
chosis is estimated at 310% in IIP (Adachi et al., 2000a,
2002a; Qin et al., 2005). Because the actual risk of IIP
based on genetic vulnerabilities is difficult to calculate at
present, the presence of family history of psychosis could
be explored not only within the first-degree relatives as in
most genetic studies with strict criteria but also in the
more extended family. Epilepsy patients with a learning
disability are more vulnerable to IIP than those without
(Adachi et al., 2000a; Mellers et al., 2000). In particular,
those with borderline intellectual functioning have 25
times higher risk for various psychotic states (Adachi
et al., 2002a).
Several epilepsy-related variables have been considered
in the pathogenesis of IIP (Trimble, 1991; Sachdev,
1998). They include epilepsy types, seizure variables, and
the lateralization of epileptogenesis. Indeed, patients with
focal epilepsy have a higher risk of IIP than those with
generalized epilepsy (Adachi et al., 2000a,b). It is note-
worthy that 1520% of IIP patients have idiopathic gener-
alized epilepsy (Adachi et al., 2000a, 2010a). As for
seizure variables, most reports have pointed to the occur-
rence of complex partial seizures and in particular those
occurring in temporal lobe epilepsy as suggested by
Gibbss (1951) report. Patients with other forms of focal
epilepsy can also develop IIP (Adachi et al., 2000b,
2002b). Because most of the recent large studies failed to
find associations between left-sided epileptogenicity and
IIP (Mendez et al., 1993; Kanemoto et al., 2001b; Adachi
et al., 2002a), the importance of lateralization of epilepto-
genesis may have been overestimated.
Inconsistent characteristics
Features that are subject to change, such as regimens
and doses of antiepileptic drugs (AEDs) and seizure
frequency, are also likely to affect IIP. Modifying such
conditions by appropriate medical approaches can conse-
quently prevent or improve IIP.

Table 1. Screening questions for psychoses (Viron et al., 2012)

A lead-in statement helps to normalize the experiences for the patient and reduces the potential shame and embarrassment of sensitive topic, for
example:
Sometimes when people are [under stress/feeling anxious/feeling depressed], they can have strange experiences such as trouble with their
thinking or seeing or hearing things that others dont. Affirmative responses to the question below should be followed by: Tell me about that.
Questions to elicit delusional thinking
Have you had any strange or odd experiences lately that are difficult to explain or that others would find hard to believe?
Have you felt like people are watching or following you or they want to harass or hurt you?
Have you felt like others can hear your thoughts or that you can hear another persons thoughts?
Questions to elicit hallucinations
Do your eyes or ears ever play tricks on you?
Have there been times when you heard or saw things that other people could not?

Epilepsia, 54(Suppl. 1):1933, 2013

doi: 10.1111/epi.12102
22
N. Adachi et al.
AEDs may sometimes induce psychotic symptoms. A
high serum level of AED, particularly in the context of
polypharmacy, can often cloud consciousness, precipitat-
ing development of psychotic symptoms (Onuma, 1987).
Whereas any of the AEDs has the potential to cause psy-
chotic symptoms (Schmitz, 1999), some AEDs, for
example, ethosuximide (Fischer & Pedersen, 1965), phe-
nytoin (Noguchi et al., 2012), zonisamide (Matsuura &
Trimble, 1997; Noguchi et al., 2012), topiramate (Mula
& Monaco, 2009), and vigabatrin (Mula & Monaco,
2009), seem to be more potent in this regard than others.
Although most findings on AED-related psychosis have
been based on single case reports or small series of cases
without systematic examinations, it is arguably safer to
avoid these agents in patients at high risk. Approximately
3040% of patients who had AED-induced psychosis
also developed chronic IIP or AED-unrelated IIP at dif-
ferent times (Matsuura, 1999; Kanemoto et al., 2001a,b).
These results may suggest that patients with individual
vulnerabilities to psychosis tend to exhibit IIP irrespec-
tive of types of AEDs.
The association of seizure frequency with occurrence of
IIP has been a matter of debate. Several early studies (Sla-
ter et al., 1963; Flor-Henry, 1969; Kristensen & Sindrup,
1978) reported a lower frequency of seizures in patients
with IIP. This is in line with the concept of antagonism
between epilepsy (seizures) and psychosis, which may be
represented by descriptions of forced normalization (Lan-
dolt, 1958) and alternative psychosis (Tellenbach, 1965).
Applying these theories to clinical practice needs careful
evaluation for each IIP episode. The same individual may
develop an episode of IIP consistent with the phenomenon
of forced normalization on one occasion while having an
episode of IIP without any changes in electroencephalog-
raphy (EEG) and/or seizure frequency at a different time.
Furthermore, Mendez et al. (1993) reported a higher fre-
quency of complex partial seizures (CPS) in IIP. System-
atic study has not as yet been conducted to verify these
hypothetical theories.
Treatment principles for IIP
In the absence of specific treatment guidelines, psy-
chotic symptoms in IIP have hitherto been treated in line
with well-established treatment protocols for primary
schizophrenia and related psychotic illnesses (Kerr et al.,
2011). Few data are available on the treatment of IIP
specifically.
It is not uncommon in day to day clinical practice for
nonpsychiatrist epileptologists to be the first clinicians to
face the management of a patient developing IIP. Aware-
ness of the potential for the syndrome to develop in any
epilepsy patient and knowledge of common psychopatho-
logic phenomena as described above is important.
The next step is to set a treatment target. IIP symptoms
can be difficult to manage for a variety of reasons that
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
commonly include intractability of psychotic symptoms,
the individual variation in tolerability of antipsychotic
treatment, the treatments potential for adverse conse-
quences on seizure control, and the individuals adherence
to psychiatric treatment (Onuma, 1987; Adachi, 2005). In
cases of primary psychotic episodes, at least one half of
patients are partially or completely nonadherent (Lacro
et al., 2002; Abdel-Baki et al., 2012). If this is the case,
treatment modalities should be offered aiming at overall
functional recovery and improved quality of life, rather
than aiming at complete symptomatic remission.
There are some advantages for patients with IIP to
remain in the care of their treating epileptologists at the
time of initial psychiatric treatment. The epileptologists
are positioned to observe and identify early signs of IIP
even before the individual reports it. They are also best
suited to simultaneously manage factors common in epi-
lepsy and IIP (Onuma, 1987). The existing therapeutic
relationship helps ensure that epilepsy patients with psy-
chosis are more likely to be cooperative with their treating
doctors than are patients with first-episode psychosis who
are treatment-naive (Adachi, 2005). The good doctor
patient relationship enhances therapeutic outcome (Day
et al., 2005).
A significant proportion of patients with psychosis
have limited insight into their psychotic symptoms and
related behavior, and the need for treatment (McGorry &
McConville, 1999; Mintz et al., 2004). It is not uncom-
mon for patients to consent to epilepsy treatment but
refuse psychiatric treatment. Assessing their capacity to
provide informed consent to treatment is important
(Brabbins et al., 1996; Pollack & Billick, 1999; Capdevi-
elle et al., 2009). The management of epilepsy should
continue alongside regardless. At the very least, this will
allow for monitoring of the evolving psychiatric presen-
tation and arranging appropriate intervention when
needed.
How to use medical treatment
Timing of initiating antipsychotic drug (APD). In general,
psychosis is better managed earlier rather than at a later,
more advanced stage. Early initiation of APD therapy rel-
ative to time of onset of IIP shortens the duration of the IIP
episode (Adachi et al., 2012). This finding is in line with
studies on first-episode psychosis and schizophrenia
(White et al., 2009). Therefore, an early introduction of
APD is recommended where clinically indicated, in
particular if the patients present with their first episode.
On the other hand, approximately 15% of IIP episodes
remitted without any APD treatment (Adachi et al.,
2012), indicating that a short delay in commencement of
APDs may not be harmful for first-episode patients if they
are well supported with psychosocial interventions
(Francey et al., 2010). For patients with chronic IIP, it is
 23
Treatment of Psychosis in Epilepsy

prudent to seek patient consent to continued psychiatric
treatment.
Choice of APD. The recent consensus report of the Inter-
national League Against Epilepsy (ILAE) commission
(Kerr et al., 2011) states that IIP can be treated with APDs
similarly to functional psychoses, for example, schizo-
phrenia, brief/transient psychosis, and delusional
disorders. APDs are often divided into two categories:
first-generation (mostly typical/conventional) APDs
(FAPDs); that is, butyrophenones, phenothiazines, benza-
mides, and thiepins), and second-generation (atypical)
APDs (SAPDs); that is, serotonin-dopamine antagonists,
dibenzothiazepines, and multiacting receptor-targeted an-
tipsychotics). In principle, choosing an APD depends on
its efficacy and tolerability. Although some differences in
efficacy have been reported, there is no conclusive evi-
dence that SAPDs are more effective than FAPDs (Cross-
ley et al., 2010; Girgis et al., 2011; Hara et al., 2012).
The dose of APDs is often converted into chlorpromazine
equivalent (CE mg/day) to help compare different APDs
(American Psychiatric Association, 1998; Toru, 1998;
Table 2). This is not always possible or reliable, espe-
cially for some SAPDs.
Given the paucity of evidence for the relative efficacy
of one APD over another in treating IIP, the choice is
largely based on adverse effects. The main adverse effects
of APDs are as follows:
1 Sedation, such as somnolence and hypersomnia, is the
most common side effect of APDs, either FAPDs or
SAPDs. Low potency APDs except for sulpiride, for
example, chlorpromazine, are more likely to cause
these effects.
2 Weight gain and metabolic syndrome occur with any of
the APD treatments, although SAPDs are generally less
favorable in this regard. In particular, most SAPDs
(e.g., olanzapine, quetiapine, risperidone; Correll et al.,
2009), with the possible exception of aripiprazole, and
some FAPDs (e.g., sulpiride) are likely to be associated
with these problems.
3 Cardiovascular effects can occur with any APD treat-
ment (Mackin, 2008). Orthostatic hypotension is the
most common adverse effect of APDs, in particular
with low potency FAPDs. QTc prolongation and subse-
quent arrhythmia can be caused with any APDs; how-
ever, this risk is increased with pimozide, thioridazine,
sertindole, and zotepine.
4 Hyperprolactinemia and sexual dysfunction are some-
times in the context of treatment with most FAPDs
(e.g., haloperidol and sulpiride) and some SAPDs (e.g.,
risperidone and amisulpride; Rosenbloom, 2010; Holt
& Peveler, 2011).
5 Extrapyramidal symptoms (EPS), such as akathisia
and parkinsonism, occur mostly with FAPDs (in par-
ticular high potency agents, that is, haloperidol),
although some degree of EPS can be seen with SAP-
Ds. EPS can be a primary cause of noncompliance
with medication. Low doses of anti-parkinsonism/
antispasmodic drugs (e.g., trihexyphenidyl 410 mg/
day or biperiden 26 mg/day) can be prescribed
together with FAPDs to ameliorate EPS (Toru,
1998).

Table 2. Types of antipsychotic drugs and their chlorpromazine equivalent dosages

Generation Groups Medicines CE
First-generation APD Phenothiazines Chlorpromazine 1
Levomepromazine 2
Thioridazine 1
Properithiazine 6.7
Fluphenazine 50
Trifluoperazine 20
Perphenazine 10
Butyrophenones Haloperidol 50
Bromperidol 50
Pimozide 50
Benzamides Sulpiride 0,5
Sultopride 0.7
Thiepins Zotepine 2
Second-generation APD Serotonin-dopamine antagonists (SDA) Risperidone 67 (50100)
Perospirone 12.5
Dibenzodiazepines Quetiapine 1.4 (12)
Clozapine 2
Multiacting receptor-targeting antipsychotics (MALTA) Olanzapine 40 (3050)
Dopamine system stabilizer Aripiprazole 40 (3050)
Modified from American Psychiatric Association, 1998; Toru, 1998. Chlorpromazine equivalent dose (CE): 1 mg of each medicine can be converted into
certain dose (mg) of CP, for example, 1 mg haloperidol is 50 mg CP.

Epilepsia, 54(Suppl. 1):1933, 2013

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N. Adachi et al.
Costbenefit analyses are also important to take into
account, since treatment for IIP is often required over long
periods. In addition to already long-term financial com-
mitment to epilepsy treatment, treatment cost for IIP could
be a burden, becoming a barrier to adherence to treatment
(Perkins, 2002; Abdel-Baki et al., 2012). In the WHO
multinational cost-effectiveness study (Chisholm et al.,
2008), the most cost-effective interventions in the devel-
oping world were those using typical APDs combined
with psychosocial treatment, delivered via a community-
based service.
Some AEDs, such as carbamazepine, valproate, and
lamotrigine, are known to have certain psychotropic
effects; however, these are mainly for affective and not for
psychotic symptoms, and these drugs are not useful for
treating IIP per se. Minor tranquilizers (particularly ben-
zodiazepines) have some antiepileptic and psychotropic
effects. Although minor tranquilizers normally suppress
anxiety, irritability, and psychomotor-excitements, they
often induce somnolence, loss of concentration, and disin-
hibition and have dependence potential (Toru, 1998).
Judicious use in the short term when required is necessary
to avoid such undesirable effects. Antidepressants may
have some beneficial effects for IIP with depressive/affec-
tive symptoms (Blumer et al., 2000), and judicious use of
these drugs is recommended.
Special considerations. Concerns over the propensity of
APDs to lower seizure threshold can lead to the under-
treatment of IIP. Some APDs are recognized to increase
seizure risk more than others, including chlorpromazine
and zotepine. Among SAPDs, clozapine, olanzapine, and
quetiapine appear to have a higher seizure risk. It is impor-
tant to bear in mind that in addition to drug-related factors,
predisposing factors in the individuals contribute to drug-
induced aggravation of seizures. Most reports are based
on animal studies, APD overdose cases, or patients with
mental disorders who are not treated with AEDs. In epi-
lepsy patients treated with AEDs, most APDs, either
FAPD or SAPD, can be safely administered in patients
with epilepsy (Okazaki et al., 2012).
Pharmacokinetic interactions between APDs and AEDs
need to be considered (Trimble & Mula, 2008). Via cyto-
chrome P450 (CYP) systems, serum concentrations will
be altered depending on the combination of the drugs of
interest, potentially leading to adverse events or reduced
efficacy. Enzyme inducers, such as carbamazepine, may
decrease the serum level of some APDs. Patients with
multiple disorders often take a combination of drugs,
either enzyme inducers, enzyme inhibitors, or both. The
drug interactions are often difficult to calculate accurately
when the patients are on polypharmacy, since interactions
between two drugs (e.g., one AED and one APD) observed
experimentally or clinically can often be altered in unex-
pected directions when further drugs are added. Pragmatic
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
approaches are (1) to simplify medication regimens as far
as possible, (2) to monitor efficacy and adverse effects
clinically, and (3) to check the serum level if appropriate
and adjust the dose of the medication accordingly
(Onuma, 1987; Adachi, 2005).
APD dose titration. General rules of APDs titration are to
commence at low doses, titrate slowly to a minimum ther-
apeutic dose, and continue at a steady dose for a sufficient
period of time. Of 320 IIP episodes in Japanese neuropsy-
chiatric institutions, the maximum dose of APDs required
ranged from 12.5 to 3,425 mg/day CE (mean 454.7 mg/
day CE; Hara et al., 2012). Empirically, for patients with
mild IIP episodes, the target dose of APD ranges from 50
to 300 mg/day CE. Some mild psychotic episodes disap-
pear without any APD treatment; therefore, IIPs can be
observed without medication under some conditions.
Examples include situations in which (1) the patients and
people around them are not distressed or disturbed by the
symptoms, (2) the patients do not give a consent to take
APDs and the risk profile is favorable, and (3) risks of
administering APDs is greater than their benefits. Slow
and careful titration from low dose (around 50100 mg/
day CE) can significantly reduce the occurrence of
adverse effects (Mula & Monaco, 2009). When IIP
patients show moderate episodes, which are determined
not only by symptom severity but also by functional dis-
turbance, the patients with moderate episodes should take
3001,000 mg/day CE of APDs. For serious episodes, in
particular those accompanying characteristics such as
excessive psychomotor excitement or attempted suicide,
they may need to take sufficient dosages (1,000
3,000 mg/day CE) of APDs. Because dose required does
not necessarily correlate with present severity, other con-
ditions, such as individual responsiveness, course of ill-
ness, and history of violent behaviors, should also be
considered. Depending on their risks to self and/or others,
a transfer of care to psychiatric services, including psychi-
atric emergency, may be required. Keeping up to date with
mental health legislation and local procedures would min-
imize delay for involvement of specialist services.
Careful titration is recommended for patients with par-
ticular conditions by an international consensus study
(Gardner et al., 2010). They include patients with distinct
brain damage, that is, postencephalitis and cerebrovascu-
lar disease, with physical conditions, in the younger or
older age groups, or in certain ethnic groups. The starting
dose should be smaller, and titration regimens should be
slower than those for patients without such conditions. For
patients with brain damage, the target dose should be set
at 3050% lower. Patients with physical diseases, such as
impaired hepatic function ( 45%) and impaired renal
function ( 30%) should also be prescribed a lower dos-
age. Age-related dosing changes of APD treatment should
be as follows; that is, children (age 6 to puberty; 60%),

adolescence ( 30%), and elderly (>65 years; 50%).
Likewise dosages of APDs reflect ethnic metabolic char-
acteristics; East Asian patients may take a 2040% lower
dose than Western patients (Lawson, 1986; Matsunaga
et al., 2009).
Duration of APD treatment. There is insufficient evi-
dence on the duration of treatment with APDs for IIP
episodes. Effectiveness of APD use for maintenance
and prevention of IIP is also little known. In pharmaco-
logic management in functional psychoses, it is advised
that the patients remain on the optimized dose of APD
for at least 6 months after reaching remission for the
first couple of episodes, and then come off medication
gradually. In patients who already have had multiple
episodes are advised to stay on medication long term.
Due to its chronic nature and relatively high rate of
exacerbation, the international commission recom-
mended a long-term administration of APDs after a
remission of IIP (Kerr 2011). This is in line with find-
ings in first-episode psychosis that the maintenance of
treatment is more effective for preventing relapse and
deterioration than targeted intermittent treatment
(Gaebel et al., 2011). Sudden discontinuation of APDs
may disrupt serum levels of AEDs; thus, seizure con-
trol and adverse effects of AEDs should be carefully
monitored. It is possible that IIP episodes recur after
discontinuing APDs (Onuma et al., 1991; Adachi,
2005); careful follow-up is needed.
Psychotherapeutic approaches
Psychosocial functions are adversely affected by psy-
chotic symptoms as well as nonpsychotic symptoms, that
is, apathy and neurocognitive dysfunction, which are
sometimes difficult to treat with medication. Although
there is no systematic study on effectiveness of psycho-
therapeutic approaches in epilepsy patients with psycho-
ses, ample evidence in functional psychoses (Francey
et al., 2010) gives us insight into the value of such inter-
ventions in the management of these patients, leading to
better adherence to treatment and improved quality of life.
Limited resources and experience in this area may be a
deterrent, although basic interventions listed below could
be provided by nonspecialists.
1 Psychoeducation: It is essential to ensure that patients
understand the diagnosis of psychosis and need for
treatment over a long period (Perkins, 2002).
Improved awareness and understanding of the condi-
tion can help them remain motivated in continuing
treatment. Tackling stigma surrounding psychiatric
conditions and their treatment may be one of the keys
for successful treatment (Iyer et al., 2011; McCann
et al., 2011).
2 Self-help and reframing: Stress may play a role in
development of IIP. Poor coping skills could have
25
Treatment of Psychosis in Epilepsy
detrimental effects on the patients, leading to reduced
quality of life and low self-esteem. Assisting the
patients in developing more helpful coping strategies
can improve their self-monitoring of the conditions,
and long-term management, particularly in patients
with mildly impaired to borderline intellectual func-
tioning (Harris, 1998; Adachi, 2005).
3 Support for family and carers, and networking: Good
support by family members, carers, and social networks
is a significant determinant for adherence to medication
(Rabinovich et al., 2009). In patients with schizophre-
nia, the relapse rate can be reduced by 20% if relatives
are involved in treatment (Addington & Addington,
2008). Providing psychoeducation and practical and
emotional support for family and carers often leads to
better management of the conditions as a whole
(Onuma, 1987; Adachi, 2005).
Prognosis of IIP
Episodes of IIP generally take a longer time than PIP,
lasting for months in many cases. In a large cohort
study, approximately 75% of all IIP episodes lasted for
1 month or more, regardless of APD treatment; the
mean duration of 320 IIP episodes in 155 patients was
82.7 weeks (median 17 weeks; Adachi et al., 2012).
This study considered only the periods during which the
patients manifested hallucinations and/or delusions. Epi-
sodes are likely to be more prolonged if formal thought
disorders and/or nonpsychotic symptoms (e.g., emo-
tional withdrawal, depression, anxiety, and irritability)
were included.
Episodes often recur in patients with IIP. Onuma et al.
(1991) reported that almost two thirds of IIP patients had
episodes of relapse after remission or worsening of
chronic episodes during a 10-year follow-up period. A
longitudinal observation disclosed that approximately
90% of the IIP patients had psychotic episodes that lasted
for 1 month or more and 65% had episodes that lasted for
6 months or more (Adachi et al., 2012). In the course of
illness, patients sometimes exhibit different types of psy-
chosis, for example, acute-transient and chronic (Adachi
et al., 2012), AED-induced and AED-unrelated (Matsu-
ura, 1999; Kanemoto et al., 2001a,b), and even IIP and
PIP (Tarulli et al., 2001; Adachi et al., 2003). Some IIPs
recur after discontinuation of APD treatment (Onuma
et al., 1991; Adachi, 2005).
Patients with mental disorders have an increased risk of
premature death, from either natural or unnatural causes
(Harris & Barraclough, 1998; Tiihonen et al., 2009).
Patients with epilepsy also have particular risks to early
death, for example, sudden unexpected death, status
epileptics, suicide, and accidents, in addition to common
etiologies (Hitiris et al., 2007). It is therefore possible that
synergism of the two conditions can lead to an increase in
mortality.
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
26
N. Adachi et al.

Table 3. Treatment principles for IIP

Establish a diagnosis of IIP episodes by excluding ictal/periictal/postictal psychotic phenomena; evaluate the severity of their symptoms and level of
their disturbances
Assess the patients capacity to give a consent to treatment and/or to participate in the decision-making process; seek views from family members
and/or carer when necessary
Make a treatment strategy, for example, psychosocial interventions or watchful wait in outpatient clinics, pharmacologic treatment (with or without
other treatment options) as an outpatient or inpatient
Optimize AED regimens where possible by reducing polypharmacy and adjusting the dose to aim for therapeutic serum levels
Administer APDs: following issues should be taken into account
Timing: early intervention is preferable
Choice of APD: any APD with fewer or lesser adverse effects, availability, and affordability
Dose titration: 50300 mg (CE)/day for mild episodes, 3001,000 mg (CE)/day for moderate episodes, 1,0003,000 mg (CE)/day for severe
episodes
Duration: long-term treatment (usually months or years) with APD is required
Provide basic psychosocial approaches, for example, psychoeducation, self-help, and reframing, and support for family and carers
CE, chlorpromazine equivalent.

Future issues Definition of PIP

We have proposed treatment guidelines for IIP based
on limited data and the consensus statements currently
available (Table 3). Whereas treatment systems for IIP
are predominantly borrowed from standard treatment
systems for functional psychoses, they have been found to
be safe and effective. Specific aspects of treatment that
would improve outcome in IIP have not been researched.
Particularly, few data are available for maintenance and
prophylaxis in IIP (Adachi, 2006). Large-scale studies in
patients with IIP are required in a prospective manner,
which can be challenging due to the relatively low preva-
lence of IIP. In addition, despite growing interest in qual-
ity of life in people with epilepsy, usefulness of
psychosocial interventions has been rarely mentioned or
investigated in patients with IIP. The field remains open
for more research.
Postictal Psychosis
As is the case for other types of epileptic psychoses,
PIP is defined by two features: its chronologic rela-
tionship to seizures and the nature of the mental state.
For the chronologic relationship, most authors have
adapted the criterion proposed by Logsdail and Toone
(1988), that is, episodes of psychosis that develop
within 1 week after a seizure, or usually a cluster of
seizures, qualify as PIP. This operational delineation is
not as arbitrary as it seems in light of accumulated
data that now indicate that PIP generally occurs within
3 days after the last seizure (Logsdail & Toone, 1988;
Devinsky et al., 1995; Kanemoto et al., 1996a).
Indeed, the presence of a lucid interval between the
last seizure and start of changes in mental state guar-
antees a qualitative difference between PIP and simple
postictal confusion, and constitutes an integral part of
the clinical picture of nuclear PIP (Fig. 2). However,
inclusion of a lucid interval in the essential diagnostic

Postictal psychosis (PIP) had not drawn wide attention

until the iatrogenic provocation of seizures in seizure
monitoring units for preoperative evaluation became pre-
valent (Savard et al., 1991; Devinsky et al., 1995; Kanner
et al., 1996), and neurologists and neurosurgeons were
frequently confronted with PIP requiring urgent interven-
tion. Pertinent knowledge of this phenomenon has there-
fore become indispensable for clinicians (Trimble, 1991;
Kanemoto et al., 1996a; Kanemoto, 2011). Although PIP
is, in most cases, a self-remitting condition, individuals in
the midst of PIP can be astonishingly violent, extremely
agitated, or confused, such that immediate protection
under strict custody often becomes mandatory (Devinsky,
Figure 2.
2008). PIP is a psychiatric emergency that every neurolo-
Definition of PIP and closely related conditions (with
gist or neurosurgeon involved in epilepsy surgery or
permission from Kanemoto, 2011).
treatment of long-standing limbic epilepsy could be Epilepsia ILAE
confronted with.

Epilepsia, 54(Suppl. 1):1933, 2013

doi: 10.1111/epi.12102

criteria would exclude nearly half of the cases from
PIP (Levin, 1952; Kanemoto et al., 1996a) and most
authors have not automatically excluded cases without
a lucid interval from their study subjects. Indeed, the
lucid interval could be very short and may therefore
go unnoticed.
The second part of the definition, the nature of the men-
tal state, relates to the psychotic presentation. Indeed, the
original criteria proposed by Logsdail and Toone (1988)
included the presence of delusions or hallucinations in
clear consciousness. However, because a manic presenta-
tion is a frequent precursor of nuclear PIP (Kanemoto
et al., 1996a; Kanner et al., 1996), it seems reasonable
that postictal manic state should be included in this defini-
tion. The fact that appropriate and timely therapeutic
intervention can prevent subsequent transition into full-
brown psychosis also shows the practical value of this
idea. In Figure 2, PIP and various related conditions are
schematically summarized.
Diagnosing PIP
In seizure-monitoring units, PIP lends itself to being
easily recognized such that no specific advice seems neces-
sary, except for knowing that such a state exists. However,
without careful attention, an initial sign of elevated mood
or emotional lability may be overlooked, which could
result in failure to apply early intervention, and an other-
wise avoidable psychiatric emergency may ensue. It should
be also noted that a sensitive inquiry can disclose subtle
changes of subjective feeling such as derealization (outer
world looks as if it was not real) or an otherwise barely
noticeable lowering of cognitive function even in a seem-
ingly normal lucid interval (Ito, 2010; Schulze-Bonhage &
van Elst, 2010). In principle, it is highly advisable that a
careful examination of psychiatric as well as neuropsycho-
logical status should be repeated at least within 3 days
following a seizure cluster in seizure monitoring units.
As for outpatients, especially in cases of the first epi-
sode of PIP, a preceding seizure or seizure cluster can be
overlooked, which may obscure the true nature of the
presentation. If an otherwise taciturn person with long-
standing temporal lobe epilepsy (TLE) becomes suddenly
eloquent or if a reticent one becomes unexpectedly irrita-
ble or sticky, medical personnel should be on alert, as it
may herald the beginning of PIP even if preceding sei-
zures cannot be confirmed. If it is truly an initial sign of
PIP, frank psychosis or seriously annoying behavioral
changes including menacing aggression (Gerard et al.,
1998; Kanemoto et al., 2010) will develop, in the absence
of appropriate intervening measures, within 48 h.
Associated characteristics
Long-standing (average duration >15 years) TLE is a
typical comorbid condition of PIP (Savard et al., 1991;
Devinsky et al., 1995; Kanemoto et al., 1996a; Kanner
27
Treatment of Psychosis in Epilepsy
et al., 1996; Adachi et al., 2002a; Kanemoto, 2011).
Other types of focal epilepsies, especially frontal lobe epi-
lepsy, are also associated at times (Adachi et al., 2000a;
Nishida et al., 2006; Alper et al., 2008). On the other
hand, coexistence of idiopathic generalized epilepsies and
PIP is quite exceptional (Chakrabarti et al., 1999).
In a substantial proportion of cases, involvement of the
medial temporal structures is indicated on MRI, which
may also extend to the lateral temporal and extratemporal
regions (Kanemoto et al., 1996b; Sundram et al., 2010).
Furthermore, epileptiform discharges on surface EEG in
temporal regions tend to be bilateral (Kanner & Ostrovs-
kaya, 2008a; De Toffol, 2009). In patients with repetitive
episodes of PIP, a specific personality trait such as hyp-
erreligiosity or viscosity may supervene (Trimble, 2007;
Devinsky & Lai, 2008).
Treatment principles for PIP
The therapeutic approach to PIP comprises acute protec-
tive measures and the prevention of repeat episodes (Lanc-
man et al., 1994; Kanemoto, 2002; Devinsky, 2008).
Acute management of PIP or imminent PIP
Initial stage preceding PIP. In the nuclear type, elevated
mood or peculiar irritability often precedes a full-blown
PIP episode (Schulze-Bonhage & van Elst, 2010). If
patients are successfully treated at this stage, development
of frank psychosis might be thwarted. As noted above, PIP
is closely linked with various abnormal behaviors that can
do great harm to the subsequent social life of the patient.
In cases of long-standing TLE, patients and families
should be warned beforehand to seek medical help as soon
as possible and not leave the patient alone if any suspi-
cious change in behavioral patterns appear after a seizure
or seizure cluster (Krauss & Theodore, 2010). In the sei-
zure monitoring unit, every seizure cluster or secondarily
generalization should be taken as a possible precipitant of
PIP, and indicates the need for intensified observation.
Full-blown PIP. Once PIP develops fully, immediate pro-
tective custody is unavoidable in many cases and any
delay in protection may lead to serious problems, includ-
ing destructive or self-harming behavior (Devinsky et al.,
1995; Kanner et al., 1996; Kanemoto et al., 1999;
Fukuchi et al., 2002). In patients with a history of violent
PIP episodes in the past, the risk of similar behaviors being
repeated is particularly high. A potent sedative agent is
worth trying, which may shorten the duration of the epi-
sode. Paradoxically, ECT may be helpful in terminating
violent PIP attacks in exceptional cases (Pascual-Aranda
et al., 2001). Repetitive transcranial magnetic stimulation
might be more safely applied than ECT in the future,
although it remains an experimental treatment for PIP at
present (Krauss & Theodore, 2010).
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
28
N. Adachi et al.
Preventive strategy in the long term
In contrast to interictal psychosis inclusive of alterna-
tive psychosis, seizure control generally prevents recur-
rence of PIP episodes (Kanemoto et al., 2001a,b). In some
patients, a simple reappraisal of pharmaceutical therapy
can succeed in stopping seizures or seizure clusters, con-
sequently preventing PIP episodes as well. However, a
considerable number of patients have already tried nearly
all available antiepileptic agents by the time PIP appears,
which shows a rather discouraging prospect for drug ther-
apy to achieve complete seizure freedom. In addition, in a
clinical setting like this, intensive antiepileptic pharmaco-
therapy may be prone to induce various psychiatric symp-
toms, including interictal psychosis and depression.
Operative intervention, if applicable, is often the last hope
for a breakthrough in affected patients. Indeed, successful
operative intervention leads to cessation of PIP episodes
as well, except in some cases (Christodoulou et al., 2002).
Nevertheless, it should be noted that epilepsy-related vari-
ables associated with PIP such as structural changes
beyond medial temporal lesion and bilateral EEG foci
may predict poor surgical outcome (Alper et al., 2001; De
Toffol, 2009), although that has not yet been confirmed by
actual investigations (Winesett & Benbadis, 2010). An
additional cautionary note is also in order. Patients with
preoperative episodes of PIP or even prolonged postictal
confusion may have a higher risk of developing serious
depression (or even a manic state) within 3 months after
surgery (Kanemoto et al., 2001a,b). Furthermore, in pre-
surgical evaluations of patients with a history of PIP, sei-
zure cluster or secondary generalization is highly likely to
replicate similar episodes, so that every step should be
taken in advance to avoid inducing PIP episodes and, once
PIP manifests, to treat it as soon as possible (Kanner,
2009). Although these anticipated troubles may discour-
age surgical intervention, successful surgery can dramati-
cally change the life of affected patients, even more
dramatically than in those with epilepsy but without PIP.
Therefore, patients with PIP should not be deprived of a
chance for surgical intervention beforehand, as some are
in fact excellent candidates.
How to use medical treatment
For psychoses associated with epilepsy, a systemic
review of literature up to 2008 revealed only one under-
powered, randomized controlled trial, from which obvi-
ously few conclusions can be drawn (Farooq & Sherin,
2008). When it comes to pharmacotherapy for PIP, limita-
tions in the evidence should be always kept in mind, since
nearly all advice remains at the level of expert opinion. Fur-
thermore, the initial target of pharmacotherapy often needs
to be directed toward violent or agitated behavior, rather
than the psychosis itself. This means that measures estab-
lished for rapid tranquilization of patients with schizophre-
nia may not automatically be applicable to those with PIP.
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
Acute phase
In both the initial stage preceding PIP and during the
episode, sedative drugs are generally needed, as they not
only stop socially inappropriate behaviors but can also
abort or alleviate symptoms of PIP. Some experts have
recommended benzodiazepines (Lancman et al., 1994),
whereas others prefer a combination of both benzodiaze-
pines and antipsychotics (Kanner et al., 1996). Although
antipsychotics are known to lower seizure threshold in vi-
tro, except for some notable exceptions, such as zotepine
and clozapine (Devinsky et al., 1991), their proconvulsive
effects seem to be at a tolerable level, at least as long as
they are given within a therapeutic range. In most cases,
imminent need of sedation has priority over a possible
proconvulsive risk.
In some exceptional cases, early stage PIP can be man-
aged and thwarted with a relatively low dose of oral ben-
zodiazepines. However, in other extreme cases, sedatives
should be given swiftly as well as massively enough to
force immediate tranquilization. Depending on how seri-
ous the detrimental impact is on the patient and their sur-
roundings, and whether an inpatient or outpatient situation
is in question, different combinations of pharmaceutical
interventions can be chosen, as follows.
1 Oral administration of benzodiazepine (e.g., loraze-
pam).
2 Combined oral administration of benzodiazepine and
dopamine-blocker (e.g., risperidone, olanzapine, que-
tiapine, chlorpromazine).
3 Intramuscular administration of dopamine-blocker (e.
g., haloperidol plus promethazine).
In cases without seriously alarming behaviors either
during precedent or current PIP episodes, regimen A may
suffice. However, even when observed signs are confined
to slightly elevated mood or irritability, the patient should
be kept under strict scrutiny at least for the next 24 h.
Meanwhile, if any sign of increasing excitability is
noticed, a switch to regimen B may be necessary, because
benzodiazepines alone may precipitate paradoxical
excitement and are not as potent as dopamine-blockers for
rapid tranquilization of violent or agitated patients in a
psychiatric emergency (Alexander et al., 2004; Allen
et al., 2005). When confronted with seriously alarming
current behaviors or in the presence of past violent
episodes during PIP, if the patient is unable to cooperate,
regimen C may be left as the only choice. Again, it should
be noted that there are no reliable data to favor one anti-
psychotic over another.
Interepisodic phase
Robust manifestations of PIP usually fade away within
a week and patients seem to superficially return to their
former selves. However, unexpected outbursts caused by
minimal stimuli can occur sporadically within the
next few weeks afterward (Oshima et al., 2006). In this
 29
Treatment of Psychosis in Epilepsy

unstable stage, a reduced amount of regimen A or B often
needs to be maintained. Sedatives should be reduced grad-
ually and can be tapered completely on average within
4 weeks and mostly within 3 months. Except for cases
with combined chronic psychosis and severe personality
change, continuous use of psychotropic agents is not gen-
erally recommended during the interepisodic phase. No
reliable data are available to judge whether a switch of an-
tiepileptic drug to one with more psychotropic efficacy,
such as valproate, carbamazepine, and lamotrigine, is ben-
eficial for the prophylaxis of PIP (Krauss & Theodore,
2010).
Prognosis of PIP
In considering prognosis, each episode of PIP is essen-
tially a benign, self-remitting condition. Only temporary
measures such as physical restriction or medical sedation
are needed to cope with risk behaviors aimed at protecting
the safety of patients and others. In comparison with IIP,
the duration of PIP is clearly shorter. In a recent collabora-
tive study, approximately 95% of PIP episodes resolved
within 1 month (Adachi et al., 2007). In another study,
PIP episodes tended to resolve within 1 week in an
overwhelming majority of patients in a seizure monitoring
setting (Devinsky et al., 1995; Kanner et al., 1996).
Nevertheless, it should be noted that suicidal attempts are
frequent complications of PIP episodes and without inter-
vention there may be a heightened risk of mortality
(Devinsky et al., 1995; Kanemoto et al., 1996a; Kanner
et al., 1996; Fukuchi et al., 2002).
In half of affected patients, PIP remains as a single
episode. In the other half, PIP episodes tend to repeat,
which may occur even quasiregularly after a cluster of
complex focal seizures or secondary generalization in
extreme cases (Logsdail & Toone, 1988; Kanemoto
et al., 1996a,b; Kanner et al., 1996; Liu et al., 2001).
In some patients, repetitive PIP episodes finally develop
into chronic interictal psychosis (Tarulli et al., 2001;
Adachi et al., 2003; Kanner & Ostrovskaya, 2008b).
not seem to be directly linked with epileptiform dis-
charge. Some authors have speculated that postictal
alterations of neurochemical settings may be found
somewhere in the limbic circuit. Stevens (1983)
regarded these alterations as excessive inhibitory sur-
round and, more specifically, Bortolato and Solbrig
(2007) assumed that increased hippocampal dynorphin
release may serve as a psychotomimetic agent via
overstimulation of kappa opioid receptors in PIP. From
an electrophysiologic point of view, Kuba et al. (2012)
recently found a unique slow rhythmicity in depth-EEG
recordings during PIP episodes, which clearly differed
from ictal epileptiform discharge appearing in limbic
status epilepticus. Also, as was recently suggested
(Oshima et al., 2006), subcategorizing of PIP into
nuclear type with a lucid interval and initial hypomanic
stage and atypical periictal type may be helpful for
understanding the underlying pathophysiology of PIP
(Fig. 3A,B). Further accumulation of relevant cases is
highly anticipated.
There are genetic as well as phenomenologic data sug-
gesting a close affinity of PIP with bipolar disorder (Alper
et al., 2001; Kanemoto et al., 2001a,b). PIP episodes can
be well observed and investigated because of their limited
duration and clear-cut on-and-off psychotic states.
Increased knowledge of how PIP develops may also help
to clarify the mechanisms related to how relevant psychi-

Future issues
Although data gathered from cases with invasive
EEG recordings during PIP are highly limited (Wieser
et al., 1985; So et al., 1990; Mathern et al., 1995;
Kanemoto, 1997; Seeck et al., 1999; Takeda et al.,
2001; Schulze-Bonhage & van Elst, 2010), it has
become increasingly clear that only a limited propor-
tion of PIP or related conditions correspond to ictal
EEG correlates. Indeed, sporadic single photon emis-
sion computed tomography (SPECT) studies have sug-
gested that early frontal and late medial temporal
Figure 3.
hyperactivities may play some role in the genesis of
(A) Nuclear PIP; (B) Periictal psychosis (with permis-
PIP (Fong et al., 2000; Leutmezer et al., 2003; Nishida
sion from Kanemoto, 2011).
et al., 2006; Oshima et al., 2011). However, in a
Epilepsia ILAE
substantial number of cases, these hyperactivities do
Epilepsia, 54(Suppl. 1):1933, 2013
doi: 10.1111/epi.12102
30
N. Adachi et al.
atric disorders without epilepsy develop, which may help
bridge neurology and psychiatry.
Conclusion
Psychotic disorders are not infrequent in epileptic
patients. IIP reportedly occurs in 4.57.0% (Trimble,
1991) and PIP in <2% (Kanemoto et al., 2001b). In those
with PEs, the incidence of PIP is doubled (Kanner et al.,
1996; Kanemoto et al., 2002; Oshima et al., 2006; Falip
et al., 2009), whereas the incidence is threefold in seizure
monitoring units (Kanner et al., 1996; Alper et al., 2001,
2008; Falip et al., 2009). IIP and PIP are serious disorders
with significant effects on patients and their families. A
number of cases may become psychiatric emergencies or
pose significant risk to others. Such risks can be reduced
or avoided if prompt and adequate treatment is put in
place. There is now international consensus among
experts that all medical personnel involved in providing
health care to patients with epilepsy should be well-
informed about IIP and PIP (Kerr et al., 2011).
Based on the limited data and consensus statements cur-
rently available, we have proposed treatment procedures
for IIP and PIP that are concise and practical. We hope that
this article will raise awareness of the importance of these
matters and the need for further studies. With the accumu-
lation of further evidence, the proposed treatment systems
should be refined and placed on even greater empirical
footing.
Disclosure
None of the authors have any conflicts of interests. We confirm that
we have read the Journals position on issues involved in ethical publica-
tion and affirm that this report is consistent with those guidelines. The
contents of this supplement reflect the opinions of the individual authors
and do not necessarily represent official policy or position of the ILAE.
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