Epilepsiu, 4O(Suppl.
1O):S2-S20, I999
Lippincott Williams & Wilk~ns,Philadelphia
0 International League Against Epilepsy
Behavioral, Psychotic, and Anxiety Disorders in Epilepsy:
Etiology, Clinical Features, and Therapeutic Implications
Riccardo Torta and Roberto Keller
Department of Neurosciences, University of Turin, Turin, Italy
Summary: This chapter deals with some aspects of psychiat-
ric disturbances in people with epilepsy. Because depression
and its treatment are extensively described later in this issue,
they are not discussed here. The same pertains to forced nor-
Although most people with epilepsy lead a normal
emotional and cognitive life, neurobehavioral problems
can be found in a large number of patients. Higher rates
of psychopathology are observed in people with epilepsy
relative to the general population (1,2), to other neuro-
logic control groups (3), and to people with chronic non-
neurologic disorders (1,4). In particular, increased psy-
chopathology is more common in temporal lobe epilepsy
(TLE) than in generalized epilepsy (5). Nevertheless,
many issues remain highly controversial, owing in part to
several methodologic problems, such as the nosographic
approach, the sample examined, the type of control
groups, the comparison among nonhomogeneous forms
of epilepsy, and the different antiepileptic drugs (AEDs).
Psychiatric disturbances can be related either to in-
volvement of brain structures (biologic pathogenesis) or
to the chronic characteristics of epilepsy (psychosocial
pathogenesis). These psychiatric symptoms may develop
in relationship to the seizures (in prodromal, ictal, or
postictal periods) but more commonly are present in a
chronic interictal condition.
The wide range of clinical diversity is related to the
anatomic foci, to patterns of spread, and to biologic or
psychological differences among patients. Interictal be-
havioral changes in epilepsy remain controversial and
difficult to define, mainly because pathogenesis may be
attributable to several factors, such as epilepsy itself,
possible brain lesions, the AEDs prescribed, and psycho-
social problems (6). On the other hand, the existence of
cognitive changes in epilepsy is well established, and
Addrress correspondence and reprint requests to Dr. Riccardo Tom
at Dipartimento di Neuroscienze, via Cherasco 11, 10126 Torino, Italy.
s2
malization. Key Words: Epilepsy-Anxiety-Psychosis-
Depress ion-Qua1 i t y of 1i fe-Ps e u do s ei zure s-A nti-
depressants-Antipsychotics-Antiepileptic drugs.
sometimes the presence of cognitive disorders can facili-
tate the appearance of psychiatric disturbances (7).
One of the most widely discussed problems is the
incidence of psychiatric pathology in epilepsy, with a
wide range of values in the literature related to the type
of study. Epilepsy is characterized by a broad spectrum
of severity. Ideally, patients for study trials should be
selected consecutively from a general epilepsy popula-
tion, but most epidemiologic studies are carried out in
centers for epilepsy and include many refractory subjects
who demonstrate a range of pathologic disturbances
more severe than those observed in the general popula-
tion of patients with epilepsy. In community studies, the
prevalence of associated psychiatric disorders is low,
whereas in specialty referral centers, particularly those
serving indigent populations, the prevalence can rise to
25-50%: Among patients with epilepsy who are confined
to mental hospitals or who attend psychiatric clinics, the
prevalence reaches 100% (8).
RISK FACTORS FOR PSYCHOPATHOLOGY
IN EPILEPSY
The high incidence of psychiatric disorders in epilepsy
largely reflects the increased risk for psychopathology in
these patients. This risk that is related to a wide range of
factors that can be conceptualized into several major cat-
egories, as follows.
Clinical factors, mainly represented by age at onset of
epilepsy (particularly if onset occurs during critical
periods of neurologic development, such as during
the increase in formation of synaptic links), duration
of disorder, type and frequency of seizure, the hemi-
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
sphere of cerebral dysfunction (if present), and in-
terictal and ictal EEG abnormalities.
Psychosocial factors, such as the chronic nature of the
disease, low socioeconomic status, low educational
level, a negative cultural approach to epilepsy, dif-
ficulties in adjustment to the consequences of the
illness, fear of seizures, social stigma, frequent
overprotection by families, legal limitations (such
as not being able to hold a driver’s license), and
psychological feelings of low self-esteem.
Biological factors, represented by neuropathologic
damage to areas connected with psychic functioning
(such as the amygdala, limbic system, frontal cor-
tex, basal ganglia), emotional and cognitive side
effects induced by some AEDs (either related to the
mechanism of action or to AED interaction with
folate metabolism, or to a direct action on neuro-
transmitters), and forced normalization.
This differentiation is partially theoretical, because
each type of factor (biologic, clinical, psychosocial) is
related to the others. Psychiatric and neurologic illnesses
involve different aspects of the brain. Therefore, any
statement about the relationship among these factors en-
tails certain epistemologic assumptions, some of which
have undergone considerable change and rapid evolution
during the past century (9).
PERSONALITY AND BEHAVIORAL
DISORDERS IN EPILEPSY
Epilepsy can be accompanied by changes in cognition,
personality, affect, and other elements of behavior. There
is no true epileptic personality complex: “the only uni-
fying theme to the behaviour in epilepsy is diversity” (6).
Extremes of behavior can be accentuated, sometimes in
one direction, often in both directions. Thus, some pa-
tients may be irritable and aggressive whereas others are
timid and apathetic. Psychosis, depression, paranoia, and
personality disorders may represent a negative pole of
epilepsy-related behavioral changes. On the other hand,
however, the impressive list of people with epilepsy who
play important roles in politics, religion, arts, and sci-
ences also suggests a positive expression of this behav-
ioral spectrum. Among the more common behavioral
features in epilepsy are changes in emotional state, with
deepening or increase in emotionality (6).
A relationship between personality and behavioral dis-
orders has been hypothesized for many centuries. In the
Malleus Maleficarum, a witch-hunters’ handbook written
by two Dominican friars during the Middle Ages, epi-
leptic seizures were considered to represent behavioral
features of witches and their victims (10). Centuries of
stigma and misinformation regarding people with epi-
lepsy led to a persistent and widespread stereotypical
s3
concept that epileptic patients invariably exhibit cogni-
tive and behavioral deterioration.
During the past 50 years, new interest in epilepsy and
behavior was stimulated by the works of Gibbs et al.
(1 1). According to these authors, patients with psycho-
motor epilepsy exhibited increased psychopathology
compared with those with other focal or generalized sei-
zures. A few years later, Gastaut et al. (12) observed
global hypoexcitability or slowness in almost three-
quarters of people with psychomotor epilepsy, associated
with cognitive deficits, depressed mood and hyposexu-
ality.
In 1975, Waxman and Geschwind (13) described an
interictal behavioral syndrome in temporal lobe epilepsy
that was characterized by deepened emotions, altered re-
ligious and sexual concerns, circumstantiality, and hy-
pergraphia. Some behavioral changes were later con-
firmed and better defined by Bear and Fedio (14).
The most common personality traits reported histori-
cally in people with epilepsy are viscosity, circumstan-
tiality, and hypergraphia and, less frequently, hyperreli-
giosity (6).
Viscosity is more common in patients with left-sided
temporal foci. It is characterized by a sticky and cohesive
interpersonal style, with prolonged verbal contacts and
an emotional need to seek and maintain contact with
others. Viscosity is associated with certain combinations
of linguistic impairment, slowness in cognitive perfor-
mance, psychological dependence, and a peculiar ten-
dency to seek social cohesion. On the other hand, limbic
lesion models in animals, particularly when septa1 dam-
age is involved, can stimulate stronger contacts among
animals in an open field (15).
Viscosity is often associated with circumstantiality
and, in 8% of TLE patients, with hypergraphia (16). The
latter involves a tendency toward extensive and compul-
sive writing, with preoccupation with detail, detailed
definition of words and concepts, and excessive response
length (17).
In the past, in a small group of TLE patients, an un-
usually pronounced attention to moral or religious con-
cerns (hyperreligiosity) was noted (6). A special relation-
ship between epilepsy and religion was recognized by
Hippocrates (18) and is also described in some classic
monographs on mysticism (19). Like all human experi-
ence, religious experience is also brain-based (20). Cer-
tain brain disorders (e.g., temporolimbic epilepsy) and
some conditions (e.g., near-death experiences, hallucino-
gen ingestion) may produce sensations of depersonaliza-
tion, derealization, ecstasy, timelessness and spaceless-
ness, and other experiences that foster religious interpre-
tation. A strong relationship between prophetic power
and epilepsy (21) has frequently been suggested, with
sudden religious conversions related to seizures (22) and
epileptic seizures during ecstatic phenomena (23).
Epilepsia, Vol. 40, Suppl. 10, 1999
s4 R. TORTA AND R. KELLER
It is evident that several of the personality traits ob-
served in TLE (particularly viscosity, hypergraphia, cir-
cumstantiality, dependence, and hyperreligiosity) have
psychopathologic characteristics (e.g., perseverance, re-
petitiveness, compulsiveness) that are related to the spec-
trum obsessive-compulsive disorders (OCDs). Accord-
ing to a serotoninergic theory of OCD, such behavioral
disorders in people with TLE can be effectively treated
with serotoninergic agents (such as the selective seroto-
nin reuptake inhibitors, SSRIs), that moreover demon-
strate good safety in epilepsy (see Lambert and Robert-
son, this issue) (24).
PSYCHOSIS IN EPILEPSY
The link between epilepsy and psychosis has been
discussed during the past century, suggesting the con-
cepts of antagonism, i.e., a protection by seizures vs.
psychotic disorders, or agonism, i.e., epileptic facilitation
vs. the appearance of psychosis. In 1854, Falret (25) and
Baillarger (26) described intermittent, periodic, phasic
psychotic states that were, for 50 years, considered as
manifestations of “larval epilepsy” and “grands maux
intellectuels,” which accounted for the regularity of
symptom fluctuations common both to epilepsy and to
these periodic psychoses. When the concept of larval
epilepsy fell into disfavor, the belief that dementia pre-
cox and epilepsy were commonly associated was sup-
ported by Kraepelin (27), who reported an incidence of
18% of epilepsy in dementia praecox. On the other hand
Glaus (28), in 1931, observing in eight patients an alter-
nation of psychoses and convulsions, stated that epilepsy
and schizophrenia were antagonistic.
von Meduna (29), reporting histologic examinations of
brain sections from people with epilepsy characterized
by glial proliferation, which was highly differentiated
from those of people with schizophrenia showing atro-
phy, introduced artificially induced convulsive therapy
for management of psychotic states. Soon after that,
electroconvulsive therapy (ECT) became widely utilized
in management of psychoses. This was also conceptually
supported, 30 years later, by the observation of Landolt
(30) that some people with epilepsy, after recovery from
their crisis with AED therapy, demonstrated a psychotic
or depressive pathology. That inverse correlation be-
tween epilepsy and psychosis was labeled as “forced
normalization”(see article by Krishnamoorty and
Trimble, this issue, S56-S63).
The antagonism theory, in its original and general for-
mulation, was criticized in studies that observed that cer-
tain forms of epilepsy, on the contrary, predisposed to
chronic hallucinatory psychoses similar to schizophrenia.
In 1963, Slater and Beard (31) published a study on
schizophrenia-like psychoses of epilepsy and stated that
the emergence of epileptic psychoses was related to the
duration of the epilepsy and to the brain damage, and was
particularly linked to TLE.
The problem concerning the relationship between epi-
lepsy and psychoses was later considered from another
point of view (32). Epilepsy and convulsions are not
always coincident, and if certain forms of epilepsy, such
as cerebral involvement, can predispose to certain forms
of psychosis, convulsive attacks might protect against the
psychotic manifestation. Therefore, the theory of ago-
nism would be correct when related to epilepsy but an-
tagonistic theory would also be correct when related to
seizures.
On the other hand, unilateral nerve cell loss and gliosis
in the CA1 subfield of the hippocampus is the most
common brain lesion both in “idiopathic” generalized
epilepsies and in TLE. Sclerosis of the anterior hippo-
campus can be both a cause and an effect of epileptic
seizures, and a significant factor in determining psycho-
pathologic disturbances (33).
In this way, seizures can simultaneously exert an ad-
vantageous action on psychotic symptoms, through short-
term neurophysiologic action and a detrimental action on
psychotic illness, through an induced long-term neuro-
pathologic modification.
EPIDEMIOLOGY
The prevalence of psychosis in epileptic populations
differs according to the sample examined. In the general
epileptic population (e.g., patients evaluated in a general
practice survey), psychotic disturbances are present in
0.67%. Large-scale community surveys found a 2% and
7.1% incidence of psychosis in epileptic populations of
Norway and Iceland, respectively (34). The different
prevalence depends on factors such as geographic varia-
tion, the interval of time over which data are collected,
nosographic criteria, and particularly the type of sample
considered. These percentages can increase to 19-27% in
selected samples, e.g., among people with epilepsy ob-
served in epilepsy centers, in which more severe patholo-
gies are obviously present (6). In developing countries,
the rate of schizophrenic forms of psychosis can reach
12-19% in patients with epilepsy who are referred to
neurologic clinics (35,36). Larger surveys of 666 (37)
and 11,000 (38) patients attending epilepsy clinics
yielded psychosis rates of 3.2% and 2.8%, respectively,
and Mendez et al. (39) found interictal schizophrenic
disorders in 9.25% of 1,611 outpatients with epilepsy.
On the other hand Whitman et al. (40), who used the
Minnesota Multiphasic Personality Inventory (MMPI) in
2,786 patients, found that overall rates of psychopathol-
ogy were not increased in epilepsy. However, when psy-
chopathology was present, the level of psychosis was
greatest in patients with epilepsy (40).
In the only prospective study of psychosis and epi-
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
lepsy, chiIdren with TLE demonstrated a 10%chance of
developing interictal psychoses during a 30-year follow-
up period compared with an incidence of psychosis in the
general population of around 0.8%, particularly when
their seizures continued through adolescence into matu-
rity (41). This suggests a special vulnerability during
adolescence that can be related to the remarkable
changes in both physiologic activity and synaptic struc-
tures in the hippocampus and amygdala (42). During this
period, high-frequency neuron discharges, similar to
those of epilepsy, normally occur from restricted areas of
the amygdala, hippocampus, hypothalamus and other
limbic nuclei during pulsatile endocrine release, estrus,
ovulation, and copulation (33,43). If excessive, these
“microseizures” could induce excitotoxic cell death or,
as in kindling, could provoke sprouting and synaptic re-
organization, including expansion of dopaminergic bind-
ing sites, whose hyperactivity can elicit psychotic symp-
toms (33,44). In fact, clusters of intractable seizures can
be much more detrimental if they occur before or during
adolescence, when some systems, e.g., the prefrontal cor-
tex, are reaching functional maturity (45).
In conclusion, epidemiologic studies have identified a
variety of psychoses in about 7-8% of epilepsy patients
(46), and studies of chronic psychoses in groups of pa-
tients with treatment-refractory TLE (mostly before sur-
gery) have found prevalence rates ranging from 0 to 16%
(47,48). Of 300 consecutive patients with epilepsy who
were refractory to treatment and therefore were candi-
dates for surgery, a schizophrenia-like psychosis was
seen in 4.3% (49). Incidence studies therefore suggest
that the risk for psychosis may be 6-12-fold greater in
patients with epilepsy than in the general population
(5031).
CLINICAL ASPECTS
Epileptic psychoses can be classified as peri-ictal (ic-
tal and postictal), usually of short duration, or interictal,
usually prolonged. Postictal psychosis accounts for 25%
of epileptic psychoses. They typically appear after an
increase in seizure frequency or after prolonged tonic-
clonic seizures, often with a lucid interval of 24-72 hours
between cessation of seizures and onset of psychosis.
Mood alterations are also associated with postictal psy-
choses, with high risk for suicide, but recovery is usually
spontaneous.
Devinsky et al. (52) observed that postictal psychoses
most often develop in patients with bilateral dysfunction
after a cluster of or generalized tonic-clonic seizures,
with a lucid interval between last seizure and onset of
psychosis ranging from 2.3 to 72 h (mean 25 h) and a
duration of postictal psychotic symptoms ranging from
16 to 432 h (mean 83 h).
A differential diagnosis between postictal psychosis
s5
and delirium is necessary. Postictal psychosis occurs
with relative preservation of attention and with delusions
and hallucinations that are more systematized and struc-
tured than those of delirium. Delirium is characterized by
greater impairment of attention and by confusion and
autonomic dysfunction. Occasionally, nonconvulsive
status epilepticus can mimic a psychotic state but more
often induces delirium. An EEG is necessary for a cor-
rect diagnosis to be made (50,52).
Brief psychotic episodes in epilepsy frequently end in
a convulsion. Therefore, the clinical benefit of pro-
grammed seizures might be considered for some patients
(53). Most patients achieve a full recovery, and only 10%
develop a chronic psychosis or a cognitive disorder.
Interictal psychoses, i.e., the persistent psychotic
manifestations also known as schizophrenia-like psycho-
sis of epilepsy, typically have a paranoid or schizophre-
nia-like presentation, often with Schneiderian first-rank
symptoms (54). Nevertheless the interictal psychoses can
be differentiated from functional schizophrenia in terms
of phenomenology, course, and outcome. They comprise
a heterogeneous group of psychoses (45,55,56) that dif-
fer clinically from schizophrenia by the preponderance
of purely delusional states, preservation of warm affect
and personality, and predominance of visual rather than
auditory hallucinations. Less common features include
formal thought disorders and negative symptoms, a rela-
tively rare familial schizophrenia or schizoid premorbid
personality, and a generally more favourable outcome
(31,5237).
Several years ago it was suggested that patients with
generalized epilepsy tended to develop psychosis char-
acterized by normal affect, whereas patients with TLE
and psychosis showed a tendency toward depression
(58). Other authors observed that people with epilepsy
who develop psychoses demonstrate a good affect, in
contrast to the blunted affect of nonepileptic individuals
with schizophrenia (59,60). In children with complex
partial epilepsy, left temporal lobe impairment and in-
terictal schizophrenia-like psychosis, the affect remains
intact, without the negative signs of schizophrenia
(61,62).
TEMPORAL LOBE EPILEPSY
AND PSYCHOSES
In 1948, Gibbs et al. (1 1) found, in a sample of 1,675
patients, a 12% incidence of psychosis in TLE and less
than a 1% incidence in generalized epilepsy. These au-
thors stated that “. . . a patient bearing the diagnosis ‘epi-
leptic with psychosis’ is almost invariably a psychomo-
tor epileptic . . .” Later, Slater and Beard (31) noted that
55 of their 69 patients with schizophrenia-like psychoses
and epilepsy had a temporal lobe focus. Several further
studies demonstrated that epileptic psychoses were most
Epilepsia. Vol. 40, Suppl. 10. 1999
S6 R. TORTA AND R. KELLER
often related to TLE, whereas others failed to find such
an association (50,63,64).
More agreement among authors concerns the relation-
ship between interictal psychoses and left-sided (65) or
bilateral seizure foci (45,65,66). In this regard, although
high rates of bitemporal foci were noted in some studies
(45,56,67), other authors reported more lateralized foci
(63,68). However in most of the studies that reported a
preponderance of left temporal foci among psychotic pa-
tients, these patients were being considered for temporal
lobectomy. In these samples, patients with bitemporal
foci were not included because they were not eligible for
surgery (45).
The importance of a mediobasal temporal localization
compared with a lateral localization, independent of fo-
cus side, has been related by some authors to the pres-
ence of auras (69). In fact aura-mediated disruption of
reality testing can potentiate the disinhibition of the me-
solimbic dopamine system related to kindling phenom-
ena (39,70).
RISK FACTORS FOR INTERICTAL PSYCHOSIS
Possible risk factors for interictal psychosis in epi-
lepsy include onset of epilepsy before age 20 (47), usu-
ally around puberty, a duration of epilepsy greater than
10 years, with a latent period between onset of seizures
and onset of psychosis of around 14 years, female gender
(71,72), left-handedness (7 1,73), relative absence of fe-
brile convulsions (459, history of complex partial sei-
zures (56,63,74), history of clustering of seizures
(45,56), temporal lobe seizure focus, especially left-sided
(63,65,75) or bilateral (49, histopathologic findings of
abnormal tissue (56), such as gangliogliomas occurring
at an early developmental stage and focal neuropatho-
logic lesions (74,75), social deterioration, and AED poly-
therapy, particularly with high doses of AEDs (52,66).
Several authors reported the appearance of psychosis
when AEDs were reduced during intensive EEG moni-
toring in preparation for a surgical approach to intrac-
table seizures (56,76). However, postictal psychosis does
not constitute a contraindication to surgical treatment of
epilepsy (56).
The average age at onset of epilepsy in patients with
chronic psychoses was shortly before the beginning of
puberty, whereas the corresponding age at onset for pa-
tients with postictal psychoses was the end of adoles-
cence (45). Other authors reported that median age at
onset of psychosis was 34 years, after a history of epi-
lepsy of 21 (median) years’ duration (73).
EPILEPTIC SURGICAL PATIENTS
AND PSYCHOSIS
Studies of epileptic surgical patients demonstrate that
people with left-sided temporal lobe epileptogenic le-
Epilepsia, Vol. 40, Suppl. 10, 1999
sions are at special risk for development of a schizo-
phrenic-like psychosis (65). The prevalence of sinistrals
in the psychotic group can be explained by the hypoth-
esis that a left-sided epileptogenic lesion that develops
early, even perinatally, can induce a shift to right cere-
bral dominance (65).
Epileptic psychoses are strongly correlated with sei-
zures. Interictal disorders usually appear after long-term
epilepsy, when seizures have been reduced in frequency
or have disappeared entirely as a result of medical or
surgical treatment. In particular, the occurrence of
chronic schizophrenia-like psychoses in 3-1 2% of pa-
tients many months after anterior temporal lobectomy for
relief of seizures is consistent with a hypothesis of ab-
errant regeneration and a pathologic reorganization of
deafferented projection sites in the remaining brain, with
a resultant “miswiring,” as a causative factor, probably
related to a pathologic enhancement of brain dopamine,
as confirmed by the favorable response of postlobectomy
psychoses to treatment with low doses of neuroleptics
(63,77). Possible interpretations of this clinical feature
include a kindling mechanism or a syndrome of subcor-
tical neurotransmitter imbalance (78).
Psychotic disturbances can also develop in people
with epilepsy who have been previously cognitively nor-
mal, between 6 months and 1 year after temporal lobec-
tomy for medically intractable seizures (77). This severe
complication after surgery occurs in about 1 . 3 4 8 % of
patients (79,80). The development of psychosis or dete-
rioration in psychiatric status after surgery is more com-
mon in patients with later age of onset, unreality or dkja
vu rather than epigastric aura, preoperative evidence of
bilateral brain damage, and persistence of EEG or clini-
cal seizure activity (77). In addition, right temporal lo-
bectomy may increase susceptibility to postictal psycho-
sis (81), particularly in patients who do not become sei-
zure-free after surgery (79).
FEBRILE CONVULSIONS AND PSYCHOSIS
Umbricht et al. (45) found a relative absence of history
of febrile convulsions among patients with TLE and psy-
choses, whereas other authors have not found differences
in history between chronically psychotic patients and
normal patients (72). Recurrence of febrile convulsions
is often associated with sclerosis of Ammon’s horn (me-
siotemporal sclerosis) that was previously related to the
TLE and psychoses. Nevertheless, some authors hypoth-
esized that patients with treatment-refractory epilepsy
and Ammon’s horn sclerosis are at reduced risk for psy-
chosis (45,47,72). Patients with a history of febrile con-
vulsions exhibit specific cell loss in the CA fields of the
hippocampus (82,83). This great reduction in cells of
these areas might provide some protection against over-
activity of hippocampal neurons induced by interictal
 BEHA VIORAL, PSYCHO TIC, AND ANXIETY DISORDERS
epileptiform activity and related to development of de-
lusions (45).
Finally, it has been hypothesized that a greater rate of
clustering of seizures among the psychotic patients may
exert an excitotoxic effect similar to that of kindling,
particularly during the period of brain development (45).
ETIOPATHOGENESIS OF PSYCHOSES
IN EPILEPSY
Epileptic psychoses can be related to neuropathologic
changes, to neurophysiologic modifications, or to over-
lapping among biologic factors, personality changes, and
social problems related to epilepsy.
Structural hypothesis of epileptic psychosis
The structural hypothesis of epileptic psychosis argues
that cerebral lesions increase susceptibility to psychoses.
However, some authors state that cerebral damage in the
development of epileptic psychosis would exert only a
minor facilitative influence (84). Psatta et al. (8.5) main-
tain that different EEG foci locations can be significantly
related to the type of psychotic syndrome. In their view,
patients with frontobasal (temporal anterior) foci were
particularly paranoid, patients with temporal lobe foci
were particularly depressive, and patients with sagittal
line foci presented a predominantly expansive, hypo-
manic behavior (85). These data suggest that EEG moni-
toring of patients with atypical and remittent psychotic
symptoms might be helpful in evaluation of the possible
epileptic pathogenesis of such disturbances (86,87).
Recently a more specific study concerning the contin-
gent negative variation (CNV) in epilepsy, a long-
latency, event-related potential elicited by paired or as-
sociated stimuli, demonstrated that patients with both
epilepsy and psychosis had a significantly lower area
under the CNV curve (AUC) but did not differ from
nonpsychotic patients in CNV amplitude (88).
In episodes of brief psychosis that are spontaneously
remitting and are not associated with structural cerebral
changes, epileptic mechanisms are implicated mostly in
the form of focal subclinical seizure discharges. During a
psychotic episode, clinical seizures appear to be inhibited
until the psychosis culminates in a convulsion, which is
followed by resolution of the psychotic state. Observa-
tions in patients with TLE and periods of psychosis, us-
ing chronically implanted subcortical electrodes, show,
during psychotic episodes, polyspike and spike-wave
discharges in amygdala, hippocampal, and septa1 areas.
The discharges were rarely detectable on the scalp end
were seen only during psychotic episodes. They were not
observed in epileptic patients without psychosis (89,90).
Recently, Faber et al. (91) observed, in a population of
patients with epilepsy with psychotic symptoms, that at-
tacks of dysphoria and psychosis occur spontaneously
and in response to biologic (hypoglycemia, sleep depri-
s7
vation, alcohol, menses) or psychosocial stimulation
(agitation, quarrels, fear of redundancy, psychic trauma)
and that these states (attacks, dysphoria, “neurotic,” or
even psychotic episodes) often provoke one another.
They called this syndrome “epileptosis.” The authors be-
lieve that such a mechanism can be caused by lesions of
the limbic and brainstem modulation systems. At the
start of the process, they postulate the presence of an
epileptic focus in the amygdalo-hippocampal complex
(AHC) which in itself can trigger a simple or complex
partial seizure and that electric stimulation of the AHC
can lead to states of dysphoria, anxiety, and psychotic
hallucinations (91).
MESIOTEMPORAL SCLEROSIS,
HAMARTOMATOUS LESIONS,
AND PSYCHOSIS
Substantial interest in the past was related to the fact
that the neuropathologic finding in many patients with
TLE, in which SLPE are more common, demonstrated a
mesiotemporal sclerosis (MTS) and that schizophrenia
was associated with lesions at the same sites (92). Pa-
tients with schizophrenia appear to be more prone to
seizures than the general population. This vulnerability
can be related both to the neuropathologic substrate of
schizophrenia itself and to the secondary effects of the
illness, including exposure to psychotropic medications
that lower the seizure threshold. Neuropathologic inves-
tigations into the anatomic substrate of seizures in pa-
tients with psychosis or schizophrenia are consistent with
the notion that there are neurodevelopmental abnormali-
ties involving the mesiotemporal lobe (92). Nevertheless,
Taylor (47) reported that among psychotic patients with
TLE there was an excess of hamartomatous lesions but a
relative absence of MTS. Similarly, Roberts et al. (72),
evaluating clinical and pathologic data from a series ( n
= 249) of patients with TLE, found that the develop-
ment of schizophrenia-like psychosis was significantly
correlated with lesions of fetal or perinatal origin involv-
ing neurons in the mediotemporal lobe. In particular, the
presence of gangliogliomas, which are developmental le-
sions of the mediotemporal lobe containing aberrant neu-
rons, was found to be disproportionately (p < 0.001)
associated with risk for psychosis. The proportion of pa-
tients with gangliogliomas who developed chronic psy-
chosis appears to be significantly greater than those with
Ammon’s horn sclerosis (72). Moreover, Bruton et al.
(93) found that MTS occurred with equal frequency in
the psychotic and nonpsychotic groups studied.
Neuropathologic similarities between idiopathic schizo-
phrenia and schizophrenia-like states are represented by
the disorganization of neurons and the involvement pri-
marily of the hippocampus. In MTS, which is often
unilateral, there is a gliosis that is not present in schizo-
Epilepsia. Vol. 40, Suppl. 10, 1999
S8 R. TORTA AND R. KELLER
phrenia. More recently, the significance of MTS was
reduced by the observation that this alteration occurred
with equal frequency in both psychotic and nonpsychotic
patients with epilepsy (94). Furthermore, epileptic pa-
tients with schizophrenia-like psychoses were distin-
guished from nonpsychotic patients by the presence of
larger cerebral ventricles, excess periventricular gliosis,
and more focal cerebral damage and, above all, by a
significant excess of punctate perivascular white-matter
softening (94).
Other authors related the structural alterations to axon
sprouting induced by the abnormal electrical activity in
hippocampus and amygdala (95,96). In a kainate-
induced model of anterior hippocampal sclerosis, the de-
generation of C4 axons provokes sprouting of collaterals
from the axons (mossy fibers) and formation of new
excitatory synapses on other granule cells (95). Similar
anomalous axon sprouting from dentate granule cells has
been described in the kindling model of epilepsy (96).
Several authors have demonstrated abnormal sprouting
of mossy fibers in human temporal lobe removed for
treatment of epilepsy (97,98).
Neuroimaging in epileptic psychoses
With regard to neuroimaging of epileptic psychoses, in
an MRI study Conlon et al. (99) found no significant
differences in T1 relaxation time between 12 patients
with epilepsy and psychosis and 17 patients with epi-
lepsy and without psychiatric illness. However patients
with hallucinations demonstrated higher T1 values in the
left temporal lobe compared to those without hallucina-
tions (99).
In a PET study, Gallhofer et al. (100) observed a lower
frontal, temporal, and basal ganglion oxygen extraction
rate in SLPE patients than in patients with epilepsy with-
out psychosis and in normal controls. The psychotic
group also demonstrated a lower regional cerebral blood
flow (rCBF) in the left than in the right temporal area.
A pilot SPECT study was carried out to compare rCBF
in patients with epilepsy with and without a schizophre-
nia-like psychosis: SLPE patients exhibited a significant
reduction in the normalized rCBF index in the left hemi-
sphere that was confined to the mediotemporal region
(101).
Jibiki et al. (102), studying the rCBF patterns with
SPECT, suggested that temporolimbic dysfunction, par-
ticularly hyperfunction in the temporolimbic system in
the dominant left hemisphere, appears to arise at the time
of the psychotic state in epileptic psychosis (102).
Dopaminergic hypothesis of SLPE
Reith et al. (103) discovered an increase in the rate of
metabolism of an exogenous DOPA tracer (6-[ "FI-
fluoro-L-dopa) in the neostriatum of a subgroup of pa-
tients with complex partial seizures of the mesial lobe
associated with a history of psychosis. These findings are
Epilepsia, Vol. 40, Suppl. 10, 1999
consistent with the theory that a state of psychosis arises
when episodic dopamine excess is superimposed on a
trait of basic dopamine deficiency in the striatum. The
findings can be explained by the hypothesis that cortical
insufficiency causes upregulation of the enzymes respon-
sible for DOPA turnover in the neostriatum and the re-
ceptors that mediate dopaminergic neurotransmission
(103).
Another study concerning the nature of dopaminergic
activity in epileptic psychoses, through the investigation
of striatal dopamine receptor binding, was carried out by
Ring et al. (104). Fourteen patients with epilepsy who
had recently developed a peri-ictal schizophreniform
psychosis underwent SPECT scanning with [ 1231]-IBZM,
a specific dopamine D, receptor ligand. Comparison of
mean basal ganglia to occipital cortex activity ratios in
the two groups demonstrated significantly reduced spe-
cific binding of ['231]-IBZMto striatal D, receptors in the
psychotic patients compared to those without psychosis.
KINDLING, EPILEPSY, AND PSYCHOSES
Etiologically, psychotic syndromes in epilepsy may
have a counterpart in the experimental phenomenon of
kindling, first described in 1969 by Goddard et al. (l05),
in which repeated, low-intensity electric stimulation can
progressively reduce the epileptic threshold, particularly
at the limbic and amygdaloid levels (105). In parallel
with these progressive changes in cerebral excitability,
kindling induces behavioral changes both in animals
(rage, fear, hyperactivity) and in humans (psychotic a n d
or affective symptoms). These changes are related to
neurotransmitter modifications, particularly to altered
postsynaptic function in dopamine receptors (106).
As reported by Adamec (107), the effects of kindling
on emotional behavior may also offer a model of how
limbic seizures in humans increase the vulnerability of
patients to external precipitants of psychopathology, in-
cluding anxiety and depression. However, recent experi-
mental studies investigated the effect of seizures on emo-
tional responses in the kindling model of complex partial
seizures (CPS) in male Wistar rats through changes in
magnitude of the acoustic startle response (ASR), which
is a sensitive measure of anxiety or fear. These rats, after
kindling, did not show a change in the amplitude of the
ASR, but kindling may tend to sensitize the ASR in those
electrode-implanted rats (106).
A possible corollary to this etiological hypothesis of
psychosis in patients with epilepsy is represented by the
role of some AEDs that specifically inhibit the propaga-
tion of kindling-associated afterdischarges. Carbamaze-
pine, valproate, and lamotrigine, have all demonstrated a
beneficial effect in some psychotic factors and particu-
larly in rapid cyclic bipolar disorders that are strictly
related to kindling phenomena (108,109).
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
AEDs AND PSYCHOSES
Psychoses can represent a rare complication of all con-
ventional AEDs (1 10). Mechanisms related to psychiat-
ric adverse events are principally represented by forced
normalization, folate deficiency, drug toxicity, and drug
withdrawal but, in particular, are associated with bio-
logic and genetic predispositions in each epileptic indi-
vidual.
Psychoses are more frequently associated with forced
normalization (see Krishnamoorty and Trimble, this
issue, S56-S63), the risk with ethosuximides is 2% in
children (1 11) and 8% in adults (1 12). Schizophrenia-
like psychoses were also described with phenytoin when
serum levels were above 35 mg/dl (113).
With the newer AEDs, it appears that forced normal-
ization and alternative psychoses are more related to the
use of GABAergic substances, particularly with the more
powerful agents such as vigabatrin (GVG) and topira-
mate (114). In this way, forced normalization, particu-
larly when related to a change in AED regimen, is also
observed in childhood epilepsy, with clinical features of
schizophrenia-like psychosis and autistic withdrawal
(115).
Sander et al. (1 16), shortly after the marketing of
GVG, reported an incidence of psychiatric complications
in 7% of GVG-treated patients, with 14 cases of psycho-
sis occurring in patients with severe intractable epilepsy.
The authors concluded that the mechanism of this be-
havioral change was unclear but in some instances might
reflect GVG’s powerful antiepileptic action and that this
agent should be started with caution in patients with
severe epilepsy, particularly in the presence of a previous
history of psychosis.
Ring et al. (104), using [‘2’I]-IBZM and SPECT, ob-
served that 1 month of treatment with GVG was associ-
ated with a decrease in specific binding of [‘231]-IBZM
to D, receptors in the left hemisphere basal ganglia and
that this change may provide one explanation for the
development of psychosis in vulnerable patients (1 17).
A meta-analysis of psychoses and severe behavioral
reactions in six GVG-placebo-controlled studies was re-
cently carried out by Ferrie et al. (118). These authors
found that the incidence of this psychiatric complication
was 3.4% with GVG and 0.6 with placebo and concluded
that the risk for psychoses was similar to the incidence
rates of psychiatric disorders in patients with epilepsy.
Moreover the published incidence rates range from 1 to
12% in the different studies. This suggests that the risk is
more related to the patient group than to the drug in itself
(118).
Psychoses with GVG are frequently seen in patients
with more severe epilepsy (119), and this group of
patients, especially those with TLE, often exhibits
GABAergic cortical-subcortical alteration favorable for
SY
appearance of the psychoses after introduction of a
GABAergic drug such as vigabatrin (120). Less common
but similar in the clinical context of induction and analo-
gous hypothetical mechanisms were psychoses associ-
ated with topiramate (12 1,122), felbamate ( 1 23), and ti-
agabine (124).
ANXIETY DISORDERS IN EPILEPSY
Patients with epilepsy commonly report anxiety. Anxi-
ety and related disorders may manifest as simple partial
seizures (auras), psychological reactions to symptoms
that alert the patient to a coming seizure, postictal states,
and interictal behavioral and panic attacks (6).
Recently, Ettinger et al. ( 1 25) observed that 16% of
pediatric patients with epilepsy, not previously recog-
nized as anxious by care providers, met criteria for sig-
nificant anxiety symptomatology. Moreover, compared
with normal controls, children with epilepsy had much
higher rates of sleep disorders, particularly poor-quality
sleep and anxieties about sleep. In children with epilepsy
there was also a significant association between seizure
frequency and anxieties about sleeping.
Ictal fear and anxiety
Seizure disorders can produce an anxiety that is almost
indistinguishable from psychiatric disorders ( 126). Fear
and anxiety are common symptoms in spontaneous and
electrically induced simple partial seizures (6,21).
Among partial seizure patients, fear is reported as an aura
by 10 to 15%. Anteromedial temporal seizures and cin-
gulate seizures may cause fear. Symptoms vary from a
slight “uneasy” and “nervous” feeling to intense emo-
tions of fear and horror (6).
Differentiation of spontaneous fear (sudden emotion
not evoked by a frightening thought or stimulus) and
reactive fear (the patient’s response to the realization that
a seizure may occur) is often difficult. The onset of ictal
fear is paroxysmal and duration is brief (30-120 min)
(6). In contrast, panic attacks often build up over minutes
and, core symptoms usually last more than 5 min but no
longer than 10 min (6,127). Another distinguishing fea-
ture between partial seizures and panic attacks is a more
stereotyped clinical manifestation ( 1 28). Careful clinical
evaluation, EEG, and correlation with video telemetry
and electroencephalography are important in distinguish-
ing seizure activity from panic disorder ( 1 26). Patients
with anxiety disorders may exhibit abnormal background
activity related to the effect of oxygen starvation on ce-
rebral metabolism, and in panic attacks paroxysmal ac-
tivity can be seen.
Anxiety may also be related to nonepileptic attack
disorder (NEAD), which constitutes a major concern for
clinicians in arriving at the differential diagnosis. Moore
and Baker (129) identified the psychological character-
istics of 185 patients with NEAD. Psychological factors
Epilepsia, Vol. 40, Suppl. 10, 1999
SIO R. TORTA AND R. KELLER
that are important in the understanding of the develop-
ment and maintenance of NEAD include anxiety or
stress, physical abuse, significant bereavement, family
dysfunctioning, relationship problems, depression, and
sexual abuse. An absence of relevant psychological fac-
tors was found in only 5% of patients. From patients'
descriptions of their attacks, it appears that many symp-
toms are related to anxiety (129).
Psychogenic seizures or psychogenic nonepileptic sei-
zures occur in various psychiatric disorders. Obsessive-
compulsive symptoms can also imitate epileptic partial
seizures, but detailed observations of this phenomenon
are rare in the literature. Wolanczyk and Brynska (130)
recently reported a case of psychogenic seizures (chronic
falling in response to a behavioral therapy) in OCD.
Interictal fear and anxiety
Interictal anxiety symptoms are reported by as many
as 66% of patients with epilepsy. Although interictal
anxiety and panic have reported most frequently among
patients with partial seizures related to limbic foci,
Devinsky and Vazquez (6) also observed an increased
rate of these disorders among patients with primarily
generalized epilepsy.
Dissociative disorders
Ictal dissociative phenomena include depersonaliza-
tion, derealization, autoscopy and, rarely, personality
changes (such as dual or multiple personalities). Fugue
states (prolonged periods of confusion in which the pa-
tient may travel and subsequently have no memory of
events during this period) have been occasionally re-
ported in patients with epilepsy. Dual personalities and
the Capgras syndrome (a misidentification delusional
syndrome in which the patient holds a strong belief that
a person has been replaced by an imposter) have been
reported in association with seizures and forced normal-
ization (6).
Psychological anxiety reaction to epilepsy
Survey data have suggested that patients with epilepsy
commonly fear death and/or brain damage as a result of
their seizures, but documented cases of seizure phobia
are rare and only infrequently address issues of treatment
(131).
Preoperatively, depressive and anxiety disorders are
also the most common psychiatric conditions diagnosed
in candidates for surgical treatment of epilepsy (132). In
a prospective study of the early postsurgical psychiatric
associations of epilepsy surgery, Ring et al. (133) found
that, 6 weeks after surgery, half of patients who were
without psychopathology preoperatively developed
symptoms of anxiety or depression. By 3 months after
surgery, anxiety symptoms had diminished, whereas the
depressive states persisted. These authors also observed
Epilepsia, Vol. 40, Suppl. 10, 1999
that patients with a left hemispheric focus were more
likely to experience persisting anxiety.
Biologic basis of anxiety related to epilepsy
Roth and Harper in 1962 hypothesized that the tem-
poral lobes might represent one substrate for phobic-
anxious patients with depersonalization-derealization
(134). Today the panic disorder agoraphobia (PDA) is
nosologically distinct from complex partial epilepsy
(CPE), but there are clinical and pathogenetic hints of
overlap between manifestations of the two disorders con-
cerning the evaluation of psychosensorial phenomena in
PDA or affective phenomena in CPE. Toni et al. (135),
investigating the psychosensorial symptoms in PDA and
CPE outpatients, found broad similarities between the
two conditions: This symptomatologic overlapping
further supports the hypothesis of a common neuro-
physiologic substrate linking CPE phenomena with
PDA.
The limbic system may be involved, and clinical data
suggest that patients with limbic seizures are the most
prone to develop behavioral interictal disorders. In ani-
mal models, repetitive electrical stimulation (kindling) or
local applications of a neuroexcitotoxin in limbic struc-
tures (mainly the amygdala and hippocampus) can in-
duce changes in emotional reactivity in cats and rats.
These changes appear as anxiety-related reactions ex-
pressed as hyperdefensiveness in the cat and a reduction
of spontaneous exploration in tests predictive of anxio-
genic effects in the rat. During epileptogenesis, some
neuroplasticity processes (such as neuronal hyperexcit-
ability or modulation of GABA transmission) may occur
in structures involved in the control of fear-promoted
reactions (e.g., in amygdala or periaqueductal gray mat-
ter), and these phenomena may determine changes in
behavior (136). However, other authors, investigating the
effect of seizures on emotional responding in the kin-
dling model of CPS in male Wistar rats, found that
amygdala kindling does not in itself induce a state of
anxiety or fear but may interfere with response habitua-
tion (106).
On the other side, epilepsy without anxiety and anxi-
ety without epilepsy may also show some different bio-
logic bases. Tokunaga et al. (137), undertaking a study
with ['231]-iomazenil, a radioligand that acts on benzo-
diazepine receptors (BZR) as a partial inverse agonist, to
evaluate the function of central BZR by SPECT, ob-
served that the mean binding potential (BP) of patients
with anxiety and somatoform disorders was significantly
decreased in the superior frontal, temporal, and parietal
cortices compared with those of patients with epilepsy. A
significant correlation was observed between the anxiety
levels scored on the Hamilton anxiety scale and BP in the
right temporal and left superior frontal cortices (137).
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
QUALITY OF LIFE IN EPILEPSY
The problem of psychopathologic disorders in epi-
lepsy is closely related to the patients’ satisfaction with
their lives: this agent has to do with the concept of “qual-
ity of life” (QoL). This concept has been much debated
in recent years, particularly in relationship to chronic
diseases, such as epilepsy, that can induce impairment
(such as organic alterations), disability (impact of illness
on functional abilities), or handicap (disease-related dis-
advantages in comparison to other people). However, the
definition of QoL is difficult because it can concern ei-
ther the identification of general criteria regarding the
quality of life or differentiated individual criteria of well-
being and satisfaction.
General criteria of QoL involve several variables (e.g.,
physical, social, and emotional functioning, coping with
the illness, personal traits, daily living, personal interac-
tions, illness costs), general areas (e.g., activities, atti-
tudes, and psychological situation, well-being, support),
and other dimensions (e.g., symptoms and side effects of
drugs, functional possibilities, psychological distress, so-
cial interactions, sexuality and body image, treatment
satisfaction) (138,139).
Different individual criteria are represented by satis-
faction from the activities of daily life, sense of well-
being, satisfaction, or happiness (140). In this regard,
Calman (141) proposed that QoL can be measured only
in individual terms and that it depends on past experi-
ences and future hopes, dreams, and ambitions. In par-
ticular, future expectations are a major component of
perceived QoL (141). Because epilepsy involves more
than seizures, the QoL is related to approximately four
areas:
Seizures, in relationship to their type, frequency,
unpredictability, and severity.
Treatment, particularly regarding the presence of
side effects and compliance.
Social problems, such as occupation, indepen-
dence, and ability to hold a driver’s license.
Psychic aspects, with particular regard to depres-
sion, anxiety, cognition and self-esteem.
Very important in this regard is to determine each pa-
tient’s most important concerns. Gilliam et al. (142) in-
structed 8 1 consecutive patients with moderately severe
epilepsy to list in order of importance their concerns of
living with recurrent seizures, for the purpose of studying
the effects of epilepsy from the patients’ perspective and
stating health-related QoL measures. Twenty-four dis-
tinct domains were generated by the patients. Concerns
about driving (64%), independence (54%), employment
(51%), social embarrassment (36%), medication depen-
dence (33%), moodstress (32%), and safety (31%) were
listed by more than 30% of patients. Driving was listed
SI I
as the most important concern by 28% of patients, fol-
lowed by employment ( 2 I %), independence (9%), safety
(6%), AED side effects (5%), seizure unpredictability
(5%), and seizure aversion (5%).
Smith et al. (143) explored the relationship between
seizure severity, seizure frequency, and the psychosocial
consequences of intractable epilepsy in 100 patients with
medically refractory partial seizures, evaluated by a QoL
questionnaire including measures of physical (seizure se-
verity and frequency), social, and psychological well-
being (anxiety, depression, self-esteem, locus of control
and happiness). Seizure severity was the most significant
predictor of self-esteem (p = 0.005), locus of control (p
= 0.039), and anxiety (p = 0.048), whereas seizure
frequency did not contribute significantly to variations in
any of the psychological factors (143).
Measuring quality of life in epilepsy
Measuring the QoL in people with epilepsy is only a
recent development with regard to the possible instru-
ments useful to improve this parameter (e.g., treatment
modification, surgery, psychosocial education, new
drugs). The assessment of QoL in epilepsy can be carried
out by traditional forms of clinical evaluation (concern-
ing seizure type, frequency, severity, AED side effects)
or by evaluating some epilepsy-specific measures (e.g.,
cognitive ability, psychological status, psychosocial sta-
tus) or, more recently, by using models from health-
related quality of life (HRQOL) measures. Several QoL
scales have been developed in recent years for use in
people with epilepsy. Particularly interesting because of
its different levels of possible utilization is the QOLIE
(Quality of Life in Epilepsy) questionnaire, available in
an 89-item instrument (for researchers), in a 10-item in-
strument (for screening), and in an intermediate form (for
clinical purposes) (144).
The 10-item questionnaire (QOLIE- 10) covers general
and epilepsy-specific domains, grouped into three fac-
tors: Epilepsy Effects (memory, physical effects, and
mental effects of medication), Mental Health (energy,
depression, overall quality of life), and Role Function-
ing (seizure worry, work, driving, social limits). The
QOLIE-10 can be completed by a patient in several min-
utes and reviewed rapidly by the physician. This screen-
ing tool can provide potentially useful information for
initial assessment or follow-up of problem areas that are
not commonly evaluated during routine clinical visits
with patients with epilepsy (145).
PSEUDOSEIZURES
The term “pseudoseizures” defines paroxysmal behav-
ioral events andor disturbances of consciousness that do
not originate as a result of a paroxysmal neurophysi-
ologic change within the brain (146). It therefore con-
cerns patients that have seizures but they do not suffer
from epilepsy. More correct terminology would be “non-
Epilepsiu, Vol. 40, Suppl. 10. 1999
s12 R. TORTA AND R. KELLER
epileptic seizures,” “nonepileptic attack disorders,” or
“pseudoepileptic seizures” (66). Alternative terms such
as “hysterical seizures” have a pejorative connotation,
and “psychogenic seizures” would be related only to re-
flex seizures induced by mental activities.
Pseudoseizures have been recognized since ancient
times. Hippocrates and Araeteus in 200 B.C. described
convulsive attacks clearly not associated with epilepsy
and speculated on their pathophysiological mechanism
(147). Charcot, in 1874, stated that epileptic and nonepi-
leptic attacks may occur in the same patient, using the
term “hystkrie ti crises distinctes” for a patient who dem-
onstrated only pseudoseizures and the term “hystkrie h
crises combinkes” when the same patient exhibited both
pseudoseizures and true epileptic seizures (148). The
first detailed description of clinical pseudoseizures was
finally proposed by Gowers in 1881 (149).
Pseudoseizures are the most common nonepileptic
situation observed in epilepsy centers, often concerning a
significant number of patients previously considered to
have intractable seizures. The prevalence range is esti-
mated to be 5-35% (150). Pseudoseizures can be related
either to nonpsychiatric pathologies (e.g., vasovagal at-
tacks, hypoglycemia, vertebrobasilar drop attacks, tran-
sient ischemic episodes, sleep disorders) or can be asso-
ciated with psychiatric disorders (e.g., example panic at-
tacks, somatization disorders, conversion disorders,
schizophrenic catatonic manifestations). Panic attacks
can be misdiagnosed as epilepsy, particularly when as-
sociated with episodes of dkja vu, depersonalization, de-
realization, or autoscopy. The differential diagnosis is
complicated by sudden onset, short duration, and auto-
nomic elements present in panic attacks that can simulate
a complex partial seizure. More rarely patients with
schizophrenia may demonstrate catatonic outbursts of
motor activity which are misinterpreted as paroxysmal
epileptic events.
Differential diagnosis
Several authors suggest the existence of a “typical”
profile of a patient with pseudoseizures, characterized by
an overrepresentation of female patients, low intelli-
gence, an underlying hysterical personality disorder, and
sexual maladjustment (151,152). More recently, it has
been suggested that there is no standard psychological
profile that will distinguish a patient with pseudosei-
zures, because many patients with chronic epilepsy can
demonstrate many of the previously mentioned person-
ality and behavioral disturbances (153,154).
On the other hand, personality inventories and psychi-
atric assessments can be useful as diagnostic tools for
some pseudoseizure patients (155,156). Recently, Bow-
man (157) reported, in 27 outpatients with video-EEG-
documented pseudoseizures, that 88% had sustained sig-
nificant trauma, including sexual abusehape (77%) and
Epilepsiu, Vul. 40, Suppl. 10. 1999
physical abuse (70%) and that, most commonly, pseudo-
seizures can originate from dissociated personalities or
ego states as expressions of dissociated memories of
child abuse, often triggered by recent stresses or traumas
(157).
Another important problem is the emergence of pseu-
doseizures after surgery for epilepsy. Ney et al. (158),
evaluating a sample of 96 patients who underwent sur-
gery for epilepsy between 1985 and 1996, found five
patients (three men and two women) with postsurgery
new-onset pseudoseizures. Compared with the surgical
cohort, these patients had a higher frequency of preop-
erative psychopathologic conditions (three patients were
diagnosed with psychoses, one with borderline person-
ality disorder, and one with generalized anxiety), lower
mean full-scale IQ (mean full-scale IQ was 73), and pre-
sented a greater occurrence of operative complications.
These clinical features (low IQ, preoperative psycho-
pathologic conditions, and major surgical complications)
should represent risk factors for development of postsur-
gery pseudoseizures (158).
The problem of differential diagnosis concerns the dif-
ferentiation of pseudocrises vs. different types of true
epileptic seizures (such as generalized tonic-clonic sei-
zures, partial temporal seizures, partial frontal seizures)
or vs. other nonepileptic events (e.g., panic attacks and
conversion episodes). Compared with tonic-clonic sei-
zures, the loss of consciousness in pseudoseizures is less
obvious, with some evidence of responsiveness to envi-
ronmental stimuli. Therefore, the patient can demon-
strate persistence of corneal reflexes, some forceful re-
sistance to the examiner’s attempt to open the eyes, and
some recall of ictal events (159). Pseudoseizures can
have a longer duration than true epileptic convulsions
(160) and tend to present more different clinical types of
attacks in the same patient, unlike organically based at-
tacks (1 59). In addition, the toniceclonic movement is
mostly asynchronous and the tongue exhibits only slight
dista1,injury rather than a lateral side involvement by a
canine or molar lesion (161). During a pseudoseizure, the
eyes usually exhibit several irregular voluntary saccades
before staring toward the ground. The pupils are normal
in size and reactive to light (162). Suggestive of pseu-
doseizures are shouting obscenities and vulgar language
(163), but other authors have also noted these character-
istics in CPS of frontal lobe origin (153,159).
Compared with partial seizures of temporal lobe ori-
gin, the differential diagnosis with pseudoseizures can be
very difficult and the problem may be particularly com-
plicated in patients with both epileptic and nonepileptic
episodes. Furthermore, pseudoseizures without major
motor manifestations are more common than those with
convulsive attacks (1 64,165). In these cases, the most
frequent ictal feature is impaired consciousness with
complex behavior simulating an epileptic automatism.
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS S13

Partial seizures of frontal lobe origin are of different (169). The results of serum prolactin analysis should also
types (e.g., jacksonian seizures, contraversive head and be interpreted with caution because prolactin levels can
eye deviation from the supplementary motor area, speech increase in relation to other factors, such as emotional
arrest, olfactory hallucinations and illusions from orbital stress, fear, and anger (170).
frontal cortex, gestural automatism), often with minimal
Instrumental differential diagnosis with EEG
impairment of consciousness, short duration, and ab-
or video-EEG
sence of a postictal state. This symptomatologic hetero-
It is well known that standard interictal scalp electro-
geneity is responsible for a high percentage of diagnostic
encephalography (EEG) is often not helpful in discrimi-
errors vs. pseudoseizures. Moreover, even if unilateral or
nating patients with pseudoseizures. Furthermore, the
asymmetrical tonic attacks are uncommon in pseudosei-
presence of paroxysmal interictal EEG abnormalities
zures, they have been described by some authors (1 64).
does not confirm the diagnosis of epilepsy, nor does it
Clinical differential diagnosis versus conversion dis-
exclude the diagnosis of pseudoseizures. Only the pres-
orders will be facilitated by a history of other conversion
ence or absence of ictal EEG seizure activity during a
phenomena in the same patient, by the presence of ele-
clinical attack can confirm or exclude the diagnosis of an
ments of secondary gain in relationship to pseudosei-
epileptic seizure, depending on the brain areas sampled
zures (family protection, to attract attention) and by high
and the electroclinical correlation of the attack (146,
frequency of seizure-precipitating events or situations.
171). The problem is further complicated by the fact that
Other clinical differential aspects versus true seizures are
is possible for both pseudoseizures and epileptic seizures
represented by the presence of emotional behaviors (such
to coexist in a single patient. The reported incidence of
as crying) immediately after the attacks.
these co-morbidities can be variable in relationship to a
On the other hand, it is often a mistake to believe that
selection bias of monitoring by psychiatric or epilepto-
self-injury is not present in pseudoseizures. Self-injury
logic centers. Some authors find both pseudoseizures and
can in fact be common, with falls, bums, and even bone
epilepsy in 10% of patients (146,150,172) and others
fractures.
report this combination in 50% of patients (164).
Although a distinction between epileptic seizures and
The clinical pattern of some pseudoseizures can so
pseudoseizures should be possible in most patients, in
closely resemble epilepsy that a specific video-EEG may
some instances pseudoseizures are clinically indistin-
be necessary to make a correct diagnosis. Video-EEG
guishable from epileptic attacks and the diagnosis cannot
monitoring is crucial because it allows careful and re-
be based only on clinical observation.
peated analysis of the clinical characteristics and pos-
Different techniques of suggestion have been used to
sible electroclinical correlations. Recently, in two cases
provoke pseudoseizures: hypnosis, hyperventilation, and
in which the use of video-monitored EEG alone was
intermittent light stimulation, IV injection of saline or
insufficient to make definitive diagnoses, Blend et al.
magnesium sulfate, or placement of a placebo skin patch:
(173) proposed the use of compared ictal and interictal
Suggestion can increase both specificity and sensitivity
Tc-99m HMPAO brain perfusion SPECT imaging ex-
of video-EEG monitoring, but only induced events that
aminations.
are typical of those previously experienced by the patient
can be used for a diagnosis of pseudoseizures (166).
Patients with true epilepsy can also be induced by sug- PHARMACOLOGIC TREATMENT OF
gestion to have a pseudoseizure (153). PSYCHOSES AND BEHAVIORAL DISORDERS
IN PATIENTS WITH EPILEPSY
Serum prolactin levels
Management of psychiatric problems in patients with
It has long been known that seizures can influence
epilepsy is no different from that in patients without
endocrine regulation. An increase in prolactin levels after
epilepsy, but it is necessary to apply a few caveats be-
ECT was first described by Oehman et al. in 1976 (167).
cause all neuroleptics, like most antidepressants, can
Several authors have since evaluated plasma prolactin
lower the seizure threshold, although in different ways.
levels in the differential diagnosis between epilepsy and
pseudoseizures (150,168) Psychoses
Within 20 min after generalized tonic-clonic seizures, Patients with epilepsy develop psychosis at a rate ex-
in more than 90% of patients, prolactin levels demon- ceeding what would be predicted if the two disorders
strate a dramatic increase, at least three-fold from the were independent. In addition, patients with schizophre-
normal baseline, to over 1,000 IUL. This increase does nia are more prone to seizures than the general popula-
not occur after a pseudoseizure. The problem is that the tion. This excess vulnerability may be related to the neu-
same test is less reliable after a CPS (only in 60% of ropathologic substrate of schizophrenia itself and also to
patients with CPS without secondary generalization) and exposure to psychotropic medications that lower the sei-
is completely unreliable after a simple partial seizure zure threshold (92).

Epilepsia, Vol. 40, Suppl. 10, I999

S14 R. TORTA AND R. KELLER
Dopamine and epilepsy
The clinical benefits of dopamine agonists in the man-
agement of epilepsy have been known for a century, and
the introduction of neuroleptics into psychiatric practice
40 years ago led to the appearance of seizures as a side
effect of dopamine receptor blockade. The discovery of
multiple dopamine receptor families (principally D I and
D,, and also D,, D,, and D5), sometimes mediating op-
posing influences on neuronal excitability, heralded a
new era of dopamine-epilepsy research (174). The tra-
ditional anticonvulsant action of dopamine was attrib-
uted to D, receptor stimulation in the forebrain. The
advent of selective D, agonists with proconvulsant prop-
erties revealed for the first time that dopamine could also
lower the seizure threshold from the midbrain (174). It is
also known that seizures might be precipitated as a con-
sequence of treating other neurologic disorders with D,
antagonists (neuroleptics) or D, agonists (175).
Kindling and neuroleptics
The electrical kindling model is characterized by a
progressive behavioral response related to EEG modifi-
cations. Although some limbic areas (such as the amyg-
dala) demonstrate a high susceptibility, the cerebral cor-
tex appears to be less responsive.
Post et al. (176) demonstrated that both behavioral
responses and increased seizures can be elicited in ani-
mals with the use of cocaine and lidocaine. Nevertheless,
whereas electrical kindling appears to be more related to
convulsions, pharmacologic kindling is more likely to
elicit behavioral responses ( 176).Therefore, repeated ad-
ministration of dopamine agonists produces a transient
modification of behavioral response, and prolonged
stress can interfere with the dopaminergic system and
with neurohormones such as the neurocorticoids (107,
177). In addition, alterations in the balance of glutama-
tergic and GABAergic activity can cause psychosis un-
der predisposing conditions, as demonstrated by several
new AEDs such as vigabatrin, topiramate, and tiagabine
(178-1 80). In this way, amygdaloid kindling can be re-
markably facilitated by dopamine receptor antagonists
such as the neuroleptics.
Neuroleptics and seizures
Several years ago, Oliver et al. (181), in order to es-
timate the relative risk of various neuroleptic medica-
tions for patients who had epilepsy or who were likely to
experience neuroleptic-induced seizures, studied their
action on spike activity in perfused guinea pig hippo-
campal slices. Within the range of concentrations stud-
ied, molindone, pimozide, and fluphenazine produced
the least increase in excitability, with some differences in
the dose-response curves. Chlorpromazine, thioridazine,
and pimozide produced an inverted U-shaped curve and,
for haloperidol and fluphenazine, the excitability tended
to increase until it reached a plateau. Molindone and
Epilepsia, Vol. 40, Suppl. 10, 1999
butaclamol produced no increase in excitability. Combi-
nations of neuroleptics demonstrated synergistic effects,
whereas the AED diazepam inhibited such neuroleptic-
induced excitability ( 1 81).
In clinical practice the epileptogenicity of a neurolep-
tic is not only related to the differentiated D,/D2 dopa-
mine blockage but also can be associated with the
agent’s antihistaminergic activity. Nevertheless, the
clinical risk for seizures induced by a neuroleptic is more
related to the epileptic threshold of the individual than to
the differential epileptogenetic power of a single drug.
Atypical antipsychotics and seizures
Clozapine is an atypical antipsychotic that does not
induce extrapyramidal side effects in humans or cata-
lepsy in the rat. However, clozapine frequently causes
epileptiform EEG changes and seizures in 3-5% of pa-
tients treated with this drug, even at therapeutic doses.
Stevens et al. (182) demonstrated that clozapine can in-
duce dose-dependent myoclonus in the partially re-
strained rat. These effects are consistent with a kindling
phenomenon. In fact, clozapine-kindled animals exhib-
ited a significantly different pattern of early gene expres-
sion in the ventral tegmental area, and the positive coun-
terpart of this excitation with clozapine may be important
in the treatment of schizophrenic negative symptoms
(182).
Electroencephalographic abnormalities observed in 10
patients with schizophrenia without epilepsy during
clozapine treatment (250-900 mg daily), were princi-
pally characterized by background slowing in the theta
and often the delta range. In addition, several patients
exhibited bilateral spike, polyspike, and slow-wave dis-
charges, one with a photoparoxysmal response (1 83).
Clozapine dosage and rapid titration appear to be the
two most important predictors of seizure development.
The occurrence of seizures appears to be dose related,
possibly occurring at a dosage rate of 0.7% per 100 mg.
At doses below 300 mg/day, seizure risk is comparable
to that for other antipsychotic drugs (about 1-2%). At
higher doses, seizure risk rises accordingly, reaching 5%
at doses of 600-900 mg/day (184).
Patients who experience seizures with clozapine can
be treated with concurrent AEDs. However, carbamaze-
pine should be avoided because of its tendency for oc-
casional bone marrow suppression in addition to the risk
for clozapine-induced agranolocytosis. Therefore, val-
proate may be the safest and best-tolerated AED in
clozapine-treated patients, and its inhibition of the me-
tabolism of clozapine can help to reduce the dose of the
antipsychotic needed.
Zotepine, a dibenzothiepine tricyclic atypical antipsy-
chotic agent with high affinity for serotonin and dopa-
mine receptors, demonstrated an incidence of seizures
directly correlated with the daily doses. In 229 patients
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
receiving zotepine, 17 (7.4%) exhibited generalized sei-
zures. Patients receiving <150 mg/day of zotepine did
not develop seizures and patients with a dosage of <300
rng/day had an incidence of seizures significantly lower
than for those receiving >300 mg/day (2.9 vs. 11.3%;
p < 0.05) (185). Two studies demonstrated a dose-related
incidence of zotepine-induced seizures in a range of 17%
(221129 patients) (186) to 20% (5/25 patients; in combi-
nation, however, with other antipsychotic drugs) (187).
Olanzapine, a thienobenzodiazepine atypical antipsy-
chotic, has a binding profile similar to that of clozapine
(188). The two drugs display a similar radioligand profile
for 5-HT receptor subtypes, with both a higher affinity
for 5-HT2, receptors than for D, receptors, for musca-
rinic receptors subtypes, and for histaminergic H, recep-
tors. Olanzapine demonstrates a higher affinity than
clozapine for D, and D2 receptors but is slightly less
potent at D, receptors. Another pharmacodynamic dif-
ference between the two drugs is represented by the fact
that the affinity of olanzapine for a ,-adrenergic receptors
is about one-half of the dopamine D, affinity, whereas,
the affinity of clozapine for au,-adrenergicreceptors is
about 18 times higher than the dopamine D, affinity
(188).
Despite their similarity, clozapine and olanzapine
demonstrate a great clinical difference concerning induc-
tion of seizures. In clinical trials, seizures have occurred
in a small number (0.88%, 22/2,500) of olanzapine-
treated patients and there were possible confounding fac-
tors in addition (such as patients with epilepsy and other
at-risk patients) that may have contributed to the occur-
rence of seizures in many of these cases, after exclusion
of which the incidence of seizure is lower (6/2,500;
0.24%) ( 1 89).
No difference in the incidence of seizures was ob-
served in patients treated with quetiapine or placebo (in-
cidence of 0.4% or 3 events/100 patient-years in patients
given quetiapine, compared with 0.5% or 6.9 eventdl00
patient-years for placebo). In addition, for risperidone
and sertindole only a few patients with seizures were
reported. Nevertheless, as with other antipsychotics, cau-
tion is recommended in treating patients with a history of
seizures or with conditions associated with a lowered
seizure threshold (1 89).
Behavioral disorders
The management of behavioral disorders in patients
with epilepsy should be initially oriented toward the
identification of the possible causes, biologic, psychoso-
cial, or both. For a patient whose psychiatric disorder is
hypothesized to be induced by AED therapy, the first
step can be the rationalization of the patient’s AED
medication. If possible, it is advisable to reduce poly-
pharmacy and to discontinue drugs that have been cor-
S1.5
related with psychic disturbances, such as the barbitu-
rates, phenytoin, and vigabatrin.
If psychosocial causes appear to be more relevant, one
can first opt for supportive therapy or a combination of
formal psychotherapies (such as cognitive, interpersonal,
or behavioral approaches) in association with medica-
tion. Behavioral disorders have historically been ex-
plained in terms of psychodynamic-developmental mod-
els. Therefore, psychotherapy was believed to be the
most important form of treatment. Today it is known that
biologic factors may play an important role in the patho-
genesis of personality disorders, and therefore pharma-
cologic treatment can be used.
Low-dose antipsychotic medications have received the
greatest attention in studies conducted over the past two
decades in patients with behavioral or personality disor-
ders. The problem of the use of antipsychotic drugs in
patients with epilepsy has been discussed above. How-
ever several of the personality traits observed in temporal
epilepsy (viscosity, hypergraphia, circumstantiality, de-
pendence, hyperreligiosity) demonstrate psychopatho-
logic characteristics (perseveration, repetitiveness, com-
pulsivity) that can be referred to as the OCD spectrum.
According to the serotoninergic theory of OCD, those
behavioral disorders in people with TLE can be effec-
tively treated with serotoninergic agents (such the TCA
clomipramine and the SSRIs, such as fluoxetine, fluvox-
amine, paroxetine, citalopram, and sertraline) ( 1 90,19 1 ).
Another validated use of SSRIs is the treatment of im-
pulsiveness~and aggression (1 92), disturbances that are
sometimes described in patients with TLE. On the other
hand it is well known that the risk for antidepressant-
induced seizures, particularly in patients with epilepsy, is
different among antidepressant drugs (see the article by
Pisani, Spina and Oteri, this issue, S47-S55).
Evaluation of the incidence of seizures after overdoses
of antidepressants demonstrates that fluoxetine and tra-
zodone overdoses are generally safer than overdoses of
conventional TCAs (195). However, seizures do occur at
therapeutic doses of antidepressants in a dose-dependent
fashion, with an incidence that ranges between 0.1 and
4% ( I 94). Seizure rates for bupropion and clomipramine
are also strongly dose-dependent. For fluoxetine, the sei-
zure incidence is about 0.2%, which includes patients
with overdoses, those with predisposing factors, and the
use of higher doses.
A further increased risk for worsening of seizures can
be related to the use of antidepressant at higher doses,
both with TCAs and SSRIs. A medium to high dosage
range is frequently used in the treatment of OCD and
related disorders (191). At 20 mg/day, seizure risk for
fluoxetine appears to be lower (194-196). Another risk
factor for worsening of seizures in patients with epilepsy
and a co-morbidity behavioral disturbance in the OCD
Epilepsia, Vol. 40. SuppL 10, 1999
S16 R. TORTA AND R. KELLER
spectrum is neuroleptic augmentation in patients who are
nonresponders to only antidepressant treatment.
Concerning the possible role of pharmacodynamics in
antidepressant-induced seizures, the data are still contro-
versial. For 5-HT, it is generally agreed that CNS de-
creased turnover of this monoamine is often associated
with epilepsy (1 97).
Among the SSRIs, fluoxetine has been claimed to ex-
ert an anticonvulsant action in animal studies (198-201).
Other favorable data are coming from a few controlled
clinical studies, particularly with fluoxetine, in which a
possible anticonvulsant action of this drug as adjunctive
therapy of partial complex seizures was suggested
(202,203). Moreover, the efficacy or, at least, the safety
of SSRIs in the treatment of partial complex seizures is
particularly interesting because TLE is the epileptic pa-
thology most often related to behavioral disturbances, for
which SSRIs constitute the first-line class of drugs. Nev-
ertheless, caution is suggested with the use of SSRIs in
patients with epilepsy, because in some anecdotal reports
a few cases of fluoxetine-fluvoxamine-induced seizures
have been described (204-207). Moreover, a lack of po-
tentiation of anticonvulsant effects of fluoxetine in dmg-
resistant epilepsy has been reported (208). The observa-
tion of anti- or proconvulsant effects of SSRIs confirm
that it is simplistic to ascribe a specific role to a given
neurotransmitter in a complex process such as epilepsy.
Finally, considering the high risk for suicide and at-
tempted suicide in patients with epilepsy, particularly
those who have TLE with behavioral disturbances,
SSRIs should be prescribed because they are safer than
TCAs when an overdose is deliberately taken. (193).
REFERENCES
1. Betts TA, Trimble MR, Neuropsychiatry. In: Laidlaw J, Richens
A, eds. A textbook of epilepsy. London: Churchill-Livingston,
1988:350405.
2. Smith DB, Craft BR, Collins J. Behavioural characteristics of
epilepsy patients compared with normal controls. Epilepsia 1986;
27:760-8.
3. Schiffer RB, Babigian H. Behavioral disorders in multiple scle-
rosis, temporal lobe epilepsy and amyotrophic lateral sclerosis.
Arch Neurol 1984;41:1067-9.
4. Hermann BP Psychopathology in epilepsy and learned helpless-
ness. Med Hypotheses 1979; 5:723-9.
5. Gibbs FA, Gibbs EL. Atlas of electroencephalography. Vol. 3,
Reading, MA: Wesley, 1964.
6. Devinsky 0, Vazquez B. Behavioral changes associated with epi-
lepsy. Neurol Clin 1993;11:127-49.
7. Steffemburg S, Gillberg C, Steffemburg U. Psychiatric disorders
in children and adolescents with mental retardation and active
epilepsy. Arch Neurol 1996;53:904-12.
8. Stevens JR. Psychiatric aspects of epilepsy. J Clin Psychiatry
1988;49(suppl):49-57.
9. McNamara ME. Psychological factors affecting neurological con-
ditions. Depression and stroke, multiple sclerosis, Parkinson’s
disease, and epilepsy Psychosomatics 1991;32:255-67.
10. Malleus Maleficarum. Translated and with an introduction, bib-
liography, and notes by Summers M. London: John Rodker, 1928.
11. Gibbs FA, Gibbs EL, Fuster B. Psychomotor epilepsy. Arch Neu-
rol Psychiatr 1948;60:331-9.
12. Gastaut H, Morin G, Leserve N. Etude du comportement des
Cpileptiques psychomoteurs dans I’intervalle de leur crises. Ann
Med Psichol 1955;113:1-27.
13. Waxman SG, Geschwind N. The interictal behavior syndrome in
temporal lobe epilepsy. Arch Gen Psychiatry 1975;32: 1580-6.
14. Bear DM, Fedio P. Quantitative analysis of interictal behavior in
temporal lobe epilepsy. Arch Neurol 1977;34454-57.
15. Meyer DR, Ruth RA, Lavond DG. The septa1 social cohesiveness
effect: its robustness and main determinants. Physiol Behav 1978;
2 1:1027-9.
16. Waxman SG, Geschwind N. Hypergraphia in temporal lobe epi-
lepsy. Neurology 1974;24:629-3 I .
17. Sachdev HS, Waxman SG. Frequency of hypergraphia in tempo-
ral lobe epilepsy: an index of interictal behavior syndrome J
Neurol Neurosurg Psychiatry 1981;44:35840.
18. Hippocrates: The sacred disease. In: The genuine works of Hip-
pocrates. London: Sydenham Society, 1846:843-58.
19. Leuba JH. The psychology of religious mysticism. London: Kegan
Paul, Trench, Trubner, 1925.
20. Saver JL, Rabin J. The neural substrates of religious experience.
J Neuropsychiatry Clin Neurosci 1997;9:498-5 10.
21. Devinsky 0, Feldmann E, Emoto S. Structured interview for par-
tial seizures: clinical phenomenology and diagnosis. J Epilepsy
I99 1;3: 107-1 6.
22. Dewhurst K, Beard AW. Sudden religious conversions in tempo-
ral lobe epilepsy. Br J Psychiatry 1970;117:497-507.
23. Cirignotta F, Todesco CV, Lugaresi E. Temporal lobe epilepsy
with ecstatic seizures (so-called Dostoyevsky epilepsy). Epilepsia
1980;21:705-10.
24. Torta R. Depressione: Parkinson ed Epilessia. Milano: Me-
diserve 1995.
25. Falret JP. Memoire sur la folie circulaire. Bull Acad Nut Med
(Paris) 1854;19:382-400.
26. Baillarger- JGF. Note sur un genre- de folie dont les acces sont
caracterisis par deux periodes regulieres, l’un de depression et
I’autre d’excitation. Bull Acad Nat Med (Paris) 1854;19:34&52.
27 Kraepelin E. Clinical psychiatry. 7th ed. New York: MacMillan,
1915.
28 Glaus A. Ueber kombinationen von Schizophrenie und Epilepsie.
Z Ges Neurol Psychiatr 1931;135:450-500.
29 von Meduna L. Die Konvulsionstherapie der Schizophrenic.
Halle: Marhold, 1937.
30. Landolt H. Some clinical electroencephalographic correlations in
epileptic psychosis (twilight states). Electroencephalogr CIin
Neurophysiol 1953;5: 121.
31. Slater E, Beard AW. The schizophrenia-like psychoses of epi-
lepsy: psychiatric aspects. Br J Psychiatry 1963;109:95-112.
32. Torta R. Epilessia, convulsiviti e psicosi [Abstract]. Proc X
Congr Nazionale Soc Ital Neuropsicofarmacologia 1995;s307.
33. Stevens JR. Abnormal reinnervation as a basis for schizophrenia:
an’hypothesis. Arch Gen Psychiatry 1992;49:238-43.
34. Krohn W. A study of epilepsy in northern Norway, its frequency
and character. Acra Psychiatr Neurol Scand 1961;150(suppl):
2 15-25.
35. Matuja WB. Psychological disturbance in African Tanzanian epi-
leptics. Trop Geogr Med 1990;42:359-64.
36. Gureje 0. Interictal psychopathology in epilepsy. Prevalence and
pattern in a Nigerian clinic. Br J Psychiatry 1991;158:700-5.
37. Currie S, Heathfield KWG, Henson RA. Clinical course and
prognosis of temporal lobe epilepsy: a survey of 666 patients.
Brain 1971;94: 173-90.
38. Gibbs FA, Gibbs EL. Atlas of electroencephalography. Vol 11.
Epilepsy. Cambridge, MA: Addison-Wesley, 1952.
39. Mendez MF, Grau R, Doss RC, Taylor JL. Schizophrenia in
epilepsy: seizure and psychoses variables. Neurology 1993;43:
1073-7.
40. Whitman S, Hermann BP, Gordon AC. Psychopathology in epi-
lepsy: how great is the risk? Biol Psychiatry 1984;19:213-36.
41. Lindsay J, Ounstead C, Richards P. Long term outcome in chil-
dren with temporal lobe seizures, 111: psychiatric aspects in child-
hood and adult life. Dev Med Child Neurol 1979;21:630-6.
42. Taylor D. Mental state and temporal lobe epilepsy: a correlative
 BEHA vromL, PSYCHOTIC,AND ANXIETY DISORDERS
account of 100 patients treated surgically. Epilepsia 1972;13:
72745.
43. Kawakami M, Terasawa E, Ibuki T. Changes in multiple unit
activity or the brain during the estrous cycle. Neuroendocrinology
1970;6:30-48.
44. Csernansky JG, Mellentin J. Beauclaire L, Lombrozo L. Meso-
limbic dopaminergic supersensitivity following electrical kin-
dling of the amygdala. Biol Psychiatry 1988;23:285-94.
45. Umbricht D, Degreef G, Barr WB, Lieberman JA, Pollack S,
Schaul N. Postictal and chronic psychoses in patients with tem-
poral lobe epilepsy. Am J Psychiatry 1995;152;2:22&30.
46. Trimble M. The psychoses of epilepsy. New York: Raven Press,
1991.
47. Taylor DC. Factors influencing the occurrence of schizophrenia-
like psychosis in patients with temporal lobe epilepsy. Psychol
Med 1975;5:249-54.
48. Bruton CJ. The neuropathology of temporal lobe epilepsy:
Maudsley monograph 31. New York: Oxford University Press,
1988.
49. Manchanda R, Schaefer B, McLachlan RS, et al. Psychiatric dis-
orders in candidates for surgery for epilepsy. J Neurol Neurosurg
Psychiatry 1996:61:82-9.
50. McKenna PJ, Kane JM, Parrish K. Psychotic syndromes in epi-
lepsy. Am J Psychiatry 1985:142:895-904.
51. Stefansson SB, Olafsson E, Hauser WA. Psychiatric morbidity in
epilepsy: a case controlled study of adults receiving disability
benefits. J Neurol Neurosurg Psychiatry 1998;64:238-41.
52. Devinsky 0, Abramson H, Alper K, et al. Postictal psychosis: a
case control series of 20 patients and I50 controls. Epilepsy Res
1995;20247-53.
53. Swartz CM. Seizure benefit: grand ma1 or grand bene? Neurol
Clin 1993;11:151-60.
54. Toone BK. The psychoses of epilepsy. J R Soc Medicine 1991;
84:457-9.
55. Perez MM, Trimble MR. Epileptic psychosisdiagnostic com-
parison with process schizophrenia. Br J Psychiatry. 1980;137:
245-9.
56. Savard G, Andermann F, Olivier A, Remillard GM. Postictal psy-
choses after partial complex seizures. A multiple case study. Epi-
lepsia 1991;32:225-3 1.
57. Onuma T, Adachi N, Hisano T, Uesugi S. 10-year follow-up
study of epilepsy with psychosis. Jpn J Psychiatry Neurol 1991;
45: 360-1.
58. Dongier S. Statistical study of clinical and electroencephalo-
graphic manifestations of 536 psychotic episodes occurring in 516
epileptics between clinical seizures. Epilepsia 1959;l:11742.
59. Pond DA. Psychiatric aspects of epilepsy. J. Indian Med Prof
1957;4:1441-51.
60. Hill D. Psychiatric disorders of epilepsy. Med Press 1953;229:
473-5.
61. Caplan R, Shields WD, Mori L, Yudovin S. Middle childhood
onset of interictal psychosis. J Am Acad Child Adolesc Psychiatry
1991;30:893-6.
62. Caplan R, Arbelle S, Guthrie D, et al. Formal thought disorder
and psychopathology in pediatric primary generalized and com-
plex partial epilepsy. J Am Acad Child Adolesc Psychiatrj 1997;
36:1286-94.
63. Flor-Henry P. Psychosis and temporal lobe epilepsy. A controlled
investigation. Epilepsia 1969;10:363-95.
64. Stevens IR. Interictal clinical manifestations of complex partial
seizures. In: Penry JK, Daly D, eds. Advances in neurology Vol.
2. New York, Raven Press, 1975:85-112.
65. Sherwin I, Perin-Magnon J, Bancaud J, Bonk A, Talairirach J.
Prevalence of psychosis in epilepsy as a function of laterality of
epileptogenic lesion. Arch Neurol 1982;39:621-5.
66. Cummings JL, Trimble MR. Concise guide to neuropsychiatry
and behavioral neurology. Washington: American Psychiatric
Press, 1995.
67. Logsdail SJ, Toone BK. Postictal psychoses: a clinical and phe-
nomenological description. Br J Psychiatry 1988;152:246-52.
68. Sherwin I. Psychosis associated with epilepsy: significance of the
laterality of the epileptogenic lesion. J Neurol Neurosurg Psy-
chiatry 1981;44:83-5.
SI 7
69. Nielsen H, Kristensen 0. Personality correlates of sphenoidal-
EEG foci in temporal lobe epilepsy. Acia Neurol Scand I98 1 ;64:
289-300.
70. Stevens JR, Livermore A. Kindling of the mesolimbic dopamine
system: animal model or psychosis. Neurology 1978;28:3646.
71. Hermann BP, Withman S. Behavioral and personality correlates
of epilepsy: a review, methodological critique and conceptual
model. Psychol Bull 1984;95:451-97.
72. Roberts GW, Done DJ, Crow TJ. A “mock-up” of schizophrenia:
temporal lobe epilepsy and schizophrenia-like psychosis. Biol
Psychiatry 1990;28: 127-43.
73. Kristensen 0, Sindrup EH. Psychomotor epilepsy and psychosis.
I: Physical aspects. Acta Neurol Scand 1978;57:361-9.
74. Sachdey P. Schizophrenia-like psychosis and epilepsy: the status
of the association. Am J Psychiatry 1998;155:325-36.
75. Taylor DC, Lochery M. Temporal lobe epilepsy; origin and sig-
nificance of simple and complex auras. J Neurol Neurosurg Psy-
chiatry I987;50:673-68 1.
76. Sander JW, Duncan JS. Vigabatrin In: Shorvon S, Dreifuss F,
Fish D, Thomas D, eds. The treatment ofepifepsy.Oxford: Black-
well Science, 1996:491-9.
77. Stevens JR. Psychiatric consequences of temporal lobectomy for
intractable seizures: a 20-30-year follow-up of 14 cases. Psychol
Med 1990;20:52945.
78. Carlsson M, Carlsson A. Schizophrenia: a subcottical neurotrans-
mitter imbalance syndrome? Schizophren Bull 1990; 16:425-32.
79. Manchanda R, Miller H, McLachlan RS. Postictal psychosis after
right temporal lobectomy. J Neurosurg Psychiatry 1993;56:
277-9.
80. Leinonen E, Tuunainen A, Lepola U. Postoperative psychoses in
epileptic patients after temporal lobectomy. Acta Neurol Scand
1994;90:394-9.
81. Mace CJ, Trimble MR. Psychosis following temporal lobe sur-
gery: a report of 6 cases. J Neurol Neurosurg Psychiatry 1991;
54:63944.
82. Babb TL, Brown WL Pathological findings in epilepsy. In: Engel
J, ed. Surgical treatment of the epilepsies. New York: Raven
Press, 1987.
83. Levesque MF, Nakasato N, Vinters HV, Babb TL. Surgical treat-
ment of limbic epilepsy associated with extrahippocampal le-
sions: the problem of dual pathology. J. Neurosurg 1991;75:
364:370.
84. Davison K, Bagley CR. Schizophrenia-like psychoses associated
with organic disorders of the central nervous system: a review of
the literature. Br J Psychiatry Spec Pub 1969;4:113-83.
85. Psatta DM, Tudorache B, Matei M, Diacicov S. Cerebral dys-
function revealed by EEG mapping in the schizoform epileptic
psychosis. Rom J Neurol Psychiatry 1991;29:81-98.
86. Smith Doody R, Hrachovy RA. Feher EP. Recurrent fluent apha-
sia associated with a seizure focus. Brain Lung 1992;42:419-30.
87. Hatotani N. The concept of ‘atypical psychoses’: special refer-
ence to its development in Japan. Psychiatry Clin Neurosci 1996;
50:1-10,
88. Drake ME Jr, Weate SJ, Newell SA. Contingent negative varia-
tion in epilepsy. Seizure 1997;6:297-301.
89. Heath R, Mickle WA. Evaluation of seven years experience with
depth electrode studies in human patiens. In: Ramey ER,
O’Doherty DS, eds. Electrical studies on the unanaesthetized
brain. New York: Hoeber, 196O:XX-XX.
90. Mendez MF, Grau R. The postictal psychosis of epilepsy: inves-
tigation in two patients. Int J Psychiatry Med 1991;21:85-92.
91. Faber J, Vladyka V, DufkovA D, et al. “Epileptosis” a syndrome
or useless speculation? Sb Lek, 1996:97:71-95.
92. Hyde TM, Weinberger DR. Seizures and schizophrenia. Schizo-
phren Bull 1997;23:611-22.
93. Bruton CJ, Stevens JR, Frith CD. Epilepsy, psychosis and schizo-
phrenia. Neurology 1994;44:34-42.
94. Bolwig TG. Seizures in therapy of psychoses [Abstract]. Eur
Psychiatry 1994;9:79s.
95. Cotman CW, Nieto-Sampedro M, Hams EW. Synapse replace-
ment in the nervous system of adult vertebrates. Physiol Rev
1981;6 1 :68&784.
96. Sutula T, He XX, Cavawoa J, Scott G. Synaptic reorganization
Epilepsia, Vol. 40,Suppl. 10. 1999
 S18 R. TORTA AND R. KELLER
induced in the hippocampus by abnormal functional activity. Sci-
ence 1988;239: 1147-50.
97. Ben Ary Y, Represa A. Brief seizure episodes induce long-term
potentiation and mossy fibre sprouting in the hippocampus.
Trends Neurosci 1990;13:312-9.
98. Mathern GW, Pretorius JK, Babb TL, Quinn B. Unilateral hip-
pocampal mossy fiber sprouting and bilateral asymmetric neuron
loss with episodic postictal psychosis. J Neurosurg 1995;82:228-
33.
99. Conlon P, Trimble MR, Rogers D. A study of epileptic psychosis
using magnetic resonance imaging. Br J Psychiatry. 1990; 156:
231-5.
100. Gallhofer B, Trimble MR, Frackowiak R. A study of cerebral
flow and metabolism in epileptic psychosis using positron emis-
sion tomography and oxygen. J Neurol Neurosurg Psychiatry
1985;48:20 1-6.
101. Marshall EJ, Syed GMS, Fenwick PBC, Lishman WA. A pilot
study using single photon emission computerised tomography. Br
J Psychiatry 1993;163:32-6.
102. Jibiki I, Maeda T, Kubota T, Yamaguchi N. 1231-IMP SPECT
brain imaging in epileptic psychosis: a study of two cases of
temporal lobe epilepsy with schizophrenia-like syndrome. Neu-
ropsychobiology 1993;28:207-1 1.
103. Reith J, Benkelfat C, Sherwin A, et al. Elevated dopa decarbox-
ylase activity in living brain of patients with psychosis. Proc Natl
Acad Sci USA 1994;91:11651-4.
104. Ring HA, Trimble MR, Costa DC, Moriarty J, Verhoeff NP, Ell
PJ. Striatal dopamine receptor binding in epileptic psychoses.
Biol Psychiatry 1994;35:375-80.
105. Goddard GV, McIntyre DC, Leech CK. A permanent change in
brain function resulting from daily electrical stimulation. Exp
Neurol 1969;25:296-330.
106. Ebert U, Koch M. Amygdala kindling does not change emotional
responding as measured by the acoustic startle response in the rat.
Brain Res 1996;733:193-202.
107. Adamec RE. Does kindling model anything clinically relevant?
Biol Psychiatry 1990;27:249-79.
108. Post RM, Ketter TA, Denicoff K, et al. The place of anticonvul-
sant therapy in bipolar illness. Psychopharmacology 1996:128:
1 15-29,
109. Dunn RT, Frye MS, Kimbrell TA, Denicoff KD, Leverich GS,
Post RM. The efficacy and use of anticonvulsants in mood dis-
orders. Clin Neuropharmacol 1998;21:215-35.
110. Trimble MR. Psychiatric profiles and patterns of cerebral blood
flow in focal epilepsy: interactions between depression, obses-
sionality, and perfusion related to the laterality of the epilepsy. J
Neurol Neurosurg Psychiatry 1997;62:458-63.
I 1 1. Schmidt D. Epilepsien und epileptische Anfalle. Stuttgart: Thi-
eme, 1992.
112. Wolf P, Inoue Z , Roder-Wanner UU, Tsai JJ. Psychiatric com-
plications of absence therapy and their relations to alterations of
sleep. Epilepsia 1984;25:56-9.
113. McDanal CE, Bolman WM. Delayed idiosyncratic psychosis with
diphenylhytantoin. JAMA 1975;231: 1063.
114. Trimble MR. Forced normalisation and the role of anticonvul-
sants. In: Trimble MR, Schmitz B, eds. Forced normalization.
Petersfield: Wringtson Biomedical Publishing, 1998:169-78.
115. Amir N, Gross Tsur V. Paradoxical normalization in childhood
epilepsy. Epilepsia 1994;35: 1060-4.
116. Sander JW, Hart YM, Trimble MR, Shorvon SD. Vigabatrin and
psychosis J Neiirol Neurosurg Psychiatry 199 1;54:435-9.
117. Ring HA, Trimble MR, Costa DC, George MS, Verhoeff P, Ell
PJ. Effect of vigabatrin on striatal dopamine receptors: evidence
in humans for interactions of GABA and dopamine systems. J
Neurol Neurosurg Psychiatry 1992;55:758-6 1.
118. Ferrie CD, Robinson RO, Panaziotopoulos CP. Psychotic and
severe behavioural reactions with vigabatrin: a review. Acta Neu-
rol Scand 1996;6:30-7.
119. Thomas L, Trimble M, Schmitz B. Ring H. Vigabatrin and be-
haviour disorders: a retrospective survey. Epilepsy Res 1996;25:
21-7.
120. Torta R, Monaco F, Bergamasco L, et al. Lack of adverse cog-
nitive effects of vigabatrin in epileptic patiens: neuropsycholog-
Epilepsia, V d 40, Suppl. 10, 1999
ical and neurophysiological evaluation [Abstractl. It01 J Neurol
Sci 1993;suppI 14:110.
121. Theodore WH, Albert P, Stertz B, et al. Felbamate monotherapy:
implications for antiepileptic drug development. Epilepsirc 1995;
36: 1105-10.
122. Luef G, Bauer G. Topiramate in drug-resistant partial and gen-
eralized epilepsies. Epilepsiu 1996;37:69-73.
123. McConnel H, Snyder PJ, Duffy JD, et al. Neuropsychiatric side
effects related to treatment with felbamate. J Neuropsychiotr Clin
Neurosci 1996;8:3414.
124. Schmit B. Psychiatrische Symptome bei Epilepsie-welchen Ef-
feckt haben Antiepileptika? German League Agninst Epileps!
1966;24-27.
125. Ettinger AB, Weisbrot DM, Nolan EE, et al. Symptoms of de-
pression and anxiety in pediatric epilepsy patients. Epilepsia
I998;39:595-9.
126. Lee DO, Helmers SL, Steingard RJ, DeMaso DR. Case study:
seizure disorder presenting as panic disorder with agoraphobia. J
Am Acnd Child Adolesc Psyhicitry 1997;36: 1295-8.
127. Monaco F, Torta R. Spettro d'azione dei farmaci antiepilettici
nella terapia delle crisi, pseudocrisi ed attacchi di panico. In:
Murri L, Iudice A, Cassano GB, eds. Crisi, pseudocrisi ed citroc-
chi di panico. Milano: Springer-Verlag. 1998:200-8.
128. Young GB, Chandarana PC, Blume WT, McLachlan RS, Muiioz
DG, Girvin JP. Mesial temporal lobe seizures presenting as anxi-
ety disorders. J Neuropsychiatry Clin Neurosci I995;7:352-7.
129. Moore PM, Baker GA. Non-epileptic attack disorder: a psycho-
logical perspective. Seizure 1997;6:429-34.
130. Wolanczyk T, Brynska A. Psychogenic seizures in obsessive-
compulsive disorder with poor insight: a case report. Pediatr
Neurol 1998;18:854.
131. Newsom Davis I, Goldstein LH, Fitzpatrick D. Fear of seizures:
an investigation and treatment. Seizure I998;7: I0 1-6.
132. Krahn LE, Rummans TA, Peterson GC. Psychiatric implications
of surgical treatment of epilepsy. Mayo Clin Proc 1996;71:
12014.
133. Ring HA, Moriarty J, Trimble MR. A prospective study of the
early postsurgical psychiatric associations of epilepsy surgery. J
Neurol Neurosurg Psychiatry I998;64:6014.
134. Roth M, Harper M. Temporal lobe epilepsy and phobic anxiety-
depersonalisation syndrome. Part 11: practical and theoretical con-
siderations. Comp Psychiatq I962;3:215-26.
135. Toni C, Cassano GB, Perugi G, et al. Psychosensorial and related
phenomena in panic disorder and in temporal lobe epilepsy.
Comp Psychiatry 1996;37: 125-33.
136. Depaulis A, Helfer V, Deransart C, Marescaux C. Anxiogenic-
like consequences in animal models of complex partial seizures
Neurosci Biobehav Rev 1997;21:767-74.
137. Tokunaga M, Ida I, Higuchi T, Mikuni M. Alterations of benzo-
diazepine receptor binding potential in anxiety and somatoform
disorders measured by '*'I-iomazenil SPECT. Rudint Med 1997;
15:163-9.
138. Spitzer WO, Dobson AJ, Hall J, et al. Measuring the quality of
life of cancer patients. A concise QL-Index for use by physicians.
J Chron Dis 1981;34:585-97.
139. Aaronson NK, van Dam FSAM, Polak C, Zittoun R. Prospects
and problems in psychosocial oncology research in Europe: a
manners survey of EORTC Study Group on Quality-of-Life [Ab-
stract]. Proc EORTC 6th Workshop Study Group on Qualit! of
Life 1984;95:117.
140. Barofksy I. Quality of Life assessment. Evolution of the concept.
In: Ventafridda V, van Dam FSAM, Yancik R. Tamburini M, eds.
Assessment of quality of life and cancer treatment. Milano: Ex-
cerpta Medica, 1985 Amsterdam: 1986.
141. Calman CK. Definitions and dimensions of quality of life. In:
Aaronson NK, Beckman JK, eds. The qucilii3 of' life of cancer
patients. EORTC Monographs. Vol 17. New York. Raven Press,
1987:l-9.
142. Gilliam F, Kuzniecky R, Faught E, Black J, Carpenter G, Schrodt
R. Patient-validated content of epilepsy-specific quality-of-life
measurement. Epilepsia 1997;38:2334.
143. Smith DF, Baker GA, Dewey M, Jacoby A, Chadwick DW. Sei-
zure frequency, patient-perceived seizure severity and the psy-
 BEHAVIORAL, PSYCHOTIC, AND ANXIETY DISORDERS
chosocial consequences of intractable epilepsy. Epilepsy Res
1991;9:231-41.
144 Cramer JA, Perrine K, Devinsky 0, Meador K. A brief question-
naire to screen for quality of life in epilepsy: the QOLIE-10.
Epilepsia 1996;37:577-82.
145. Baker GA, Smith DF, Dewey M, Jacoby A, Chadwick DW. The
initial development of a health-related quality of life model as an
outcome measure in epilepsy. Epilepsy Res 1993; 16:65-8 1.
146. Boon PA, Williamson PD. The diagnosis of pseudoseizures. Clin
Neurol Neurosurg 1993;95:1-8.
147. Waitwell JR. Historical notes on psychiatry. London: HK Leivis,
1936.
148. Charcot JM. Lectures on the disease of the nervous snstem. Lon-
don: New Sydenham Society, 1877.
149. Gowers WR. Epilepsy and other conidsive diseases: their cases,
symptoms and treatment. New York: Dover, 1881.
150. Trimble MR. Pseudoseizures. Neurol Clin, 1986;4:531-548.
151. Lishe E, Forster FM. Pseudoseizures: a problem in the diagnosis
and management of epileptic patients. Neurology 1964; 14:41-9.
152. Scott DF. Recognition and diagnostic aspects of nonepileptic sei-
zures. In: Riley TL, Rog A, eds. Pseudoseizures. Baltimore:
Williams & Wilkins, 198221-34.
153. Boon PA, Williamson PD, Drieghe C, Novelly RA, Mattson RH.
Psychogenic seizures; clinical characteristics and diagnostic cri-
teria. [Abstract]. Epilepsia 1991;32(suppl 3):63.
154. Kalogjera Sackellares D, Sackellares JC. Personality profiles of
patients with pseudoseizures. Seizure 1997;6:1-7.
155. Wilson-Barnet J, Trimble MR. An investigation of hysteria using
the illness behavior questionnaire. Br J Psychiatry 1985; 146:
601-8.
156. Henricks TF, Tucker DM, Farba J, Novellv RA. MMPI indices in
the identification of patient evidencing pseudoseizure. Epilepsia
29: 184-7.
157 Bowman ES.Etiology and clinical course of pseudoseizures. Re-
lationship to trauma, depression, and dissociation. Psychosomar-
ics 1993;34:333-42.
158 Ney GC, Barr WB, Napolitano C, Decker R, Schaul N. New-
onset psychogenic seizure after surgery for epilepsy. Arch Neurol
1998;55:726-30.
159. Boon PA, Williamson PD. The diagnosis of pseduoseizures. Clin
Neurol Neurosurg 1993;95:1-8.
160. Garcia FL, Iragui VJ, Watson DP. Ictal characteristics of non-
convulsive pseduoseizures. Epilepsia 1988;29:703.
161. Rodin EA. Differential diagnosis of epileptic versus psychogenic
seizures. In: Dam M, Gram L, Penry JK, eds. Advances in epi-
leptology: XIIth Epilepsy International Symposium. New York:
Raven Press, 1981:337-41.
162. Gates JR, Ramani V, Wallen S, Loewenson R. Ictal characteris-
tics of pseudoseizures. Arch Neurol 1985;42:1183-7.
163. Defrius FE, Holmes GL, Sackellares JC. Epilepsy and pseudo-
seizures in childhood. In: Dam M, Gram L, Penry JK, eds. Ad-
vances in epileptology: XIIth Epilepsy International Symposium.
New York: Raven Press, 1981:323-7.
164. Gulick TA, Spinks IP, King DW. Pseudoseizures: ictal phenom-
ena. Neurology 1982;32:24-30.
165. Leis AA, Ross MA, Summers AK. Psychogenic seizures: ictal
characteristics and diagnostic pitfalls. Neurology 1992;42:95-9.
166. Cohen RJ, Suter C. Hysterical seizures: suggestion as a provoca-
tive EEG test. Ann Neurof 1981;1:391-5.
167. Oheman R, Walinder J, Balldin J, Wallin J, Abrahamson L. Pro-
lactin response to electroconvulsive therapy. Lancet 1976;2:
936-7.
168. Meldrum BS, McWilliam JR. Hormone changes following sei-
zures. In: Dam M, Gram L, Penry JK, eds. Advances in epilep-
tology: XIIth Epilepsy International Symposium New York:
Raven Press, 1981:443-7.
169. Johansson F. von Knorrine . L. Changes in serum orolactin after
electroconvulsive and epileptic seizures. Eur Arch Psvchiatq
Neurot Sci 1987;236:312-8.
170. Engel J. Seizures and Epilepsy. F A Davis Co: Philadelphia,
1989:350-2.
171. Mattson RH. Neurophysiological (EEG) findings in nonepileptic
SI 9
seizures. In: Rowan J, Gates J, eds. Psychogenic (nonepilepiic)
seizures New York: Raven Press, 1991:XX-XX
172. Lesser RP. Psychogenic seizures. Rec Adv Epilepsy 1985:273-96.
173. Blend MJ, de Ledn OA, Jobe TH, Lin Q, Sychra JJ, Gaviria M.
Cerebral perfusion SPECT imaging in epileptic and nonepileptic
seizures. Clin Nucl Med 1997;22:363-8
174. Starr MS. The role of dopamine in epilepsy. Synapse 199622:
159-94.
175. Burke K, Chandler CJ, Starr BS, Starr MS. Seizure promotion and
protection by D-l and D-2 dopaminergic drugs in the mouse.
Pharmacol Biochem Behav 1990;36:729-33.
176. Post RM, Rubinow DR, Ballanger JC. Conditioning, sensitizia-
tion and kindling: for the course of affective illness. In: Post RM,
Bal JC, eds. Neurobiology of mood disorders. Baltimore: Willi-
ams & Wilkins, 1984:43246.
177. Torta R, Biggio G. Gli ansiolitici. In: Bizzi 6, Trabucchi M, eds.
Farmacorerapia. Torino: Utet, 1995:93-142.
178. Monaco F. Cognitive effects of vigabatrin. A review. Neurolog!
1996;47(suppI 1);SGI 1.
179. Monaco F, Torta R, Cicolin A, Borio R, Varetto A. Lack of
association between vigabatrin and impaired cognition. J Inr Med
Res 1997;25:296-301.
180. McConnell H W ,Duncan D. Behavioral effects of antiepileptic
drugs. In: McConnell HW, Snyder PJ, eds. Psychiairic conzor-
bidity in epilepsy. Basic mechanisms diagnosis nnd treaimenr.
Washington, DC: American Psychiatric Associarion, I998:205-
44.
181. Oliver AP, Luchins DJ, Wyatt RJ. Neuroleptic-induced seizures.
An in vitro technique for assessing relative risk. Arch Gen f s y -
chiatry 1982;39:206-9.
182. Stevens JR, Denney D, Szot P. Sensitization with clozapine: be-
yond the dopamine hypothesis. Biol Psychiatry 1997;42:771-80.
183. Malow BA, Reese KB, Sat0 S, et al. Spectrum of EEG abnor-
malities during clozapine treatment. Electroencephologr Clin
Neurophysiol 1994;91:205-11.
184. Owens MJ, Risch SC. Atypical Antypsychotic. In: Schatzberg
AF, Nemeroff CB, eds. Texrbook ofpsychopharmacolog!. Wash-
ington: American Psychiatric Press, 1995:263-80.
185. Tsuchiya H, Kawahara R, Tanaka Y. Generalized seizures during
treatment of schizophrenia with zotepine. Yonugo Acia Merl
1986;29:103-11.
186. Hori M, Suzuki T, Sasaki M. Convulsive seizures in schizo-
phrenic patients induced by zotepine administration. Jpn J Psy-
chiatry Neurol I992;46: 161-7.
187. Manmaru S.Five cases of schizophrenia with convulsive seizures
during zotepine administration ( i n Japanese). Seishin lgoku 1985;
27~59-70.
188. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor
binding profile of the atypical antipsychotic olanzapine. Nertru-
psychopharmacology 1996;14:87-96.
189. Long PW. Internet Mental Health (www.mentalhealth.com)
Olanzapine drug monograph October, 1996 (from data on file
Lilly) and Zotepine Drug Monograph.
190. Ravizza L, Maina G, Torta R, Bogetto F. Are serotoninergic
antidepressants more effective in episodic obsessive-compulsive
disorders? In: Cassano GB, Akiskal HS, eds. Serotonin-system-
related psychiatric syndromes clinical and therapeutic links. Lon-
don, New York: Royal Society of Medicine Services, 1991:61-5.
191. Montgomery SA. Psychopharmacology of obsessive-compulsive
disorders. CNS Specfrum I998;5(suppI 1 ):33-7.
192. Yudofsy SC, Silver JM, Hales RE. Treatment of aggressive dis-
orders. In: Schatzberg AF, Nemeroff CB, eds. Texrbook of Psy-
chophannacology. Washington, DC: American Psychiatric Press.
1 9 9 5 : ~735-52.
193. Zaccara G, Muscas GC, Messori A. Clinical features, pathogen-
esis and management of drug-induced seizures. Drug Safer!
1990;5:109-51.
194. Edwards JG. Antidepressant and convulsions. Lancer 19792:
1368-9.
195. Tortn R, Borio R, Cicolin A, Monaco F, Ravizza L. Therapeutic
aspects of depression and epilepsy: new vs old antidepressant
drugs [Abstract]. Pror 8rh Congr Assoc Eur Psychiutrists
1996;s57.
Epilepsia. Vol. 40. Suppl 10. I Y Y Y
s20 R. TORTA AND R. KELLER
196. Skowron DM, Stimmel GL. Antidepressant and the risk of sei-
zures. Phurmacotherupy 1992;12: 18-22.
197. Monaco F, Torta R, Borio R. Ravizza L. Epilepsy, depression and
the selective serotonin reuptake inhibitor drugs [Abstract]. Epi-
lepsia 1995;36:S175.
198. Buterbaugh GG. Effect of drugs modifying central serotonergic
function on the response of extensor and nonextensor rats to
maximal electroshock. Life Sci 1978;23:2393-404.
199. Dayley JW, Yan QS, Mishra PK. Effects of fluoxetine on con-
vulsions and on brain serotonin as detected by microdyalisis in
genetically epilepsy-prone rats. Phannacol Exp Ther 1992;250:
533-40.
200. Leander JD. Fluoxetine, a selective serotonin-uptake inhibitor,
enhances the anticonvulsant effects of phenytoin, carbamazepine
and ameltolide. Epilepsia 1992;33:573-6.
201. Prendville S, Gale K. Anticonvulsant effect of fluoxetine on fo-
cally evoked limbic motor seizures in rats. Epilepsiu 1993;34
381-4.
202. Favale E, Rubino V, Mainardi P, Lunardi G, Albano C. Anticon-
Epilepsia, Vol. 40, Suppl. 10, 1999
vulsant effect of fluoxetine in humans. Neurology 1995;45:
1926-7.
203. Troisi A, Vicario E, Nuccetelli F, Ciani N, Pasini A. Tor Vergata,
Italy. Effects of fluoxetine on aggressive behavior of adult pa-
tients with mental retardation and epilepsy. Pharmacopsychiatn
1995;28:73-6.
204. Tata MR, Lettieri B, Vicario C. Osservazioni su di un caso con
inaspettato stato di male convulsivo: ruolo della fluoxetina. Boll
Lega It Epil 1993;84:167.
205. Weber JJ. Seizure activity associated with fluoxetine therapy.
Clin Pharm 1989;8:296-8.
206. Ware MR, Stewart RB. Seizures associated with fluoxetine
therapy. Ann Phannacother 1989;23:428.
207. Deahl M, Trimble MR. Serotonin reuptake inhibitors, epilepsy
and myoclonus. Br J Psychiurry I99 1;159:433-5.
208. Gigli GL, Diomedi M, Troisi A, et al. Lack of potentiation of
anticonvulsant effect by fluoxetine in drug-resistant epilepsy. Sei-
zure 1994;3:2214.