Review

What are the similarities and differences between schizophrenia and

schizophrenia-like psychosis of epilepsy? A neuropathological approach
to the understanding of schizophrenia spectrum and epilepsy
Ludmyla Kandratavicius
a,b
, Jaime Eduardo Hallak
a,b,c
, Joao Pereira Leite
a,b,

a
Ribeirao Preto School of Medicine, Department of Neurosciences and Behavior, University of Sao Paulo (USP), Brazil
b
Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Brazil
c
National Institute of Science and Technology in Translational Medicine (INCT-TMCNPq), Brazil
a b s t r a c t a r t i c l e i n f o
Article history:
Revised 10 January 2014
Accepted 12 January 2014
Available online xxxx
Keywords:
Temporal lobe epilepsy
Schizophrenia
Psychosis
Psychiatric comorbidities
Neuropathology
Temporal lobe epilepsy (TLE) and psychosis coexist more frequently than chance would predict. In this short review,
clinical and neuropathological ndings of schizophrenia, TLE, and psychosis of epilepsy are described to enhance our
understanding of the noncoincidental association betweenthese conditions. Inaddition, psychosis of epilepsy was in-
cluded for the rst time in the Diagnostic and Statistical Manual of Mental Disorders (DSM), in the recently launched
5thedition, andimprovement indiagnostic criteria was highlighted. Since the hippocampus has long beenconsidered
an anatomical area involved in the pathophysiology of TLE and schizophrenia, neuropathological studies of psychoses
of epilepsy may contribute to our understanding of the pathophysiology of psychosis in general. The discovery of
shared mechanisms and/or affected neurochemicals in TLE and schizophrenia might disclose important clues on
the vulnerability of patients with TLE to psychotic symptoms and be an opportunity for newtreatment development.
This article is part of a Special Issue entitled NEWroscience 2013.
2014 Elsevier Inc. All rights reserved.
1. Introduction
Temporal lobe epilepsy (TLE) is a neurological condition in which
seizures may spread and disturb a whole set of limbic structures and
neighboring cortices [1]. In the mesial subtype (MTLE), seizures origi-
nate mainly from the hippocampal formation, where sclerosis, neuron
loss, and other characteristic neuropathological changes take place [2].
In contrast, various forms of psychosis are not clearly related to any
consistent pathological localization. Instead, they have been attributed
to neurochemical and structural dysfunctions in a much wider domain
of limbic circuits, including the hippocampal circuitry, which is directly
affected by TLE [3]. The high prevalence of psychoses in patients with
TLE [48], indicating a possible shared mechanism between them,
despite their possible distinct degree of substrate involvement and
localization [9] is noteworthy, though. In the present review, we sum-
marize the key clinical and neuropathological features comparing
schizophrenia and TLE schizophrenia-like psychosis, with emphasis on
the changes related to the hippocampal formation.
2. Historical background and clinical aspects
2.1. Schizophrenia spectrumand other psychotic disorders: fromKraepelin/
Bleuler to DSM-5
Despite the high incidence of psychotic manifestations nowadays, rel-
atively fewrecords are available fromthe 5th century BC through Biblical
times [10,11]. In 1809, Harlamand Pinel published their rst case reports,
and the term schizophrenia was coined by Bleuler shortly after the com-
plete clinical description of Kraepelin's dementia praecox in 1896 [12].
Since then, schizophrenia has been extensively studied, but its precise
clinical nature remains undened. Current views favor the hypothesis
that several etiological factors and pathophysiological processes might
be relevant to the development of schizophrenia, meaning that it is likely
a constellation of conditions rather than a singular disease entity [13].
Core clinical features are generally classiedinto positive, negative, cogni-
tive, disorganization, mood, and motor symptoms, with psychopathology
differentially expressed across patients and through the course of the ill-
ness [14]. Positive symptoms involve reality distortions such as delusions
and hallucinations (these include the classical Schneiderian symptoms)
[15]. Negative symptoms involve a blunting or loss of a range of affective
andconative functions. Disorganizationrefers tofragmentationof the log-
ical, progressive, andgoal-directed nature of normal thought process [16].
Depressive symptoms and increased emotional arousal, in conjunction
with positive symptoms (the emotional paradox of schizophrenia), are
Epilepsy & Behavior xxx (2014) xxxxxx
Corresponding author at: Ribeirao Preto School of Medicine, Department of
Neurosciences and Behavior, University of Sao Paulo, Av Bandeirantes 3900, CEP 14049-
900 Ribeirao Preto, SP, Brazil. Fax: +55 16 3633 0866.
E-mail address: jpleite@fmrp.usp.br (J.P. Leite).
YEBEH-03726; No. of pages: 5; 4C:
1525-5050/$ see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.yebeh.2014.01.005
Contents lists available at ScienceDirect
Epilepsy & Behavior
j our nal homepage: www. el sevi er . com/ l ocat e/ yebeh
Please cite this article as: Kandratavicius L, et al, What are the similarities and differences between schizophrenia and schizophrenia-like
psychosis of epilepsy? A neuropathological ..., Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.01.005
also sources of signicant burden [17]. Slowing of psychomotor activity is
commonly associated with negative and depressive symptom clusters,
and excessive motor activity is more often associated with exacerbations
of positive symptoms [16]. Impaired cognition in varying degrees was
implied in Kraepelin's dementia praecox original term and is highly
prevalent in patients with schizophrenia [18].
The Kraepelian and DSM-IV-TR [19] denitions of schizophrenia
attempted to classify the heterogeneous clinical features into subtypes:
(a) catatonic type is characterized by marked psychomotor disturbance
involving stupor, negativism, rigidity, excitement, and posturing; (b)
disorganized type is associated with marked loosening of associations,
incoherence, grossly disorganized behavior, and at or grossly inappro-
priate affect; (c) paranoid type is characterized by preoccupation with
one or more systematized delusions or presence of frequent hallucina-
tions related to a single theme; (d) schizoaffective type is associated
with an admixture of prominent mood disturbance in conjunction
with psychotic symptomatology; (e) undifferentiated type is considered
when a patient presents with psychotic symptoms that meet the criteria
for schizophrenia but not for any specic subtype; and (f) residual type
is diagnosed by the occurrence of at least one prior episode of orid
phase of schizophrenia with a current clinical picture free from promi-
nent psychotic symptoms but with minimal residual symptoms of
the illness (mainly cognitive and negative symptoms). The clinical and
research utility of this traditional approach is limited, since these sub-
types of schizophrenia are unstable over the course of the illness
[reviewed by [16]].
In the recently launched 5th edition of DSM[20], psychotic disorders
are under the chapter Schizophrenia Spectrum and Other Psychotic
Disorders. Schizophrenia remains as a specic diagnostic entity but
without the previous subtype characterization. Instead, domains of psy-
chopathology and gradients and dimensions of psychosis are in the core
of this new nosological delineation. As reviewed by Heckers et al. [21],
there are ve domains: hallucinations, delusions, disorganized thought
(speech), disorganized or abnormal motor behavior (including catato-
nia), and negative symptoms. Two negative symptoms have been
highlighted as particularly prominent: diminished emotional expres-
sion and avolition. Assessment for the presence of psychosis should
consider whether beliefs are exible; whether perceptions are linked
to an external stimulus; whether thoughts are logical, coherent, and
goal-directed; whether the individual engages readily in normal verbal
communication and motor acts; and whether affect is modulated and of
full range. If any of these assessments raise concern, further evaluation
for a psychotic disorder is warranted. The authors also state that a cru-
cial difference between schizophrenia and all other psychotic disorders,
including the closely related schizophreniform and schizoaffective dis-
orders, is a decrease in the level of functioning belowthe level achieved
prior to the onset of psychosis [21]. Variable degrees of association
and expression of these symptom dimensions may reect distinct
pathogenic processes associated with distinct risk factors and, possibly,
differences in prognosis, treatment, and pathology. It is hoped that a
dimensional/endophenotype approach in conjunction with clinical
staging may better help explain the signicant heterogeneity of schizo-
phrenic illness [16], since excessive stagnated categorical diagnosis
might have contributed to the lack of progress in unraveling the mech-
anisms of schizophrenia and other psychotic disorders [22].
2.2. Schizophrenia-like psychosis of epilepsy or interictal psychosis, a
psychotic disorder due to another medical condition
Temporal lobe epilepsy (TLE) and psychiatric symptoms coexist
more frequently than chance would predict [9,23]. The oldest known
detailed account of schizophrenia-like psychosis in epilepsy dates
from around the middle of the second century BC in Babylon [24]. The
description made then resembles remarkably the rst ofcial and
explicit clinical recognition of schizophrenic-like psychoses of epilepsy,
a description made by Desmond Pond in 1957 [25]. Typically, the
psychotic state closely resembles schizophrenia, with paranoid ideas
which might become systematized, ideas of inuence, and auditory hal-
lucinations often of a menacing quality. The points of difference with
classic schizophrenia are the common religious coloring of the paranoid
ideas, tendency of the affect to remain warm and appropriate, and no
typical deterioration to the hebephrenic state [25]. Although auditory
hallucinations are common, visual hallucinations are relatively rare.
Other forms of delusions, including grandiose, referential, religious,
and Schneiderian (with symptoms such as auditory hallucinations;
thought echo, insertion, and broadcasting; and delusional perception),
have also been reported, especially when a history of traumatic brain
injury is present [26].
Careful clinical examination of psychosis in epilepsy is mandatory.
Apparent clinical differences between schizophrenia-like psychosis in
cerebral diseases and true schizophrenia are largely illusionary (espe-
cially when Schneider's categories are used), and transitional states
are frequent [27]. Since diagnosis of schizophrenia/psychotic symptoms
based upon subjective descriptive criteria may lead to controversy,
structured interviews could provide important information. More than
20 years ago, an innovative approach from Perez and Trimble [28]
attempted to use the Present State Examination (PSE-CATEGO) struc-
tured interview, even though this interview had not been recommend-
ed for psychosis with a known organic brain pathology. Their study
showed that more than half of patients with TLE with psychosis pre-
sented with schizophrenic psychosis, although one-third had paranoid,
manic, or depressive psychosis [28]. It remains to be investigated which
clinical differences would be seen between psychosis of epilepsy and
schizophrenia under DSM-5 guidelines and other recent structured
diagnostic tools.
Psychosis of epilepsy has beenincluded inthe 5theditionof the DSM
series for the rst time. It appears under the section Psychotic disorder
due to another medical condition, and diagnostic criteria include the
following: (a) prominent hallucinations or delusions; (b) evidence
that the disturbance is the direct pathophysiological consequence of
another medical condition; (c) the disturbance is not better explained
by another mental disorder; (d) the disturbance does not occur exclu-
sively during the course of a delirium; and (e) the disturbance causes
clinically signicant distress or impairment in social, occupational, or
other important areas of functioning [20]. Complying with several past
authors who have warned against the danger of assuming that all psy-
choses of epilepsy are schizophrenia-like and the need for careful diag-
nostic classication of psychotic patients with TLE, DSM-5 recommends
a quantitative severity scale of the primary symptoms of psychosis in-
cluding delusions, hallucinations, abnormal psychomotor behavior,
and negative symptoms.
According to the temporal relationship between the onset of psychi-
atric symptomatology and seizure occurrence, psychiatric disorders in
epilepsy can be classied into ictal (the psychiatric symptoms are a clin-
ical manifestation of the seizure), periictal (symptoms precede and/or
follow the seizure occurrence), and interictal (symptoms occur inde-
pendently of the seizure occurrence). In the present short review, our
focus will primarily be the interictal psychosis, which includes
schizophrenia-like psychosis of epilepsy, as dened by the International
League Against Epilepsy (ILAE, Commission on Neuropsychiatric
Aspects) [29]. Since interictal symptoms are not related to any seizure
collateral effect, psychiatric manifestations are muchlike the pure form
of the psychopathology. For instance, chronic interictal psychosis of
epilepsy is also referred to as schizophrenia-like psychosis of epilepsy
because of its resemblance to schizophrenia's phenomenological mani-
festations [30]. Interictal psychosis usually presents with increased fre-
quency of orid symptoms, whereas postictal psychosis may exhibit
few schizophreniform psychotic traits such as perceptual delusions or
voices commenting [31], and, in some cases, symptoms may be similar
to interictal psychosis ones [32]. Of note, recurrent postictal psychosis
in human TLE is considered a risk factor for the development of
interictal psychosis [32]. Considering the close association between
2 L. Kandratavicius et al. / Epilepsy & Behavior xxx (2014) xxxxxx
Please cite this article as: Kandratavicius L, et al, What are the similarities and differences between schizophrenia and schizophrenia-like
psychosis of epilepsy? A neuropathological ..., Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.01.005
postictal and interictal psychoses, animal models of postictal psychosis
could be helpful tools to the study of possible gradual commitment of
limbic circuits.
The increased risk of psychiatric symptoms in epilepsy may be relat-
ed to several aspects that are liable to facilitate psychopathological man-
ifestations suchas genetic backgroundandTLE chronicity. Frequent ictal
symptoms in patients with TLE also include psychic or experiential phe-
nomena such as intellectual aurae or dreamy states, complex visual or
auditory hallucinations or illusions, memory ashbacks, dj vu,
jamais vu, and emotions, most commonly fear [33]. These patients char-
acteristically exhibit a preserved or even deepened affect and do not fall
into any established nosologic category and often do not appear schizo-
phrenic [34]. Indeed, as described by Gloor et al. [35], the patient knows
that what he sees, hears, or feels is out of context, and this insight
distinguishes the experiential phenomena from psychotic hallucina-
tions and illusions. At some point and depending on specic albeit
still unknown neuropathological and psychopathological mecha-
nisms, these relatively conscious ictal-related events might evolve into
a postictal or aninterictal psychosis. The clinical observation of transito-
ry psychosis/psychosis proneness (e.g., postictal psychosis) that may
become abnormally persistent (e.g., interictal psychosis) depending on
the degree of environmental/genetic background agrees with the con-
cept of a psychosis continuum [36]. If there is a psychosis continuum,
the same symptoms that are seen in patients with psychotic disorders
could be measured in nonclinical populations [37]. In addition to the
observations made by Gloor, where patients with epilepsy and without
psychiatric illness are able to experience the so-called dreamy states
[35], it has been recently described that auditory hallucinations elicit
similar brain activation in psychiatric patients and in nonpsychiatric
controls [38]. Another study has shownthat healthy control participants
with several degrees of schizotypal traits presented with variable im-
paired frontotemporal connectivity that correlated with their scores in
the Schizotypal Personality Questionnaire [39].
Based on the assumption that psychotic symptoms may constitute a
scale that may range fromabsence of psychosis, subclinical psychotic ex-
periences, low-impact psychotic symptoms, and high-impact psychotic
symptoms to full-blown clinical psychotic disorder [36], which is part
of the DSM-5 proposal, a similar scale of symptomatology could be
built up for psychotic manifestations in epilepsy. In fact, the suggestion
of a possible continuum between TLE and psychosis was made by Diehl
in an extensive review25 years ago [27]. Our hypothesis is that this neu-
ropsychiatric mechanism would resemble a kindling process. As postu-
lated by Racine et al. [40], the classical kindling process may gradually
develop and spread through brain structures distal to the stimulated
focus. In patients with epilepsy, there is evidence of a time-dependent
spread of epileptic excitability that is independent of tissue pathology
[41]. It is generally assumed that human limbic seizures result in the
enhancement of affective limbic functions, rather than a attening of
them [42]. Again, the relatively long interval between TLE onset and
comorbid psychiatric symptomonset suggests that damage to key struc-
tures is necessary and builds up over time [26,43]. Suchgradual commit-
ment of connected systems might be a determinant to the sum of
neurobiological events that eventually will lower the psychopathological
threshold from a normal condition to a prodromal/psychiatric state.
Although there is evidence of association between amygdala kindling
and primary affective disorders [44,45], psychosis and affective symp-
toms may lie on different continuums [46]. Despite sustained effort, the
mechanismof schizophrenia andrelatedpsychosis has remainedelusive.
As for schizophrenia, different dimensions of symptoms in interictal psy-
chosis may suggest that different neurobiological substrates are engaged.
3. Neurobiology and hippocampal neuropathology of schizophrenia
spectrum and epilepsy
The nature of the relationship between psychosis and epilepsy is con-
troversial. Some lines of evidence suggest that there is a basic antagonism
betweenepilepsy and psychosis. Psychosis inTLE may be associated with
fewer or no psychomotor seizures [4,47], but there are also reports of in-
creasedseizure frequency [48,49]. Normalizationof the EEGandelimina-
tion of seizures through anticonvulsant medication, while relieving
epileptic symptomatology, often exacerbated an underlying psychiatric
disorder leading to the emergence of a psychotic state [50]. Indeed, this
mutual antagonism concept was the basis for the development of the
electroconvulsive therapy, where seizure induction is used as a method
to treat psychosis, as reviewed by Pollock [51]. Gamma-amino butyric
acid (GABA) and dopamine also exert antagonistic effects in epilepsy
and psychosis. For instance, dopamine antagonists are commonly
used as antipsychotic drugs and might trigger seizures [52]. On the
other hand, dopamine agonists are able to exacerbate or trigger
psychotic symptoms and exhibit anticonvulsant properties [53,54].
Nevertheless, other authors have provided evidence of an agonistic
relationship between epilepsy and schizophrenia rather than an antago-
nism[8,27,47,55]. Unlike the antagonistic view, the converging viewis in
agreement with the recognition of epileptic psychoses as truly organic,
caused by structural damage to the limbic parts of the temporal lobe
responsible for both epilepsy and psychosis.
Several structural, functional, neurophysiological, neurochemical,
and neuropathological abnormalities throughout the brain have been
described in schizophrenia and in psychosis of epilepsy (for review,
see [9,14,56]). Although many studies have shown that the hippocam-
pal formation (comprising the hippocampus proper, subicular complex,
entorhinal cortex, and parahippocampal gyrus [57]) is central to the
pathophysiology of schizophrenia [58], we agree that studying only
the hippocampus will not lead to a complete understanding of epilepsy
or of epilepsy-related psychiatric disorders [59]. Nonetheless, hippo-
campi from patients who underwent epilepsy surgery constitute a
unique opportunity to concurrently examine neuropathological and
biochemical changes and relate those to comorbid psychiatric symp-
toms in patients with chronic epilepsy [60].
Since the 1960s, studies have suggested that any given brain tumor
affecting the limbic system can present as classical schizophrenia [6].
In Malamud's series of eighteen patients with temporal lobe tumors,
ten had been diagnosed with and treated for schizophrenia, three for
melancholia, one for psychotic depression, one for mania, two for psy-
choneurosis, and one for anxiety [61]. In Taylor's series of TLE speci-
mens, 23% of the cases with alien tissue (tumors, hamartomas, and
focal dysplasias) were psychotic, contrasting with only 5% in the
group with mesial temporal sclerosis [7]. Although some authors
agree that psychiatric symptoms are frequently associated with tempo-
ral lobe tumors and that the presence of mesial temporal sclerosis
would be protective against schizophrenia-like psychosis in patients
with epilepsy [62], recent neuropathological evidence suggest that
there is a structural basis for psychiatric symptoms in patients with
MTLE with hippocampal sclerosis [60,63,64]. Other studies also indicate
that the presence of hippocampal sclerosis is not protective against psy-
chosis. In Roberts's series of 249 patients with TLE, 6.4% had a preoper-
ative diagnosis of TLE and psychosis; 40% of the cases with TLE and
psychosis had left-sided hippocampal sclerosis, and about 20% had
gangliogliomas [5]. Noteworthy is the fact that gangliogliomas usually
have origin in and predilection for the temporal lobe [5], meaning that
more important than the type of lesion, the location of a lesion within
hippocampalamygdalartemporal gyri may represent a true predis-
posing factor to psychosis.
Neuropathological abnormalities are frequently observed in brains
of patients withschizophrenia [65] and TLE [66]. Patients with MTLE ex-
hibit hippocampal neuronal loss, often accompanied by neuronal loss
and gliosis in the amygdala and entorhinal cortex [2,67]. The search
for an organic basis in postmortem brains of patients with schizophre-
nia has resulted in controversial ndings, mostly because methodologi-
cal approaches are rarely consistent in their selection of patients and
controls [65]. Common ndings include neuronal loss, shrinkage or dis-
array of cortical layers, and, sometimes, gliosis; affected areas comprise
3 L. Kandratavicius et al. / Epilepsy & Behavior xxx (2014) xxxxxx
Please cite this article as: Kandratavicius L, et al, What are the similarities and differences between schizophrenia and schizophrenia-like
psychosis of epilepsy? A neuropathological ..., Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.01.005
prefrontal cortical areas; pons; nucleus accumbens; hypothalamus;
substantia innominata (part of the basal forebrain); cingulate; superior,
middle, and inferior temporal gyri; amygdala; and hippocampus
[65,68,69]. The hippocampal formation has been particularly the subject
of intensive study. Left hemisphere Ammon's horn neuronal loss with-
out gliosis, entorhinal cortex neuronal loss, and reduced density of
interneurons have been described in postmortem brains of patients
with schizophrenia, with pyramidal cell loss being more noticeable in
patients with paranoid schizophrenia than in patients with catatonic
schizophrenia [68,70]. Other ndings include nonpyramidal cell loss in
CA2 [71] and decreased glutamic acid decarboxylase (GAD) expression
in the Ammon's horn and dentate gyrus [7274] but increased in the
subiculum and parahippocampal gyrus [75]. Microtubule-associated
protein type 2 (MAP2) was found increased in the Ammon's horn and
subiculum [76], while overall loss of somatostatin- and parvalbumin-
positive interneurons has been reported [74,77]. Decreased BDNF
expression [72,78], loss of mossy ber synapses [79], and decreased ex-
pression of several synaptic proteins have also been described in hippo-
campi of patients with schizophrenia [80,81]. Although Kraepelin in the
early 1900s believed that schizophrenia had an organic cause and likely
the characteristics of a degenerative process, the majority of contempo-
rary neuropathological studies have failed to show signs of progressive
features such as reactive gliosis or correlations between structural
abnormalities and the length of illness [68].
The progressive nature of TLE has been extensively demonstrated
[66,82,83]. We have observed neuronal loss in the hippocampus proper
and entorhinal cortex, increased MAP2 in the granular layer, CA2 and a
trend of increase in the subicular complex, loss of somatostatin and
parvalbumin interneurons, and decreased synaptophysin expression
(with exception of the dentate gyrus molecular layer) in the MTLE
hippocampus without psychiatric comorbidities [2,8487] similar to
the ndings in schizophrenia. Discordant results from those in schizo-
phrenia include hippocampal GAD and BDNF upregulation and mossy
ber sprouting in MTLE [2,8789]. Interestingly, in MTLE with comorbid
interictal psychosis, we have seen decreased mossy ber sprouting [60],
MAP2 preservation in CA3 (while there is loss in MTLE without psychi-
atric comorbidities [64]), decreased BDNF (while there is increase in
MTLE without psychiatric comorbidities [63]), and neuronal loss in the
entorhinal cortex in different patient cohorts [60,63,64]. These ndings
are in agreement with the ndings observed in schizophrenia. In addi-
tion, similarities between schizophrenia and interictal psychosis have
also been detected in hippocampal homogenates, such as increased
activity of phospholipase A2 [90].
4. Conclusions
The independent investigation of TLE and psychosis has provided
important pathophysiological hallmarks. The relatively high prevalence
of psychotic-like symptoms in patients with epilepsy suggests shared
mechanisms and/or substrates by these two conditions. However, few
studies have addressed this issue, and the denition of which neuro-
chemicals changes might contribute to the genesis or to the mainte-
nance of schizophrenia-like psychosis and other psychosis of epilepsy
is still an open challenge. We hope that future research on the morpho-
logical and biochemical abnormalities in this scenario will delineate tar-
gets for new treatments.
Acknowledgments
This work was supported by the Fundacao de Apoio a Pesquisa do
Estado de Sao Paulo FAPESP (Project numbers 05/56447-7 and 07/
56721-7), Conselho Nacional de Desenvolvimento Cientico e
Tecnologico CNPq, and Coordenacao de Aperfeicoamento de Pessoal
de Nivel Superior (CAPES Project number A034_2013).
Conict of interest
The authors declare that there are no conicts of interest.
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psychosis of epilepsy? A neuropathological ..., Epilepsy Behav (2014), http://dx.doi.org/10.1016/j.yebeh.2014.01.005